Search Results
within category "Lung Disease & Asthma"
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.
Phase 1 Dose-escalating Study of MM-398 (Irinotecan Sucrosofate Liposome Injection) Plus Intravenous Cyclophosphamide in Recurrent or Refractory Pediatric Solid Tumors
This is a Phase 1 study of the combination of two drugs: MM-398 and Cyclophosphamide. The
goal is to find the highest dose of MM-398 that can be given safely when it is used together
with the chemotherapy drug Cyclophosphamide.
• Histologically or cytologically-confirmed Ewing sarcoma, rhabdomyosarcoma,
neuroblastoma, or osteosarcoma
• Disease progression after prior therapy in locally advanced or metastatic setting
• Measurable or evaluable disease based on the Response Evaluation Criteria in Solid
Tumors (RECIST v1.1) criteria
• Age 12 months to <21 years
• Adequate bone marrow reserves, hepatic function, and renal function
• Recovered from effects of any prior surgery or cancer therapy
• Patients 18 years or older will provide written consent. A parent or legal guardian of
a patient <18 years of age will provide informed consent and patients 11 to 18 years
of age will provide written assent or as per participating institutional policy.
Exclusion Criteria:
• Clinically significant gastrointestinal disorders
• NYHA Class III or IV congestive heart failure, ventricular arrhythmias or uncontrolled
blood pressure
• Active infection or unexplained fever
• Known hypersensitivity to any of the components of MM-398 or other liposomal products
• Recent Investigational therapy
• Pregnant or breast feeding; females of child-bearing potential must test negative for
pregnancy at the time of enrollment
Drug: MM-398 (Irinotecan Sucrosofate Liposome Injection) plus cyclophosphamide
Neuroblastoma, Sarcoma, Ewing Sarcoma, Mycosis Fungoides, Rhabdomyosarcoma, Osteosarcoma, Recurrent or Refractory Solid Tumors, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Hodgkins Lymphoma, Kaposis sarcoma, Other Hematopoietic, Small Intestine, Soft Tissue
A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001) (LIBRETTO-001)
This is an open-label, first-in-human study designed to evaluate the safety, tolerability,
pharmacokinetics (PK) and preliminary anti-tumor activity of selpercatinib (also known as
LOXO-292) administered orally to participants with advanced solid tumors, including
rearranged during transfection (RET)-fusion-positive solid tumors, medullary thyroid cancer
(MTC) and other tumors with RET activation.
For Phase 1:
• Participants with a locally advanced or metastatic solid tumor that:
• Has progressed on or is intolerant to standard therapy, or
• For which no standard therapy exists, or in the opinion of the Investigator, are not
candidates for or would be unlikely to tolerate or derive significant clinical benefit
from standard therapy, or
• Decline standard therapy
• Prior multikinase inhibitors (MKIs) with anti-RET activity are allowed
• A RET gene alteration is not required initially. Once adequate PK exposure is
achieved, evidence of RET gene alteration in tumor and/or blood is required as
identified through molecular assays, as performed for clinical evaluation
• Measurable or non-measurable disease as determined by RECIST 1.1 or RANO as
appropriate to tumor type
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2 or Lansky Performance
Score (LPS) greater than or equal to (≥) 40 percent (%) (age less than [<] 16 years)
with no sudden deterioration 2 weeks prior to the first dose of study treatment
• Adequate hematologic, hepatic and renal function
• Life expectancy of at least 3 months
For Phase 2: As for phase 1 with the following modifications:
• For Cohort 1: Participants must have received prior standard therapy appropriate for
their tumor type and stage of disease, or in the opinion of the Investigator, would be
unlikely to tolerate or derive clinical benefit from appropriate standard of care
therapy
• Cohorts 1 and 2:
• Enrollment will be restricted to participants with evidence of a RET gene
alteration in tumor
• At least one measurable lesion as defined by RECIST 1.1 or RANO, as appropriate
to tumor type and not previously irradiated
• Cohorts 3 and 4: Enrollment closed
• Cohort 5:
• Cohorts 1-4 without measurable disease
• MCT not meeting the requirements for Cohorts 3 or 4
• MTC syndrome spectrum cancers (e.g., MTC, pheochromocytoma), cancers with
neuroendocrine features/differentiation, or poorly differentiated thyroid cancers
with other RET alteration/activation may be allowed with prior Sponsor approval
• cfDNA positive for a RET gene alteration not known to be present in a tumor
sample
• Cohort 6: Participants who otherwise are eligible for Cohorts 1, 2 or 5 who
discontinued another RET inhibitor may be eligible with prior Sponsor approval
• Cohort 7: Participants with a histologically confirmed stage IB-IIIA NSCLC and a RET
fusion; determined to be medically operable and tumor deemed resectable by a thoracic
surgical oncologist, without prior systemic treatment for NSCLC
Key Exclusion Criteria (Phase 1 and Phase 2):
• Phase 2 Cohorts 1 and 2: an additional known oncogenic driver
• Cohorts 3 and 4: Enrollment closed
• Cohorts 1, 2 and 5: prior treatment with a selective RET inhibitor Notes: Participants
otherwise eligible for Cohorts 1, 2, and 5 who discontinued another selective RET
inhibitor may be eligible for Phase 2 Cohort 6 with prior Sponsor approval
• Investigational agent or anticancer therapy (including chemotherapy, biologic therapy,
immunotherapy, anticancer Chinese medicine or other anticancer herbal remedy) within 5
half-lives or 2 weeks (whichever is shorter) prior to planned start of LOXO-292
(selpercatinib). In addition, no concurrent investigational anti-cancer therapy is
permitted Note: Potential exception for this exclusion criterion will require a valid
scientific justification and approval from the Sponsor
• Major surgery (excluding placement of vascular access) within 2 weeks prior to planned
start of LOXO-292 (selpercatinib)
• Radiotherapy with a limited field of radiation for palliation within 1 week of planned
start of LOXO-292 (selpercatinib), with the exception of participants receiving
radiation to more than 30% of the bone marrow or with a wide field of radiation, which
must be completed at least 4 weeks prior to the first dose of study treatment
• Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the
exception of alopecia and Grade 2, prior platinum-therapy related neuropathy
• Symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated
spinal cord compression. Participants are eligible if neurological symptoms and CNS
imaging are stable and steroid dose is stable for 14 days prior to the first dose of
LOXO-292 (selpercatinib) and no CNS surgery or radiation has been performed for 28
days, 14 days if stereotactic radiosurgery (SRS)
• Clinically significant active cardiovascular disease or history of myocardial
infarction within 6 months prior to planned start of LOXO-292 (selpercatinib) or
prolongation of the QT interval corrected (QTcF) greater than (>) 470 milliseconds
(msec)
• Participants with implanted pacemakers may enter the study without meeting QTc
criteria due to nonevaluable measurement if it is possible to monitor for QT
changes.
• Participants with bundle branch block may be considered for study entry if QTc is
appropriate by a formula other than Fridericia's and if it is possible to monitor
for QT changes.
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications
• Phase 2 Cohort 7 (neoadjuvant treatment): Participant must not have received prior
systemic therapy for NSCLC.
Drug: LOXO-292
Lymphoma, Non-Small Cell Lung Cancer, Colon Cancer, Medullary Thyroid Cancer, Any Solid Tumor, Brain and Nervous System, Eye and Orbit, Anus, Bones and Joints, Breast - Female, Breast - Male, Cervix, Colon, Corpus Uteri, Esophagus, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Stomach, Thyroid, Urinary Bladder, Hodgkins Lymphoma, Small Intestine, Soft Tissue
LOXO-292, KIF5B-RET, M918T, CCDC6-RET, RET-PTC1, NCOA4-RET, RET-PTC, RET-PTC3, RET-PTC4, PRKAR1A-RET, RET-PTC2, GOLGA5-RET, RET-PTC5, ERC1-RET, KTN1-RET, RET-PTC8, HOOK3-RET, PCM1-RET, TRIM24-RET, RET-PTC6, TRIM27-RET, TRIM33-RET, RET-PTC7, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1-RET, BCR-RET, FGRF1OP-RET, RFG8-RET, RET-PTC9, ACBD5-RET, MYH13-RET, CUX1-RET, KIAA1468-RET, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, G533C, C609F, C609G, C609R, C609S, C609Y, C611F, C611G, C611S, C611Y, C611W, C618F, C618R, C618S, C620F, C620R, C620S, C630R, C630Y, D631Y, C634F, C634G, C634R, C634S, C634W, C634Y, K666E, E768D, L790F, V804L, V804M, A883F, S891A, R912P, CLIP1-RET, Y806C, RET fusion, RET alteration, RET mutation, RET rearrangement, RET translocation, Neoplasms by Site, Neoplasms, Non-Small Cell Lung Cancer, Lung Neoplasms, Carcinoma, Non-Small-Cell Lung, Cancer of Lung, Cancer of the Lung, Lung Cancer, Neoplasms, Lung, Neoplasms, Pulmonary, Pulmonary Cancer, Pulmonary Neoplasms, Respiratory Tract Neoplasms, Lung Diseases, Respiratory Tract Diseases, Carcinoma, Bronchogenic, Bronchial Neoplasms, Medullary Thyroid Cancer, Papillary Thyroid Cancer, Thyroid Diseases, Thyroid Neoplasms, Cancer of the Thyroid, Cancer of Thyroid, Neoplasms, Thyroid, Thyroid Ademona, Thyroid Cancer, Thyroid Carcinoma, Endocrine System Diseases, Endocrine Gland Neoplasms, Head and Neck Neoplasms, Thoracic Neoplasms, CNS tumor, Primary CNS tumor, Cancer of Colon, Cancer of the Colon, Colon Cancer, Colon Neoplasms, Colonic Cancer, Neoplasms, Colonic, Malignant tumor of Breast, Mammary Cancer, Mammary Carcinoma, Human, Mammary Neoplasm, Human, Neoplasms, Breast, Tumors, Breast, Human Mammary Carcinoma, Malignant Neoplasm of Breast, Breast Carcinoma, Breast Tumors, Cancer of the Breast, Breast Neoplasms, Breast Cancer, RET Inhibitor, MTC, NSCLC, selpercatinib, neo-adjuvant treatment in early stage NSCLC
Main Study Up to 100 subjects, both non-CF volunteers and Cystic Fibrosis (CF) patients, will
participate in a single study visit that will include a DEXA scan, micro CT, and blood
collection.
Denosumab (Prolia) Sub study Approximately 10 adult subjects with CF who participated in the
main study and have results indicating bone disease will receive treatment with Denosumab for
up to 5 years. They will be asked to return annually for repeat DEXA scans, micro CT, and
blood collection.
• Must have CF diagnosis confirmed by sweat test or genotype analysis
• Subjects (and parents/legal guardians as applicable) must have the ability to read and
write in English
Sub-study
Exclusion Criteria:
• No CF diagnosis
• Men or women without osteoporosis
• Less than 18 years of age
• Unwilling to return annually for study visits for up to 5 years
• Unwilling and/or medically unable to take denosumab
• Stratum I
• Patients must be less than 18 years of age at the time of diagnosis.
• Patients must have histological verification of the diagnosis of Langerhans cell
histiocytosis according to the criteria described in Section 6.1
• Signed informed consent form
• Stratum II
• Patients of Stratum I who have:
• Progressive disease (AD worse) in non-risk organs after 6 weeks (Initial Course
• AD intermediate or worse in non-risk organs or AD better in risk organs after 12
weeks (Initial Course 2)
• Disease progression (AD worse) in non-risk organs at any time during continuation
treatment
• Active disease at the end of Stratum I treatment
• Disease reactivation in non-risk organs at any time after completion of Stratum I
treatment
• Stratum III
• Patients from Stratum I who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2).
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as
• Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency
• PLT <20 x109/L (20,000/μL) and/or transfusion dependency (both criteria have
to be fulfilled) AND/OR
• Liver dysfunction (or digestive involvement with protein loss)
• Total protein <55 g/L or substitution dependency
• Albumin <25 g/L or substitution dependency (at least one of the two criteria
to be fulfilled)
• Stratum IV
• Patients from Stratum I or Stratum III who fulfill the following criteria:
• AD worse in risk organs after week 6 (after Initial Course 1), or AD worse or AD
intermediate in risk organs after week 12 (after Initial Course 2) of Stratum I
OR
• AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or AD
intermediate after the 4th 2-CdA/Ara-C course of Stratum III AND
• Presence of unequivocally severe organ dysfunction at the above mentioned
evaluation points (hematological dysfunction, liver dysfunction, or both of them)
as defined in Table XI (see Section 10.3.1).
• Informed consent: All patients or their legal guardians (if the patient is <18
years of age) must sign an Ethics or institutional Review Board approved consent
form indicating their awareness of the investigational nature and the risks of
this study. When appropriate, younger patients will be included in all
discussions in order to obtain assent.
