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.
Stereotactic Ablative Radiotherapy for Early-stage GlotticLarynxCancer
The goal of treatment with radiation therapy is to deliver as high of a dose as possible to
the target (tumor), while minimizing the dose to the normal tissues where late-side effects
can drastically affect patient quality of life.
1. Pathologically-proven diagnosis of squamous cell carcinoma in situ, squamous cell
carcinoma or squamous cell variants (sarcomatoid, verrucous, basaloid, and papillary
subtypes) involving the glottic larynx.
2. Clinical stage I-II (American Joint Committee on Cancer AJCC, 7th edition) with direct
laryngoscopy showing no evidence of greater than stage II true glottic larynx cancer
and PET/CT or CT neck showing no evidence of regional disease.
3. Age ≥ 18 years.
4. ECOG Performance Status 0-2
5. Women of child-bearing potential and men 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.
5.1 A female of child-bearing potential is any woman (regardless of sexual
orientation, having undergone a tubal ligation, or remaining celibate by choice) who
meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e.,
has had menses at any time in the preceding 12 consecutive months).
6. Negative serum or urine pregnancy test within 2 weeks before registration for women of
childbearing potential.
7. Ability to understand and the willingness to sign a written informed consent.
8. Patients with cognitive impairment or other limited decision making capacity with the
ability to understand and willingly sign written informed consent or have the consent
signed by a designated legally authorized representative (LAR)
Exclusion Criteria:
1. AJCC stage III or stage IV larynx cancer
2. Involvement of the arytenoid cartilage beyond the vocal process.
3. Prior chemotherapy for treatment of the targeted larynx lesion
4. Synchronous primaries in the head and neck
5. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation fields.
6. Subjects smoking in excess of 1 pack of cigarettes per day.
7. Subjects may not be receiving any other investigational agents.
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 would limit compliance with
study requirements.
9. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)
This is a randomized, active-controlled, open-label study of pembrolizumab (Pembro) given
prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or
without cisplatin), as post-surgical therapy in treatment naïve participants with newly
diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell
carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1
(PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab
given before surgery and after surgery in combination with radiotherapy (with or without
cisplatin) improves major pathological response and event-free survival compared to
radiotherapy (with or without cisplatin) given after surgery alone.
• Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous
cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive
oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no
distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or
IVA larynx/hypopharynx/oral cavity primaries
• Is eligible for primary surgery based on investigator decision and per local practice
• Female and male participants of reproductive potential must agree to use adequate
contraception throughout the study period and for up to 180 days after the last dose
of study therapy
• Male participants must refrain from donating sperm throughout the study period and for
up to 180 days after the last dose of study therapy
• Female participant that is not pregnant or breastfeeding
• Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed
by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST
version 1.1
• Has provided newly obtained core or excisional biopsy of a tumor lesion not previously
irradiated
• Has results from testing of HPV status for oropharyngeal cancer defined as p16
• Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed
within 10 days of randomization
Exclusion Criteria:
• Has Stage T4B and/or N3 LA HNSCC and/or distant metastases
• Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity, such as
nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer
(HNC)
• Female participant who has a positive urine pregnancy test within 72 hours prior to
study start or within 24 hours prior to the start of radiotherapy with or without
cisplatin
• Has received prior therapy with an anti-programmed cell death receptor 1(PD-1),
anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death
receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory
T-cell receptor
• Has received prior radiotherapy treatment or systemic anti-cancer therapy including
investigational agents for the HNC under study prior to study start
• Has received a live vaccine within 30 days prior to randomization
• Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to randomization
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
immunosuppressive therapy within 7 days prior to randomization
• Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years with the exception of basal cell carcinoma of the skin,
squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical
cancer or breast carcinoma) that have undergone potentially curative therapy
• Has radiographically detectable (even if asymptomatic and/or previously treated)
central nervous system metastases and/or carcinomatous meningitis
• Has Grade ≥2 audiometric hearing loss
• Has Grade ≥2 neuropathy
• Has Grade 3-4 bleeding due to the underlying malignancy
• Has received major surgery or has not recovered adequately from the toxicity and/or
complications from the intervention prior to study start
• Has had previous allogeneic tissue/solid organ transplant
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients,
radiotherapy, cisplatin or their analogs
• Has an active autoimmune disease that has required systemic treatment in past 2 years
• Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of human immunodeficiency virus (HIV) infection
• Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface
antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus
[HCV] ribonucleic acid is detected).
• Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the participant's
participation for the full duration of the study, or is not in the best interest of
the participant to participate, in the opinion of the investigator
• Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study
Individualized Treatment in Treating Patients With Stage II-IVB NasopharyngealCancerBased on EBV DNA
There are two study questions we are asking in this randomized phase II/III trial based on a
blood biomarker, Epstein Barr virus (EBV) deoxyribonucleic acid (DNA) for locoregionally
advanced non-metastatic nasopharyngealcancer. All patients will first undergo standard
concurrent chemotherapy and radiation therapy. When this standard treatment is completed, if
there is no detectable EBV DNA in their plasma, then patients are randomized to either
standard adjuvant cisplatin and fluorouracil chemotherapy or observation. If there is still
detectable levels of plasma EBV DNA, patients will be randomized to standard cisplatin and
fluorouracil chemotherapy versus gemcitabine and paclitaxel. Radiation therapy uses high
energy x rays to kill tumor cells. Drugs used in chemotherapy, such as cisplatin,
fluorouracil, gemcitabine hydrochloride, and paclitaxel 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 cisplatin and fluorouracil
is more effective than gemcitabine hydrochloride and paclitaxel after radiation therapy in
treating patients with nasopharyngealcancer.
• Biopsy proven (from primary lesion and/or lymph nodes) diagnosis of cancer of the
nasopharynx
• Patients must have detectable pretreatment plasma EBV DNA, determined by the central
lab prior to Step 2 registration
• Stage II-IVB disease (American Joint Committee on Cancer [AJCC], 7th edition [ed.])
with no evidence of distant metastasis, based upon the following minimum diagnostic
workup:
• History/physical examination by a Medical Oncologist or Clinical Oncologist or
Radiation Oncologist or Ear, Nose, Throat specialist (ENT), which must include an
endoscopic evaluation, a complete list of current medications, and assessment of
weight and weight loss in the past 6 months within 21 days prior to registration
• Evaluation of tumor extent with magnetic resonance imaging (MRI) of the
nasopharynx and neck within 28 days prior to registration; if MRI is medically
contraindicated, obtain computed tomography (CT) scan with =< 3 mm contiguous
slices with contrast and bone windows (to evaluate base of skull involvement);
Note: If a treatment planning CT scan is used, it must be with =< 3 mm contiguous
slices with contrast and be read by a radiologist
• To rule out distant metastasis, patients must undergo the following imaging
within 28 days prior to registration:
• A CT scan with contrast of the chest, abdomen, and/or pelvis or a total body
positron emission tomography (PET)/CT scan (non-contrast PET/CT is
acceptable)
• A bone scan only when there is suspicion of bone metastases (a PET/CT scan
can substitute for the bone scan)
• Zubrod performance status 0-1 within 21 days prior to registration
• Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
• Platelets >= 100,000 cells/mm^3
• Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 1.5 x
institutional ULN
• Alkaline phosphatase =< 1.5 x institutional ULN
• Serum creatinine =< 1.5 mg/dl or calculated creatinine clearance (CC) >= 50 ml/min
determined by 24-hour urine collection or estimated by Cockcroft-Gault formula
• Negative serum pregnancy test within 14 days prior to registration for women of
childbearing potential
• Women of childbearing potential and male participants who are sexually active must
agree to use a medically effective means of birth control throughout protocol
treatment
• Patient must provide study specific informed consent prior to study entry, including
the mandatory pre-treatment plasma EBV DNA assay
Exclusion Criteria:
• Prior invasive malignancy (except node negative, non-melanomatous skin cancer) unless
disease free for a minimum of 1095 days (3 years) (for example, carcinoma in situ of
the breast, oral cavity, or cervix are all permissible)
• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a
different cancer is allowable; however, at least 6-weeks recovery is necessary if the
