Here are the studies that match your search criteria. If you are interested in participating, please reach out to the contact listed for the study. If no contact is listed, contact us and we'll help you find the right person.
Safety and Efficacy of Retifanlimab (INCMGA00012) Alone or in Combination With Other Therapies in Participants With Advanced or Metastatic Endometrial Cancer Who Have Progressed on or After Platinum-based Chemotherapy. (POD1UM-204)
This is a multicenter, open-label, nonrandomized, Phase 2 umbrella study of retifanlimab in
participants who have advanced or metastatic endometrial cancer that has progressed on or
after platinum-based chemotherapy. retifanlimab will be administered as monotherapy or in
combination with other immunotherapy or targeted agents.
• Ability to comprehend and willingness to sign a written ICF for the study. Women 18
years of age or older (or as applicable per local country requirements).
• Histologically confirmed diagnosis of advanced or metastatic endometrial cancer with
disease progression on or after treatment with at least 1 platinum-containing regimen
for advanced or metastatic disease.
• Groups A and B: Have not been previously treated with a PD-(L)1 inhibitor.
• Group A only: Tumor tissue tested as MSI-High
• Group B only: Tumor tissue tested as deficient MMR or an ultra-mutated POLE tumor.
• Group D only: Tumor tissue tested as having an FGFR 1,2,3 mutation or alteration
characterized as per protocol.
• Must have at least 1 measurable tumor lesion per RECIST v1.1.
• Willing to provide tumor tissue sample (fresh or archived).
• ECOG performance status 0 to 1.
• Willingness to avoid pregnancy.
Exclusion Criteria:
• Group A only: Histologically confirmed diagnosis of carcinosarcoma of the uterus.
• Histologically confirmed diagnosis of sarcoma of the uterus.
• Has disease eligible for potentially curative treatment.
• Receipt of anticancer therapy within 28 days of the first administration of study
treatment, with the exception of localized radiotherapy.
• Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline unless
approved by the medical monitor.
• Groups C and D (combinations): limiting immune-related toxicity during prior
checkpoint inhibitor therapy.
• Has an active autoimmune disease requiring systemic immunosuppression with
corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs
within 14 days before the first dose of study treatment.
• Receiving chronic systemic steroids (> 10 mg/day of prednisone or equivalent):
• Known active CNS metastases and/or carcinomatous meningitis.
• Has known active hepatitis B or C.
• Has received a live vaccine within 28 days of the planned start of study treatment.
• Evidence of interstitial lung disease or active, noninfectious pneumonitis.
• Participants who are known to be HIV-positive with some protocol exceptions.
DuRvalumab With chEmotherapy as First Line treAtment in Advanced Pleural Mesothelioma (DREAM3R)
Patients with pleural mesothelioma (PM) that cannot be surgically removed will receive
standard chemotherapy (cisplatin or carboplatin and pemetrexed) given with durvalumab, a type
of immunotherapy, or a treatment chosen by the study doctor, which is either standard
chemotherapy or immunotherapy combination (ipilimumab and nivolumab).
Durvalumab is an antibody (a type of human protein) that works by blocking a body substance
called Programmed Death-Ligand 1 (PD-L1). Blocking PD-L1 helps the body's immune system
attack cancer cells. Research has shown that durvalumab can slow tumor growth and shrink
tumors in some people with cancer. Previous studies of combining durvalumab and chemotherapy
showed that this combination is active in advanced mesothelioma.
The purpose of this study is to see whether adding durvalumab to standard chemotherapy will
improve overall survival (OS) in patients with PM.
• Adults (18 years or over) with a histological diagnosis of epithelioid pleural
mesothelioma that is not amenable to curative surgical resection. Histological
diagnosis requires tumour tissue from an open biopsy, or a core biopsy with a needle
of 19 gauge or wider.
• Measurable disease as per modified RECIST 1.1 (mRECIST 1.1) criteria for assessment of
response in pleural mesothelioma, without prior radiotherapy to these sites.
• Body weight >30 kg,
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Tumour tissue (Formalin-Fixed Paraffin-Embedded [FFPE]) available from standard of
care diagnostic biopsy for PD-L1 testing and other correlative biomarker testing at a
central laboratory.
• Life expectancy of at least 12 weeks.
• Adequate blood tests (done within 14 days prior to randomisation) and with values
within the ranges specified below. Blood transfusions are permissible if completed at
least 7 days prior to treatment start.
• Haemoglobin ≥ 9.0 g/L
• Absolute neutrophil count ≥ 1.5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except participants with
Gilbert's Syndrome, who are eligible with bilirubin ≤ 2.5 ULN)
• Alanine transaminase ≤ 2.5 x upper limit of normal (ULN), unless liver metastases
or invasion are present, in which case it must be ≤ 5 x ULN
• Aspartate aminotransferase ≤ 2.5 x ULN, unless liver metastases or invasion are
present, in which case it must be ≤ 5 x ULN
• Creatinine clearance (CrCl) ≥ 45 mL/min (Cockcroft-Gault formula). NOTE:
Carboplatin AUC 5 must be the initial platinum agent of choice in patients with
creatinine Cl <60 mL/min but ≥ 45 mL/min, or those with clinically reported
hearing loss.
• Patient consent must be appropriately obtained in accordance with applicable local and
regulatory requirements. Each patient or legal representative must sign a consent form
prior to enrolment in the trial to document their willingness to participate.
• Willing and able to comply with all study requirements, including treatment, timing
and/or nature of required assessments.
• Women of childbearing potential must use a reliable means of contraception during
treatment and for at least 90 days thereafter. Breastfeeding is not permissible during
or for at least 90 days after the final study treatment. Men must have been surgically
sterilised or use a barrier method of contraception if they are sexually active with a
woman of child bearing potential.
• Evidence of post-menopausal status or negative serum pregnancy test for female
pre-menopausal patients. Women will be considered post-menopausal if they have been
amenorrheic for 12 months without an alternative medical cause.
Exclusion Criteria:
• Non-epithelioid histology (biphasic or sarcomatoid).
• Prior chemotherapy or other systemic anti-cancer or immunotherapy for PM.
• Diagnosis based only on cytology or aspiration biopsy with a needle narrower than 19
gauge.
• Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g. colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:
1. Patients with vitiligo or alopecia
2. Patients with hypothyroidism (e.g. following Hashimoto syndrome) stable on
hormone replacement
3. Any chronic skin condition that does not require systemic therapy
4. Patients without active disease in the last 5 years may be included
5. Patients with celiac disease controlled by diet alone
• Any condition requiring systemic treatment with either corticosteroids (>10 mg daily
prednisone or equivalent dose of an alternative corticosteroid) or other
immunosuppressive medications within 28 days of durvalumab or ipilimumab or nivolumab
administration. Intranasal, inhaled or topical steroids or local steroid injections
(e.g. intra-articular injection) are permitted in the absence of active autoimmune
disease. Standard steroid premedication given prior to chemotherapy or as prophylaxis
for imaging contrast allergy should not be counted for this criterion.
• Participants with symptomatic or uncontrolled brain metastases or leptomeningeal
disease are excluded.
• Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any
other antibody or drug specifically targeting T cell co-stimulation or immune
checkpoint pathways.
• Current treatment or treatment within the last 12 months with any investigational
anti-cancer products.
• Concurrent enrolment in another clinical study testing an anticancer treatment.
• Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 msec
in screening ECG measured using standard institutional method or history of familial
long QT syndrome.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of study treatment on protocol. Note: Local surgery of isolated lesions for
palliative intent is acceptable. Limited pleural biopsy procedures do not apply.
• No other malignancy that requires active treatment. Participants with a past history
of adequately treated carcinoma in situ, non-melanoma skin cancer or lentigo maligna
without evidence of disease or superficial transitional cell carcinoma of the bladder
are eligible.
• Hearing loss or peripheral neuropathy considered by the investigators to
contraindicate administration of either cisplatin, carboplatin or pemetrexed.
• History of allergy or hypersensitivity to investigational product, cisplatin,
carboplatin, pemetrexed, ipilimumab, nivolumab or any excipient.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive cardiac failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, active peptic ulcer
disease or gastritis, serious chronic gastrointestinal conditions associated with
diarrhoea, active bleeding diatheses.
• Hepatitis B, hepatitis C or human immunodeficiency virus (HIV). Exceptions include
past or resolved Hepatitis B (defined as the presence of hepatitis B core antibody
[anti-HBc] and absence of HBsAg) and patients positive for hepatitis C (HCV) antibody
if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in
absence of clinical suspicion of HIV.
• Known history of primary immunodeficiency, allogeneic organ transplant, pneumonitis or
active tuberculosis.
• Receipt of live attenuated vaccination within 30 days prior to enrolment or within 30
days of receiving durvalumab, ipilimumab, nivolumab.
• Specific comorbidities or conditions or concomitant medications which may interact
with the investigational product(s).
• Any condition that, in the opinion of the investigator, would interfere with
evaluation of study treatment or interpretation of patient safety or study results.
• Serious medical or psychiatric conditions or social situation that might limit
compliance with study requirements, substantially increase risk of incurring adverse
events or compromise the ability of the patient to give written informed consent.
Drug: Durvalumab, Drug: Standard Chemotherapy, Drug: Ipilimumab and Nivolumab
A phase 3 randomized partial blind storage duration ranging study in patients undergoing
complex cardiac surgery that will compare the transfusion of cold stored platelets to
standard room temperature stored platelets. The primary objective is to establish that cold
stored platelets have a non-inferiority (or superiority) to room temperature platelets.
• Age greater than 28 days and less than 85 years
• Planned complex cardiac surgery with planned use of cardiopulmonary bypass
Exclusion Criteria:
• Expected order for washed or volume reduced platelets
• Patient with known anti-platelet antibodies
• Platelet transfusion refractoriness due to anti-HLA antibodies
• Known or suspected pregnancy
• Previously randomized in this study
• Conscious objection or unwillingness to receive blood products
• Known IgA deficiency
• Known congenital platelet disorder
• Known congenital bleeding disorder
• Planned post-operative extracorporeal membrane oxygenation (ECMO), ventricular assist
device (VAD), and/or continuous renal replacement therapy (CRRT)/ hemodialysis
• Patients intended to receive whole blood either intra-operative or post-operative for
bleeding
• Platelet transfusion (of any type) within 24 hours prior to the date of surgery
• Pre-operative thrombocytopenia, defined as platelet count <75x10(9)/L, based on the
most recent labs completed within 72 hours prior to the date of surgery.
Biological: Cold Stored Platelets, Biological: Room Temperature Platelets
Cardiovascular, Acute Blood Loss
platelets, cold-stored platelets, bleeding, hemostasis, complex cardiac surgery
UT Southwestern; Children’s Health; Parkland Health & Hospital System
Safety and Efficacy Trial of Epcoritamab Combinations in Subjects With B-cell Non-Hodgkin Lymphoma (B-NHL) (EPCORE™ NHL-2)
A phase 1b/2, open-label, multinational, interventional trial to evaluate the safety,
tolerability, pharmacokinetics (PK), pharmacodynamics/biomarkers, immunogenicity, and
preliminary efficacy of epcoritamab in combination with other standard of care (SOC) agents
in subjects with B-cell Non-Hodgkin Lymphoma (B-NHL).
Key Inclusion Criteria
1. Subject must sign an Informed Consent Form (ICF)
2. At least 18 years of age
3. Measurable disease defined as ≥1 measurable nodal lesion (long axis >1.5 cm and short
axis >1.0 cm) or ≥1 measurable extra-nodal lesion (long axis >1.0 cm) on computed
tomography (CT) or magnetic resonance imaging (MRI)
4. Eastern Cooperative Oncology Group (ECOG) PS score of 0, 1 or 2
5. Acceptable organ function at screening
6. CD20-positive non-Hodgkin lymphoma (NHL) at most recent representative tumor biopsy
7. If of childbearing potential subject must practicing a highly effective method of
birth control
8. A man who is sexually active with a woman of childbearing potential must agree to use
a barrier method of birth control
Arm 1:
• Newly Diagnosed Documented diffuse large B-cell lymphoma (DLBCL)
• DLBCL, NOS
• "double-hit" or "triple-hit" DLBCL
• FL Grade 3B
Arm 2: R/R FL
Arm 3: Newly diagnosed, previously untreated FL grade 1-3A
Arm 4:
• Documented DLBCL and eligible for HDT-ASCT
• DLBCL, NOS
• "double-hit" or "triple-hit" DLBCL
• FL Grade 3B
Arm 5:
• Relapsed or refractory documented DLBCL and ineligible for HDT-ASCT
• DLBCL, NOS
• "double-hit" or "triple-hit" DLBCL
• FL Grade 3B
Arm 6: Newly diagnosed, previously untreated FL grade 1-3A
Arm 7:
• FL Grade 1-3A
• If PR or CR per Lugano criteria following first-line or second-line treatment with SOC
regimen, and last dose of SOC within 6 months prior to enrollment.
Arm 8:
• DLBCL, NOS
• T-cell/histiocyte rich DLBCL
• "double-hit" or "triple-hit" DLBCL
• FL Grade 3B
Key Exclusion Criteria
1. Chemotherapy, radiation therapy, or major surgery within 4 weeks prior to the first
dose of epcoritamab
2. Any prior treatment with a bispecific antibody targeting CD3 and CD20.
3. Treatment with CAR-T therapy within 30 days prior to first dose of epcoritamab
4. Clinically significant cardiovascular disease
5. Evidence of significant, uncontrolled concomitant diseases that could affect
compliance with the protocol or interpretation of results
6. CNS lymphoma or known CNS involvement by lymphoma at screening as confirmed by MRI/CT
scan of the brain and, if clinically indicated, by lumbar puncture
7. Active positive tests for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection
8. Known history of seropositivity of human immunodeficiency virus (HIV)
9. Active tuberculosis or history of completed treatment for active tuberculosis within
the past 12 months
10. Neuropathy > grade 1
11. Receiving immunostimulatory agent
12. Prior allogeneic HSCT
13. Current seizure disorder requiring anti-epileptic therapy
NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.
Drug: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, Drug: rituximab and lenalidomide, Drug: rituximab and bendamustine, Drug: rituximab, cytarabine, dexamethasone, and oxaliplatin/carboplatin, Drug: gemcitabine and oxaliplatin, Biological: Epcoritamab, Biological: Epcoritamab Maintenance, Drug: rituximab, cyclophosphamide, reduced dose of doxorubicin, vincristine, and prednisone
Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Non-Hodgkins Lymphoma
Elimusertib for the Treatment of Relapsed or Refractory Solid Tumors
This phase I/II trial tests the safety, best dose, and whether elimusertib works in treating
patients with solid tumors that have come back (relapsed) or does not respond to treatment
(refractory). Elimusertib may stop the growth of tumor cells by blocking some of the enzymes
needed for cell growth.
• Part A: Patients between >= 12 months and < 18 years of age
• Part B:
• Patients between >= 12 months and =< 30 years of age for the phase 2 expansion
cohorts for both EWS and PAX3-FOXO1 ARMS.