• Adequate organ function: Patients should have adequate hepatic, renal, cardiac
and pulmonary function to undergo reduced intensity HCT based upon local
institutional guidelines, or at a minimum meet requirements noted in eligibility
checklist Appendix A-VIII_1. However, significant hepatic and pulmonary
dysfunction, if secondary to underlying LCH disease activity, will not exclude
patients from protocol enrollment and should be discussed with the National PI
Coordinator and the Coordinating Principal Investigator.
• Stratum V
• All patients with verified diagnosis of LCH and MRI findings consistent with
ND-CNSLCH irrespective of previous treatments (also those not registered to other
Strata ofLCH-IV).
• Patients with isolated tumorous CNS-LCH (including isolated DI with mass lesion
in the hypothalamus-pituitary axis). In patients with already established
diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a
biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion
is needed for inclusion into the study
• Stratum VI
-- Patients with newly diagnosed SS-LCH and localization other than "multifocal
bone",isolated tumorous CNS lesion, or isolated "CNS-risk" lesion.
• Stratum VII -- All patients registered in LCH IV (regardless of treatment) as long as
consent for longterm follow-up has not been withheld.
Exclusion Criteria:
• Stratum I
• Pregnancy (patients of child-bearing age must be appropriately tested before
chemotherapy)
• LCH-related permanent consequences (e.g. vertebra plana, sclerosing cholangitis,
lung fibrosis, etc.) in the absence of active disease
• Prior systemic therapy
• Stratum II
• Patients with progressive disease in risk organs
• Permanent consequences (e.g. sclerosing cholangitis, lung fibrosis, etc.) without
evidence of active LCH in the same organ or in any other locations
• No written consent of the patient or his/her parents or legal guardian
• Stratum III
• The presence of any of the following criteria will exclude the patient from the
study:
• Isolated sclerosing cholangitis without evidence of active hepatic LCH as the
only evidence of risk organ involvement.
• Inadequate renal function as defined by serum creatinine > 3x normal for age
• Stratum IV
• Pulmonary failure (requiring mechanical ventilation) not due to active LCH.
• Isolated liver sclerosis or pulmonary fibrosis, without active LCH.
• Uncontrolled active life-threatening infection.
• Decreased renal function with a GFR of less than 50ml/1.73m2/min.
• Pregnancy or active breast feeding
• Failure to provide signed informed consent
• Stratum VI
• Patients with SS-LCH who have an isolated tumorous CNS lesion (they are eligible
for Stratum V),
• Patients with isolated "CNS-risk" or multifocal bone lesions (they are eligible
for Stratum I, Group 2)
Safety and Efficacy Study of IMSA101 in Refractory Malignancies
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients
receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor
(ICI) (Phase I and II)
1. Signed informed consent and mental capability to understand the informed consent
2. Male or female patients > 18 years of age
3. Histologically or cytologically documented locally advanced or metastatic solid tumor
malignancies refractory to or otherwise ineligible for treatment with standard-of-care
agents/regimens, including but not limited to:
• Malignant melanoma
• Hormone receptor negative breast cancer
• Gastro-esophageal cancer
• Non-small cell lung cancer
• Head and neck cancer
• Hepatoma
• Renal cell carcinoma
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1
5. Evaluable or measurable disease as follows:
• A minimum of 3 RECIST-evaluable lesions: one that is suitable for injection and
biopsied; one non-injected that will be biopsied for abscopal effect; and one
measurable lesion that will be followed for response only.
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous
injection only, including those lesions that are visible, palpable, or detectable
by standard radiographic or ultrasound methods. Neither surgical procedures nor
endoscopically-guided injections including those to endobronchial, endoluminal,
or endosinusial spaces shall be allowed. While no anatomic locations are required
or disallowed, lesions selected for intratumoral injection must, in the opinion
of the investigator:
• Not be immediately adjacent to blood vasculature or other physiologic landmarks
in such a way that will accrue undue safety risk to the patient
• Have longest diameter ≥ 10 mm and ≤ 50 mm
• Be fully efficacy evaluable per RECIST v1.1 criteria
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA)
7. ECG without evidence of clinically meaningful conduction abnormalities or active
ischemia as determined by the investigator
8. Acceptable organ and marrow function as defined below:
• Absolute neutrophil count > 1,500 cells/μL
• Platelets > 50,000 cells/μL
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If
liver metastases are present, AST/ALT < 5 times ULN
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min
using the Cockcroft-Gault formula
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN
9. Women of child-bearing potential (defined as a female who has experienced menarche and
who has not undergone successful surgical sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at
the appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy
test prior to first dose of study drug
10. Male and female patients with reproductive potential must agree to use two forms of
highly effective contraception throughout the study
11. Phase I combination only: Demonstrated RECIST stable disease through ≥ 4 consecutive
cycles of an approved PD-1 or PD-L1 targeted ICI with no Grade ≥ 3 CTCAE events
considered by the investigator to be drug-related.
Exclusion Criteria:
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug.
2. Failure to recover to Grade 1 or less from clinically significant AEs due to prior
anti-cancer therapy.
3. Known untreated brain metastases or treated brain metastases that have not been stable
(scan showing no worsening of central nervous system (CNS) lesion[s] and no
requirement of corticosteroids) ≥ 4 weeks prior to study enrollment
4. Baseline prolongation of QT/QTc interval (QTc interval > 470)
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 opinion of the
investigator would limit compliance with study requirements
6. Women who are pregnant or breastfeeding
7. Phase I combination only: Prior tumor progression through PD-1 or PD-L1 targeted ICI
therapy.
Durvalumab vs Placebo Following Stereotactic Body Radiation Therapy in Early Stage Non-small Cell Lung Cancer Patients (PACIFIC-4)
This is a Phase III, randomized, placebo-controlled, double-blind, multi-center study
assessing the efficacy and safety of durvalumab versus placebo following SoC SBRT in patients
with unresected clinical Stage I/II lymph node-negative (T1 to T3N0M0) NSCLC.
1. Age ≥18 years
2. Histologically or cytologically documented Stage I to II NSCLC, with clinical Stage
I/II lymph node-negative (T1 to T3N0M0) disease and planned to receive definitive
treatment with SBRT. Patients may be medically inoperable or are medically operable
and refusing surgery or choosing to have SBRT (Stereotactic Body Radiation Therapy) as
definitive therapy
3. Completion of SoC SBRT as definitive treatment prior to randomization
4. World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) PS of 0, 1,
or 2
5. Life expectancy of at least 12 weeks
6. Body weight >30 kg
7. Tumor sample required
8. Adequate organ and marrow function required
9. Patients with central or peripheral lesions are eligible
10. Staging studies must be done within 8 weeks before randomization
Key
Exclusion Criteria:
1. Mixed small cell and non-small cell cancer histology
2. History of allogeneic organ transplantation
3. History of another primary malignancy with exceptions
4. History of active primary immunodeficiency
5. Any unresolved toxicity National Cancer Institute (NCI) CTCAE Grade ≥2 from SBRT
(Stereotactic Body Radiation Therapy)
Drug: Durvalumab, Other: Placebo
Carcinoma, Non-Small-Cell Lung, Lung/Thoracic
NSCLC, Double- Blind, PD-L1, MEDI4736, Durvalumab, PFS, OS
UT Southwestern; Parkland Health & Hospital System
This is a Phase 3, randomized, masked, active-controlled, multicenter trial designed to
determine whether early intratracheal administration of a combination of budesonide with
surfactant, as compared to surfactant alone, will reduce the incidence of physiologic
bronchopulmonary dysplasia (BPD) or death by 36 weeks' post-menstrual age in extremely
preterm infants.
• Liveborn infants 22 0/7 •28 6/7 weeks gestation or 401 •1000 grams (inclusive) birth
weight
• Clinical decision to give surfactant
• Less than or equal to 48 hours postnatal age
Exclusion Criteria:
• Terminal illness (heart rate < 100 beats per minute, unresponsiveness to
resuscitation) or unlikely to survive as judged by the clinician
• Decision to redirect or limit support
• Use of surfactant before enrollment (first dose of surfactant must be study drug)
• Infant received systemic steroids prior to enrollment
• Use of indomethacin, either received by the mother within 24 hours prior to
delivery,received by the infant prior to enrollment, or intent to administer to the
infant for IVH prophylaxis or PDA management from enrollment up to 7 days of final
dose of study drug
• Serious chromosomal abnormalities or major malformations
• Known congenital infections including, but not limited to, confirmed sepsis,
congenital CMV, etc.
• Infants with a permanent neuromuscular condition that affects respiration
• Enrollment in a conflicting clinical trial
Phase I/II Study of SBRT and GC4711 for Centrally Located or Large NSCLC (GRECO-1)
GTI-4711-101 is a Phase I/II study of the safety of GC4711, its effect on in-field tumor
response and its potential to reduce radiation-related pulmonary injury due to SBRT for lymph
node negative (T1 to T3N0M0) peripheral or central localized (within 2cm of the proximal
bronchial tree) NSCLC.
After an open-label, Phase 1, safety cohort of 5 subjects has been completed, a randomized,
placebo-controlled Phase 2 portion of 66 subjects will be conducted.
1. Male or female subjects at least 18 years of age.
2. Ability to understand and the willingness to sign a written informed consent.
3. Histological or biopsy proven NSCLC.
4. ECOG performance status of 0-3.
5. Node negative (T1 to T3N0M0), centrally located (within 2cm in all directions around
the proximal bronchial tree, including ultra-central tumors, abutting the bronchial
tree or trachea) or large (>1-7cm) Non-Small Cell Lung Cancer (NSCLC), judged
acceptable for SBRT by the treating Investigator
6. Adequate end-organ function, based on routine clinical and laboratory workup:
1. ANC >1,000 cells/µl, Platelets ≥ 75,000 cells/µl, Hemoglobin ≥ 7.0 g/dl
2. Serum creatinine ≤ 2 x ULN or calculated creatinine clearance ≥ 30 ml/min
3. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤
2.5 x ULN
7. Males and females of must agree to use effective contraception starting prior to the
first day of treatment and continuing after the last dose of GC4711/Placebo for 30
days (females) and 90 days (males).
Exclusion Criteria:
1. Subjects with confirmed nodal and/or distant disease(including brain), according
standard workup by local investigator
2. Subjects with peripheral lesions 1cm or smaller
3. Prior treatment with immunotherapy within 3 months prior to Day 1 dosing.
4. Prior intra-thoracic radiotherapy or surgery with substantial overlap to planned
radiation fields as determined by the treating radiation oncologist.
5. Subjects not recovered/controlled from prior treatment-related (chemotherapy or
targeted therapy) toxicities judged by treating physician.
6. Uncontrolled malignancy other than lung cancer that requires active treatment or is
deemed by the treating physicians to be likely to affect the subject's survival
duration.
7. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to GC4711.
8. 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.
9. Participation in other clinical trials actively testing new anti-cancer treatments,
unless previously written approval is provided by the Sponsor.
10. Requirement for concurrent treatment with nitrates or other drugs that may, in the
judgment of the treating investigator, create a risk for a precipitous decrease in
blood pressure.
11. Female subjects who are pregnant or breastfeeding.
12. Any other conditions that, in the Investigator's opinion, might indicate the subject
to be unsuitable for the study.
Drug: GC4711, Drug: Placebo
NSCLC, Lung/Thoracic, SBRT, Non-metastatic
lymph node negative NSCLC, centrally located NSCLC, large NSCLC, SBRT
UT Southwestern; Parkland Health & Hospital System
Phase II Randomized Trial of Carboplatin+Pemetrexed+Bevacizumab+/- Atezolizumab in Stage IV NSCLC
While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma
in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer
typically present with different molecular profiles from that of smokers, which results in
prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic
significance include mutations in the epidermal growth factor receptor (EGFR) and
rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically
are present in lung tumors found in never or light smokers.
The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of
non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone,
12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that
carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel +
bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has
emerged as a form of treatment that can lead to robust responses in a subset of patients. The
PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival
in comparison to docetaxel in patients who previously progressed with chemotherapy,
irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent
atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy
(carboplatin and pemetrexed).
• Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer
• Patients must either have tumors that harbor an EGFR mutation in exon 19 or exon 21,
or must be never smoker wild-types. Never smoker wild-types are defined as patients
with tumors without an ALK or ROS1 rearrangement, and are not harboring any EGFR
mutation (this includes exons 19 or 21, exon 20, and any other rare EGFR mutations).
Never smoker wild-type patients must have smoked less than 100 cigarettes in a
lifetime. Patients with an EGFR mutation in exon 19 or 21 may be included irrespective
of their smoking history. If tissue-based testing for EGFR mutation status is not
available, blood-based EGFR testing that confirms presence of a mutation in exon 19 or
21 is acceptable, and these patients may be included in the study
• Patients must have measurable disease by CT or MRI, defined as at least one lesion
that can be accurately measured in at least one dimension in accordance with RECIST
criteria v 1.1
• Patients with tumors that harbor an EGFR exon 19 or exon 21 mutation must have
received prior treatments with one or more TKIs. A washout period of at least 2 weeks
is required to begin treatment in this trial. Patients who are never smoker wild-types
must be treatment naïve
• All patients must be chemotherapy, VEGF therapy, and immunotherapy naive, with the
exception of prior oral TKIs which are required for EGFR mutated patients. The number
of prior oral TKIs and duration of use is neither specified nor limited.