last regimen included nitrosourea or mitomycin
• Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields
• Patients with hearing loss assessed to be primarily sensorineural in nature, requiring
a hearing aid, or intervention (i.e. interfering in a clinically significant way with
activities of daily living); a conductive hearing loss that is tumor-related is
allowed
• >= Grade 2 peripheral sensory neuropathy (CTCAE, v. 4.0)
• Severe, active co-morbidity, defined as follows:
• Major medical or psychiatric illness, which in the investigator's opinion would
interfere with the completion of therapy and follow up or with full understanding
of the risks and potential complications of the therapy
• Unstable angina and/or uncontrolled congestive heart failure within the past 6
months
• Myocardial infarction within the last 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration; note that patients switched from IV antibiotics and currently on
oral antibiotics whose infection is assessed to be adequately treated or
controlled are eligible
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days prior to
registration
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for Disease
Control and Prevention (CDC) definition; note, however, that human
immunodeficiency virus (HIV) testing is not required for entry into this protocol
• Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception
• Prior allergic reaction to the study drug(s) involved in this protocol
• Patients with undetectable pre-treatment plasma EBV DNA
Epstein-Barr Virus Infection, Stage II NasopharyngealCarcinoma, Stage III NasopharyngealCarcinoma, Stage IVA NasopharyngealCarcinoma, Stage IVB NasopharyngealCarcinoma, Head and Neck
SBRT +/- Pembrolizumab in Patients With Local-Regionally Recurrent or Second Primary Head and Neck Carcinoma (KEYSTROKE)
This phase II trial with a safety run-in component will evaluate whether the addition of
pembrolizumab to Stereotactic Body Radiation Therapy (SBRT) re-irradiation will improve the
progression-free survival for patients with recurrent or new second primary Head and Neck
Squamous Cell Carcinoma (HNSCC).
• Histologically or cytologically-confirmed diagnosis of locoregional recurrent or any
new primary squamous cell carcinoma of the head and neck that is not amenable to
curative resection. A new primary HNSCC is defined where any one of the following
criteria are met:
• Metachronous invasive SCC developing ≥ 6 months after an index HNSCC, more than 3
cm from the index lesion;
• SCC developing in the same region as the index SCC if ≥ 36 months after the index
diagnosis and if within 3 cm of a site where disease was completely resected or
complete response was documented;
• New SCC that is cytologically or molecularly distinct from index SCC (eg new HPV
negative SCC with prior index SCC that was HPV positive).
• Tumor tissue testing for p16 status is required for base of tongue, soft palate, and
tonsil cancer. If a p16 testing has been previously performed on an oropharynx cancer
that has recurred, then repeat testing for p16 status is not required. Participants
whose first cancer was an unknown primary must have p16 testing from either the new
primary tumor or the recurrent cancer.
• Prior radiotherapy (RT) to the head and neck (30 Gy minimum)
• Disease must be limited to a single site or adjacent sites that can be treated in a
single contiguous target volume for which the maximum total tumor dimension (GTV) must
be <7.5cm. Examples of eligible patients include:
1. A primary site recurrence in the oropharynx with a concurrent level 2 nodal mass,
or a laryngeal recurrence with a level 3 nodal mass
2. Multiple nodes in the same (level 2) or adjacent nodal levels (levels 2 and 3)
3. Skull base recurrence with a lateral pharyngeal or high level 2 node
Note: These cases will be eligible provided that the maximum total tumor dimension is
<7.5cm. For cases in which a tumor biopsy was performed and there is a biopsy/tumor
debulking bed adjacent to the gross residual disease, all of the preoperative radiographic
abnormalities must be included in the GTV and meet the <7.5cm maximal dimension criteria to
meet eligibility.