• Patients between >= 12 months and =< 21 years of age for the phase 2 DDR
expansion cohort
• The Phase 2 cohorts will initially open concurrently with the Phase 1
portion but will only enroll patients at least 18 years of age. Patients <
18 years of age will be included in the Phase 2 cohorts only after the
RP2D/MTD has been estimated in the Phase 1 portion
• All patients for both Parts A and B must have a minimum body surface area (BSA) >=
0.74 m^2
• All patients for both Parts A and B must have the ability to swallow BAY 1895344
(elimusertib) tablets intact
• Patients with recurrent or refractory solid tumors. Patients must have had histologic
verification of malignancy at original diagnosis or relapse
• Part A: Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one
of the following criteria:
• Any Ewing Sarcoma (histological confirmation alone is adequate) or any EWS-fusion
positive solid tumor (i.e. including related Ewing's family of tumors with EWS
fusions such as EWS-WT1, EWS-ATF1, etc.)
• Alveolar rhabdomyosarcoma (ARMS) with the PAX3-FOXO1 fusion. This does not
include PAX7-FOXO1 or other variant fusion ARMS. Please note that a FISH showing
FOXO1 breakapart is NOT sufficient for eligibility onto this cohort since it
cannot distinguish between FOXO1 partners
• Any (non-CNS primary) solid tumor including lymphoma with inactivating
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1, BRCA2,
CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, POLD1, RAD51, or XRCC2
• Part B: Any (non-CNS primary) solid tumor diagnosis including lymphoma which meets one
of the following criteria:
• B1, EWS Cohort:
• Any Ewing Sarcoma (histological confirmation alone is adequate) or any
EWS-fusion positive solid tumor (i.e. including related Ewing's family of
tumors with EWS fusions such as EWS-WT1, EWS-ATF1, etc.)
• B2, PAX3-FOXO1 ARMS Cohort:
• Alveolar rhabdomyosarcoma (ARMS) with the PAX3-FOXO1 fusion. This does not
include PAX7-FOXO1 or other variant fusion ARMS. Please note that a FISH
showing FOXO1 breakapart is NOT sufficient for eligibility onto this cohort
since it cannot distinguish between FOXO1 partners
• B3, DDR Non-statistical Cohort:
• Any (non-CNS primary) solid tumor including lymphoma with inactivating
alterations of any of the DNA Damage Repair (DDR) genes: ATM, ATRX, BRCA1,
BRCA2, CDK12, CHEK1, CHEK2, FANCA, MSH2, MRE11, PALB2, PARP1, POLD1, RAD51,
or XRCC2
• All the genes on the DDR panel are annotated with OncoKB, a precision oncology
knowledge base which is publicly available here: https://www.oncokb.org/. Alterations
which are categorized either 'Oncogenic' or 'Likely Oncogenic' would be considered
sufficient for eligibility on either the phase 1 or phase 2 portions of this study.
Alterations which are not annotated in OncoKB will need to be reviewed with locally
qualified experts in molecular pathology, such as via an established molecular tumor
board, in order to determine the likely oncogenicity AND will require approval by the
study chair, Dr. Michael Ortiz. If such experts are not available at any institution,
the study chair will review
• In cases where multiple mutations are present or multiple samples are available,
either at different locations or different points in time, the presence of a single
qualifying genomic alteration in any of those samples will is considered sufficient
for eligibility on the phase 2 portions of this study
• Qualifying aberrations must be detected in either DNA or ribonucleic acid (RNA) in any
tumor tissue sample (i.e. detection of a variant on circulating tumor DNA/RNA is not
sufficient to qualify) using a somatic (and/or germline) mutational testing approach
with either a targeted panel or whole exome/genome sequencing in the context of a
Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory setting. Any
CLIA certified laboratory is acceptable to use
• Part A: Patients must have either measurable or evaluable disease
• Part B (1, 2, 3): Patients must have measurable disease
• Patients with a prior history of CNS metastases may enroll on study provided there is
no current evidence of active disease at the time of enrollment
• Patient's current disease state must be one for which there is no known curative
therapy or therapy proven to prolong survival with an acceptable quality of life
• Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2. Use Karnofsky >= 50% for patients > 16 years of age
and Lansky >= 50% for patients =< 16 years of age. Note that neurologic deficits in
patients with tumors previously metastatic to the CNS (or other non-oncologic reasons)
must have been stable for at least 7 days prior to study enrollment. Patients who are
unable to walk because of paralysis, but who are up in a wheelchair, will be
considered ambulatory for the purpose of assessing the performance score
• Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment. If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately
• Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
>= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior
nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent
• Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
• Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor. For
agents that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur
• Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
• Stem cell Infusions (with or without total-body irradiation [TBI]):
• Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
cell infusion including donor lymphocyte infusions (DLI) or boost infusion:
>= 84 days after infusion and no evidence of graft versus host disease
(GVHD)
• Autologous stem cell infusion including boost infusion: >= 30 days
• Cellular therapy: >= 42 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >=
50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
• Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I MIBG): >= 42 days
after systemically administered radiopharmaceutical therapy
• Study specific prior therapy: Patients must not have received prior exposure to
BAY 1895344 (elimusertib) or any other specific ATR inhibitors including
berzosertib (M6620, VX-970), ceralasertib (AZD6738), M4344 (VX-803), M1774, and
RP-3500. Treatment with other DNA damage repair inhibitors which do not
specifically inhibit ATR (e.g. PARP inhibitors, WEE1 inhibitors, CHEK1
inhibitors, etc.) does not exclude them from eligibility on this study
• For patients with solid tumors without known bone marrow involvement
• Peripheral absolute neutrophil count (ANC) >= 1000/uL
• For patients with solid tumors without known bone marrow involvement
• Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment)
• For patients with solid tumors without known bone marrow involvement
• Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC]
transfusions)
• Patients with known or possible bone marrow metastatic disease will be eligible for
study provided they meet the blood counts in above inclusion criteria (may receive
transfusions provided they are not known to be refractory to red cell or platelet
transfusions). These patients will not be evaluable for hematologic toxicity. At least
5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the
dose-escalation part of the study. If dose-limiting hematologic toxicity is observed,
all subsequent patients enrolled must be evaluable for hematologic toxicity
• Serum creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a creatinine based on age/gender as follows:
• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male); 0.6 (female)
• Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male); 1 (female)
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
• Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)
• Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
(ULN) for age
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L. For the purpose of this study, the ULN for SGPT is 45 U/L
• Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled as evidenced by no increase in seizure frequency in the prior 7 days. For
patients a history of seizure but not on anticonvulsants, no seizure in the past 3
months
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
version [v]5) resulting from prior therapy must be =< grade 2, with the exception of
decreased tendon reflex (DTR). Any grade of DTR is eligible
Exclusion Criteria:
• Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because there
is yet no available information regarding human fetal or teratogenic toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of
reproductive potential may not participate unless they have agreed to use two
effective methods of birth control, including a medically accepted barrier or
contraceptive method (e.g., male or female condom) for the duration of the study and
for 3 months + 2 days for males and 6 months + 2 days for females after receiving the
last dose of BAY 1895344 (elimusertib) on the study. Abstinence is an acceptable
method of birth control. Female patients must not breastfeed during treatment and
until 4 months after last study drug administration
• Corticosteroids: Patients receiving corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment are not
eligible. If used to modify immune adverse events related to prior therapy, >= 14 days
must have elapsed since last dose of corticosteroid
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who are currently receiving drugs that are strong inducers or inhibitors of
CYP3A4 are not eligible. Strong inducers or inhibitors of CYP3A4 should be avoided
from 14 days prior to enrollment to the end of the study. Drugs that are considered
sensitive or narrow therapeutic range CYP3A4 substrates should be avoided for the
duration of protocol therapy
• Dedicated CNS imaging is not required but patients with current active CNS metastasis
whether symptomatic or discovered incidentally without clinical symptoms, will be
excluded from study participation
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible
A Study of VX-121 Combination Therapy in Participants With Cystic Fibrosis (CF) Who Are Homozygous for F508del, Heterozygous for F508del and a Gating (F/G) or Residual Function (F/RF) Mutation, or Have At Least 1 Other Triple Combination Responsive (TCR) CFTR Mutation and No F508del Mutation
The purpose of this study is to evaluate the efficacy and safety of
VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in CF participants who are homozygous for
F508del, heterozygous for F508del and a gating (F/G) or residual function (F/RF) mutation, or
have at least 1 other TCR CF transmembrane conductance regulator (CFTR) gene mutation and no
F508del mutation.
• Participant has one of the following genotypes:
• Homozygous for F508del;
• Heterozygous for F508del and a gating (F/G) mutation;
• Heterozygous for F508del and a residual function (F/RF) mutation;
• At least 1 other TCR CFTR gene mutation identified as responsive to ELX/TEZ/IVA
and no F508del mutation
• Forced expiratory volume in 1 second (FEV1) value >=40% and <=90% of predicted mean
for age, sex, and height for participants currently receiving CFTR protein modulator
therapy; FEV1 >=40% and <=80% for participants not currently receiving CFTR protein
modulator therapy
Key
Exclusion Criteria:
• History of solid organ or hematological transplantation
• Hepatic cirrhosis with portal hypertension, moderate hepatic impairment (Child Pugh
Score 7 to 9), or severe hepatic impairment (Child Pugh Score 10 to 15)
• Lung infection with organisms associated with a more rapid decline in pulmonary status
• Pregnant or breast-feeding females
Other protocol defined Inclusion/Exclusion criteria may apply
Drug: VX-121/TEZ/D-IVA, Drug: ELX/TEZ/IVA, Drug: IVA, Drug: Placebo (matched to VX-121/TEZ/D-IVA), Drug: Placebo (matched to ELX/TEZ/IVA), Drug: Placebo (matched to IVA)
A Comparison of TULSA Procedure vs. Radical Prostatectomy in Participants With Localized Prostate Cancer (CAPTAIN)
Men with localized, intermediate risk prostate cancer will be randomized to undergo either
radical prostatectomy or the TULSA procedure, with a follow-up of 10 years in this
multi-centered randomized control trial. This study will determine whether the TULSA
procedure is as effective and more safe compared to radical prostatectomy.
• Male
• Age 40 to 80 years, with >10 years life expectancy
• Biopsy-confirmed, NCCN (favorable and unfavourable) intermediate-risk prostate
acquired within last 12 months
• Stage ≤cT2c, N0, M0
• ISUP Grade Group 2 or 3 disease on TRUS-guided biopsy or in-bore biopsy
• PSA ≤20ng/mL within last 3 months
• Treatment-naïve
• Planned ablation volume is < 3 cm axial radius from urethra on mpMRI acquired within
last 6 months
Exclusion Criteria:
• Inability to undergo MRI or general anesthesia
• Suspected tumor is > 30 mm from the prostatic urethra
• Prostate calcifications is > 3 mm in maximum extent obstructing ablation of tumor
• Unresolved urinary tract infection or prostatitis
• History of proctitis, bladder stones, hematuria, history of acute urinary retention,
severe neurogenic bladder
• Artificial urinary sphincter, penile implant, or intraprostatic implant
• Patients who are otherwise not deemed candidates for radical prostatectomy
• Inability or unwillingness to provide informed consent
• History of anal or rectal fibrosis or stenosis, or urethral stenosis, or other
abnormality challenging insertion of devices
A Study of Abemaciclib (LY2835219) With Abiraterone in Men With Prostate Cancer That Has Spread to Other Parts of the Body and is Expected to Respond to Hormonal Treatment (Metastatic Hormone-Sensitive Prostate Cancer) (CYCLONE 3)
The purpose of this study is to learn whether adding abemaciclib to abiraterone plus
prednisone prolongs the time before prostate cancer gets worse. Participation may last
approximately 60 months.
• Adenocarcinoma of the prostate (as the predominant histology)
• High-risk metastatic hormone-sensitive prostate cancer. High risk is defined as:
• Greater than or equal to (≥)4 bone metastases by bone scan and/or
• ≥1 visceral metastases by computed tomography or magnetic resonance imaging
• Must have initiated androgen deprivation therapy (ADT) with luteinizing
hormone-releasing hormone (LHRH) agonist/antagonist or bilateral orchiectomy prior to
randomization. Up to 3 months of ADT prior to randomization is permitted with or
without first-generation anti-androgen.
• Adequate organ function
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Exclusion Criteria:
• Prior treatment with abemaciclib or any other cyclin dependent kinase 4 and 6 (CDK4 &
6) inhibitor
• Development of metastatic prostate cancer in the context of castrate levels of
testosterone
• Received any prior systemic therapy for metastatic prostate cancer (including
investigational agents), except for ADT and first-generation anti-androgen
• Clinically significant cardiovascular disease as evidenced by myocardial infarction,
arterial thrombotic events, or severe/unstable angina in the past 6 months, or New
York Heart Association Class II to IV heart failure
• History of syncope of cardiovascular etiology, ventricular arrhythmia of pathological
origin, or sudden cardiac arrest. Chronic and hemodynamically stable atrial arrhythmia
well-controlled on medical therapy is permitted
• Uncontrolled hypertension
• Clinically active or chronic liver disease, moderate/severe hepatic impairment
• Known untreated central nervous system (CNS) metastasis. Participants with a history
of treated brain metastases are eligible if stable for at least 8 weeks prior to
randomization and off corticosteroid for at least 2 weeks prior to randomization
Drug: Abemaciclib, Drug: Abiraterone, Drug: Prednisone or Prednisolone, Drug: Placebo for Abemaciclib
A Study to Test if Fremanezumab is Effective in Preventing Episodic Migraine in Patients 6 to 17 Years of Age
The primary objective of the study is to evaluate the effectiveness of fremanezumab as
compared to placebo for the preventive treatment of episodic migraine (EM).
Secondary objectives are to further demonstrate the efficacy of Fremanezumab as compared to
placebo for the preventive treatment of EM, to evaluate the safety and tolerability of
Fremanezumab in the preventive treatment of EM and to evaluate the immunogenicity of
Fremanezumab and the impact of antidrug antibodies (ADAs) on clinical outcomes in
participants exposed to Fremanezumab.
The total duration of the study is planned to be up to 36 months.
• The participant has a clinical history of recurrent headache consistent with the
diagnosis of migraine for at least 6 months before screening, consistent with ICHD-3
criteria (Headache Classification Committee of the IHS 2013), and a history of ≤=14
headache days per month in each of the 3 months prior to screening (visit 1).
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant does not have chronic daily headache. For the purposes of this study,
chronic daily headache is operationally defined as <4 headache-free days during the
28-day baseline period.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria:
• The participant is using medications containing opioids (including codeine) or
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing
butalbital) for the treatment of migraine during the 3 months prior to the day of the
screening visit.
• The participant or parent/caregiver maintain a prospectively collected headache diary
• The participant has used an intervention/device (eg, scheduled nerve block or
transcranial magnetic stimulation) for the treatment of migraine or in the head or
neck area for any condition during the 2 months prior to the day of the screening
visit.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a past or current history of cancer.
• The participant is pregnant or nursing.