• Patients with a history of treated asymptomatic CNS metastases are eligible, provided
they meet all of the following criteria:
• Only supratentorial and cerebellar metastases allowed (i.e., no metastases to
midbrain, pons, medulla or spinal cord)
• No ongoing requirement for corticosteroids as therapy for CNS disease
• No stereotactic radiation within 7 days or whole-brain radiation within 14 days
prior to randomization
• No evidence of interim progression between the completion of CNS-directed therapy
and the screening radiographic study
Patients with new asymptomatic CNS metastases detected at the screening scan must receive
radiation therapy and/or surgery for CNS metastases. Following treatment, these patients
may then be eligible without the need for an additional brain scan prior to randomization,
if all other criteria are met
• Age > 18 years
• ECOG performance status 0 or 1
• Patients must have normal organ and marrow function as defined below. The use of G-CSF
should follow standard recommendations and physician discretion. If blood transfusion
is performed for achieving hemoglobin levels, the levels should stay at ≥ 9.0 mg/ml
for at least a week after transfusion.
Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL Total
bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) < 3 times
institutional normal limits, or up to 5 times institutional normal limits if the patient
has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR > 40 Ml/min/1.73 m2
for patients with creatinine levels above institutional normal as per Cockcroft-Gault
formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) <1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants Thyroid stimulating hormone (TSH)
Within normal limits a
a: If TSH is not within normal limits at baseline, the subject will still be eligible if
total T3 or free T4 are within normal limits.
• Patients on full-dose anticoagulation must be on a stable dose (minimum duration 14
days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving
warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no
clinically significant active bleeding (with no bleeding within 14 days prior to first
dose of protocol therapy) or pathological condition present that carries a high risk
of bleeding (for example, tumor involving major vessels or known varices).
• Ability to understand and willingness to sign a written informed consent and HIPAA
consent document.
• A core biopsy must be available for the study. The biopsy sample must be adequate for
analyses. If the sample is not adequate, the patient must agree to provide a fresh
biopsy specimen before the start of treatment. Any available archival tissue will also
be collected.
• Urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick
or routine analysis is ≥2+, a 24 hour urine collection for protein must demonstrate
<1000 mg of protein in 24 hours to allow participation in the protocol).
• Female subjects of child-bearing potential must be willing to use an effective method
of contraception, for the course of the study through at least 6 months after the last
dose of study medication.
• Male patients who have WOCBP partners must agree to use effective method of
contraception for the course of the study through 8 months after the last dose of
study medication.
• Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
Exclusion Criteria:
• Patients currently receiving any other investigational agents, immunomodulatory
agents, chemotherapy, or TKIs. EGFR mutation-positive patients must have received
prior TKI treatment
• The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first
dose of protocol therapy.
• The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or
any other significant thromboembolism (venous port or catheter thrombosis or
superficial venous thrombosis are not considered "significant") during the 3 months
prior to the first dose of protocol therapy.
• Subjects with untreated CNS metastases are excluded, even if they are asymptomatic.
Patients with treated brain metastases will be allowed if brain imaging obtained
within 28 days of trial enrollment reveals stable disease.
• Cirrhosis at a level of Child-Pugh B or worse, or cirrhosis of 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.
• The patient has 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 first dose of protocol therapy.
• The patient has uncontrolled or poorly-controlled hypertension (>150 mmHg systolic or
> 100 mmHg diastolic for >4 weeks) despite standard medical management
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to randomization
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
anticoagulation)
• History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
6 months prior to randomization
• Clinical signs of gastrointestinal obstruction or requirement for routine parenteral
hydration, parenteral nutrition, or tube feeding
• Evidence of abdominal free air not explained by paracentesis or recent surgical
procedure
• Serious, non-healing wound, active ulcer, or untreated bone fracture within 28 days
prior to first dose of protocol therapy
• Subjects with a history of smoking greater than a 100 cigarettes in a lifetime, unless
their tumor has an EGFR exon 19 or exon 21 mutation.
• Patients with active, suspected, or known autoimmune disease that has required
systemic treatment in the past one year (i.e., with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Hormone replacement therapy (e.g.
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Patients with a history of hemoptysis (defined as bright red blood or ≥1/2 teaspoons)
within 1 month prior to first dose of protocol therapy or with radiographic evidence
of major blood vessel invasion or encasement by cancer.
• The patient has undergone major surgery within 28 days prior to first dose of study
treatment, or minor surgery/ subcutaneous venous access device placement within 7 days
prior to first dose of protocol therapy. The patient has elective or planned major
surgery to be performed during the course of the clinical trial.
• The patient is receiving chronic anti-platelet therapy other than aspirin, including
non-steroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and
others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use
(maximum dose 325 mg/day) is permitted. Occasional use of NSAIDs is allowed (for
example daily use for less than a week; treating physician discretion is permitted to
differentiate between occasional vs chronic use)
• Patients who have not recovered from adverse events due to agents administered earlier
except neuropathy and alopecia. Physician's discretion is allowed to decide which
unresolved adverse events from previous therapy (for NSCLC) prohibit patient
participation in this study.
• Patients requiring more than 10 mg prednisolone (or its equivalent) per day are
excluded.
• Patients with any evidence of interstitial lung disease (ILD) or pneumonitis or a
prior history of ILD or pneumonitis requiring oral or IV glucocorticoids. History of
radiation pneumonitis in the radiation field (fibrosis) is permitted
• Patients with active tuberculosis infection are excluded.
• Patients who have received a live vaccine within 30 days prior to cycle 1 Day 1.
• Uncontrolled illness including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
(significant), cirrhosis, or psychiatric illness/ social situations that would limit
compliance with the study requirements.
• Known history of testing positive for immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS).
• Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
indicating chronic infection that is not cured.
• Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
cancers, such as, bladder, gastric, colon, cervical/ dysplasia, melanoma, or breast)
are excluded unless a complete remission was achieved at least 2 years prior to study
registration and no additional therapy is required or anticipated to be required
during the study period.
• Leptomeningeal disease
• Uncontrolled tumor-related pain
Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic
lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing
nerve impingement) should be treated prior to randomization. Patients should be recovered
from the effects of radiation. There is no required minimum recovery period.
Asymptomatic metastatic lesions whose further growth would likely cause functional deficits
or intractable pain (e.g., epidural metastasis that is not currently associated with spinal
cord compression) should be considered for locoregional therapy, if appropriate, prior to
randomization.
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
Patients with indwelling catheters (e.g., PleurX®) are allowed.
• Ca > 12 mg/dl or corrected serum calcium > ULN
Patients who are receiving denosumab prior to randomization must be willing and eligible to
receive a bisphosphonate instead while in the study
• Pregnant or breast feeding
• Prior allogeneic bone marrow transplantation or solid organ transplant
• Known hypersensitivity to Chinese hamster ovary cell products or any of the study
drugs.
• Clear tumor infiltration into the thoracic great vessels is seen on imaging
• Clear cavitation of pulmonary lesions is seen on imaging
• Subjects with squamous cell carcinoma of the lung.
• Subjects with a lung tumor with a known ALK or ROS1 rearrangement or an EGFR mutation
other than in exon 19 or exon 21.
Drug: Arm A, Drug: Arm B
Lung/Thoracic, Non-Small Cell Carcinoma of Lung, TNM Stage 4
Durvalumab and Stereotactic Radiotherapy for Advanced NSCLC
This is a randomized Phase II study which is designed to determine the impact of stereotactic
radiotherapy and durvalumab on quality-of-life and oncologic outcomes in patients with
advanced non-small cell lung cancer. Durvalumab (Imfinzi) and stereotactic radiotherapy, with
each fraction of radiotherapy is given every other day on a standard stereotactic ablative
radiotherapy (SAbR) schedule or every four weeks on the personalized ultra-fractionated
stereotactic adaptive radiotherapy (PULSAR) schedule. Subjects will be followed for a period
of 2 years after completion of treatment or until death, whichever occurs first.
Specifically, subjects will be followed at 1, 3, 6, 9, 12, 15, 18, 21, and 24 months
following treatment. After the 2 year follow up, the patient can continue routine follow up
with their physicians, per standard of care. Subjects removed from therapy for unacceptable
adverse events will be followed until resolution or stabilization of the adverse event.
• Patients must have biopsy-proven metastatic non-small cell lung cancer and eligible
for receipt of immunotherapy
Patients can present with either de novo metastatic disease or recurrent disease
Patients must have at least one (1) symptomatic or progressive metastatic sites with no
more than 10 metastatic sites, based on standard imaging studies
Patients cannot have received any prior radiation therapy or surgery to the intended
radiation treatment area (index lesion)
Patients with brain metastases may be enrolled if all lesions are treated with radiation
therapy or surgery prior to start of protocol therapy
Metastases in major lower extremity weight-bearing bones or spine should undergo surgical
stabilization if indicated
Age greater than or equal to 18 years.
Both men and women and members of all races and ethnic groups will be included
Eastern Cooperative Oncology Group Performance status 0 to 2 (Appendix A)
Adequate normal organ and bone marrow function as defined by:
• Haemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC) ≥ 1.0 × 109 /L
• Platelet count ≥75 × 109/L
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply
to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician.
• AST (SGOT)/ALT (SGPT) ≤2.5X institutional upper limit of normal unless liver
metastases are present, in which case it must be ≤5X ULN
• Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by
the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection
for determination of creatinine clearance:
Males:
Creatinine CL (mL/min) = Weight (kg) x (140 •Age) 72 x serum creatinine (mg/dL)
Females:
Creatinine CL (mL/min) = Weight (kg) x (140 •Age) x 0.85 72 x serum creatinine (mg/dL)
All men, as well as women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry, for the duration of study participation, and for 90 days following completion of
therapy. Should a woman become pregnant or suspect she is pregnant while participating in
this study, she should inform her treating physician immediately.
Medically accepted forms of birth control include male condoms plus spermicide, diaphragm,
cervical cap, the placement of a Copper T intrauterine device (IUD), birth control pills,
Levonorgesterel-releasing intrauterine system (IUS), hormone implants or injections, or
combined pill, minipill patch, or a partner who has undergone a vasectomy (surgical
sterility).
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).
Life expectancy greater than six (6) months
Body weight greater than 30 kg
Capable of giving signed informed consent which includes compliance with the requirements
and restrictions listed in the informed consent form (ICF) and in this protocol. Written
informed consent and any locally required authorization (e.g., Health Insurance Portability
and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU)
obtained from the patient/legal representative prior to performing any protocol-related
procedures, including screening evaluations.
Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow up.
Exclusion Criteria:
• 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:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
• Patients with celiac disease controlled by diet alone
Administration of two or more lines of systemic therapy for the diagnosis of metastatic
lung cancer
• Prior receipt of systemic therapy for the management of high-risk early stage or locally
advanced non-small cell lung cancer, prior to the development of metastatic disease, would
not count towards the number of receipt of systemic therapy
Subjects may not be receiving any other investigational agents for the treatment of the
cancer under study.
Patients with untreated brain metastases
Patients with progressive metastatic disease involving the skin or subcutaneous tissues,
esophagus, stomach, intestines, or mesenteric lymph nodes that are felt to be too high risk
to treat with radiation therapy to protocol dose.
Patients cannot have pathologic fracture at the evaluated site
Patients cannot have untreated spinal cord compression
History of allergic reactions attributed to compounds of similar chemical or biologic
composition to durvalumab or other agents used in study
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
Subjects must not be pregnant or nursing due to the potential for congenital abnormalities
and the potential of this regimen to harm nursing infants
Male or female patients of reproductive potential who are not willing to employ effective
birth control from screening to 90 days after the last dose of durvalumab monotherapy
Participation in another clinical study with an investigational product during the last 3
months
Concurrent enrolment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an interventional
study
Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) ≤7
days prior to the first dose of study drug If sufficient wash-out time has not occurred due
to the schedule or PK properties of an agent, a longer wash-out period will be required, as
agreed by AstraZeneca/MedImmune and the investigator
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria:
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the Study
Physician.
Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g.,
hormone replacement therapy) is acceptable.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the first
dose of immunotherapy. Note: Local surgery of isolated lesions for palliative intent is
acceptable
History of allogenic organ transplantation
History of another primary malignancy except for:
• Malignancy treated with curative intent and with no known active disease ≥5 years
before the first dose of immunotherapy and of low potential risk for recurrence
• Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of
disease
• Adequately treated carcinoma in situ without evidence of disease
History of leptomeningeal carcinomatosis
History of active primary immunodeficiency
Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with local
practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C.
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
Current or prior use of immunosuppressive medication within 14 days before the first dose
of durvalumab. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or
its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Receipt of live attenuated vaccine within 30 days prior to the first dose of immunotherapy.