Note: Patients who meet these criteria only after surgical removal of a portion of the
patient's disease (e.g. removal of level 4 nodal mass in a patient with a tongue base
primary; or of a contralateral nodal mass in an N2c patient) are ineligible.
• Patients who have undergone a recent biopsy (e.g. incisional) are eligible. Any
preceding surgical procedure beyond a biopsy (e.g. debulking) must be reviewed as
follows:
• Patients rendered free of gross disease are not eligible.
• Patients with gross residual disease postoperatively, must be reviewed by the
Surgical Co-PI for determination of eligibility.
• Patients eligible for study must have cutaneous wounds healed for 4-6 weeks prior
to the initiation of SBRT.
• History/physical examination within 56 days prior to entry
• Examination by a Radiation Oncologist and Medical Oncologist within 56 days prior to
entry; [Note: Baseline dental assessment is strongly recommended prior to start of
therapy but is not required for eligibility]
• Contrast enhanced CT or MRI, of the tumor and neck within 56 days prior to entry.
• Chest CT scan or full body PET/CT within 56 days prior to entry; patients with
equivocal pulmonary nodules that are < 1.5 cm, that cannot be safely biopsied, or that
are negative on PET/CT imaging are eligible.
• Zubrod Performance Status of 0-1 within 28 days prior to entry.
• Age ≥ 18
• Trial is open to all genders
• Hematologic: Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3, Platelets ≥ 100,000
cells/mm3, Hemoglobin ≥ 9 g/dL
• Hepatic: Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 x ULN, AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN
• Creatinine ≤ 1.5 x ULN, OR measured or calculated creatinine clearance > 60 mL/min for
subject with creatinine levels > 1.5 x institutional ULN [NOTE: Calculated creatinine
per institutional standard; GFR may be used in place of creatinine or CrCl]
• Negative serum pregnancy test within 14 days prior to entry for women of childbearing
potential. (Note: A pregnancy test must be repeated within 3 days prior to the
administration of the first dose of pembrolizumab)
• The patient or legally authorized representative must provide study-specific informed
consent prior to study entry.
Exclusion Criteria:
• Distant metastases.
• Tumors that involve more than 180 degrees of the carotid artery on diagnostic CT or
MRI of the neck within 56 days prior to entry. Investigators are encouraged to review
the CT simulation imaging and ensure that tumor progression has not occurred whereby
patients who were initially eligible based on diagnostic imaging, would be rendered
ineligible based on CT simulation imaging (e.g. tumor size >7.5cm, skin involvement,
>180 degrees of carotid encasement by tumor). If this does occur, the patient should
be removed from the study and the Radiation Oncology Co-PIs should be notified via
email. Note: It is strongly recommended that CT simulation be performed prior to
entry.
• Patients with gross skin involvement (i.e. tumor ulceration through the skin) are
excluded. Patients with tumor approaching the skin but in which the overlying skin
remains intact are eligible, providing that planning constraints can be achieved
without the use of bolus.
• Disease that requires two or more discontiguous target volumes will be ineligible.
Examples of such cases include:
• Bilateral nodal targets
• Level 2 and level 4 nodes
• An oropharyngeal recurrence with a low level 4 node;
• Patients for whom the maximal total tumor dimension (GTV) is >7.5cm
• Prior radiation to primary tumor within 6 months of entry
• Prior systemic therapy, investigational agent or investigational device within 28 days
of start of study treatment.
• Surgical resection of the qualifying cancer is not permitted. (Patients who have
undergone biopsies are eligible). Patients without radiographically apparent gross
tumor are ineligible. For cases where an operation more extensive than a biopsy was
performed but radiographically apparent gross residual tumor remains, will be reviewed
by the Surgical Co-PI for determination of eligibility.