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Drug: Fremanezumab, Drug: Placebo
Migraine, Brain and Nervous System, Cardiovascular
A Study to Test if Fremanezumab is Effective in Preventing Migraine in Children and Adolescents
The primary objective of the study is to evaluate the long-term safety and tolerability of
subcutaneous fremanezumab in the preventive treatment of migraine in pediatric participants 6
to 17 years of age (inclusive at enrollment in the pivotal study).
Secondary objectives are to evaluate the efficacy of subcutaneous fremanezumab in pediatric
participants with migraine and to evaluate the immunogenicity of fremanezumab and the impact
of ADAs on clinical outcomes in pediatric participants exposed to fremanezumab.
The total duration of the study is planned to be up to 60 months.
Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 or TV48125-CNS-30083):
• Participants have completed the pivotal efficacy study and, in the opinion of the
Investigator or the Sponsor, are able to complete the study in a safe and compliant
way.
• Participants may continue with a stable dose/regimen of the preventive medication they
were taking during the pivotal efficacy studies.
• The participant continues to meet appropriate criteria carried forward from the
pivotal efficacy study/
• The participant has received all recommended age-appropriate vaccines according to
local standard of care and schedule.
• The participant weighs at least 17.0 kg on the day of study enrollment.
NOTE: Additional criteria apply; please contact the investigator for more information.
Inclusion Criteria for Participants Rolling Over from the Phase 1 Pediatric Pharmacokinetic
Study (Study TV48125-CNS-10141):
• The participant/caregiver has demonstrated compliance with the electronic headache
diary during the 28-day baseline period by entry of headache data on a minimum of 21
out of 28 days (approximately 75% diary compliance).
• The participant has received all recommended age-appropriate vaccines according to
local standard of care and schedule.
• The participant weighs at least 17.0 kg on the day of study enrollment.
• The participant has a body mass index ranging from the 5th to 120% of the 95th
percentile, inclusive, on the day of study enrollment.
• Not using preventive medications or using no more than 2 preventive medications for
migraine or other medical condition, as long as the dose and regimen have been stable
for at least 2 months prior to screening (visit 1).
NOTE: Additional criteria apply; please contact the investigator for more information.
Inclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 and TV48125-CNS-30083) for Safety and antidrug antibody (ADA) Assessment
Only:
• Participants may be included in this study if they sign and date the informed consent
document or upon consent of a parent or guardian, if the participant is younger than the
age of consent, accompanied by assent of the participant.
Exclusion Criteria:
Exclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 or TV48125-CNS-30083):
• In the judgment of the investigator, the participant has a clinically significant
abnormal finding on study entry, including hematology, blood chemistry, coagulation
tests, or urinalysis values/findings (abnormal tests may be repeated for
confirmation).
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The participant is pregnant or nursing.
• In the judgment of the investigator, the participant has an abnormal finding on the
baseline 12-lead ECG considered clinically significant.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria for Participants Rolling Over from the Phase 1 Pharmacokinetic Study
(TV48125-CNS-10141):
• The participant has any clinically significant cardiovascular (including congenital
cardiac anomalies or thromboembolic events), endocrine, gastrointestinal,
genitourinary, hematologic, hepatic, immunologic, neurologic, ophthalmic, pulmonary,
renal disease, or complications of an infection, at the discretion of the
investigator.
• The participant has a current history of a clinically significant psychiatric
condition, any prior history of a suicide attempt, or a history of suicidal ideation
with a specific plan within the past 2 years, at the discretion of the investigator.
• The participant has an ongoing infection or a known history of human immunodeficiency
virus infection, tuberculosis, Lyme disease, or chronic hepatitis B or C, or a known
active infection of coronavirus disease 2019 (COVID-19).
• The participant has a history of hypersensitivity reactions to injected proteins,
including mAbs, or a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis
syndrome, or the participant is concomitantly using lamotrigine.
• The participant received a live attenuated vaccine (eg, intranasal flu vaccine, and
measles, mumps, and rubella vaccine) within the 12-week period prior to screening.
Note: If a medical need arises during the study, the participant may receive a live
attenuated vaccine.
• The participant is pregnant or nursing.
• In the judgment of the investigator, the participant has an abnormal finding on the
baseline 12-lead ECG considered clinically significant.
• The patient has a current or past medical history of hemiplegic migraine.
NOTE: Additional criteria apply; please contact the investigator for more information.
Exclusion Criteria for Participants Rolling Over from the Pivotal Efficacy Studies
(TV48125-CNS-30082 and TV48125-CNS-30083) for Safety and antidrug antibody (ADA) Assessment
Only: Not Applicable
A Multi-center Trial to Evaluate Multiple Regimens in Metastatic Pancreatic Cancer
Precision Promise is a multi-center, seamless Phase 2/3 platform trial designed to evaluate
multiple regimens in metastatic pancreatic cancer.
Primary Objectives
- To compare each investigational arm versus standard of care (SOC) for superiority in
overall survival in 1st and/or 2nd line metastatic pancreatic cancer patients and
determine which, if any, patients benefit from each investigational arm.
Secondary Objectives
- To determine short and long-term safety signals of each investigational arm in
pancreatic cancer patients vs. SOC.
- To determine progression-free survival (PFS) for each investigational arm vs. SOC.
- Rates of overall response, CR, and PR; duration of overall response, CR or PR (whichever
occurs first).
- Rate of clinical benefit; duration of clinical benefit.
Inclusion Criteria
A subject will be eligible to participate in Precision PromiseSM if all the below inclusion
criteria are met:
• Age ≥ 18 years
• Histologically or cytologically confirmed metastatic pancreatic ductal adenocarcinoma
(PDAC) and eligible for treatment in the first line or second line settings.
• Acceptable histologies include adenosquamous carcinoma, mucinous adenocarcinoma,
hepatoid carcinoma, medullary carcinoma, signet ring cell carcinoma, undifferentiated
carcinoma, and undifferentiated carcinoma with osteoclast-like-cells, and
adenocarcinoma. Pancreatic neuroendocrine tumors (PNET) are excluded.
• Radiographically measurable disease of at least one site by computed tomography (CT)
scan or magnetic resonance imaging (MRI) as defined by Response Evaluation Criteria In
Solid Tumors (RECIST) 1.1. Imaging results must be obtained within the 21-day window,
prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Adequate organ function (lab results must be obtained within the 21-day window prior
to randomization)
• Absolute neutrophil count ≥ 1500/mm3
• Hemoglobin ≥ the lower limit of normal (LLN) or 9g/dL
• Platelets ≥ 100,000/mm3
• Serum creatinine ≤ 1.0 x upper limit normal (ULN), or calculated creatinine
clearance ≥ 50 mL/min (Cockcroft Gault)
• Albumin ≥ 3.0 g/dL
• Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)
and/or alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT)
≤ 2.5 x ULN (up to ≤ 5 x ULN in presence of liver metastasis).
• Total bilirubin ≤ 1.5 x ULN
• INR ≤ 1.5 x ULN (up to ≤ 2 x ULN for subjects on anticoagulation therapy).
• Subjects must be willing to provide protocol-mandated tissue and blood samples for
diagnostic and research purposes as a condition of enrollment into the trial.
• Able to swallow pills, capsules or tablets.
• Able to adhere to study visit schedule and other protocol requirements.
• Females of childbearing potential [defined as a sexually mature woman who (1) has not
undergone hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy
(the surgical removal of both ovaries) or (2) has not been naturally postmenopausal
for at least 24 consecutive months (i.e., has had menses at any time during the
preceding 24 consecutive months)] must:
• Have a negative serum or urine pregnancy test (β-human chorionic gonadotropin
[β-hCG]) as verified by the study doctor within 14 days prior to randomization.
• Commit to complete abstinence from heterosexual contact or agree to use medical
doctor-approved contraception throughout the study without interruption while
receiving study treatment and for at least 6 months following last dose of study
treatment.
• Males must practice complete abstinence or agree to use a condom (even if he has
undergone a successful vasectomy) during sexual contact with a pregnant female or a
female of childbearing potential while participating in the study, during dose
interruptions and for at least 6 months following last dose of study treatment.
• HIV-infected subjects on effective anti-retroviral therapy are eligible if the most
recent viral load test performed within six months of screening (based on medical
chart review) is negative. If this is not the case, an HIV viral load test should be
performed at screening and be negative (i.e., undetectable).
• HBV-infected subjects are eligible if the most recent viral load test performed within
six months of screening (based on medical chart review) is negative. If this is not
the case, an HBV viral load test should be performed at screening and be negative
(i.e., undetectable).
• Subjects with a history of hepatitis C virus (HCV) infection must have been treated
and cured. Subjects with HCV infection who are currently on treatment are eligible if
the most recent viral load test performed within six months of screening (based on
medical chart review) is negative. If this is not the case, an HCV viral load test
should be performed at screening and be negative (i.e., undetectable).
• Subjects with a history of brain metastases are eligible provided they show evidence
of stable lesions (and no new lesions) with no evidence of tumor progression for at
least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and
brain imaging (MRI or CT) during the screening period. In addition, any neurological
symptoms that developed either as a result of the brain metastases or their treatment,
must have returned to baseline or resolved. Any steroids administered as part of this
therapy must be completed > 7 days prior to the first dose of trial therapy.
• No known leptomeningeal disease.
• Subjects with a prior or concurrent malignancy whose natural history does not have the
potential to interfere with the safety or efficacy assessment of the investigational
regimen are eligible. Subjects receiving any active therapy for a concurrent secondary
malignancy are excluded.
• Subjects with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using New York Heart Association Functional Classification. To be eligible
for this trial, subjects should be Class 2 or better. Class 2 is defined as slight
limitation of physical activity, in which ordinary physical activity leads to fatigue,
palpitation, or dyspnea; the person is comfortable at rest.
• Understands the nature of the study and has agreed to participate by voluntarily
signing the IRB approved informed consent.
Exclusion Criteria
A subject will not be eligible to participate in Precision PromiseSM if any of the
following criteria are met:
• Received any anti-cancer systemic therapy within 21 days (or 5 half-lives, whichever
is shorter,) prior to randomization.
• Has had major surgery within 14 days prior to enrollment.
• History of known allergy or hypersensitivity to any of the study treatments or any of
their excipients or contraindication to any of the study treatments as outlined in the
local prescribing information (e.g., United States Prescribing Information [USPI]).
• Pre-existing peripheral neuropathy > Grade 1, as defined by CTCAE V 4.03.
• Known active tuberculosis infection.
• Serious, non-healing wound, ulcer, or bone fracture.
• The inability to swallow pills, capsules or tablets.
• Receiving any active therapy for a concurrent secondary malignancy. Subjects with a
prior or concurrent malignancy whose natural history and/or management does not have
the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible.
• History of interstitial lung disease, history of slowly progressive dyspnea and
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, and
pulmonary hypersensitivity pneumonitis.
• QTc > 450 msec if male and QTc > 470 msec if female.
• Uncontrolled or severe cardiac disease (history of unstable angina, myocardial
infarction, coronary stenting, or bypass surgery within the prior 6 months),
symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia
[including atrial flutter/fibrillation].
• Subjects with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using New York Heart Association Functional Classification. Subjects worse
than Class 2 are excluded. Class 2 is defined as slight limitation of physical
activity, in which ordinary physical activity leads to fatigue, palpitation, or
dyspnea; the person is comfortable at rest.
• Active, uncontrolled infections (bacterial, viral, or fungal infection(s)) requiring
systemic therapy, defined as ongoing signs/symptoms related to the infection without
improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment
(i.e., subjects must be afebrile for > 48 hours off antibiotics).
• Active, known or suspected autoimmune disease, including systemic lupus erythematosus,
Hashimotos thyroiditis, scleroderma, polyarteritis nodosa or autoimmune hepatitis.
o Subjects with type I diabetes mellitus, hypothyroidism requiring only hormone
replacement, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring
systemic treatment, or conditions not expected to recur in the absence of an external
trigger are eligible to participate.
• Receiving immunosuppressive or myelosuppressive medications that would, in the opinion
of the Investigator, increase the risk of serious neutropenic complications. Subjects
receiving replacement therapy of 10 mg of prednisone (or the equivalent hydrocortisone
dose) per day are eligible.
• Receipt of live vaccines within 30 days prior to the first dose of study treatment or
while on active treatment within the trial. (examples of live vaccines include, but
are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,
rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are
generally killed virus vaccines and are permitted. However, intranasal influenza
vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not permitted).
• Any significant medical condition, laboratory abnormality or psychiatric illness that
would limit the subject's ability to comply with study requirements.
• Subjects that discontinued previous treatment for pancreatic adenocarcinoma due to a
treatment-related ≥ Grade 3 toxicity.
• For toxicity ≤ Grade 3, AE(s) must resolve to Grade 1 or baseline in order to be
considered eligible for this trial.
• Subjects that have received allogenic bone marrow or solid organ transplants are
excluded.
Drug: Gemcitabine combined with nab-paclitaxel, Drug: Dose -mFOLFIRINOX, Drug: Dose - Pamrevlumab combined with gemcitabine and nab-paclitaxel, Drug: Dose- Canakinumab and Spartalizumab combined with nab-paclitaxel and gemcitabine, Drug: Drug: Dose -SM-88
The ExTINGUISH Trial of Inebilizumab in NMDAR Encephalitis (ExTINGUISH)
Determine the difference in the modified Rankin score at 16 weeks in participants with
anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis treated with "first-line"
immunomodulatory therapies provided as standard-of-care, and either inebilizumab
(investigational agent) or placebo.
• Inclusion Criteria 1. Diagnosis of NMDAR encephalitis, defined by both (a) and (b):
1. A subacute onset of change in mental status consistent with autoimmune
encephalitis,
2. A positive cell-based assay for anti-NMDA receptor IgG antibody in the CSF
confirmed in study-specified laboratories.
2. Age ≥ 18 years 3. Written informed consent and any locally required
authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA]
in the United States of America (USA), European Union [EU] Data Privacy Directive
in the EU) obtained from the participant/legal representative prior to performing
any protocol-related procedures, including screening evaluations.
4. Females of childbearing potential who are sexually active with a nonsterilized
male partner must agree to use a highly effective method of contraception
beginning at screening or upon discharge from hospitalization/inpatient
rehabilitation (for participants who were incapacitated at the time of
screening), and to continue precautions for 6 months after the final dose of
investigational product.
5. Nonsterilized males who are sexually active with a female partner of
childbearing potential must agree to use a highly effective method of
contraception at screening or upon discharge from hospitalization/inpatient
rehabilitation (for participants who were incapacitated at the time of
screening), and to continue precautions for 3 months after the final dose of
investigational product. Male patients with female partners of childbearing
potential must have that female partner use at least one form of highly effective
contraception, starting at least one menstrual cycle before (the male patient's)
first study drug administration and continuing until at least 3 months after
their male partner's last dose of the study drug.
6. Willing to forego other immunomodulatory therapies (investigational or
otherwise) for NMDAR encephalitis during the study.
7. Patient must have received at least 3 days of methylprednisolone 1000 mg IV or
equivalent corticosteroid within 30 days prior to randomization (Day 1). In
addition, patients must have received EITHER of the following treatments within
30 days before randomization.