Other forms of vaccines, such as mRNA, recombinant protein, and non-replicating
vector-based vaccines, are permitted. Note: Patients, if enrolled, should not receive live
vaccine whilst receiving immunotherapy and up to 30 days after the last dose of
immunotherapy
Receipt of any medications listed below:
Patients on this study should not be on any targeted systemic therapies such as those
directed at EGFR mutations, ALK or ROS1 gene rearrangements, BRAF V600E mutation, or NTRK
gene fusions. Other anti-cancer treatments are also not allowed on the study and are listed
below. Supportive medications may be given at any point during treatment at the discretion
of the treating physician, such as anti-emetics, pain medications, anti-diarrheals,
nutritional supplementations, and anti-depressants. Anti-oxidant medications in excess of
daily recommended values are not allowed.
• Any investigational anticancer therapy other than those under investigation in this
study should not be given concomitantly whilst the patient is on study treatment.
• mAbs against CTLA-4, PD-1, or PD-L1 other than those under investigation in this study
should not be given concomitantly whilst the patient is on study treatment.
• Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal
therapy for cancer treatment other than those under investigation in this study should
not be given concomitantly whilst the patient is on study treatment. (Concurrent use
of hormones for non-cancer-related conditions [e.g., insulin for diabetes and hormone
replacement therapy] is acceptable. Local treatment of isolated lesions, excluding
target lesions, for palliative intent is acceptable [e.g., by local surgery or
radiotherapy])
• Immunosuppressive medications including, but not limited to, systemic corticosteroids
at doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine,
and tumor necrosis factor-α blockers should not be given concomitantly, or used for
premedication prior to the IO infusions. The following are allowed exceptions:
• Use of immunosuppressive medications for the management of IP-related AEs,
• Use in patients with contrast allergies.
• In addition, use of inhaled, topical, and intranasal corticosteroids is
permitted.
A temporary period of steroids will be allowed if clinically indicated and considered to be
essential for the management of non-immunotherapy related events experienced by the patient
(e.g., chronic obstructive pulmonary disease, radiation, nausea, etc.).
• EGFR tyrosine kinase inhibitors (TKI) should not be given concomitantly, and should be
used with caution in the 90 days post last dose of durvalumab.
• Live attenuated vaccines should not be given through 30 days after the last dose of IP
(including SoC)
• Herbal and natural remedies which may have immune-modulating effects should not be
given concomitantly unless agreed by the sponsor
Testicular Tissue Cryopreservation for Fertility Preservation
Testicular tissue cryopreservation is an experimental procedure where a young boy's
testicular tissue is retrieved and frozen. This technique is reserved for young male patients
who are not yet producing mature sperm, with the ultimate goal that their tissue may be used
in the future to restore fertility when experimental techniques emerge from the research
pipeline.
• Be male at any age.
• Be scheduled to undergo surgery, chemotherapy, drug treatment and/or radiation for the
treatment or prevention of a medical condition or malignancy with risk of causing
permanent and complete loss of subsequent testicular function.
• Or, have a medical condition or malignancy that requires removal of all or part of one
or both testicles.
• Have newly diagnosed or recurrent disease. Those who were not enrolled at the time of
initial diagnosis (i.e., patients with recurrent disease) are eligible if they have
not previously received therapy that is viewed as likely to result in complete and
permanent loss of testicular function.
• Have two testicles if undergoing elective removal of all or part of a testicle for
fertility preservation only. Note: removal of both testicles will limit fertility
preservation options.
• Sign an approved informed consent and authorization permitting the release of personal
health information. The patient and/or the patient's legally authorized guardian must
acknowledge in writing that consent for specimen collection has been obtained, in
accordance with institutional policies approved by the U.S. Department of Health and
• Consent for serum screening tests for infectious diseases [HIV-1, HIV-2, Hepatitis B,
Hepatitis C], to be performed at the time of testicular tissue harvesting.
• Undergo a full history and physical examination and obtain standard pre-operative
clearance (based on the most recent ACC/AHA Guideline for Perioperative Cardiovascular
Evaluation for Noncardiac Surgery) as determined by their primary surgeon.
• Participating in long term follow-up is a requirement of the protocol.
Exclusion Criteria:
• Diagnosed with psychological, psychiatric, or other conditions which prevent giving
fully informed consent.
• Diagnosed with an underlying medical condition that significantly increases their risk
of complications from anesthesia and surgery.
Procedure: Testicular biopsy
Lymphoma, Sarcoma, Cancer, Mycosis Fungoides, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Male, Carcinoid Tumor, Cardiovascular, Colon, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Nose, Other Digestive Organ, Other Endocrine System, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Leukemia, Other, Hodgkins Lymphoma, Heart, Leukemia, Not Otherwise Specified, Lymphoid Leukemia, Myeloid and Monocytic Leukemia, Non-Hodgkins Lymphoma, Other Hematopoietic, Small Intestine, Soft Tissue, Unknown Sites, Ill - Defined Sites, Autoimmune Disorders
Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections (DOMINIC)
This study will establish a non-invasive diagnostic approach and evaluate clinical outcomes
for children at high-risk for pulmonary invasive mold infection (PIMI).
• Males or females age > 120 days and < 22 years at any participating site
• Have at least one of the following conditions associated with a known high incidence
of IMI: hematopoietic stem cell transplantation (HSCT), aplastic anemia, or
hematologic malignancy
• New (last 96 hours) radiographic evidence of at least one of the following: at least
one nodular lesion greater than or equal to 5 mm in size, a cavitary lesion, a lesion
with a halo sign, a lesion with a reverse halo sign, or a lesion with an air crescent
sign
• Prolonged neutropenia (absolute neutrophil count < 500 cells/µl for a period of ≥ 5
consecutive days) in 30 days prior to qualifying chest MRI or CT scan date OR
currently receiving systemic therapy for acute or chronic graft-versus-host disease
(GVHD) on the date of the qualifying chest MRI or CT scan
• Subject consent or parental/guardian permission (informed consent) and if appropriate,
child assent
Exclusion Criteria:
• Weight <3 kg, so as to not exceed 3 ml/kg in a single blood draw
• Previous inclusion in this study
IV Gallium Study for Patients With Cystic Fibrosis Who Have NTM (ABATE Study) (ABATE)
The purpose of this study is to assess the safety and tolerability of two 5-day infusion
cycles of IV gallium in adult patients with CF who are infected with NTM.
Funding Source - FDA OOPD
1. Written informed consent obtained from subject or subject's legal representative
2. Be willing and able to adhere to the study visit schedule and other protocol
requirements
3. Greater than or equal to 18 years of age at Visit 1
4. Documentation of a CF diagnosis as evidenced by one or more clinical features
consistent with the CF phenotype and one or more of the following criteria:
• Sweat chloride ≥ 60 milliequivalent (mEq)/liter by quantitative pilocarpine
iontophoresis test (QPIT)
• Two well-characterized mutations in the cystic fibrosis transmembrane conductance
regulator (CFTR) gene
• Abnormal nasal potential difference (NPD) (change in NPD in response to a low
chloride solution and isoproteronol of less than -5 mV)
5. Documentation of NTM culture positive defined as follows:
• Two positive NTM culture results from sputum (or BAL) at least 28 days apart
(these are the two qualifying positive cultures)
• Both qualifying positive culture results include M. avium complex, M. abscessus
complex, or both M. avium and M. abscessus
• Both qualifying positive culture results include the same species or subspecies
• No cultures negative for NTM since the first of the two qualifying positive
culture results
6. Current NTM species or subspecies has never been treated or previous treatment was
associated with clearance of NTM and completed > 2 years prior to Day 1
7. Forced expiratory volume in 1 second (FEV1) ≥ 25 % of predicted value at Screening
8. Able to expectorate sputum
9. Clinically stable with no significant changes in health status within 7 days prior to
Day 1
10. Enrolled in the CFF Cystic Fibrosis Foundation Patient Registry (CFFPR)
11. Willing to discontinue chronic azithromycin use for the duration of the study
Exclusion Criteria:
1. Any of the following abnormal lab values at screening:
• Hemoglobin <10g/dL
• Platelets <100,000/mm3
• White blood cells (WBC) < 4,500/mm3
• Aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl
transferase (GGT), or alkaline phosphatase (ALP) ≥3 x upper limit of normal
• Serum creatinine > 2.0 mg/dl and ≥1.5 x upper limit of normal
• Ionized calcium ≤ lower limit of normal (only performed if total calcium is ≤
lower limit of normal)
2. History of solid organ or hematological transplantation
3. Use of bisphosphonates within 7 days prior to Day 1
4. Known sensitivity to gallium
5. Use of any investigational drug and/or participated in any interventional clinical
trial within 28 days prior to Day 1
6. In the opinion of the Investigator, features of active NTM disease are present (e.g.,
clinical worsening is likely due to NTM disease despite definitive treatment of
co-pathogens and/or acute exacerbations)
7. Undergoing treatment for NTM disease or anticipate beginning treatment within 3 months
8. Current diagnosis of osteoporosis
9. For people of childbearing potential:
• Positive pregnancy test at Visit 1 or
• Lactating or
• Unwilling to practice a medically acceptable form of contraception (acceptable
forms of contraception: abstinence, hormonal birth control, intrauterine device,
or barrier method plus a spermicidal agent), unless surgically sterilized or
postmenopausal during the study
10. For people able to father a child: unwilling to use adequate contraception (as
determined by the investigator) during the study
11. Has any other condition that, in the opinion of the Site Investigator/designee, would
preclude informed consent or assent, make study participation unsafe, complicate
interpretation of study outcome data, or otherwise interfere with achieving the study
objectives
12. New initiation of chronic therapy (greater than 21 days) within 28 days prior to the
Enrollment Visit
Prospective Treatment Efficacy in IPF Using Genotype for Nac Selection (PRECISIONS) Trial (PRECISIONS)
The purpose of this study is to compare the effect of n-acetylcysteine (NAC) plus standard
care with matched placebo plus standard of care in patients diagnosed with idiopathic
pulmonary fibrosis (IPF) who have the TOLLIP rs3750920 TT genotype. The study will compare
the time to a composite endpoint of relative decline in lung function [10% relative decline
in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or
all-cause mortality]
The secondary objectives will be to examine the effect of NAC on the components of the
primary composite endpoint, the rates of clinical events, change in physiology, change in
health status, and change in respiratory symptoms.
• ≥ 40 years of age
• Diagnosed with IPF according to 2018 ATS/ERS/JRS/ALAT, confirmed by enrolling
investigator
• Signed informed consent
• If taking pirfenidone or nintedanib, must be on stable dose for at least 6 weeks prior
to enrollment visit
• Confirmed rs3570920 TT TOLLIP genotype
Exclusion Criteria:
• Pregnancy or planning to become pregnant
• Women of childbearing potential not willing to remain abstinent (refrain from
heterosexual intercourse) or use two adequate methods of contraception, including at
least one method with a failure rate of <1% per year during study participation
• Significant medical, surgical or psychiatric illness that in the opinion of the
investigator would affect subject safety, including liver and renal failure
• Receipt of an investigational drug or biological agent within the previous 4 weeks of
the screening visit or 5 times the half-life, if longer
• Supplemental or prescribed NAC therapy within 60 days of enrollment
• Listed for lung transplantation at the time of screening
• History of lung cancer
• Inability to perform spirometry
• Forced vital capacity (FVC) less than 45% predicted, using the global lung function
index (GLI) equation at Visit 1
• Active respiratory infection requiring treatment with antibiotics within 4 weeks of
Visit 1
Niraparib in the Treatment of Patients With Advanced PALB2 Mutated Tumors
The purpose of this study is to further evaluate the efficacy and safety of niraparib in
patients with locally advanced or metastatic solid tumors and a pathogenic or likely
pathogenic tumor PALB2 (tPALB2) mutation.
• Participants must be at least 18 years of age or older.
• Participants must have a histologically or cytologically confirmed diagnosis of
locally advanced or metastatic solid tumor(s).
• Participants must have tested positive for a pathogenic or likely pathogenic tPALB2
gene mutation using a CLIA-certified laboratory as described in the Next-Generation
Sequencing (NGS) Laboratory Manual.
• Participants who have stable and asymptomatic Central Nervous System (CNS) disease
must be receiving a stable (for at least 7 days) or decreasing corticosteroid dose at
the time of study entry.
• Participants must submit fresh or archived (collected within 24 months of enrollment)
Formalin-Fixed Paraffin-Embedded (FFPE) tumor sample to the central laboratory for
post-enrollment confirmation of tPALB2 status.
• Participants must have received all standard therapies appropriate for their tumor
type and stage of disease or, in the opinion of the Investigator, the patient would be
unlikely to tolerate or derive clinically meaningful benefit from appropriate standard
of care therapy, or the participant has no satisfactory alternative treatments.
Exclusion Criteria:
• Participants have other active concomitant malignancy that warrants systemic,
biologic, or hormonal therapy.