• No concurrent treatment with other investigational agent or investigational device.
• Prior therapy with a checkpoint inhibitor (eg anti-CTLA-4, anti-PD-1 or anti-PD-L1
therapy).
• Patients with immunodeficiency, or receiving systemic steroid, or any form of
immunosuppressive therapy at the time of registration (e.g. history of human
immunodeficiency virus •HIV). Use of physiologic doses corticosteroids may be
approved with consultation with study chairs.
• Active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxin, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a
form of systemic therapy
• Known active hepatitis B (positive test for virus surface antigen •HBsAg) or
hepatitis C virus (e.g. positive HCV RNA qualitative test).
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Treatment with a live vaccine within 30 days of entry.
• Unstable angina and or congestive heart failure requiring hospitalization in the last
6 months.
• Myocardial infarction within the last 6 months.
• Active bacterial or fungal infection requiring intravenous antibiotic at the time of
entry
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy within 30 days of entry.
• Other significant medical, surgical or psychiatric conditions or requirements for any
medication or treatment that in the opinion of the investigator may interfere with
compliance, make administration of anti-PD-L1 therapy hazardous, or obscure
interpretation of adverse events (AEs), such as a condition associated with frequent
diarrhea.
• Pregnancy, nursing females, or women of childbearing potential and men who are
sexually active and not willing/able to use medically acceptable forms of
contraception; this exclusion is necessary because the treatment involved in this
study may be significantly teratogenic.
Drug: Pembrolizumab, Radiation: Stereotactic Body Radiation Therapy (SBRT)
Head and Neck Squamous Cell Carcinoma (HNSCC), Head and Neck
HNSCC, Head and Neck Squamous Cell Carcinoma, KEYSTROKE
ASP-1929 Photoimmunotherapy (PIT) Study in Recurrent Head/Neck Cancer for Patients Who Have Failed at Least Two Lines of Therapy
A Phase 3, Randomized, Double-Arm, Open-Label, Controlled Trial of ASP-1929 vs Physician's
Choice Standard of Care for the Treatment of Locoregional, Recurrent Head and Neck Squamous
Cell Carcinoma in Patients Who Have Failed or Progressed On or After at Least Two Lines of
Therapy
• Have a histologically confirmed locoregional persistent, recurrent or second primary
squamous cell carcinoma of the head and neck, not amenable to curative treatment
• Have failed or progressed on or after at least 2 lines of therapy for squamous cell
carcinoma of the head and neck, one of which must be prior systemic platinum-based
chemotherapy
• Have completed prior curative radiation therapy for treatment of their head and neck
region
• Have locoregional head and neck tumor site(s) that are all accessible to illumination
• Have target tumors that are clearly measurable by contract enhanced CT scan
• Have a life expectancy of > 6 months, based on Investigator judgment
• Male participants must agree to use contraception during the treatment period and for
at least 6 months after the last ASP-1929 infusion
• Female patients of childbearing potential must not be pregnant or breastfeeding and
agrees to follow the contraceptive guidance during the treatment period and for at
least 6 months after the last dose of trial intervention and must refrain from
breastfeeding for at least 2 months after the last ASP-1929 infusion
• Have an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
Overall
Exclusion Criteria:
• Have a history of significant (> Grade 3) cetuximab infusion reactions
• Have been treated with prior systematic chemotherapy or targeted small molecule
therapy or radiation therapy within 2 weeks of trial Day 1 or not recovered from
adverse events due to a previously administered agent
• Have been treated with an anticancer monoclonal antibody therapy within 4 of trial Day
1 or have not recovered from adverse events due to previously administered agent
• Have been treated with an investigational agent or intervention within 4 weeks of
trial Day 1 or have not recovered from adverse events, due to previously administered
agent or intervention