1. IVIg, at a minimum dose of 2 g/kg
2. Plasma exchange or plasmapheresis, with a minimum of 5 treatments. NOTE: These
treatments may be provided during the screening period, but must be completed
prior to randomization.
8. mRS of ≥3 at the screening visit, indicating at least moderate disability. 9.
Ability and willingness to attend study visits and complete the study
Exclusion Criteria:
1. Any condition that, in the opinion of the investigator, would interfere with
the evaluation or administration of the investigational product,
interpretation of participant safety or study results, or would make
participation in the study an unacceptable risk. This specifically includes
recent history (last 5 years) of herpes simplex virus encephalitis or known
central nervous system demyelinating disease (e.g., multiple sclerosis).
2. Presence of an active or chronic infection that is serious in the opinion of
the investigator.
3. Concurrent/previous enrollment in another clinical study involving an
investigational treatment within 4 weeks or 5 published half-lives of the
investigational treatment, whichever is the longer, prior to randomization.
4. Lactating or pregnant females, or females who intend to become pregnant
anytime from study enrollment to 6 months following last dose of
investigational agent.
5. Known history of allergy or reaction to any component of the investigational
agent formulation or history of anaphylaxis following any biologic therapy.
6. At screening (one repeat test may be conducted to confirm results prior to
randomization within the same screening period), any of the following:
1. Aspartate transaminase (AST) > 2.5 × upper limit of normal (ULN)
2. Alanine transaminase (ALT) > 2.5 × upper limit of normal (ULN)
3. Total bilirubin > 1.5 × ULN (unless due to Gilbert's syndrome)
4. Platelet count < 75,000/μL (or < 75 × 109/L)
5. Hemoglobin < 8 g/dL (or < 80 g/L)
6. Total white blood count <2,500 cells/mm3
7. Total immunoglobulin < 600 mg/dL
8. Absolute neutrophil count < 1200 cells/μL
9. CD4 T lymphocyte count < 300 cells/µL
7. Receipt of the following at any time prior to randomization:
1. Alemtuzumab
2. Total lymphoid irradiation
3. Bone marrow transplant
4. T-cell vaccination therapy
8. Receipt of rituximab or any experimental B-cell depleting agent, unless the
CD19 B-cell level has returned to above the lower limit of normal prior to
randomization.
9. Receipt of any of the following within 3 months prior to randomization
1. Natalizumab (Tysabri®)
2. Cyclosporine
3. Methotrexate
4. Mitoxantrone
5. Cyclophosphamide
6. Azathioprine
7. Mycophenolate mofetil
10. Severe drug allergic history or anaphylaxis to two or more food products or
medicines (including known sensitivity to acetaminophen/paracetamol,
diphenhydramine or equivalent antihistamine, and methylprednisolone or
equivalent glucocorticoid).
11. Known history of a primary immunodeficiency (congenital or acquired) or an
underlying condition such as human immunodeficiency virus (HIV) infection or
splenectomy that predisposes the participant to infection.
13. Confirmed positive test for hepatitis B serology (hepatitis B surface antigen
and core antigen) and/or hepatitis C PCR positive at screening.
14. History of cancer, apart from ovarian or extra-ovarian teratoma (also known
as a dermoid cyst) or germ cell tumor, or squamous cell carcinoma of the skin or
basal cell carcinoma of the skin. Squamous cell and basal cell carcinomas should
be treated with documented success of curative therapy > 3 months prior to
randomization.
15. Any live or attenuated vaccine within 3 weeks prior to Day 1 (administration
of killed vaccines is acceptable).
16. Bacillus of Calmette and Guérin (BCG) vaccine within 1 year of enrollment.
17. Recurrence of previously treated NMDAR encephalitis within the last 3 or 5
years, or suspicion of symptomatic untreated NMDAR encephalitis of greater than 3
months duration at the time of screening.
Drug: Inebilizumab, Drug: Placebo
Autoimmune Encephalitis, Brain and Nervous System, Encephalitis
Neoadjuvant Her2-targeted Therapy and Immunotherapy With Pembrolizumab
A phase 2 open-label, randomized, multi-center trial to evaluate the efficacy and safety of
neoadjuvant trastuzumab, pertuzumab and weekly paclitaxel (THP) as compared to neoadjuvant
trastuzumab, pertuzumab, pembrolizumab and weekly paclitaxel (THP-K), or neoadjuvant
trastuzumab, pembrolizumab and weekly paclitaxel (TH-K) in chemo naive patients with invasive
human epidermal growth factor receptor 2 (HER2) positive breast cancer whose primary tumors
are > 2 cm and/or clinically lymph node positive. Treatment will be followed by standard of
care breast surgery and physician's choice adjuvant therapy per standard of care.
1. Male/female patients with histologically confirmed invasive HER2-positive (by American
Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines)
unilateral breast cancer
2. Have previously untreated non-metastaic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of
clinically suspicious lymph nodes to confirm nodal status is encouraged).
3. Multifocal/centric disease is permitted if all suspicious foci have been biopsied and
are consistent with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer
4. Be a male or female subject 18 years of age on the day of signing informed consent
5. Male Participants: A male participant must agree to use a contraception as detailed in
Appendix C of this protocol during the treatment period and for at least 6 months
after the last dose of study treatment and refrain from donating sperm during this
period.
6. Female Participants: A female participant is eligible to participate if she is not
pregnant (see Appendix C), not breastfeeding, and at least one of the following
conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in
Appendix C OR b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix
C during the treatment period and for at least 6 months after the last dose of study
treatment.
7. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
8. Provides adequate archival tumor tissue sample or newly obtained core or excisional
biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded
(FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to
archived tissue. Note: If submitting unstained cut slides, newly cut slides should be
submitted to the testing laboratory within 14 days from the date slides are cut.
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
10. Have adequate organ function as defined by the following parameters. Specimens must be
collected within 7 days prior to the start of study treatment.
• Absolute neutrophil count (ANC) ≥1500/µL
• Platelets ≥100 000/µL
• Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
• Renal Creatinine (≤1.5 × ULN OR) OR Measured or calculated(b) creatinine
clearance (≥30 mL/min for participant with creatinine levels) (GFR can also be
used in place of creatinine or CrCl) (>1.5 × institutional ULN)
• Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with
total bilirubin levels >1.5 × ULN aspartate aminotransferase (AST, SGOT) and
alanine aminotransferase (ALT, SGPT) ≤2.5 × ULN (≤5 × ULN for participants with
liver metastases)
• Coagulation International normalized ratio (INR) OR prothrombin time (PT)
Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range
of intended use of anticoagulants
• Cardiac Echocardiogram or MUGA (multigated radionuclide angiography) Baseline
LVEF ≥ 55%
Exclusion Criteria:
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to
randomization. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required. Note: in the event that 72 hours have elapsed
between the screening pregnancy test and the first dose of study treatment, another
pregnancy test (urine or serum) must be performed and must be negative in order for
subject to start receiving study medication.
2. Has received prior therapy with an anti-PD-1 (programmed death protein 1), anti-PD-L1
(Programmed death-ligand 1), or anti PD L2 (Programmed death-ligand 2) agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX 40, CD137).
3. Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to randomization. Note: If participant received major surgery,
they must have recovered adequately from the toxicity and/or complications from the
intervention prior to starting study treatment.
4. Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis.
5. Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
6. Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment.
Note: Participants who have entered the follow-up phase of an investigational study
may participate as long as it has been 4 weeks after the last dose of the previous
investigational agent.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study drug.
8. Has a known additional malignancy that is progressing or has required active systemic
treatment within the past 3 years. Note: Participants with basal cell carcinoma of the
skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
are not excluded.
9. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
10. Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a known history of Human Immunodeficiency Virus (HIV).
13. Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg]
reactive) or Hepatitis C virus (i.d. HCV RNA [qualitative] is detected) infection.
14. Has a known history of active TB (Bacillus Tuberculosis).
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
16. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of trial treatment.
18. Has significant cardiovascular disease, such as:
• History of myocardial infarction, acute coronary syndrome or coronary
angioplasty/stenting/bypass grafting within the last 6 months
• Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or
history of CHF NYHA class III or IV
• Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or
uncontrolled hypertension (systolic blood pressure > 180mmHg and/or diastolic
blood pressure > 100mmHg).
Study Evaluating the Safety and Efficacy of Semaglutide, and the Fixed-Dose Combination of Cilofexor and Firsocostat, Alone and in Combination, in Participants With Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH)
The primary objective of this study is to evaluate whether the combination of semaglutide
(SEMA) with the fixed-dose combination (FDC) of cilofexor/firsocostat (CILO/FIR) causes
fibrosis improvement and Nonalcoholic Steatohepatitis (NASH) resolution in participants with
compensated cirrhosis due to NASH.
• Liver biopsy consistent with cirrhosis (F4) due to NASH in the opinion of the central
reader. In participants who have never had a liver biopsy, a screening liver biopsy
may be performed
• Screening laboratory parameters as determined by the study central laboratory:
• Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m^2, as calculated by
the Modification of Diet in Renal Disease (MDRD) equation
• HbA1c ≤ 10%
• INR ≤ 1.4, unless due to therapeutic anticoagulation
• Platelet count ≥ 125,000/uL
• Alanine Aminotransferase (ALT) < 5 x ULN
• Serum albumin ≥ 3.5 g/dL
• Serum Alkaline Phosphatase (ALP) ≤ 2 x ULN
• BMI ≥ 23 kg/m^2 at screening
Key
Exclusion Criteria:
• Prior history of decompensated liver disease, including ascites, hepatic
encephalopathy (HE), or variceal bleeding
• Child-Pugh (CP) score > 6 at screening, unless due to an alternative etiology such as
Gilbert's syndrome or therapeutic anticoagulation
• Model for End-stage Liver Disease (MELD) score > 12 at screening, unless due to an
alternative etiology such as therapeutic anticoagulation
• Other causes of liver disease based on medical history and/or central reader review of
liver histology, including but not limited to: alcoholic liver disease, autoimmune
disorders (eg, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune
hepatitis), drug-induced hepatotoxicity, Wilson disease, clinically significant iron
overload, or alpha-1-antitrypsin deficiency
• Chronic HBV infection (HBsAg positive), or Chronic HCV infection (HCV antibody and HCV
RNA positive). Participants cured of HCV infection less than 2 years prior to the
screening visit are not eligible
• History of liver transplantation
• Current or prior history of hepatocellular carcinoma (HCC)
• Men who habitually drink greater than 21 units/week of alcohol or women who habitually
drink greater than 14 units/week of alcohol (one unit is equivalent to 12 oz/360 mL of
beer, a 4 oz/120 mL glass of wine, or 1 oz/30 mL of hard liquor).
• For individuals on vitamin E regimen ≥ 800 IU/day, or pioglitazone, dose must be
stable, in the opinion of the investigator for at least 180 days prior to the
historical or screening liver biopsy
• For individuals on medications for diabetes, dose must be stable, in the opinion
of the investigator, for at least 90 days prior to the historical or screening
liver biopsy
• History of type 1 diabetes
• Treatment with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in the period
from 90 days prior to the screening visit and for individuals with a qualifying
historical liver biopsy, for 90 days prior to the date of the historical liver biopsy
• For participants who have not completed a series of an authorized COVID-19 vaccination
regimen prior to screening, a positive result for COVID-19 on SARS-CoV-2 RT-PCR test
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Study of TT-00420 Tablet as Monotherapy and Combination Therapy in Patients With Advanced Solid Tumors
This is a Phase Ib/II, multicenter, open-label study to evaluate the safety and preliminary
efficacy of TT-00420 tablet, as monotherapy or in combination regimens, in patients with
advanced solid tumors.
1. ≥ 18 years of age
2. Histopathological or cytologically documented locally advanced or metastatic solid
tumors who have no available standard therapeutic treatment options
3. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Adequate organ function confirmed at screening and within 10 days of initiating
treatment, as evidenced by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Hemoglobin (Hgb) ≥ 8 g/dl
• Platelets (plt) ≥ 75 x 10^9/L
• AST/SGOT and ALT/SGPT ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 x ULN if liver
metastases are present
• Total bilirubin ≤ 1.5 x ULN
• Calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault formula)
6. Negative pregnancy test within 72 hours before starting study treatment in all
premenopausal women and women < 12 months after the onset of menopause
7. Must agree to take sufficient contraceptive methods to avoid pregnancy during the
study and until at least 6 months after ceasing study treatment
8. Able to sign informed consent and comply with the protocol
Exclusion Criteria:
1. Women who are pregnant or lactating
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control
3. Patients with any hematologic malignancy, including leukemia (any form), lymphoma, and
multiple myeloma
4. Patients with a history of primary central nervous system tumors or carcinomatous
meningitis.
5. Patients with the following mood disorders as judged by the Investigator or a
psychiatrist:
• Medically documented history of or active major depressive episode, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia; a history of
suicidal attempt or ideation, or homicidal ideation (immediate risk of doing harm
to others)
• ≥ CTCAE grade 3 anxiety
6. Impaired cardiac function or significant diseases, including but not limited to any of
the following:
• left ventricular ejection fraction (LVEF) < 45% as determined by multigated
acquisition (MUGA) scan or echocardiogram (ECHO)
• Congenital long QT syndrome
• QTcF ≥ 480 msec on screening ECG
• Unstable angina pectoris ≤ 3 months prior to starting study drug
• Acute myocardial infarction ≤ 3 months prior to starting study drug
7. Patients with:
• unresolved diarrhea ≥ CTCAE grade 2, or
• impairment of gastrointestinal (GI) function, or
• GI disease that may significantly alter the absorption of TT-00420
8. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
uncontrolled hypertension, uncontrolled hypertriglyceridemia, or active or
uncontrolled infection) that could cause unacceptable safety risks or compromise
compliance with the protocol
9. Patients who have received chemotherapy, targeted therapy, or immunotherapy ≤ 4 weeks
(6 weeks for nitrosourea or mitomycin-C) prior to starting study drug or who have not
recovered from side effects of such therapy
10. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field
radiation for palliation ≤ 2 weeks prior to starting study drug or who have not
recovered from side effects of such therapy
11. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or
who have not recovered from side effects of such therapy
12. Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤ 4 weeks prior to starting study drug.
13. Patients who are currently receiving treatment with therapeutic doses of warfarin
sodium or any other coumarin-derivative anticoagulants
14. Patients who have received systemic corticosteroids ≤ 2 weeks prior to starting study
drug or who have not recovered from the side effects of such treatment.
15. Patients who are currently receiving treatment with strong CYP3A inhibitors or
inducers ≤ 2 weeks prior to starting study drug.
16. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
mandatory; patients with well controlled HIV might be enrolled)
17. Known history of active infection with Hepatitis B or Hepatitis C
18. Has received a live-virus vaccination within 30 days of planned first dose
19. Inability to swallow or tolerate oral medication
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that, in the opinion of the investigator, might confound the results of the trial,
interfere with the patient's safe participation and compliance in the trial.