• Participants who have ovarian or prostate cancer.
• Participants who have variants of undetermined significance (VUS), but not pathogenic
variants of PALB2, at the time of screening.
• Participants who relapsed while receiving platinum based therapy in the
adjuvant/curative setting.
• Participants progressing within 14-18 weeks while receiving platinum based therapy in
the metastatic setting.
• Participants who have received Poly (ADP-ribose) polymerase (PARP) inhibitor(s) in
prior lines of treatment.
• Participants with leptomeningeal disease, carcinomatous meningitis, symptomatic brain
metastases, or radiologic signs of CNS hemorrhage.
• Participants with germline or somatic BRCA1 or BRCA2 mutations.
• Participant has systolic blood pressure (BP) over 140 mmHg or diastolic BP over 90
mmHg, despite optimal medical therapy.
• Participants have previously or are currently participating in a treatment study of an
investigational agent within 3 weeks of the first dose of therapy preceding the study.
• Participants have received prior systemic cytotoxic chemotherapy, biological therapy,
or hormonal therapy for cancer, or received radiation therapy within 3 weeks of the
first dose therapy preceding the study.
Drug: Niraparib
Endometrial Cancer, Esophageal Cancer, Melanoma, Pancreatic Cancer, Metastatic Cancer, Head and Neck Cancer, Solid Tumor, Breast - Female, Colon, Corpus Uteri, Esophagus, Lung/Thoracic, Melanoma, skin, Other Urinary, Pancreas, Breast Tumor, Colon Tumor, Malignant, Lung Tumor, Urologic Cancer, Locally Advanced Solid Tumor
PALB2, Solid Tumor, Metastatic Solid Tumor, Locally Advanced Solid Tumor, Advanced Solid Tumor, Local Solid Tumor, PALB2 Mutation, Niraparib, tPALB2, tPALB2 Mutation, Pathogenic tumor, Lung Tumor, Breast Tumor, Colon Tumor, Zejula, Pancreatic Cancer, Urologic Cancer, Melanoma, Metastatic Cancer, Head and Neck Cancer, Endometrial Cancer, Esophageal Cancer
The iCat2, GAIN (Genomic Assessment Informs Novel Therapy) Consortium Study
This research study is evaluating the use of specialized testing of solid tumors including
sequencing. The process of performing these specialized tests is called tumor profiling. The
tumor profiling may result in identifying changes in genes of the tumor that indicate that a
particular therapy may have activity. This is called an individualized cancer therapy (iCat)
recommendation. The results of the tumor profiling and, if applicable, the iCat
recommendation will be returned.
• Age -- Age ≤ 30 years at time of initial qualifying solid tumor diagnosis
• Diagnosis -- Histologic diagnosis of solid malignancy (excluding brain tumors and
lymphoma) that meets at least one of the following criteria:
• Refractory, defined as tumor progression after initiation of standard first line
therapy without having achieved a prior partial or complete remission OR Biopsy
proven residual disease at the completion of planned standard initial front-line
therapy.
• Recurrent, defined as tumor progression after achieving a prior partial or
complete remission
• Newly diagnosed high risk disease, defined as having an expected event free
survival of < 50% at 2 years.
• Lacks definitive diagnosis or classical genomic findings after histologic review
and standard molecular testing (rare tumor group).
• Examples include (eligibility not limited to these examples):
• Histology typically associated with a fusion in which fusion is not detected.
• Ewing-like sarcoma
• Undifferentiated sarcoma
• Inflammatory myofibroblastic tumor without ALK fusion
• Infantile fibrosarcoma without NTRK fusion
• Specimen Samples
• Sufficient tumor specimen available to meet the minimum requirements for
profiling from diagnosis or progression / recurrence
--- OR
• Surgery / biopsy planned as part of clinical care that is anticipated to yield
sufficient material to meet the minimum requirements for profiling; OR
• Patient has already had molecular profiling and patient has not yet started
matched targeted therapy based on the report .
Exclusion Criteria:
• No Therapy Planned
-- Patients who have declined further anticancer therapy will be excluded.
• Performance Status
-- Patients with Lansky (age < 16 years) or Karnofsky (age ≥16 years) score < 50 will
be excluded.
• Life Expectancy -- Patients with anticipated life expectancy < 3 months will be
excluded.
Genetic: Genetic testing and GAIN report
Sarcoma, Pediatric Solid Tumor, Brain and Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Carcinoid Tumor, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, Oral Cavity and Pharynx, Liver, Lung/Thoracic, Melanoma, skin, Nose, Other Digestive Organ, Other Endocrine System, Other Female Genital, Other Male Genital, Other Respiratory and Intrathoracic Organs, Other Skin, Other Urinary, Ovary, Pancreas, Prostate, Rectum, Stomach, Throat, Thyroid, Urinary Bladder, Uterine (Endometrial), Vulva, Heart, Kaposis sarcoma, Small Intestine, Soft Tissue, Ill - Defined Sites
STaph Aureus Resistance-Treat Early and Repeat (STAR-TER) (STAR-TER)
To evaluate the micro-biologic efficacy and safety of a streamlined treatment for early onset
methicillin-resistant staphylococcus aureus (MRSA) in patients with cystic fibrosis.
1. Male or female ≥ 2 and ≤ 45 years of age at the Screening Visit.
2. Documentation of a CF diagnosis as evidenced by one or more clinical features
consistent with the CF phenotype and one or more of the following criteria:
1. sweat chloride ≥ 60 milliequivalents/liter by quantitative pilocarpine
iontophoresis test (QPIT)
2. two well-characterized mutations in the cystic fibrosis transmembrane conductive
regulator (CFTR) gene
3. abnormal nasal potential difference(NPD) (change in NPD in response to a low
chloride solution and isoproteronol of less than -5 mV)
3. First OR early MRSA colonization defined as:
1. First MRSA colonization: first documented isolation of MRSA from respiratory
tract occurred ≤ 6 months prior to screening
2. Early MRSA colonization: MRSA was previously isolated from the respiratory tract
≤ 2 times over the past 3.5 years, but this was followed by at least 1 year of
documented negative cultures for MRSA
4. MRSA is available to the central laboratory •either the incident MRSA isolate from
the clinic visit or the subject is MRSA positive at the screening visit
5. Clinically stable with no significant changes in health status within the 14 days
prior to screening
6. Written informed consent (and assent when applicable) obtained from subject or
subject's legal representative and ability for subject to comply with the requirements
of the study
Exclusion Criteria:
1. Received antibiotics with activity against MRSA within 28 days prior to screening
2. Use of an investigational agent within 28 days prior to screening
3. For subjects ≥ 6 years of age: FEV1 at screening < 25% of predicted for age based on
the Wang (males < 18 years, females < 16 years) or Hankinson (males ≥ 18 years,
females ≥ 16 years) standardized equations
4. MRSA from the screening culture or the most recent clinical care visit within 6 months
prior to screening resistant to TMP/SMX
5. History of intolerance to topical chlorhexidine or mupirocin
6. History of intolerance to both TMP/SMX and minocycline
7. < 8 years of age and allergic or intolerant to TMP/SMX
8. ≥ 8 years of age and allergic or intolerant to TMP/SMX and MRSA isolate (from
screening or clinical care visit)is resistant to minocycline
9. For females of child bearing potential: pregnant, breastfeeding, or unwilling to use
barrier contraception through Day 42 of the study
10. Subjects with history of abnormal renal function will need screening labs showing
normal function Abnormal renal function is defined as estimated creatinine clearance
<50 mL/min using the:
1. Bedside Schwartz Equation for subjects <18 years of age, and
2. Levey Glomerular filtration rate (GFR) Equation for subjects ≥ 18 years of age.
11. Subjects with a history of abnormal liver function will need to have screening labs
showing normal transaminases. Liver dysfunction is defined as ≥3x upper limit of
normal (ULN), of serum aspartate transaminase (AST) or serum alanine transaminase
(ALT) or abnormal synthetic function
12. History of solid organ or hematological transplantation
13. Presence of a condition or abnormality that in the opinion of the Investigator would
compromise the safety of the patient or the quality of the data.
A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of
ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or
PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.
1. At least 18 years of age.
2. Evidence of a personally signed and dated informed consent form indicating that the
subject has been informed of all pertinent aspects of the study prior to initiation of
any study-related procedures.
3. Subjects who are willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures
4. Primary diagnosis of symptomatic PAH.
5. Has had a right heart catheterization (RHC) performed at or within 3 years prior to
Screening (RHC will be performed during Screening if not available) that is consistent
with the diagnosis of PAH.
6. Has WHO/ NYHA functional class II to IV symptoms.
7. If on PAH-specific background oral therapy, subject is on stable therapy with either
an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 inhibitor
(PDE5-I) or a soluble guanylate cyclase (sGC) stimulator. Subjects may be naïve to
PAH-specific treatment.
8. Has a 6MWD of ≥150 meters.
9. If taking concomitant medications that may affect the clinical manifestations of PAH
(eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta
blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor
blockers), must be on a stable dose for at least 30 days prior to the Baseline Visit
and the dosage maintained throughout the study. The exception is that the dose of
diuretics must be stable for at least the 10 days prior to Baseline.
10. Both male and female subjects agree to use a highly effective method of birth control
throughout the entire study period from informed consent through to the 30-Day
Follow-up Visit, if the possibility of conception exists. Eligible male and female
subjects must also agree not to participate in a conception process during the study
and for 30 days after the last dose of IMP. Eligible male subjects must agree not to
participate in sperm donation for 90 days after the last dose of IMP.
Exclusion Criteria:
1. For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell
count <200/mm3 within 90 days of Baseline.
2. Must not have 3 or more left ventricular dysfunction risk factors as defined in the
study protocol.
3. Has evidence of more than mild lung disease on pulmonary function tests performed
within 180 days prior to, or during Screening.
4. Has evidence of thromboembolic disease as determined by a V/Q lung scan or local
standard of care diagnostic evaluation at or after diagnosis of PAH.
5. Current diagnosis of ongoing and clinically significant sleep apnea as defined by the
Investigator.
6. Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >450 msec
and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by
the central ECG laboratory. Subjects with evidence of intraventricular conduction
delay, defined as a QRS interval greater than 110 msec, will be excluded if the QTcF
is >500 msec for both males and females.
7. Severe chronic liver disease (ie, Child-Pugh Class C), portal hypertension, cirrhosis
or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage,
encephalopathy).
8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
9. Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the
upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
10. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring
dialysis at Screening.
11. Hemoglobin concentration <9 g/dL at Screening.
12. Subjects treated with an IV or SC prostacyclin pathway agent (eg, epoprostenol,
treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive
testing is permitted).
13. Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway
agent (iloprost, treprostinil, beraprost, or selexipag) within 90 days prior to
Baseline.
14. Subject has pulmonary veno-occlusive disease.
15. Malignancy diagnosed and/or treated within 5 years prior to Screening, with the
exception of localized non-metastatic basal cell or squamous cell carcinoma of the
skin or in-situ carcinoma of the cervix excised with curative intent.
16. Subject tests positive for amphetamine, cocaine, methamphetamine,
methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at
Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will
not be excluded due to a positive drug screen caused by prescribed medications.
17. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon
exercise within 90 days prior to Screening and/or planned during study participation.
18. Prior participation in any study of ralinepag or participation in another
interventional clinical study with medicinal products within 30 days prior to
Screening. Concurrent participation in registry or observational studies is allowed,
as long as the subject can fulfill all other entry criteria and comply with all study
procedures.
19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the
subject from participating in the study (eg, any previous or intercurrent medical
condition) that may increase the risk associated with study participation or that
would confound study analysis or impair study participation or cooperation.
20. Known hypersensitivity to ralinepag or any of the excipients.
21. Life expectancy <12 months based on the Investigator's opinion.
22. Women who are pregnant, lactating or breast-feeding.
Prostacyclin, Connective Tissue Disease-Associated, 6 Minute Walk Test, 6 Minute Walk Distance, Pulmonary Vascular Resistance, Right Ventricular Function
Testing the Timing of Pembrolizumab Alone or With Chemotherapy as First Line Treatment and Maintenance in Non-small Cell Lung Cancer
This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed
by pemetrexed and carboplatin with or without pembrolizumab after disease progression is
superior to induction with pembrolizumab, pemetrexed and carboplatin followed by
pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous
non-small cell lung 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. Drugs used in chemotherapy, such as pemetrexed and
carboplatin, work in different ways to stop the growth of tumor cells, either by killing the
cells, by stopping them from dividing, or by stopping them from spreading. It is not yet
known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or
without pembrolizumab works better in treating patients with non-squamous non-small cell
cancer.
• Patients must have histologically or cytologically confirmed stage IV non-squamous
non-small cell lung cancer (NSCLC) (includes M1a, M1b, and M1c stage disease, American
Joint Committee on Cancer [AJCC] 8th edition). Patients with stage IIIB and IIIC
disease are eligible if they are not candidates for combined chemotherapy and
radiation
• Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells.