• Have a present history of distant metastatic disease (M1)
• Have an active undergoing treatment or have a diagnosis of an active cancer other than
nonmelanoma skin cancer or HNSCC
• Have a tumor in enhanced CT or MRI scan invading a major blood vessel, unless the
vessel has been embolized, stented or surgically ligated to prevent potential bleeding
from a blood vessel
• Have impaired hepatic function
• Have impaired renal function
• Have 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 would limit
compliance with trial requirements
• Have been previously treated or randomized to any trial using ASP-1929 or RM-1929 PIT
as the study treatment
HYPORT: A Phase I/II Study of Hypofractionated Post-operative Radiation Therapy for Head and Neck Cancer
There is a strong radiobiological and economic rationale for hypofractionated radiation
therapy in head and neck cancer. Phase 1 of the trial aims to assess the acute toxicity and
tolerability of hypofractionated radiation therapy in the post-operative setting, and to
determine the dose/fractionation for Phase 2. Phase 2 aims to establish non-inferiority of
swallowing-related quality of life and to assess the toxicity and efficacy of
hypofractionated radiation therapy compared to conventionally fractionated radiation therapy
in the post-operative setting.
Inclusion criteria will be the same for Phase I and Phase II.
1. Pathologically proven diagnosis of stage I-IVB squamous cell carcinoma of the oral
cavity, oropharynx, hypopharynx, or larynx status post gross total resection with
pathology showing one or more of the following intermediate risk factors: T3/4
disease, positive lymph node(s), close margin(s), perineural invasion, and/or
lymphovascular invasion
2. Age ≥18 years
3. ECOG performance status 0-2
4. Women of child-bearing potential and men 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.
Medically acceptable birth control (contraceptives) includes:
• approved hormonal contraceptives (such as birth control pills, patch or ring;
Depo-Provera, Implanon), or
• barrier methods (such as condom or diaphragm) used with a spermicide
5. Negative serum or urine pregnancy test within 2 weeks before registration for women of
childbearing potential.
6. Ability to understand and the willingness to sign a written informed consent
Exclusion Criteria:
Phase I:
1. Distant metastasis
2. Stage I and II glottic squamous cell carcinoma
3. High risk factors following surgical resection requiring concurrent chemotherapy:
positive margin(s) and/or extranodal extension
4. Feeding tube dependence at baseline assessment.
5. Synchronous non-skin cancer primaries outside of the oropharynx, oral cavity, larynx,
and hypopharynx except for low- and intermediate-risk prostate cancer and synchronous
well-differentiated thyroid cancer. For thyroid cancer, surgery may occur before or
after treatment, provided all other eligibility criteria are met. For prostate cancer,
patient should not be receiving active treatment.
6. Prior invasive malignancy with an expected disease-free interval of less than 3 years
7. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation fields
8. Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study.
9. 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
10. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
11. History of severe immunosuppression, including HIV, and organ or autologous or
allogeneic stem cell transplant
Phase II:
The exclusion criteria will be the same as Phase I except for feeding tube dependence.
Patients who are feeding tube dependent are excluded from Phase I to accurately assess
treatment associated toxicity affecting swallowing and oral intake. During Phase II,
patients who are feeding tube dependent will be eligible to enroll and stratified at
randomization.
Stereotactic Radiosurgery (SRS) for Brain Metastasis (SRS)
SRS dose escalation for brain metastases in radiation-naïve patients will establish true
tolerable doses, which may exceed the current standard doses. This may lead to an improvement
in local control, patient survival, and/or quality-of life.
Inclusion Criteria
1. Biopsy-proven non-hematopoietic malignancy, except for small cell lung cancer, germ
cell cancer, or unknown primary tumor.