Prostate Cancer, Sarcoma, Gastric Cancer, Bladder Cancer, Cholangiocarcinoma, Gallbladder Cancer, Thyroid Cancer, Triple Negative Breast Cancer, HER2-negative Breast Cancer, Advanced Solid Tumor, Breast - Female, Breast - Male, Lung/Thoracic, Other Digestive Organ, Other Skin, Other Urinary, Prostate, Stomach, Thyroid, Small Intestine, Small-cell Lung Cancer
Efficacy and Safety of Inhaled Isoflurane Delivered Via the Sedaconda ACD-S Compared to Intravenous Propofol for Sedation of Mechanically Ventilated Intensive Care Unit Adult Patients (INSPiRE-ICU1) (INSPiRE-ICU1)
This is a study to compare safety and efficacy of inhaled isoflurane administered via the
Sedaconda ACD-S device system versus intravenous propofol for sedation of mechanically
ventilated patients in the Intensive Care Unit (ICU) setting.
• Adults ≥18 years of age;
• Patients who are anticipated to require >12 hours of invasive mechanical ventilation
and continuous sedation in the ICU; and
• Receipt of continuous sedation due to clinical need for sedation to RASS <0.
Exclusion Criteria:
• Need for RASS -5;
• Sedation for invasive mechanical ventilation immediately prior to Baseline for >72
hours;
• Severe neurological condition before ICU admission that causes the patient to lack
ability to participate in the study (ie, unable to be assessed for RASS and CPOT);
• Ventilator tidal volume <200 or >1000 mL at Baseline;
• Need for extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal
(ECCO2R), high frequency oscillation ventilation (HFOV), or high frequency percussive
ventilation (HFPV) at Screening;
• Comfort care only (end of life care);
• Contraindication to propofol or isoflurane;
• Known or family history of MH;
• Severe hemodynamic compromise, defined as the need for norepinephrine ≥0.3 mcg/kg/min
(or equivalent vasopressor dose) to maintain blood pressure within acceptable range,
assumed to be mean arterial pressure ≥65 mmHg unless prescribed clinically;
• Allergy to isoflurane or propofol, or have propofol infusion syndrome.
• History of ventricular tachycardia/Long QT Syndrome;
• Requirement of IV benzodiazepine or barbiturate administration for seizures or
dependencies, including alcohol withdrawal
• Neuromuscular disease that impairs spontaneous ventilation (eg, C5 or higher spinal
cord injury, amyotrophic lateral sclerosis, etc);
• Concurrent enrollment in another study that, in the Investigator's opinion, would
impact the patient's safety or assessments of this study;
• Participation in other study involving investigational drug(s) or devices(s) within 30
days prior to Randomization;
• Anticipated requirement of treatment with continuous infusion of a neuromuscular
blocking agent for >4 hours;
• Female patients who are pregnant or breast-feeding;
• Imperative need for continuous active humidification through mechanical ventilation
circuit;
• Attending physician's refusal to include the patient; or
• Inability to obtain informed consent.
A Study to Evaluate VIP152 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia or Richter Syndrome
Determine the safety, tolerability, pharmacokinetics, maximum tolerated dose (MTD) and
recommended phase 2 dose (RP2D) of VIP152 in patients with Chronic Lymphocytic Leukemia (CLL)
or Richter Syndrome
• Male or female patients aged >/=18 years
• Patients with a histologically or cytologically:
• Confirmed CLL who are refractory to or have progressed from 2 or more regimens
including BTKi and venetoclax or
• Confirmed CLL transformed to DLBCL (Richter Syndrome) who have relapsed after, or
been refractory, to at least 1 prior line of therapy for the DLBCL and having MYC
overexpression/amplification/translocation
• Adequate bone marrow, liver, and renal functions
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
Exclusion Criteria:
• Active clinically serious infections of Grade > 2; requiring parenteral therapy
• Subjects who have new or progressive brain or meningeal or spinal metastases.
• Anticancer chemotherapy or immunotherapy during the study or within one week prior to
the first dose of study drug
• Major surgery or significant trauma within 4 weeks before the first dose of study drug
• Allogeneic bone marrow transplant or stem cell rescue within 4 months before first
dose of study drug; patients must have completed immunosuppressive therapy before
enrollment
A Multiple Ascending Dose Study of ACN00177 (Pegtarviliase) in Subjects With CBS Deficiency
The purpose of this study is to evaluate the safety and tolerability of pegtarviliase in
approximately 36 subjects with homocystinuria due to CBS deficiency.
1. Diagnosis of homocystinuria due to CBS deficiency
2. Capable of providing signed informed consent/assent and to comply with all study
related procedures
3. Is ≥12 years of age (≥18 in the US) at the time of signing the informed consent/assent
4. Plasma tHcy ≥50 µM (rounded to the nearest whole number) and documentation of previous
tHcy ≥80 µM
5. Female subjects of child-bearing potential must have a negative serum pregnancy test
during the screening period and a negative urine pregnancy test prior to dosing on the
first day of treatment
6. If the subject (male or female) is engaging in sexual activity, he/she must be unable
to become pregnant/cause pregnancy or must agree to use highly effective contraception
7. Subjects receiving pyridoxine and/or betaine must be on the same dose of the
medication(s) for at least 6 weeks prior to the first administration of study drug and
be willing and able to remain on a stable dose for the duration of the study.
Similarly, those on prescribed dietary therapy must be on a consistent dietary regimen
for at least 6 weeks prior to study drug and should maintain this regimen for the
duration of the study
Exclusion Criteria:
1. Other medical conditions or co-morbidity(ies) that, in the opinion of the
investigator, would put the subject at increased medical risk or interfere with study
compliance or data interpretation (eg, severe intellectual disability that precludes
completion of the required study assessments)
2. Currently participating in another therapeutic clinical study or has received any
investigational agent within 30 days or 5 half-lives, whichever is longer, prior to
the first dose of study drug in this study
3. Surgery requiring general anesthesia within 8 weeks prior to the first dose of study
drug or planned surgery druing the treatment period
4. Active infection requiring anti-infective therapy <2 weeks prior to the first dose of
study drug in this study; anti-infective therapy that completes ≥2 weeks prior to
first dose of study drug is acceptable
5. Pregnant or nursing
6. Females of child-bearing potential who are using or plan to use estrogen-containing
contraception during the study (unless the subject currently using estrogen-containing
contraceptives is willing to switch to a non-estrogen-containing contraceptive at
least 1 week before dosing and for the duration of the study) and for 30 days after
the last dose
7. History of hypersensitivity to polyethylene glycol (PEG) that, in the judgment of the
investigator, puts the subject at unacceptable risk for adverse events (AEs)
8. Serum creatinine level >1.5× the upper limit of normal (ULN)
9. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin
level > 2× the ULN
Drug: Pegtarviliase, Drug: Pegtarviliase
Homocystinuria Due to Cystathionine Beta-Synthase Deficiency
A Study of Belzutifan (MK-6482) Plus Pembrolizumab (MK-3475) Versus Placebo Plus Pembrolizumab in Participants With Clear Cell Renal Cell Carcinoma Post Nephrectomy (MK-6482-022)
The purpose of this study is to assess the efficacy and safety of oral belzutifan (MK-6482)
plus intravenous (IV) pembrolizumab (MK-3475) compared to placebo plus pembrolizumab, in the
adjuvant treatment of Clear Cell Renal Cell Carcinoma (ccRCC) post nephrectomy.
The primary study hypothesis is that belzutifan plus pembrolizumab is superior to placebo
plus pembrolizumab with respect to disease-free survival (DFS).
The main inclusion and exclusion criteria include but are not limited to the following:
Inclusion Criteria:
• Has a histologically or cytologically confirmed diagnosis of RCC with clear cell
component per American Joint Committee on Cancer (AJCC) (8th Edition), with or without
sarcomatoid features
• Has intermediate-high risk, high risk, or M1 no evidence of disease (NED) RCC as
defined by the following pathological tumor-node metastasis and tumor grading:
1. Intermediate-high risk RCC: pT2, Grade 4 or sarcomatoid, N0, M0; pT3, any grade,
N0, M0
2. High risk RCC: pT4, any Grade N0, M0; pT any stage, any Grade, N+, M0
3. M1 NED RCC participants who present not only with the primary kidney tumor but
also solid, isolated, soft tissue metastases that can be completely resected at
one of the following: the time of nephrectomy (synchronous) or, ≤2 years from
nephrectomy (metachronous)
• Has undergone complete resection of the primary tumor (partial or radical nephrectomy)
and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED
participants
• Must have undergone a nephrectomy and/or metastasectomy ≤12 weeks prior to
randomization
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10
days before randomization.
• Male participants must agree to continue contraception at least 7 days after the last
dose of belzutifan/placebo
• Female participants of childbearing potential must be willing to use an adequate
method of contraception, for the course of the study through 120 days after the last
dose of pembrolizumab or at least 30 days after last dose of belzutifan/placebo,
whichever occurs last
• Has adequate organ function
Exclusion Criteria:
• Has had a major surgery, other than nephrectomy plus resection of preexisting
metastases for M1 NED participants, within 4 weeks prior to randomization
• Has a pulse oximeter reading <92% at rest, requires intermittent supplemental oxygen,
or requires chronic supplemental oxygen
• Has clinically significant cardiovascular disease within 6 months from first dose of
study intervention
• Has other clinically significant disorders such as: serious active nonhealing
wound/ulcer/bone fracture; requirement for hemodialysis or peritoneal dialysis
• Has preexisting brain or bone metastatic lesions
• Has received prior systemic therapy for RCC
• Has received prior radiotherapy for RCC
• Has received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention; administration of killed vaccines are allowed
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
• Has a known additional malignancy (other than RCC treated with nephrectomy and/or
metastasectomy) that is progressing or has required active treatment within the past 3
years
• Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive
drugs); replacement therapy is allowed
• Has a history of (noninfectious) pneumonitis/interstitial lung disease that required
steroids or has current pneumonitis/interstitial lung disease
• Has an active infection, requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection, a known history
of Hepatitis B or known active Hepatitis C virus infection
• Has had an allogenic tissue/solid organ transplant
Chemotherapy for the Treatment of Patients With Newly Diagnosed Very Low-Risk and Low Risk Fusion Negative Rhabdomyosarcoma
Rhabdomyosarcoma is a type of cancer that occurs in the soft tissues in the body. This phase
III trial aims to maintain excellent outcomes in patients with very low risk rhabdomyosarcoma
(VLR-RMS) while decreasing the burden of therapy using treatment with 24 weeks of vincristine
and dactinomycin (VA) and examines the use of centralized molecular risk stratification in
the treatment of rhabdomyosarcoma. Another aim of the study it to find out how well patients
with low risk rhabdomyosarcoma (LR-RMS) respond to standard chemotherapy when patients with
VLR-RMS and patients who have rhabdomyosarcoma with DNA mutations get separate treatment.
Finally, this study examines the effect of therapy intensification in patients who have RMS
cancer with DNA mutations to see if their outcomes can be improved.
• All patients must be enrolled on APEC14B1 (NCT02402244) and consented to the Molecular
Characterization Initiative (Part A) prior to enrollment and treatment on ARST2032
(this trial).
• Patients must be =< 21 years at the time of enrollment.
• Patients must have newly diagnosed embryonal rhabdomyosarcoma (ERMS), spindle
cell/sclerosing RMS, or FOXO1 fusion negative alveolar rhabdomyosarcoma (ARMS)
(institutional FOXO1 fusion results are acceptable). RMS types included under ERMS
include those classified in the 1995 International Classification of Rhabdomyosarcoma
(ICR) as ERMS (classic, spindle cell, and botryoid variants), which are reclassified
in the 2020 World Health Organization (WHO) classification as ERMS (classic, dense and
botryoid variants) and spindle cell/sclerosing RMS (encompassing the historical
spindle cell ERMS variant and the newly recognized sclerosing RMS variant). Enrollment
in APEC14B1 is required for all patients.
• All patients will be evaluated for stage and clinical group. Note that clinical
group designation assigned at the time of enrollment on study remains unchanged
regardless of any second-look operation that may be performed.
• Patients will be eligible for the very low-risk stratum (Regimen VA) if they
have Stage 1, CG I disease.
• Patients will be eligible for the low-risk stratum (Regimen VAC/VA) if they
have Stage 1, CG II disease, Stage 2, CG I or II disease, or Stage 1, CG III
(orbit only) disease.
• Paratesticular Tumors: Staging ipsilateral retroperitoneal lymph node sampling
(SIRLNS) is required for all patients >= 10 years of age with paratesticular
tumors who do not have gross nodal involvement on imaging.
• Extremity Tumors: Regional lymph node sampling is required for histologic
evaluation in patients with extremity tumors.
• Clinically or radiographically enlarged nodes must be sampled for histologic
evaluation.
• Patients must have a Lansky (for patients =< 16 years of age) or Karnofsky (for
patients > 16 years of age) performance status score of >= 50. Patients who are unable
to walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing performance score.
• Peripheral absolute neutrophil count (ANC) >= 750/uL (within 7 days prior to
enrollment).
• Platelet count >= 75,000/uL (transfusion independent) (within 7 days prior to
enrollment).
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
mL/min/1.73 m^2 or a serum creatinine (within 7 days prior to enrollment) based on
age/gender as follows:
• Age: 1 month to < 6 months; Maximum serum creatinine (mg/dL): 0.4 (male) : 0.4
(female)
• Age: 6 months to < 1 year; Maximum serum creatinine (mg/dL): 0.5 (male) : 0.5
(female)
• Age: 1 to < 2 years; Maximum serum creatinine (mg/dL): 0.6 (male) : 0.6 (female)
• Age: 2 to < 6 years; Maximum serum creatinine (mg/dL): 0.8 (male) : 0.8 (female)
• Age: 6 to < 10 years; Maximum serum creatinine (mg/dL): 1 (male) : 1 (female)
• Age: 10 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male) : 1.2
(female)
• Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male) : 1.4
(female)
• Age >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male) : 1.4 (female)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to
enrollment), and
• If there is evidence of biliary obstruction by the tumor, then the total
bilirubin must be < 3 x ULN for age.
• Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the
value of 45 U/L.
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
U/L (within 7 days prior to enrollment).
• All patients and/or their parents or legal guardians must sign a written informed
consent.
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met.
Exclusion Criteria:
• Patients who have received prior chemotherapy and/or radiation therapy for cancer
prior to enrollment. Surgical resection alone of previous cancer(s) is permitted.
• Patients who have received chemotherapy or radiation for non-malignant conditions
(e.g., autoimmune diseases) are eligible. Patients must discontinue chemotherapy for
non-malignant conditions prior to starting protocol therapy.
• Vincristine is sensitive substrate of the CYP450 3A4 isozyme. Patients must not have
received drugs that are moderate to strong CYP3A4 inhibitors and inducers within 7
days prior to study enrollment.
• Patients unable to undergo radiation therapy, if necessary, as specified in the
protocol.
• Evidence of uncontrolled infection.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have
been noted for several of the study drugs. A pregnancy test is required for female
patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation.
Study to Assess the Efficacy and Safety of Adjunctive NBI-1065845 in Adults With Major Depressive Disorder (MDD) (SAVITRI)
The purpose of this study is to evaluate the efficacy of NBI-1065845 compared with placebo
used in addition to oral antidepressants in adults with MDD on improving symptoms of
depression.