If PD-L1 expression TPS is unevaluable or the testing could not be completed, the
patients are not eligible. The assay must have been performed by a Clinical Laboratory
Improvement Act (CLIA) (or equivalent) certified laboratory
• Patients must have measurable or non-measurable disease. The presence of malignant
pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline
imaging assessments and measurements used to evaluate all measurable or non-measurable
sites of disease must be done within 4 weeks prior to study registration
• NOTE: If patient receives pemetrexed, follow institutional guidelines to drain
fluids
• Patients must be >= 18 years of age
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 to 1
• Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression. CNS
progression counts as progression and patients must move on to the next phase after
CNS treatment. Patients with asymptomatic new (at screening) or progressive brain
metastases (active brain metastases at screening) or leptomeningeal disease are
eligible if the treating physician determines that immediate CNS specific treatment is
not required and is unlikely to be required during the first cycle of therapy
• Patients are eligible if off steroids for at least 14 days prior to protocol
treatment
• Palliative radiation to non-target lesions (bone metastasis) is allowed if
patient develops symptoms
• Anticonvulsants are allowed
• Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion
of investigators do not need immediate CNS directed therapies are eligible
• Patients with 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, or history of
treatment with cardiotoxic agents, 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
• Women of childbearing potential and sexually active males must use an accepted and
effective method of contraception or abstain from sexual intercourse from time of
registration, while on study treatment, and continue for 120 days after the last dose
of study treatment
• Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of randomization)
• Platelets >= 100,000/mm^3 (within 14 days of randomization)
• Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 Or if patient on
therapeutic anticoagulation, PT/INR =< 3.0 (within 14 days of randomization)
• Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if
patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN (within 14 days of
randomization)
• Total bilirubin =< 1.5 mg/dL (obtained within 14 days of randomization)
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5
x upper limit of normal (ULN) (obtained within 14 days of randomization)
• Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x
upper limit of normal (ULN) (obtained within 14 days of randomization)
• Calculated creatinine clearance >= 45 ml/min to be eligible to receive pemetrexed
(obtained within 14 days prior to randomization)
• Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (obtained within
14 days prior to randomization)
• 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 or 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
Exclusion Criteria:
• Patients must NOT have received the following:
• Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC.
Patients treated with any prior checkpoint inhibitors for metastatic lung cancer
are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy)
or immunotherapy for locally advanced Stage III disease is allowed if at least 6
months have elapsed between the last dose of the prior therapy and study
registration. Local therapy, e.g. palliative radiation, is allowed as long as a
period of 14 days has passed between completion of local therapy and study
registration. Registration prior to treatment during the 14 days is allowed.
Palliative radiation must be to non-target lesions
• Methotrexate (MTX) given in low doses for non-malignant conditions with last dose
at least 14 days prior to date of registration will be allowed. Other low dose
chemotherapeutics for non-malignant conditions will be considered, but review by
the study chair is required
• Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600)
or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors
are excluded
• Patients must not have known pre-existing and clinically active interstitial lung
disease, or a known history of (non infectious) pneumonitis that required steroids, or
current pneumonitis
• Patients must not have significant gastrointestinal disorders with diarrhea as a major
symptom (e.g. Crohn's disease, malabsorption, etc.)
• Patients must not have history of auto-immune condition requiring ongoing or
intermittent systemic treatment in the past 2 years (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, etc.) is not considered a form of systemic
treatment
• Patients must not have any other concomitant serious illness or organ system
dysfunction that in the opinion of the investigator would either compromise patient
safety or interfere with the evaluation of the safety of the study drug
• Patients must not receive any other investigational agents during the course of
therapy
• Women must not be pregnant or breast-feeding due to potential harm to the fetus or
infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab).
Patients must also not expect to conceive or father children from the time of
registration, while on study treatment, and until at least 120 days after the last
dose of study treatment
• All females of childbearing potential must have a blood test or urine study
within 72 hours prior to registration to rule out pregnancy
• A female of childbearing potential is any woman, regardless of sexual orientation
or whether they have undergone tubal ligation, who meets the following criteria:
has achieved menarche at some point; has not undergone a hysterectomy or
bilateral oophorectomy; or 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)
• Patients must not have a known history of active tuberculosis (TB)
• Patients must not have a diagnosis of immunodeficiency or receive systemic steroid
therapy or any other form of immunosuppressive therapy within 7 days prior to the
first dose of protocol treatment
• Patients must not have received a live vaccine within 30 days prior to randomization.
Seasonal flu vaccines that do not contain live virus are permitted
PROSpect: Prone and Oscillation Pediatric Clinical Trial
Severe pediatric acute respiratory distress syndrome (PARDS) is a life-threatening and
frequent problem experienced by thousands of children each year. Little evidence supports
current supportive practices during their critical illness. The overall objective of this
study is to identify the best positional and/or ventilation practice that leads to improved
patient outcomes in these critically ill children. We hypothesize that children with severe
PARDS treated with either prone positioning or high-frequency oscillatory ventilation (HFOV)
will demonstrate more days off the ventilator when compared to children treated with supine
positioning or conventional mechanical ventilation (CMV).
Inclusion criteria:
Intubated and mechanically ventilated with moderate-severe PARDS for <48 hours per PALICC
guidelines (chest imaging consistent with acute pulmonary parenchymal disease and OI ≥12 or
OSI ≥10). We require two blood gases meeting moderate-severe PARDS criteria (separated by
at least 4 ± 2 hours during which time the clinical team is actively working to recruit
lung volume and optimize the patient's hemodynamic status per PALICC guidelines;
specifically, incremental and decremental PEEP changes to optimize lung volume). A second
blood gas is not required for OI ≥16.
Exclusion criteria:
• Perinatal related lung disease
• Congenital diaphragmatic hernia or congenital/acquired diaphragm paralysis
• Respiratory failure explained by cardiac failure or fluid overload
• Cyanotic heart disease
• Cardiomyopathy
• Unilateral lung disease
• Primary pulmonary hypertension
• Intubated for status asthmaticus
• Obstructive airway disease (e.g., Severe airways disease without parenchymal
involvement or disease characterized by hypercapnia with FiO2 <0.30 and/or evidence of
increased resistance visible on the flow •time scalar and/or presence of intrinsic
PEEP)
• Active air leak
• Bronchiolitis obliterans
• Post hematopoietic stem cell transplant; specifically, patients receiving continuous
supplemental oxygen for three or more days prior to intubation; receiving noninvasive
ventilation for more than 24 hours prior to intubation; receiving more than one
vasoactive medication at time of meeting inclusion criteria; spending more than four
days in the PICU prior to intubation; supported on or with immediate plans for renal
replacement therapies; with two or more allogeneic transplants; who relapsed after the
transplant; or with diffuse alveolar hemorrhage
• Post lung transplant
• Home ventilator (including noninvasive) or home oxygen dependent (exception:
night-time noninvasive ventilation (CPAP/BiPAP) or oxygen for obstructive sleep apnea
is permitted)
• Neuromuscular respiratory failure
• Critical airway (e.g., post laryngotracheal surgery or new tracheostomy) or anatomical
obstruction of the lower airway (e.g., mediastinal mass)
• Facial surgery or trauma in previous 2 weeks
• Head trauma (managed with hyperventilation)
• Intracranial bleeding
• Unstable spine, femur or pelvic fractures
• Acute abdominal process/open abdomen
• Morbid obesity (2w-24 months: WHO weight-for-length/height z-score ≥+3; ≥2 years: WHO
body mass index (BMI)-for-age z-score ≥+3)
• Currently receiving either prone positioning or any high-frequency mode of MV with
current illness (Up to 4 hours of prone positioning and/or any mode of high-frequency
mode of MV is allowed as long as the therapies are off for least 4 hours prior to the
subject meeting oxygenation criteria.)
• Supported on ECMO during the current admission
• Family/medical team not providing full support (patient treatment considered futile)
• Previously enrolled in current study
• Enrolled in any other interventional clinical trial not approved for co-enrollment
• Known pregnancy
Other: Either supine or prone positioning and either CMV or HFOV
Acute Respiratory Distress Syndrome in Children, Lung/Thoracic
Pediatric Acute Respiratory Distress Syndrome (PARDS), Acute Respiratory Distress Syndrome (ARDS), acute respiratory failure, child, pediatric intensive care unit
A Study of Selexipag Assessing Right Ventricular Remodeling in Pulmonary Arterial Hypertension by Cardiac Magnetic Resonance Imaging (RESTORE)
The purpose of the study is to assess the effects of selexipag on right ventricular (RV)
function in participants with Pulmonary arterial hypertension (PAH).
• World health organization functional class (WHO FC) II or III. Enrollment will be
stratified by WHO FC II or III. Proportion of participants with WHO FC II and WHO FC
III are expected to be approximately 40 percent (%) and 60%, respectively
• Pulmonary arterial hypertension (PAH) etiology belonging to one of the following
groups according to 6th world symposium of pulmonary hypertension (WSPH)
classification: a) Idiopathic PAH, b) Heritable PAH, c) Drugs or toxins induced d) PAH
associated with connective tissue disease, e) PAH associated with congenital heart
disease, with simple systemic-to-pulmonary shunt at least 1 year after surgical repair
• Patients already receiving PAH-specific oral mono or dual therapy (that is,
phosphodiesterase type 5 inhibitors [PDE-5i] or soluble guanylate cyclase stimulators
[sGCs] and/or endothelin receptor antagonist [ERA]) or patients who are not candidates
for these therapies
• N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) greater than or equal to
(>=) 300 nanograms per liter (ng/L) (greater than or equal to [>=] 300 picograms per
milliliter [pg/mL]; >=35.5 picomoles per liter [pmol/L]) at screening
• Women of childbearing potential must meet the following criteria: a) Have a negative
serum pregnancy test during screening and a negative urine pregnancy test on Day 1, b)
Agree to use acceptable methods of contraception from Day 1 to at least 30 days after
study intervention discontinuation, c) If only using hormonal contraception, have used
it for at least 1 month (30 days) before Day 1, and d) Agree to perform monthly
pregnancy tests to at least 30 days after study intervention discontinuation
• 6-minute walking distance (6MWD) >=150 meter (m) during screening period
Exclusion Criteria:
• Prior use of Prostacyclin (IP)-receptor agonist, prostacyclin, or prostacyclin analog.
Use of such treatments for vasoreactivity testing is not exclusionary; intermittent
use of such treatments for digital ulcers or Raynaud's phenomenon is not exclusionary
if stopped > 6 months (180 days) prior to Day 1
• Treatment with strong inhibitors of CYP2C8 (example, gemfibrozil) within 4 weeks (28
days) prior to Day 1
• Treatment with another investigational drug planned or taken within 12 weeks (84 days)
prior to Day 1
• Severe coronary heart disease or unstable angina
• Cerebrovascular events (example, transient ischemic attack, stroke) within 3 months
(90 days) prior to Day 1
REGN5093 in Patients With MET-Altered Advanced Non-Small Cell Lung Cancer
The primary objective of the dose escalation (phase 1) part of the study is to assess the
safety, tolerability, and pharmacokinetics (PK) of REGN5093 for determination of the maximum
tolerated dose (MTD) and/or definition of the recommended phase 2 dose (RP2D) of REGN5093 in
patients with MET-altered Non-small cell lung cancer (NSCLC).
The primary objective of the dose expansion (phase 2) part of the study is to assess
preliminary anti-tumor activity of REGN5093 as measured by the objective response rate (ORR)
per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
• Histologically confirmed NSCLC that is at advanced stage. Advanced is defined as
unresectable or metastatic disease. Patients must have exhausted all approved
available therapies appropriate for the patient.
• Has available archival tumor tissue, unless discussed with the medical monitor.
• Willing to provide tumor tissue from newly obtained biopsy. Newly obtained biopsies at
screening are required unless medically contra-indicated and discussed with the
medical monitor. For patients in expansion cohorts, biopsies should be taken from
tumor site which has not been irradiated previously and is not the only measurable
target lesion.
• Previously documented presence of MET alterations: either MET-exon14 gene mutation
and/or MET gene amplification, and/or elevated MET protein expression, as defined in
the protocol.
Key
Exclusion Criteria:
• Has received treatment with an approved systemic therapy or has participated in any
study of an investigational agent or investigational device within 2 weeks or 5
half-lives of the prior treatment whichever is shorter with a minimum of 7 days from
the first dose of study therapy
• Has not yet recovered (i.e. grade ≤1 or baseline) from any acute toxicities resulting
from prior therapy except as described in the protocol
• Has received radiation therapy or major surgery within 14 days of first administration
of study drug or has not recovered (i.e. grade ≤1 or baseline) from AEs, except for
laboratory changes as described in the protocol and patients with grade ≤2 neuropathy
• For expansion cohorts only: prior treatment with MET-targeted biologic therapy
(function-blocking antibodies or ADCs)
• For expansion cohorts only (except cohort 1A) prior treatment with any MET-targeted
agent including small molecule tyrosine kinase inhibitors eg, crizotinib, capmatinib,
tepotinib, as defined in the protocol
• Untreated or active primary brain tumor, CNS metastases, leptomeningeal disease or
spinal cord compression as defined in the protocol
Note: Other protocol defined Inclusion/Exclusion criteria apply.