Subjects must meet all of these criteria for inclusion in the study:
1. The subject has completed written informed consent.
2. At the time of signing the informed consent, subject must be 18 to 65 years of age,
inclusive.
3. The subject has a primary diagnosis of Major Depressive Disorder (MDD), without
psychotic features, meeting the Diagnostic and Statistical Manual of Mental Disorders,
5th Edition (DSM-5) criteria.
4. Subject must have had inadequate response to antidepressant treatment.
5. Subject is currently on stable pharmacological treatment for depression.
6. Subject must have a total Hamilton Depression Rating Scale-17 Item (HAMD17) score ≥ 22
at screening.
7. Subjects must have been taking current antidepressant medication(s) for ≥ 8 weeks.
8. Subjects must be willing to comply with all study procedures and restrictions.
Exclusion Criteria:
Subjects will be excluded from the study if they meet any of the following criteria:
1. Subject is pregnant or breastfeeding.
2. Subject has an unstable medical condition or chronic disease.
3. Subject has a history of neurological abnormalities.
4. Subject is currently diagnosed with or prior diagnoses of psychiatric disorder which
was the primary focus of treatment other than MDD.
5. The subject's depressive symptoms have previously demonstrated nonresponse to an
adequate course of treatment with electroconvulsive therapy (ECT).
6. The subject has an alcohol or substance use disorder.
7. In the Investigator's opinion, the subject is not capable of adhering to the protocol
requirements.
Acute coronary syndromes (ACS) represent a major contributor to mortality, morbidity, and
healthcare costs. Effective therapies are widely available; however, adherence is low. This
contributes to worse patient outcomes and increased risk of morbidity and mortality. The
once-daily polypill leverages a population-based strategy that has previously demonstrated
efficacy in improving adherence and access to therapy in low-resource settings, making it an
innovative approach for improving post-ACS care. This study aims to investigate the utility
of a polypill-based strategy for patients with ACS with drug eluting stent (DES) placement.
The polypill will consist of a high-intensity statin (rosuvastatin 40 mg daily), aspirin 81
mg daily, and prasugrel 10 mg daily.
1. Patients admitted with acute coronary syndrome who undergo percutaneous coronary
intervention with drug eluting stent placement.
Exclusion Criteria:
1. Age < 18
2. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 as measured by the simplified
MDRD formula
3. Current need for inotropes or with cardiac index < 2.2 L/min/m2
4. History of coronary artery bypass graft surgery
5. Current need for systemic anticoagulation
6. Contraindication to receive any components of the polypill
7. History of allergic reaction or intolerance to aspirin, prasugrel, or rosuvastatin
8. Comorbidities that might be expected to limit lifespan within the 1-month study period
9. Inability to provide written informed consent
10. Pregnancy
• 18 to 55 years of age
• Diagnosis of RMS according to the 2017 McDonald diagnostic criteria
• At least: 1 documented relapse within the previous year. OR 2 documented relapses
within the previous 2 years, OR 1 active Gadolinium (Gd)-enhancing lesion in the 12
months.
• EDSS score of 0 to 5.5 (inclusive)
• Neurologically stable within 1 month
Exclusion Criteria:
• Diagnosis of primary progressive multiple sclerosis (PPMS)
• Disease duration of more than 10 years in participants with EDSS score of 2 or less at
screening
• History of clinically significant CNS disease other than MS
• Ongoing substance abuse (drug or alcohol)
• History of malignancy of any organ system (other than complete resection of localized
basal cell carcinoma of the skin or in situ cervical cancer),
• Participants with history of confirmed Progressive Multifocal Leukoencephalopathy
(PML) or Neurological symptoms consistent with PML
• suicidal ideation or behavior
• Evidence of clinically significant cardiovascular, neurological, psychiatric,
pulmonary , renal, hepatic, endocrine, metabolic, hematological disorders or
gastrointestinal disease that can interfere with interpretation of the study results
or protocol adherence
• Participants who have had a splenectomy
• Active clinically significant systemic bacterial, viral, parasitic or fungal
infections
• Positive results for syphilis or tuberculosis testing
• Uncontrolled disease states, such as asthma, or inflammatory bowel disease, where
flares are commonly treated with oral or parenteral corticosteroids
• Active, chronic disease of the immune system (including stable disease treated with
immune therapy (e.g. Leflunomide, Methotrexate)) other than MS (e.g. rheumatoid
arthritis, systemic lupus erythematosus, etc.) with the exception of well-controlled
diabetes or thyroid disorder.
• Participants with a known immunodeficiency syndrome (AIDS, hereditary immune
deficiency, drug induced immune deficiency), or tested positive for HIV antibody
• History or current treatment for hepatic disease including but not limited to acute or
chronic hepatitis, cirrhosis or hepatic failure or participants with moderate or
severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary
disease.
• History of severe renal disease or creatinine level
• Participants at risk of developing or having reactivation of hepatitis
• Hematology parameters at screening:
• Hemoglobin: < 10 g/dl (<100g/L)
• Platelets: < 100000/mm3 (<100 x 109/L)
• Absolute lymphocyte count < 800/mm3 (<0.8 x 109/L)
• White blood cells: <3 000/mm3 (<3.0 x 109/L)
• Neutrophils: < 1 500/mm3 (<1.5 x 109/L)
• B-cell count < 50% lower limit of normal (LLN) or total IgG & total IgM < LLN
(only required for participants who had a history of receiving B-cell therapies,
such as rituximab, ocrelizumab or ofatumumab, prior to screening)
• History or current diagnosis of significant ECG abnormalities
• Resting QTcF ≥450 msec (male) or ≥460 msec (female) at pre-treatment (prior to
randomization)
• Use of other investigational drugs
• Requirement for anticoagulant medication or use of dual anti-platelet therapy
Significant bleeding risk or coagulation disorders,
• History of gastrointestinal bleeding
• Major surgery within 8 weeks prior to screening
• History of hypersensitivity to any of the study drugs or excipients
• Pregnant or nursing (lactating) female participants, prior to randomization
• Women of childbearing potential not using highly effective contraception
• Sexually active males not agreeing to use condom
• Have received any live or live-attenuated vaccines within 6 weeks of randomization or
requirement to receive these vaccinations during study
• Use of strong CYP3A4 inhibitors or strong CYP3A4 inducers within two weeks prior to
randomization
Inclusion to Extension part:
• patient who complete the Core Part of the study on double-blind study treatment and
conduct the Accelerated Elimination Procedure (AEP)
Other inclusion and exclusion criteria may apply
Drug: Remibrutinib, Drug: Teriflunomide
Relapsing Multiple Sclerosis, Brain and Nervous System
1. Subject is able and willing to comply with all the assessments of the study,
2. Subject or subject's legal representative has been informed of the nature of the
study, agrees to participate and has signed the informed consent form,
3. ≥ 45 years of age,
4. Baseline IPSS score ≥ 13; ≥ 1 in the IPSS voiding to storage sub-score ratio
(IPSS-V/S),
5. Prostate volume 25 •80 cc by transrectal ultrasound (TRUS), measured within 120 days
post study consent,
6. Prostatic urethral length between 25 and 45 mm, as measured by cystoscopic pull-back,
7. Failed, intolerant, or subject choice to not take a medication regimen for the
treatment of LUTS.
Exclusion Criteria:
1. Obstructive intravesical median prostatic lobe as determined by ultrasound (i.e., more
than 10 mm intravesical prostatic protrusion on sagittal mid-prostate plane via
abdominal ultrasound),
2. High bladder neck with the absence of lateral lobe encroachment indicating a high
likelihood of primary bladder neck obstruction as determined by the Investigator,
3. Urethral stricture, meatal stenosis, or bladder neck stricture •either current or
recurrent,
4. Anatomical anomalies that will not accommodate the Implant, as determined by
cystoscopy (e.g., prostatic urethral length to height geometry),
5. Requires indwelling catheter or intermittent catheterization to void,
6. Baseline PSA > 10 ng/mL or confirmed or suspected prostate cancer (Subjects with a PSA
level above 2.5 ng/mL, or age specific, or local reference ranges should have prostate
cancer excluded to the Investigator's satisfaction),
7. One of the following baseline test results, taken from a single uroflowmetry reading:
1. Urinary volume void ≤ 125mL (pre-bladder urinary volume of ≥ 150 mL required),
2. Peak urinary flow rate (Qmax) of ≤ 5 ml/second or > 15 mL/second,
3. Post- void residual volume (PVR) > 250 mL
8. History of other diseases causing voiding dysfunction including urinary retention
(e.g., uncontrolled diabetes, diagnosis of neurogenic bladder, Parkinson's disease,
multiple sclerosis, etc.),
9. Subjects with overactive bladder in the absence of benign prostatic obstruction,
10. Acute urinary tract infection (UTI) or finding of asymptomatic bacteriuria (Note:
subject can be enrolled if the UTI is treated and followed with a negative urine test
result), or subjects with history of recurrent UTIs (defined as > 3 UTIs in the past
12 months),
11. Concomitant bladder stones,
12. Previous pelvic irradiation or radical pelvic surgery,
13. Previous prostate surgery, including: enucleation, resection, vaporization,
thermotherapy, ablation, stenting or prostatic urethral lift,
14. Chronic prostatitis, recurrent prostatitis, chronic pelvic pain syndrome (CPPS), or
painful bladder syndrome within the past 12 months
15. Known allergy to nickel,
16. Life expectancy less than 60 months,
17. Use of concomitant medications (e.g., anticholinergics, antispasmodics or tricyclic
antidepressants) affecting bladder function,
18. Inability to stop taking anticoagulants and/or antiplatelets for at least 3 days prior
to the procedure or coumadin for at least 5 days prior to the procedure (Note: low
dose aspirin therapy (81 mg) is permitted),
19. Taking 5-alpha-reductase inhibitors within 3 months of baseline evaluation,
20. Taking one of the following within 2 weeks of baseline evaluation:
1. alpha-blockers,
2. imipramine,
3. anticholinergics,
4. cholinergic gonadotropin releasing hormonal analogues,
5. Phosphodiesterase-5 Enzyme Inhibitors (Tadalafil) in doses for BPH,
6. Beta-3 adrenergic receptor agonist (Mirabegron),
21. Taking androgens, unless eugonadal state for at least 3 months or greater as
documented by the Investigator,
22. Taking one of the following within 24 hours of pre-treatment (baseline) evaluation:
1. phenylephrine, or,
2. pseudoephedrine,
23. Future fertility concerns, or,
24. In the Investigator's opinion, the subject has a physical, psychological, or medical
impairment that might prevent study completion or would confound study results
(including subject questionnaires).
Device: Zenflow Spring System, Device: Sham Procedure
Evaluation of Co-formulated Pembrolizumab/Quavonlimab (MK-1308A) Versus Other Treatments in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Cancer (CRC) (MK-1308A-008)
The purpose of this study is to assess the efficacy and safety of co-formulated
pembrolizumab/quavonlimab versus other treatments in participants with MSI-H or dMMR
Metastatic Stage IV Colorectal Cancer.
• Has a histologically confirmed diagnosis of Stage IV CRC adenocarcinoma (as defined by
American Joint Committee on Cancer [AJCC] version 8)
• Has locally confirmed dMMR/MSI-H
• Has a life expectancy of at least 3 months
• Female participants are eligible to participate if not pregnant or breastfeeding, and
not a woman of childbearing potential (WOCBP), or if a WOCBP then uses a contraceptive
method that is highly effective or is abstinent on a long-term and persistent basis,
during the intervention period and for at least 120 days after the last dose of study
intervention
• Has measurable disease per RECIST 1.1 as assessed by the site and verified by BICR
• Submit an archival (within 5 years of Screening) or newly obtained tumor tissue sample
that has not been previously irradiated; formalin-fixed, paraffin embedded (FFPE)
blocks are preferred to slides.
• Has adequate organ function
Cohort A:
•Has been previously treated for their disease and radiographically progressed per RECIST
1.1 on or after or could not tolerate standard treatment, which must include all of the
following agents if approved and locally available in the country where the participant is
randomized:
• Fluoropyrimidine, irinotecan and oxaliplatin (capecitabine is acceptable as equivalent
to fluorouracil in prior therapy)
• With or without an anti-vascular endothelial growth factor (VEGF) monoclonal antibody
(e.g., bevacizumab)
• At least one of the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies
(cetuximab or panitumumab) for rat sarcoma viral oncogene homolog (RAS) wild-type
participants with left-sided tumors. Prior EGFR therapy is optional for patients with
right sided RAS Wild-type (WT) tumors.
Cohort B:
•Has untreated Stage IV dMMR/MSI-H CRC with no prior chemotherapy or immunotherapy for
this disease
Exclusion Criteria:
• Has received prior therapy with an agent directed to another stimulatory or
coinhibitory T-cell receptor
• Has received prior systemic anticancer therapy including investigational agents within
4 weeks before the first dose of study intervention
• Has not recovered adequately from a surgery procedure, and/or has any complications
from a prior surgery before starting study intervention
• Has received prior radiotherapy within 2 weeks of start of study intervention
• Has received a live or live-attenuated vaccine within 30 days before the first dose of
study intervention
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks before the first dose of
study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study medication
• Has a known additional malignancy that is progressing or has required active treatment
within the past 2 years
• Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab, quavonlimab, favezelimab,
vibostolimab, MK-4830, and/or any of their excipients
• Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs)
• Has a history of (noninfectious) pneumonitis that required steroids or has current
pneumonitis
• Has a history of acute or chronic pancreatitis
• Has neuromuscular disorders associated with an elevated creatine kinase
• Has urine protein ≥1 gram/24 hours
• Has an active infection requiring systemic therapy (e.g., tuberculosis, known viral or
bacterial infections, etc.)
• Has a known history of Human Immunodeficiency Virus (HIV) infection
• Concurrent active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] positive
and/or detectable Hepatitis B Virus [HBV] deoxyribonucleic acid [DNA]) and Hepatitis C
virus (defined as anti-HCV antibody positive and detectable HCV ribonucleic acid [RNA]
infection
• Has clinically significant cardiac disease, including unstable angina, acute
myocardial infarction within 6 months from Day 1 of study intervention administration,
or New York Heart Association Class III or IV congestive heart failure. Medically
controlled arrhythmia stable on medication is permitted.
• Has present or progressive accumulation of pleural, ascitic, or pericardial fluid
requiring drainage or diuretic drugs within 2 weeks before randomization/allocation
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the treating investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study
• Has had an allogenic tissue/solid organ transplant
A Study to Evaluate the Safety and Efficacy of CNTX-6970 in Subjects With Knee Osteoarthritis Pain.
The primary objective of this study is to evaluate the safety and efficacy of two doses of
CNTX-6970 for the treatment of pain related to OA of the knee compared to placebo. CNTX-6970
is being developed as a new treatment for chronic pain, including painful osteoarthritis of
the knee.
A subject will be eligible for study participation if they meet all of the following
criteria:
1. Individuals between 40 and 90 years of age (inclusive) at the time of the Screening
Visit.
2. Willing to use a mobile smart device during the study period. Individuals who do not
have access to a mobile device will be provided with one for the duration of the study
and trained in its use.
3. Can understand the nature of the study and protocol requirements and is willing to
comply with study drug administration requirements and discontinue prohibited
concomitant medications.
4. Radiography of both knees with a posterior-anterior, fixed-flexion view taken during
the Screening visit. The Index knee must show evidence of chronic OA with a K-L
Grading Scale of 1, 2, 3, or 4. Such evidence will be provided by a central reading of
the radiography of both knees from an expert radiologist of the CCC of EPPIC-Net.
5. Moderate to severe pain in the Index knee associated with OA and stable for a minimum
of 6 months prior to Screening in the opinion of the investigator.
6. Confirmation of OA of the index knee: American College of Rheumatology (ACR)
diagnostic criteria.
7. Subjects must have failed 2 or more prior therapies. Failure is deemed to be
inadequate relief in the opinion of the investigator.
8. Body mass index (BMI) of ≤ 40 kg/m2.
9. Willing to refrain from illicit drug use during the study, and to have illicit drug
testing at screening and at later time points.
A subject will be excluded from the study if they meet any of the following criteria:
1. Any form of joint replacement surgery, open surgery, or arthroscopic surgery of the
index knee/knee joint with 12 months of Screening.
2. Any painful condition(s) of the index knee due to disease other than OA. For example,
periarticular or referred pain involving the index knee, or from joint disease other
than OA associated with the index knee.
3. Other chronic pain anywhere in the lower extremities (e.g. hips, legs, feet) that is
equal or greater in intensity or impairment than index knee pain or that requires the
use of analgesic medications. This includes radicular low back pain with radiation to
the knee.
4. Documented history of neuropathic arthropathy in the knee.
5. Significant instability (e.g., cruciate ligament tear or rupture or previous repair)
within the past 5 years or current misalignment (>10 degrees varus or valgus) of the
index knee.
6. Plans to have surgery, invasive procedures, or intra-articular (IA) injections of the
index knee or procedure or surgery otherwise contraindicated for study participation
while in the study.
a. Concomitant Medications for Pain •i. Continuous use of one of the following
medications prescribed for pain: tramadol, gabapentin, duloxetine, pregabalin,
milnacipran, or tricyclic antidepressants that is:
1. chronic for at least 12 weeks; and
2. at a stable dose for at least 4 weeks before Screening ii. Intermittent use of
opioids that is:
1. ongoing for at least 4 weeks before Screening;
2. at a frequency no more than 4 days/week; and
3. not be taken within 24 hours of a study visit iii. As needed use of acetaminophen
b. Concomitant Medications for Non-Pain Indications That May Impact Pain •i.
Continuous use of medication for non-pain indications that are known to potentially
impact pain, e.g. duloxetine for depression, that is at a stable dose for at least 12
weeks prior to Screening.
7. Corticosteroid injection in the index knee within 90 days of Screening or during study
participation.
8. Received IA viscosupplementation (e.g., Synvisc®, Hyalgan®) within 90 days of
Screening or any time during study participation.
9. History of clearly documented allergic reaction to celecoxib (Celebrex®), or to sulfa
drugs.
10. Use of an investigational medication within 30 days of Screening, or 5 pharmacokinetic
or pharmacodynamic half-lives (whichever is longer) or scheduled to receive such an
agent while participating in the current study.
11. Current therapy with any immunosuppressive therapy, including corticosteroids (>5
mg/day of prednisone).
A Study to Test the Efficacy, Safety, and Pharmacokinetics of Rozanolixizumab in Adult Study Participants With Leucine-Rich Glioma Inactivated 1 Autoimmune Encephalitis
The purpose of the study is to assess the efficacy of rozanolixizumab as measured by seizure
freedom, change in cognitive function, use of rescue medication, onset of seizure freedom and
to assess safety and tolerability.
• Study participant must be ≥18 to ≤89 years of age, at the time of signing the informed
consent
• Study participant must be seropositive for leucine-rich glioma inactivated 1 (LGI1)
antibody measured by LGI1 serum autoantibody cell-binding assay
• Study participant must have ≥2 seizures/week during the Screening Period or have
experienced such seizures that stopped following intravenous methylprednisolone (IVMP)
initiation:
• Either faciobrachial dystonic seizures (FBDS) with or without other focal
(partial) seizures including focal to bilateral tonic clonic
• Or focal (partial) seizures including focal to bilateral tonic clonic and fulfil
the following new-onset Autoimmune encephalitis (AIE) criteria:
1. Subacute onset (rapid progression of less than 3 months) of working memory
deficits (short-term memory loss), altered mental status (defined as
decreased or altered level of consciousness, lethargy, or personality
change), or psychiatric symptoms.
AND b. At least one of the following: i. New focal central nervous system (CNS) finding, as
per the investigator's assessment ii. Seizures not explained by a previously known seizure
disorder iii. Cerebrospinal fluid (CSF) pleocytosis (white blood cell count of >5
cells/mm3) iv. Magnetic resonance imaging (MRI) features suggestive of encephalitis (Brain
MRI hyperintense signal on T2-weighted fluid-attenuated inversion recovery sequences highly
restricted to one or both medial temporal lobes [limbic encephalitis], or in multifocal
areas involving grey matter, white matter, or both compatible with demyelination or
inflammation).
AND c. Reasonable exclusion of alternative causes
• Study participant is deemed appropriate for initiation of IVMP based on clinical
symptoms and history or has initiated IVMP treatment at a dose of 500 to 1000 mg/day
within 14 days prior to randomization. If the study participant has initiated a
steroid taper, the study participant cannot be receiving an oral steroid dose lower
than 60 mg/day when randomized.
• Study participant with onset of disease between 0 to 12 months prior to Screening
• Study participant weighs at least 35 kg (for males and females) at Screening
• A male participant must agree to use contraception during the treatment period and for
at least 90 days after the final dose of study treatment and refrain from donating
sperm during this period
• A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
i) Not a woman of childbearing potential (WOCBP) OR ii) A WOCBP who agrees to follow
the contraceptive guidance during the treatment period and for at least 90 days after
the final dose of study treatment
Exclusion Criteria:
• Study participant has a known hypersensitivity to any components of the study
medication or any other anti-neonatal Fc receptor (FcRn) medications. This includes a
known history of hyperprolinemia, since L-proline is a constituent of the
rozanolixizumab formulation
• Study participant has a confirmed prior diagnosis of epilepsy or new onset seizures
that are unrelated to LGI1 autoimmune encephalitis (AIE) or has any known or suspected
medical cause for the onset of seizures other than possible AIE
• Study participant has active neoplastic disease or history of neoplastic disease
within 5 years of study entry (except for basal or squamous cell carcinoma of the skin
or carcinoma in situ of the uterine cervix which has been definitively treated with
standard of care approaches)
• Study participant has 12-lead electrocardiogram (ECG) with findings considered
clinically significant upon medical review
• Study participant has renal impairment, defined as glomerular filtration rate (GFR)
<30mL/min/1.73m2 at the Screening Visit.
• Study participant has a clinically relevant active infection (eg, sepsis, pneumonia,
abscess) or has had a serious infection (resulting in hospitalization or requiring
parenteral antibiotic treatment) within 6 weeks prior to the first dose of IMP
• Study participant has a history of chronic ongoing infections (eg, Hepatitis B or C,
human immune deficiency virus [HIV], active or latent tuberculosis [TB]) or who tests
positive for HIV, Hepatitis B or C at the Screening Visit
• Presence of Hepatitis B surface antigen at the Screening Visit
• Positive Hepatitis C antibody test result at Screening or within 3 months prior
to the IMP dose
• Study participant has current unstable liver or biliary disease, per investigator
assessment, defined by the presence of ascites, encephalopathy, coagulopathy,
hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis
• Study participant has positive tuberculosis (TB) test at the Screening Visit
• Study participant has any of the following active gastrointestinal (GI) disorders:
inflammatory bowel disease, GI ulceration, or diverticulitis
• Study participant has a history of solid organ transplant or hematopoietic stem cell
transplant
• Study participant has undergone a splenectomy
• Study participant has a current or medical history of primary immune deficiency
• Study participant has been treated with prohibited immunosuppressants, biologics, and
other therapies
• Study participant has received a live vaccination within 8 weeks prior to the Baseline
Visit; or intends to have a live vaccination during the course of the study or within
8 weeks following the final dose of investigational medicinal product (IMP)
• Study participant has previously received rozanolixizumab drug product
• Alanine transaminase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase
(ALP) are >2x upper limit of normal (ULN)
• If study participant has >ULN for ALT, AST, or ALP that does not meet the
exclusion limit at Screening, the tests must be repeated prior to dosing to
ensure there was no further ongoing clinically relevant increase. In case of a
clinically relevant increase as per the investigator's judgement, the study
participant must be excluded.
• Tests that result in ALT, AST, or ALP up to 25 % above the exclusion limit
(>2xULN) may be repeated once for confirmation. This includes rescreening. If any
of the repeated tests (ALT, AST, or ALP) are >2xULN,the study participant must be
excluded
• For randomized study participants with a Baseline result >ULN for ALT, AST, ALP,
or total bilirubin but <1.5xULN, a Baseline diagnosis and/or the cause of any
clinically meaningful elevation will have to be understood and recorded in the
electronic case report form (eCRF)
• Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is
fractionated and direct bilirubin <35 %)
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Study participant has a total IgG level ≤5.5 g/L at the Screening Visit
• Study participant has absolute neutrophil count <1500 cells/mm^3 at the Screening
Visit
• Participant has QT interval corrected for heart rate using Fridericia's formula (QTcF)
>450 msec (for male participants) or QTcF >470 msec (for female participants) or QTcF
>480 msec in participants with bundle branch block
Testing the Use of Combination Immunotherapy Treatment (N-803 [ALT-803] Plus Pembrolizumab) Against the Usual Treatment for Advanced Non-small Cell Lung Cancer (A Lung-MAP Treatment Trial)
This phase II/III Lung-MAP trial studies how well immunotherapy treatment with N-803
(ALT-803) and pembrolizumab working in treating patients with non-small cell lung cancer that
has spread to other places in the body (advanced). Natural killer cells, part of our immune
system, are always on alert and ready to defend our bodies from many kinds of infection or
rogue cells, such as those that cause cancer. N-803 (ALT-803) may activate natural killer
cells so that they can stimulate an immune response to help fight cancer. Immunotherapy with
monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the
cancer, and may interfere with the ability of tumor cells to grow and spread. Giving N-803
(ALT-803) and pembrolizumab may help shrink and stabilize lung cancer or prevent it from
returning.
• Participants must have been assigned to S1800D by the Southwest Oncology Group (SWOG)
Statistics and Data Management Center (SDMC). Assignment to S1800D is determined by
the LUNGMAP or S1400 protocol
• Participants must have measurable or non-measurable disease documented by computed
tomography (CT) or magnetic resonance imaging (MRI). Measurable disease must be
assessed within 28 days prior to randomization. Non-measurable disease must be
assessed within 42 days prior to randomization. The CT from a combined positron
emission tomography (PET)/CT may be used only if it is of diagnostic quality. All
known sites of disease must be assessed and documented on the Baseline Tumor
Assessment Form (RECIST 1.1)
• Participants must have a CT or MRI scan of the brain to evaluate for central nervous
system (CNS) disease within 42 days prior to sub-study randomization
• Participants with spinal cord compression or brain metastases must have received local
treatment to these metastases and remained clinically controlled and asymptomatic for
at least 7 days following stereotactic radiation and/or 14 days following whole brain
radiation, and prior to sub-study randomization
• Participants with spinal cord compression or brain metastases must not have residual
neurological dysfunction, unless no further recovery is expected, and the participant
has been stable on weaning doses of corticosteroids (=< 10 mg daily prednisone or
equivalent) prior to sub-study randomization
• Participants must have progressed (in the opinion of the treating investigator)
following the most recent line of therapy for non-small cell lung cancer (NSCLC)
• Participants with a known sensitizing mutation for which an FDA-approved targeted
therapy for NSCLC exists (e.g. EGFR, ALK gene fusions, ROS1, BRAF, RET, NTRK, and MET
sensitizing mutations), must have previously received at least one of the approved
therapy(s)
• Participants must have received exactly one line of anti-PD-1 or anti-PD-L1 therapy
for advanced disease (stage IV or recurrent, or stage III in certain circumstances
outlined below) given alone or in combination with platinum-based chemotherapy.