Study of Radiation Therapy Followed by Atezolizumab in Stage II or III Non-small Cell Lung Cancer Patients
This trial studies the side effects of radiation therapy followed by atezolizumab in treating
patients with stage II or III non-small cell lung cancer. Hyperfractionated radiation therapy
delivers smaller doses of radiation therapy over time and may kill more tumor cells and have
fewer side effects. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help
the body's immune system attack the cancer, and may interfere with the ability of tumor cells
to grow and spread. The purpose of this study is to test the safety and effectiveness of
radiation therapy followed by atezolizumab and find out what side effects, if any, it has on
patient's non-small cell lung cancer.
• REGISTRATION STEP 1: Participants must have pathologic (cytological or histological)
proof of non-small cell lung cancer (NSCLC)
• REGISTRATION STEP 1: Participants must have stage III NSCLC with Zubrod performance
status of 2 or stage II NSCLC with Zubrod performance status of 0-2
• REGISTRATION STEP 1: Participants must not be candidates for surgical resection in the
opinion of the treating investigator. Participants whose disease was previously
resected must have experienced local or regional recurrence at least 12 months after
resection
• REGISTRATION STEP 1: Participants must not be candidates for concurrent chemoradiation
in the opinion of the treating investigator
• REGISTRATION STEP 1: 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 Registration Step 1. Non-measurable
disease must be assessed within 42 days prior to Step 1 registration. 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)
• REGISTRATION STEP 1: Participants must have an MRI or CT scan of the brain with
contrast within 28 days prior to Registration Step 1
• REGISTRATION STEP 1: Participants' disease must fit within the radiation constraints
in the opinion of a local radiation oncologist
• REGISTRATION STEP 1: Participants may have received prior treatment for their lung
cancer, including surgery, chemotherapy, targeted agents, and/or radiation treatment.
At least 12 months must have elapsed since last treatment
• REGISTRATION STEP 1: Participants may have had prior radiation therapy as long as the
irradiated area does not overlap with the radiation field targeted for this study
• REGISTRATION STEP 1: Participants must have recovered from any adverse effects of
prior major surgery to the satisfaction of the treating physician. Biopsies and
central IV access placement are not considered major surgery
• REGISTRATION STEP 1: Absolute neutrophil count (ANC) >= 1500/mcl (obtained within 28
days prior to Registration Step 1)
• REGISTRATION STEP 1: Platelet count >= 100,000/mcl (obtained within 28 days prior to
Registration Step 1)
• REGISTRATION STEP 1: Hemoglobin >= 9 grams/dL (obtained within 28 days prior to
Registration Step 1)
• REGISTRATION STEP 1: Total bilirubin =< 1.5 x institutional upper limit of normal
(IULN) (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) =< 2.5 x IULN (obtained within 28 days prior to Registration Step 1)
• REGISTRATION STEP 1: Serum creatinine =< 1.5 x IULN OR measured or calculated
creatinine clearance >= 40 mL/min (obtained within 28 days prior to Registration Step
1)
• REGISTRATION STEP 1: Participants must have percent predicted diffusing capacity of
the lungs for carbon monoxide (DLCO) of at least 50% documented within 90 days prior
to Registration Step 1
• REGISTRATION STEP 1: Patient must not have had a prior history of interstitial lung
disease or > grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version
5) pneumonitis
• REGISTRATION STEP 1: Participants must not have active autoimmune disease requiring
therapy within the past 6 months
• REGISTRATION STEP 1: Participants must not have an active infection requiring therapy
• REGISTRATION STEP 1: Participants must not be pregnant or nursing because atezolizumab
has not been studied in pregnant or nursing women and the mechanism of action is
expected to cause fetal harm. Women/men of reproductive potential must have agreed to
use an effective contraceptive method while on protocol treatment and for five months
after last dose of atezolizumab. 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 patient
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
• REGISTRATION STEP 1: Participants with known human immunodeficiency virus (HIV)
infection must be on effective anti-retroviral therapy and must have undetectable
viral load at their most recent viral load test and within 6 months prior to
Registration Step 1
• REGISTRATION STEP 1: Patient must be tested for hepatitis B within 28 days prior to
Registration Step 1. Patient must not have active (chronic or acute) hepatitis B virus
(HBV) infection. Patients may have past or resolved HBV infection. Active HBV is
defined as having a positive hepatitis B surface antigen (HBsAg) test. Past or
resolved HBV is defined as having a negative HBsAG test and a positive total hepatitis
B core antibody (HBcAb) test
• REGISTRATION STEP 1: Patients must not have active hepatitis C virus (HCV) infection.
Active HCV is defined as having a positive HCV antibody test followed by a positive
HCV ribonucleic acid (RNA) test. Patient must have an HCV antibody test within 28 days
prior to Registration Step 1. If the HCV antibody test is positive, the patient must
also have an HCV quantitative RNA test within 28 days prior to Registration Step 1
• REGISTRATION STEP 1: No other prior malignancy is allowed except for the following:
adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
adequately treated Stage I or II cancer from which the patient is currently in
complete remission, or any other cancer from which the patient has been disease free
for three years. Participants with localized prostate cancer who are being followed by
an active surveillance program are also eligible
• REGISTRATION STEP 1: Participants must be offered optional participation in banking of
specimens for future research
• REGISTRATION STEP 1: 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
• REGISTRATION STEP 1: As a part of the Oncology Patient Enrollment Network (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
• REGISTRATION STEP 2: Participants must be registered to Step 2 within 42 days after
completion of radiation treatment. Participants must have received at least 44 Gy of
radiation treatment
• REGISTRATION STEP 2: Participants must have no evidence of progression per RECIST 1.1
on CT scan of the chest, abdomen, and pelvis performed between 2 and 5 weeks after
completion of radiation therapy
• REGISTRATION STEP 2: Any toxicities from radiation therapy must have resolved to <
grade 2
• REGISTRATION STEP 2: Absolute neutrophil count (ANC) >= 1500/mcl (obtained within 28
days prior to Registration Step 2)
• REGISTRATION STEP 2: Platelet count >= 100,000/mcl (obtained within 28 days prior to
Registration Step 2)
• REGISTRATION STEP 2: Hemoglobin >= 9 grams/dL (obtained within 28 days prior to
Registration Step 2)
• REGISTRATION STEP 2: Total bilirubin =< 1.5 x institutional upper limit of normal
(IULN) (obtained within 28 days prior to Registration Step 2)
• REGISTRATION STEP 2: AST and ALT =< 2.5 x IULN (obtained within 28 days prior to
Registration Step 2)
• REGISTRATION STEP 2: Serum creatinine =< 1.5 x IULN OR measured or calculated
creatinine clearance >= 40 mL/min (obtained within 28 days prior to Registration Step
2)
• REGISTRATION STEP 2: Participants must not have received steroids in doses of more
than prednisone 10 mg daily or equivalent within 14 days prior to Registration Step 2
• REGISTRATION STEP 2: Participants must not have received a live vaccine within 28 days
prior to Registration Step 2
1. Male and female 18 years or older 2. Body Mass Index (BMI) >18kg/m2 to <=40kg/m2 3.
Symptomatic PAH belonging to one of the following 2018 WHO Clinical Group 1 subtypes:
a. Idiopathic PAH b. Heritable PAH c. Drug- or toxin-induced d. PAH associated with:
1. Connective tissue disease
2. Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal
defect, patent ductus arteriosus) repaired at least one year prior to Screening
3. Human immunodeficiency virus (HIV) infection •if diagnosed with HIV, must have stable
disease status defined as follows:
1. stable treatment with HIV medications for at least 8 weeks prior to Screening
2. no active opportunistic infection during the Screening Period
3. no hospitalizations due to HIV for at least 4 weeks prior to Screening
4. WHO FC II or III
5. Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of
a screening RHC completed prior to randomization:
1. mPAP of >20 mmHg
2. PVR ≥ 350 dyne•sec/cm5
3. Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic
pressure (LVEDP) of ≤ 12 mmHg if PVR ≥ 350 and < 500 dyne•sec/cm5, or PCWP/LVEDP
≤ 15 mmHg if PVR ≥ 500 dyne•sec/cm5
6. 6MWD of 100 to 550 meters at Screening
7. Currently on a stable treatment regimen with one or more treatments approved for PAH.
Stable therapy is defined as receiving the same medication(s) for ≥ 12 weeks prior to
the screening RHC and at a stable dose level for each for ≥ 8 weeks prior to the
screening RHC (see Protocol Section 6.6.2 for approved PAH medications). Any instances
where doses of a medication have been missed prior to RHC must be discussed with the
Medical Monitor prior to performing the RHC.
8. Meet all of the following criteria determined by pulmonary function tests completed no
more than 24 weeks prior to Screening (performed with or without bronchodilation):
1. Forced expiratory volume in one second (FEV1) ≥ 60% of predicted normal, and
2. Total lung capacity (TLC) ≥ 70% of predicted normal or FVC ≥ 70% predicted if TLC
is not available; For subjects with CTD associated PAH, if TLC is ≥ 60% of
predicted but < 70% of predicted of if FVC ≥ 60% or predicted but < 70% of
predicted, high resolution computed tomography [HRCT] obtained within 6 months of
screening may be utilized to demonstrate limited interstitial lung disease
9. If participating in an exercise program for pulmonary rehabilitation, the program must
have been initiated ≥ 12 weeks prior to Screening, and patient must agree to maintain
the current level of rehabilitation for the first 24 weeks of receiving IP. If not
participating in an exercise training program for pulmonary rehabilitation, patient
must agree not to enroll in an exercise training program for pulmonary rehabilitation
during the Screening Period and the first 24 weeks of receiving IP.
Exclusion Criteria:
1. Women of childbearing potential who are pregnant, planning to become pregnant, or
lactating or female/male patients unwilling to use effective contraception
2. WHO pulmonary hypertension (PH) Group 1 PAH associated with portal hypertension or
schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or
hypoxia (WHO PH Group 3), chronic thromboembolic PH (WHO PH Group 4), or PH with
unclear multifactorial mechanisms (WHO PH Group 5)
3. PH associated with significant venous or capillary involvement (PCWP > 15 mmHg),
pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital
heart defects (CHD)
4. Three or more of the following risk factors for left ventricular disease:
1. BMI > 30 kg/m2
2. Diagnosis of essential hypertension that is actively treated
3. Diabetes mellitus
4. History of significant coronary artery disease (e.g., chronic stable angina,
history of coronary intervention within the last 3 months, or a stenosis > 70% at
coronary angiography)
5. Atrial fibrillation
6. Left atrial volume index > 41 mL/m2 [or left atrial diameter (LA) > 4 cm if LAVi
unavailable]
5. Known genetic hypertrophic cardiomyopathy
6. Known cardiac sarcoidosis or amyloidosis
7. The patient has a history of, or currently has, a constrictive cardiomyopathy.
8. Known history of any left ventricular ejection fraction (LVEF) < 40% by echocardiogram
within 3 years of randomization (Note: a transient decline in LVEF below 40% that
occurred and recovered more than 6 months before the start of Screening and was
associated with an acute intercurrent condition [e.g., atrial fibrillation] is
allowed).
9. Hemodynamically significant valvular heart disease as determined by the Investigator,
including:
1. greater than mild aortic and/or mitral stenosis and/or
2. severe mitral and/or aortic regurgitation (> Grade 3)
10. Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of
the Investigator, is the cause of the patient's functional limitation and would affect
the patient's ability to perform or complete the 6MWT.
Live Music Therapy to Reduce Anxiety, Pain and Improve Sleep in Post-Operative Lung Transplant Patients: A Pilot Study
The purpose of this prospective pilot study is to determine if live music therapy reduces
patients' perception of pain and anxiety, reduces benzodiazepine use and pain medication use,
length of stay in the ICU, and length of stay in hospital, and improves sleep in post-lung
transplant patients.
The purpose and objectives of the study are the following:
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention will reduce participant's perceived anxiety in post-lung transplant
patients.
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention will reduce participant's perceived pain in post-lung transplant patients.
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention in post-lung transplant patients will reduce participant's use of
benzodiazepine medication for anxiety.
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention three times in post-lung transplant patients will reduce participant's use
of pain medication.
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention in post-lung transplant patients will reduce participant's total time of
intubation, length of stay in ICU, and length of stay in the hospital.
- To determine if music therapist delivered patient preferred live music and therapeutic
intervention will improve the quality and length of sleep in post-lung transplant
patients.
Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101)
To evaluate the safety and tolerability of sotorasib administered in investigational regimens
in adult participants with KRAS p.G12C mutant advanced solid tumors.
• Men or women greater than or equal to 18 years old.
• Pathologically documented, locally-advanced or metastatic malignancy with, KRAS p.G12C
mutation identified through molecular testing performed according to in-country
requirements. In the United States, this test must be performed in a Clinical
Laboratory Improvement Amendments (CLIA)-certified laboratory.
Exclusion Criteria:
• Primary brain tumor.
• Spinal cord compression, or untreated, or symptomatic, or active brain metastases, or
leptomeningeal disease from non-brain tumors.
• Myocardial infarction within 6 months of study day 1.
• Gastrointestinal (GI) tract disease causing the inability to take oral medication.
Effects of Hypoglossal Nerve Stimulation on Cognition and Language in Down Syndrome and Obstructive Sleep Apnea
This study is a prospective, single-arm study conducted under a common implant and follow-up
protocol. The objective will be to follow fifty-seven (57) adolescents and young adults
(10-21 years of age), with Down syndrome, moderate to severe sleep apnea, and
post-adenotonsillectomy, for 12 months after undergoing implant of the Inspire Upper Airway
Stimulation (UAS) System. The study is being conducted in order to evaluate objective change
in cognition and expressive language after implant and therapy with the Inspire UAS System.
• Diagnosis of Down syndrome
• Age 10-21 years
• Prior adenotonsillectomy
• Severe OSA (AHI > 10, AHI < 50, no more than 25% AHI attributable to central events)
based on prior in-lab PSG performed after adenotonsillectomy and within 18 months of
enrollment
• Approval from at least two of the three physician reviewers based upon the results of
a routine drug-induced sleep endoscopy (DISE) having occurred within 12 months of
enrollment
• Subjects must have either tracheotomy or be ineffectively treated with CPAP due to
non-compliance, discomfort, un-desirable side effects, persistent symptoms despite
compliance use, or refusal to use the device
• Children and their parents/guardians must be willing to have stimulation hardware
permanently implanted, and be willing to participate in follow-up visits,
postoperative PSG, and questionnaire completion
• Children's parents/guardians must complete a questionnaire confirming that their child
is capable of communicating feelings of pain or discomfort. They must also confirm
they are able to assess their child for adverse effects related to device implantation
• Children and their parents/guardians must be proficient in English
Exclusion Criteria:
• Body mass index (BMI) above the 95th percentile for subject's age
• Circumferential airway collapse at the level of the velopharynx observed during DISE
• Other medical conditions resulting in medical instability (eg. congestive heart
failure, recent open heart surgery, immunosuppression, or chronic lung disease or
aspiration)
• Presence of another medical condition requiring future magnetic resonance imaging
(MRI) of the chest
• Patients with another implantable device which could interact unintentionally with the
Inspire system
• Any contraindication for general anesthesia
• History of bleeding or clotting disorders and those on blood thinning or NSAID
medications for the week prior to implantation surgery. Subjects will be asked to
refrain from the use of NSAIDS for two weeks after implantation or any revision
surgeries
• Subject is currently taking muscle relaxant medication
• Life expectancy less than 12 months
• Subject's inability to communicate pain or discomfort to their caretaker/parent, based
on parental or investigator assessment
• Nonverbal candidates will be excluded due to an inability to complete testing
procedures including expressive language sampling
• Subjects with a co-occurring diagnosis of autism spectrum disorder
• Subjects that have a positive β-HCG
• Subjects deemed unfit for participation by the investigator for any other reason
Device: Inspire Upper Airway Stimulation (UAS) System
Obstructive Sleep Apnea, Down Syndrome, Ear, Nose, Throat
Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
This phase III trial compares the effect of open thoracic surgery (thoracotomy) to
thoracoscopic surgery (video-assisted thoracoscopic surgery or VATS) in treating patients
with osteosarcoma that has spread to the lung (pulmonary metastases). Open thoracic surgery
is a type of surgery done through a single larger incision (like a large cut) that goes
between the ribs, opens up the chest, and removes the cancer. Thoracoscopy is a type of chest
surgery where the doctor makes several small incisions and uses a small camera to help with
removing the cancer. This trial is being done evaluate the two different surgery methods for
patients with osteosarcoma that has spread to the lung to find out which is better.
• Patients must be < 50 years at the time of enrollment.
• Patient must have eligibility confirmed by rapid central imaging review.
• Patients must have =< 4 nodules per lung consistent with or suspicious for
metastases, with at least one of which being >= 3 mm and all of which must be =<
3 cm size.
• Lung nodules must be considered resectable by either open thoracotomy or thoracoscopic
surgery. Determination of resectability is made by the institutional surgeon.
• Patients must have a histological diagnosis of osteosarcoma.
• Patients must have evidence of metastatic lung disease at the time of initial
diagnosis, or at time of 1st recurrence following completion of therapy for initially
localized disease.
• Patients with newly diagnosed disease must have completed successful gross tumor
resection for their primary tumor or surgical local control of primary tumor must be
planned to be performed simultaneously with thoracic surgery.
• Newly diagnosed patients must be receiving systemic therapy considered by the treating
physician as at least equivalent to methotrexate, doxorubicin and cisplatin (MAP) at
the time of enrollment on this study.
• Patients at time of 1st recurrence must have previously completed initial systemic
therapy for their primary tumor, considered by the treating physician as at least
equivalent to MAP.
Exclusion Criteria:
• Patients with unresectable primary tumor.
• Patients with pulmonary metastatic lesions that would require anatomic resection
(lobectomy or pneumonectomy) or lesions that are defined as "central" (i.e., central
lesion involves or is proximal to segmental bronchi and peripheral is lesion distal to
segmental bronchi).
• Patients with pleural or mediastinal based metastatic lesions, or with pleural
effusion.
• Patients with disease progression at either the primary or pulmonary metastatic site
while on initial therapy. Note: Once the patient has been enrolled on the study,
additional computed tomography (CT) scans are not anticipated prior to thoracic
surgery. Note: Some variation in nodule size measurements over the course of
pre-operative therapy is anticipated and does not qualify for exclusion unless deemed
true disease progression by the primary treatment team.
• Patients with evidence of extrapulmonary metastatic disease.
• Patients who received pulmonary surgery for lung metastasis 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.
A Study of HMBD-002, a Monoclonal Antibody Targeting VISTA, as Monotherapy and Combined With Pembrolizumab
This is a phase 1/2, open-label, multi-center, first-in-human, two-stage (Part 1: dose
escalation and Part 2: dose expansion) study evaluating multiple doses and schedules of
intravenously (IV) administered HMBD-002, with or without pembrolizumab, in patients with
advanced solid tumors (i.e., locally advanced and unresectable, or metastatic).
Inclusion Criteria (Phase 1 and 2 Stages)
1. Histologic or cytologic evidence of a malignant solid cancer (any histology) with
advanced or metastatic disease and no available therapies known to confer clinical
benefit.
2. Tumor tissue, or paraffin block, ideally from the patient's most recent biopsy. A
fresh tumor biopsy will be obtained if archival samples are not available.
3. Measurable by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
4. At least 18 years old.
5. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
6. Adequate hematopoietic, kidney, and liver functions.
7. A left ventricular ejection fraction (LVEF) ≥ 45%.
8. Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding. A WOCBP
must agree to follow contraceptive guidance during the treatment period and for at
least 120 days after the last dose of study treatment.
9. Male subjects must agree to follow contraceptive guidance during the study period and
for at least 120 days after the last dose of study treatment.
10. Patient must give informed written consent for the study.
Inclusion Criteria for HMBD-002 Phase 2 Stage
Triple Negative Breast Cancer (TNBC)
1. Histologic or cytologic evidence of TNBC that is advanced or metastatic.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of
treatment.
3. Must have received appropriate treatment with at least one prior regimen for TNBC and
there are no available therapies known to confer clinical benefit.
Non-Small Cell Lung Cancer (Monotherapy and Combination)
1. Histologic or cytologic evidence of NSCLC that is advanced or metastatic.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of
treatment.
3. Absence of an activating mutation of the EGFR or ALK.
4. Must have received treatment with an approved therapy if there are other genomic
aberrations for which targeted therapies are approved and available.
5. Must have had disease progression on at least one approved or comparable standard
therapy for NSCLC.
6. Must have received appropriate prior treatment with a mAb to PD-1 or PD-L1.
Multiple Other Cancers (Combination Therapy Baskets)
1. Histologic or cytologic evidence of an advanced or metastatic cancer aside from TNBC
and NSCLC with no available therapies known to confer clinical benefit.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of
treatment.
3. Must have had appropriate treatment for their specific cancer and there is an absence
of available therapy with a reasonable likelihood of conferring clinical benefit.
Exclusion Criteria
1. If the patient received prior therapy with an anti-PD-1 or anti-PD-L1 mAb or with an
agent targeting stimulatory or co-inhibitory T-cell receptor and was discontinued from
that treatment due to a Grade 3 or higher immune related adverse event.
2. Received radiotherapy within 2 weeks of treatment.
3. Received radiotherapy exceeding 30 Gray (Gy) to the lung within 6 months of the first
dose of study medication.
4. Received an allogeneic tissue/solid organ transplant.
5. Received a live or live-attenuated vaccine within 30 days prior to the first dose of
study medication.
6. Received a VISTA targeting agent.
7. The patient must have recovered from all AEs due to previous therapies to ≤Grade 1 or
baseline.
8. The patient has an active autoimmune disease that required systemic treatment in the
past.
9. Presence of an uncontrolled endocrine disorder.
10. Presence of clinically significant cardiovascular disease.
11. History of (non-infectious) pneumonitis or interstitial pulmonary disease that
required steroids or has current pneumonitis or interstitial pulmonary disease.
12. Presence of uncontrolled, clinically significant pulmonary disease.
13. A previous a severe hypersensitivity reaction (≥ Grade 3) to pembrolizumab and/or any
of its excipients.
14. A diagnosis of immunodeficiency or is receiving chronic systemic corticosteroids at a
dose that exceeds 10 mg daily of prednisone equivalent or any other form of
immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or
topical steroids are permitted in the absence of active autoimmune disease.
15. An uncontrolled intercurrent illness that would limit compliance with the study.
16. A positive status for human immunodeficiency virus (HIV).
17. A known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C
viral (defined as HCV RNA detected) infection.
18. Oxygen-dependence.
19. A medical condition which, in the opinion of the Investigator, places the patient at
an unacceptably high risk for toxicity.
20. A positive COVID test within one week of study treatment if not fully vaccinated.
21. Another active malignancy that is progressing or has required active treatment within
the past 3 years.
22. Known active central nervous system metastases and/or carcinomatous meningitis.
Drug: HMBD-002, Drug: Pembrolizumab
Cancer, Metastatic Cancer, Triple Negative Breast Cancer, Advanced Solid Tumor, Nonsmall Cell Lung Cancer, Malignant Neoplasm, Breast - Female, Breast - Male, Lung/Thoracic, Melanoma, skin, Other Skin, Tumor, Solid
4D-710 in Adult Patients With Cystic Fibrosis (CF)
This is a Phase 1/2 multicenter, open-label, single dose trial of 4D-710 investigational gene
therapy in adults with CF who are ineligible for or unable to tolerate CFTR modulator
therapy.
1. 18 years and older
2. Confirmed diagnosis of cystic fibrosis (CF) and CF lung disease including:
• Bi-allelic mutations in the CFTR gene, and
• Ineligible for CFTR modulator therapy, or previously received modulator therapy
but discontinued due to adverse effects.
3. Forced expiratory volume in 1 second (FEV1) ≥50% and ≤100% of predicted (per Global
Lung Function Initiative) at Screening
4. Resting oxygen saturation ≥ 92% on room air at Screening
Key
Exclusion Criteria:
1. Any prior gene therapy for any indication
2. History of positive culture for Burkholderia cenocepacia, B. dolosa, or Mycobacterium
abscessus within the past 24 months
3. Active allergic bronchopulmonary aspergillosis requiring management with systemic
corticosteroids or antifungal therapy
4. Contraindication to systemic corticosteroid therapy
5. Requires chronic use of systemic corticosteroids or immunosuppressants to treat
another condition
6. If no known diagnosis of cystic fibrosis related diabetes (CFRD), Type I, or Type II
diabetes: Hemoglobin A1C ≥6.5% at Screening
7. If known diagnosis of CFRD, Type I or Type II diabetes: Hemoglobin A1C >7.5% at
Screening
8. Recent history of symptomatic hyperglycemia or unstable blood glucose levels as per
Investigator's assessment
9. Other conditions that, in the Investigator's opinion, may interfere with management of
corticosteroid-related hyperglycemia
10. Body Mass Index (BMI) <16
11. Laboratory abnormalities at screening:
• ALT, AST or GGT ≥ 3 × the upper limit of normal (ULN)
• Total bilirubin ≥ 2 × ULN
• Hemoglobin < 10 g/dL
12. Requirement for continuous or night-time oxygen supplementation
13. Known CF liver disease with evidence of cirrhosis
14. History of thrombosis (excluding catheter-related thrombosis) or conditions associated
with increased risk of thrombosis