Participants must have experienced disease progression during or after this regimen
• Continuing the same agent(s) after progression counts as a single line of
therapy. However, a change or addition in agent(s) after progression (e.g. the
addition of chemotherapy to anti-PD-1 monotherapy after progression) counts as a
subsequent line of therapy and would exclude the participant
• For participants who received consolidation anti-PD-1 or anti-PD-L1 therapy
following concurrent chemoradiation for Stage III disease as their only line of
anti-PD-1 or anti-PD-L1 therapy:
• If they experienced disease progression less than (<) 365 days from the
first date of anti-PD-1 or anti-PD-L1 therapy, this counts as the single
line of anti-PD-1 or anti-PD-L1 therapy for advanced disease
• If they experienced disease progression more than or equal to (>=) 365 days
from the first date of anti-PD-1 or anti-PD-L1 therapy, this is not
considered a line of anti-PD-1 or anti-PD-L1 therapy for advanced disease
• Participants must have recovered (=< grade 1) from any side effects of prior therapy,
except for alopecia
• Participants must be able to safely receive at least one of the investigator's choice
of standard of care regimens, per the current FDA-approved package insert
• Note: Pemetrexed is not FDA-approved for squamous cell NSCLC and must not be used
to treat participants with squamous cell NSCLC
• Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (obtained within 28 days prior to
sub-study randomization)
• Platelet count >= 100 x 10^3/uL(obtained within 28 days prior to sub-study
randomization)
• Hemoglobin >= 9 g/dL (obtained within 28 days prior to sub-study randomization)
• Serum bilirubin =< institutional upper limit of normal (IULN) (within 28 days prior to
sub-study randomization). For participants with liver metastases, bilirubin must be =<
5 x IULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2 x IULN
(within 28 days prior to sub-study randomization). For participants with liver
metastases, ALT and AST must be =< 5 x IULN
• Serum creatinine =< the IULN or calculated creatinine clearance >= 50 mL/min using
Cockcroft-Gault formula. This specimen must have been drawn and processed within 28
days prior to sub-study randomization
• Participants' most recent Zubrod performance status must be 0-1 and be documented
within 28 days prior to sub-study randomization
• Participants must have history and physical exam must be obtained within 28 days prior
to sub-study randomization
• Participants with known human immunodeficiency virus (HIV) infection must be receiving
anti-retroviral therapy and have an undetectable viral load at their most recent viral
load test within 6 months prior to sub-study randomization
• Participants must also be offered participation in banking and in the correlative
studies for collection and future use of specimens
• Note: As a part of the OPEN registration process the treating institution's identity
is provided in order to ensure that the current (within 365 days) date of
institutional review board approval for this study has been entered in the system
• Participants must be informed of the investigational nature of this study and
must sign and give written informed consent in accordance with institutional and
federal guidelines
Exclusion Criteria:
• Participants must not have leptomeningeal disease that requires CNS-specific treatment
prior to registration and must not be planning to receive the CNS-specific treatment
through the first cycle of the protocol therapy
• Participants must not have experienced the following:
• Any grade 3 or worse immune-related adverse event (irAE). Exception: asymptomatic
nonbullous/nonexfoliative rash
• Any unresolved grade 2 irAE
• Any toxicity that led to permanent discontinuation of prior anti-PD-1/PD-L1
immunotherapy
• Exception to the above: Toxicities of any grade that requires replacement therapy
and has stabilized on therapy (e.g., thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency) are
allowed
• Participants must not have any history of organ transplant that requires use of
immunosuppressives
• Participants must not have history of (non-infectious) pneumonitis that required
steroids or current pneumonitis/interstitial lung disease
• Participants must not have any known allergy or reaction to any component of the
investigational formulations. If there is a known allergy or reaction to standard of
care formulations, participants must be able to safely receive at least one of the
standard of care options
• Participants must not have any grade III/IV cardiac disease as defined by the New York
Heart Association Criteria (i.e., participants with cardiac disease resulting in
marked limitation of physical activity or resulting in inability to carry on any
physical activity without discomfort), unstable angina pectoris, and myocardial
infarction within 6 months prior to sub-study randomization, or serious uncontrolled
cardiac arrhythmia
• Participants must not have experienced any arterial thromboembolic events, including
but not limited to myocardial infarction, transient ischemic attack, cerebrovascular
accident, or unstable angina, within 6 months prior to sub-study randomization
• Participants must not have an active or uncontrolled infection in the opinion of the
treating investigator
• Participants must not have a prior or concurrent malignancy whose natural history or
treatment has the potential to interfere with the safety or efficacy assessment of the
investigational regimen
• Participants must not have any of following:
• Cirrhosis at a level of Child-Pugh B (or worse)
• Cirrhosis (any degree) and a history of hepatic encephalopathy
• Or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful
ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis
• Participants must not have received anti-CTLA4 therapy (e.g. ipilimumab,
tremelimumab), or other immune-modulatory therapy (e.g. anti-TIM-3, anti-LAG-3,
anti-GITR, IL-2, IL-15)
• Participants must not have received any prior systemic therapy (systemic chemotherapy,
immunotherapy or investigational drug) within 21 days prior to sub-study randomization
• Participants must not have received any radiation therapy within 14 days prior to
sub-study randomization
• Participants must not have received nitrosoureas or mitomycin-c within 42 days prior
to sub-study randomization
• Participants must not have received systemic treatment with corticosteroids (> 10 mg
daily prednisone or equivalent) or other immunosuppressive medications within 7 days
prior to sub-study randomization. Inhaled or topical steroids, and adrenal replacement
doses =< 10 mg daily prednisone or equivalent are permitted in the absence of active
autoimmune disease
• Participants must not have received a live attenuated vaccination within 28 days prior
to sub-study randomization. All COVID-19 vaccines that have received Food and Drug
Administration (FDA) approval or FDA emergency use authorization are acceptable
• Participants must not be planning to receive any concurrent chemotherapy,
immunotherapy, biologic or hormonal therapy for cancer treatment while receiving
treatment on this study
• Participants must not have had a major surgery within 14 days prior to sub-study
randomization. Participant must have fully recovered from the effects of prior surgery
in the opinion of the treating investigator
• Participants must not have an active autoimmune disease that has required systemic
treatment within two years prior to sub-study randomization (i.e., with use of disease
modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency) is not considered a form of systemic treatment and
is allowed
• Participants must not have any history of primary immunodeficiency
• Participants must not be pregnant or nursing. Women/men of reproductive potential must
have agreed to use an effective contraceptive method during the study and 4 months
after completion of study treatment. A woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months.
In addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation. However, if at any point a previously celibate participant
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for beginning
contraceptive measures during the study and 4 months after study completion
1. Histologically confirmed GBM (MGMT unmethylated, IDH wild type) at first, second,
third, or fourth recurrence after concurrent chemoradiotherapy. Patients with an
initial diagnosis of a lower-grade glioma are eligible if a subsequent biopsy
determined the progressive tumor to be GBM.
2. Imaging confirmation of first tumor progression or regrowth as defined by the Response
Assessment in Neuro-Oncology (RANO) criteria. A minimum of 12 weeks must have elapsed
from the completion of radiotherapy to study entry to minimize the potential for MRI
changes related to radiation necrosis that might be misdiagnosed as progression of
disease, unless there is a new lesion outside the radiation field or unequivocal
evidence of viable tumor on histopathological sampling.
3. Karnofsky Performance Status (KPS) ≥ 60%.
4. Patients must be willing and able to provide written informed consent and to comply
with the study protocol as judged by the investigator.
5. Age ≥ 18 years.
6. Patients must be able to swallow oral medications.
7. For women who are of child-bearing potential and who are sexually active and who are
not surgically sterile (absence of ovaries and/or uterus): to use an adequate method
of contraception (oral contraceptives, intrauterine contraceptive device, barrier
method of contraception in conjunction with spermicidal jelly) during the treatment
period and for at least 6 months after last dose of study drug. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. For male patients who are partners of
premenopausal women: agreement to use a barrier method of contraception during the
treatment period and for at least 6 months after the last dose of study drug.
7.1 A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
8. Patients who have undergone recent surgery for recurrent or progressive tumor are
eligible provided that:
8.1 Surgery must have confirmed the recurrence.
8.2 A minimum of 28 days must have elapsed from the day of surgery to study entry. For
core or needle biopsy, a minimum of 7 days must have elapsed prior to study entry.
8.3 Craniotomy or intracranial biopsy site must be adequately healed and free of
drainage or cellulitis, and the underlying cranioplasty must appear intact at the time
of randomization.
9. Patients must have recovered (Common Terminology Criteria for Adverse Events CTCAE
version 6] Grade ≤1) from the acute effects of chemotherapy except for residual
alopecia or Grade 2 peripheral neuropathy prior to randomization. Minimum times from
prior therapies include:
9.1 Greater than or equal to 28 days elapsed from the administration of any
investigational agent.
9.2 Greater than or equal to 28 days elapsed from the administration of any prior
cytotoxic agents, except ≥ 42 days from nitrosoureas. NOTE: Prior treatment with
Novo-TTF therapy is allowed at initial diagnosis but must be discontinued prior to
study entry.
10. GBMs of the study patients must have EGFR gene amplification, which will be detected
by next generation sequencing of tumor tissue from resected sample.
11. Prior use of bevacizumab is allowed, however patient must be off of this medication
for 180 days.
12. Patients must have adequate organ and marrow function as defined by the following
criteria:
• ANC ≥1.5 × 10(9)/L
• Platelets ≥100 × 10(9)/L
• Hemoglobin ≥8 g/dL
• Total bilirubin ≤1.5 × ULN Patients with Gilbert's syndrome with a total
bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted.
ALT and AST ≤3 × ULN
Exclusion Criteria:
1. Prior treatment with an EGFR or JAK inhibitor.
2. Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study.
3. Patients unable to undergo brain MRI scans with IV gadolinium contrast.
4. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to Tofacitinib
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
7. Prior history of hypertensive crisis, hypertensive encephalopathy, or inadequately
controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or
diastolic blood pressure > 100 mmHg while on antihypertensive medication).
8. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to
swallow the formulated product, or previous significant gastrointestinal resection
that would preclude adequate absorption of the trial medications.
9. History of another malignancy in the previous 3 years, with a disease-free interval of
< 3 years. Patients with prior history of in situ cancer or basal or squamous cell
skin cancer are eligible.
10. Concurrent use of Bevacizumab.
Osimertinib With or Without Bevacizumab as Initial Treatment for Patients With EGFR-Mutant Lung Cancer
This phase III trial compares the effect of bevacizumab and osimertinib combination vs.
osimertinib alone for the treatment of non-small cell lung cancer that has spread outside of
the lungs (stage IIIB-IV) and has a change (mutation) in a gene called EGFR. The EGFR protein
is involved in cell signaling pathways that control cell division and survival. Sometimes,
mutations in the EGFR gene cause EGFR proteins to be made in higher than normal amounts on
some types of cancer cells. This causes cancer cells to divide more rapidly. Osimertinib may
stop the growth of tumor cells by blocking EGFR that is needed for cell growth in this type
of cancer. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of
tumor cells to grow and spread. Giving osimertinib with bevacizumab may control cancer for
longer and help patients live longer as compared to osimertinib alone.
• Patient must have a pathologically-confirmed diagnosis of non-squamous, non-small cell
lung cancer (NSCLC)
• Patient must have advanced disease, defined as •either stage IV disease, stage IIIB
disease not amenable to definitive multi-modality therapy, or recurrent disease after
a prior diagnosis of stage I-III disease. All staging is via the American Joint
Committee on Cancer (AJCC)/International Association for the Study of Lung Cancer
(IASLC) 8th edition staging criteria
• Patient must have somatic activating sensitizing mutation in EGFR (e.g. but not
limited to Exon 19 deletion, L858R, E709X, G719X, exon 19 insertions, L861Q, S768I).
Patients with non-sensitizing mutations in EGFR (EGFR exon 20 insertions) are not
eligible. Test results originating from a Clinical Laboratory Improvement Act
(CLIA)-certified or similarly accredited laboratory are acceptable; no specific assay
is mandated. Plasma, cytology, or tumor tissue can be utilized for mutation testing
• Patients that have received prior radiation therapy are eligible. Radiation (limited
field stereotactic radiation or conventional radiation) must have been completed at
least one week prior to study drug initiation and more extensive field radiation
(i.e., whole-brain radiotherapy [WBRT]) must have been completed at least two weeks
prior to drug initiation
• Patient must have measurable disease. Baseline measurements of sites of disease must
be obtained within 4 weeks prior to study registration. If a potential target lesion
is previously irradiated without subsequent growth and/or is radiated after the
imaging from which baseline measurements are obtained, they cannot be included as
target lesions, and additional target lesions are required to meet criteria for
measurable disease
• Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 2
• All females of childbearing potential must have a blood test or urine study within 14
days prior to registration to rule out pregnancy
• A female of childbearing potential is defined as any woman, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy
or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea
following cancer therapy does not rule out childbearing potential) for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months)
• Patient of childbearing potential and sexually active males must not expect to
conceive or father children by using accepted and effective method(s) of contraception
or by abstaining from sexual intercourse for 2 weeks prior to the start of treatment,
while on study treatment, and for
• 6 weeks after the last dose of protocol treatment for female patients on the
osimertinib (AZD9291) alone arm
• 4 months after the last dose of protocol treatment for male patients on
osimertinib (AZD9291) alone arm
• 6 months after the last dose of protocol treatment for all patients on
osimertinib (AZD9291) plus bevacizumab combination arm
• NOTE: Female patients should also not breastfeed while on treatment and for 6
months after the last dose bevacizumab
• Leukocytes >= 3,000/mcL (obtained =< 14 days prior to registration)
• Absolute neutrophil count >= 1,500/mcL (obtained =< 14 days prior to registration)
• Platelets >= 100,000/mcL (obtained =< 14 days prior to registration)
• Hemoglobin >= 9 g/dL (obtained =< 14 days prior to registration)
• Total bilirubin and creatinine =< 1.5 x institutional upper limit of normal (ULN)
(obtained =< 14 days prior to registration)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN (obtained =< 14 days prior to registration)
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if neurologically stable without
glucocorticoid therapy after the stated washout period from radiation therapy (RT) or
surgery provided the metastatic lesions are non-hemorrhagic
• Patients with untreated brain metastases or leptomeningeal disease are eligible if the
treating physician determines that immediate CNS specific treatment is not required
provided the metastatic lesions are non-hemorrhagic and are neurologically stable
without glucocorticoid therapy
• Patients with a prior or concurrent malignancy whose natural history or treatment does
not have the potential to interfere with the safety or efficacy assessment of the
investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, should have a
clinical risk assessment of cardiac function using the New York Heart Association
Functional Classification. To be eligible for this trial, patients should be class 2B
or better
• Patient must have the ability to understand and the willingness to sign a written
informed consent document and comply with study requirements
Exclusion Criteria:
• Patient must not have received any prior treatment with an EGFR TKI or with an
anti-VEGF agent
• Patient must not have any risk factors for anti-VEGF administration, specifically,
hemoptysis, active cardiovascular disease, uncontrolled hypertension, significant
proteinuria (screening urinalysis > 300 mg/dl) and tumor invading major blood vessels
• Patient must not have had any prior systemic treatment for metastatic disease
• Patient must not be pregnant or breast-feeding due to the potential harm to an unborn
fetus and possible risk for adverse events in nursing infants with the treatment
regimens being used
• Patient must not have had treatment with any investigational drug within five
half-lives or 3 months (whichever is greater), prior to study initiation
• Patient must not be currently receiving (or unable to stop use prior to receiving the
first dose of study treatment) medications or herbal supplements known to be strong
inducers of CYP3A4. For any patient currently receiving such inducers of CYP3A4, they
must discontinue use prior to first dose of study treatment. All patients must try to
avoid concomitant use of any medications, herbal supplements and/or ingestion of foods
with known inducer effects on CYP3A4
• Patient must not have any unresolved toxicities from prior therapy greater than Common
Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of registration,
with the exception of alopecia and grade 2 prior platinum-therapy-related neuropathy
• Patient must not have any evidence of severe or uncontrolled systemic diseases,
including uncontrolled hypertension and active bleeding diatheses, which in the
investigator's opinion makes it challenging for the patient to participate in the
study. Screening for chronic conditions is not required
• Patient must not have refractory nausea and vomiting, chronic gastrointestinal
diseases, the inability to swallow the osimertinib tablets or previous significant
bowel resection that would preclude adequate absorption of osimertinib
• Patient must not have a medical history of interstitial lung disease, drug-induced
interstitial lung disease, radiation pneumonitis which required steroid treatment, or
any evidence of clinically active interstitial lung disease
• Patient must not have a history of hypersensitivity to active or inactive excipients
of osimertinib or drugs with a similar chemical structure or class to osimertinib
• Patient must not have mean resting corrected QT interval (QTc) > 470 msec obtained
from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc
value (using Bezet's correction)
• Patient must not have any clinically important abnormalities in rhythm, conduction or
morphology of resting ECG e.g. complete left bundle branch block, third degree heart
block and second-degree heart block
• Patient must not have any factors that increase the risk of QTc prolongation or risk
of arrhythmic events such as heart failure, electrolyte abnormalities (including:
potassium < lower limit of normal [LLN]; magnesium < LLN; calcium < LLN), congenital
long QT syndrome, family history of long QT syndrome or unexplained sudden death under
40 years of age in first degree relatives or any concomitant medication known to
prolong the QT interval and cause torsades de pointes
Biological: Bevacizumab, Drug: Osimertinib
Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, Recurrent Lung Non-Squamous Non-Small Cell Carcinoma, Stage IIIB Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Advanced Lung Non-Squamous Non-Small Cell Carcinoma