2. Radiographic evidence by MRI (or by CT scan with CT contrast if ineligible or
intolerant of MRI) of brain metastasis. (If patient is unable to tolerate MRI
contrast, an MRI without contrast is acceptable if lesions are visible)
3. All brain metastases must be outside the brain stem (midbrain, pons and medulla).
4. Patient must have 10 or less brain metastases.
5. The maximum diameter of any lesion must be less than or equal to 3.0 cm.
6. Previous treatment with surgery, radiation, chemotherapy, immunotherapy or any
targeted agents are allowed provided that:
• Radiation was not to the brain.
• Surgery to the brain was > 7 days prior to SRS and there remains at least one
additional brain metastasis that can be targeted with SRS
7. Age ≥ 18 years.
8. ECOG Performance Score of 2 or better/Karnofsky Performance Status score of 50-60 or
better.
9. 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 and for the duration of study participation. Should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately.
10. 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).
11. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria
1. Patients had craniotomy and surgery to the brain within 7 days from the date of SRS.
2. Patients with leptomeningeal metastasis.
NOTE: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive
CSF cytology and/or equivocal radiologic or clinical evidence of leptomeningeal
involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal
enhancement by imaging (MRI) would be considered to have LMD even in the absence of
positive CSF cytology, unless a parenchymal lesion can adequately explain the
neurologic symptoms and/or signs. In contrast, an asymptomatic or minimally
symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would
not be considered to have LMD. In that patient, CSF sampling is not required to
formally exclude LMD, but can be performed at the investigator's discretion based on
level of clinical suspicion.
3. Patients with a contraindication to both MRI (with or without contrast) and CT scan
(with contrast)
4. Patients with life expectancy < 3 months.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that, in the opinion of the
investigator, would limit compliance with study requirements.
6. Subjects must not be pregnant or nursing at the time of SRS treatment due to the
potential for congenital abnormalities and the potential of this regimen to harm
nursing infants.
Radiation: Stereotactic Radiosurgery
Brain Neoplasms, Adult, Malignant, Lymphoma, Sarcoma, Multiple Myeloma, Brainand Nervous System, Other, Eye and Orbit, Anklylosing Spondylitis, Anus, Bones and Joints, Breast - Female, Breast - Male, Cardiovascular, Cervix, Colon, Corpus Uteri, Ear, Esophagus, Gall Bladder, Head and Neck, Kidney, Larynx, Lip, OralCavityand 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, Lymphoid Leukemia, Small Intestine, Soft Tissue
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, Brainand 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, OralCavityand 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
Study of Cemiplimab in Patients With Type of Skin Cancer Stage II to IV Cutaneous Squamous Cell Carcinoma
The primary objective of the study is to evaluate the efficacy of neoadjuvant cemiplimab as
measured by Pathologic complete response (pCR) rate per independent central pathology review.
The secondary objectives of the study are:
- To evaluate the efficacy of neoadjuvant cemiplimab on measures of disease response,
including:
- Major pathologic response (mPR) rate per independent central pathology review
- pCR rate and mPR rate per local pathology review
- ORR prior to surgery, according to local assessment using RECIST 1.1
- To evaluate the efficacy of neoadjuvant cemiplimab on event free survival (EFS), disease
free survival (DFS), and overall survival (OS)
- To evaluate the safety profile of neoadjuvant cemiplimab
- To assess change in surgical plan (ablative and reconstructive procedures) from the
screening period to definitive surgery, both according to investigator review and
independent surgical expert review
- To assess change in post-surgical management plan (radiation, chemoradiation, or
observation) from the screening period to post-surgery pathology review, both according
to investigator review and independent surgical expert review
Key Inclusion Criteria
• Stage II to IV (M0) CSCC, for which surgery would be recommended in routine clinical
practice. For stage II patients, lesion must be ≥3 cm at the longest diameter.
• At least 1 lesion that is measurable by RECIST 1.1
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ, bone marrow function, and hepatic function as defined in the protocol
Key Exclusion Criteria
• Solid malignancy within 5 years of the projected enrollment date, or hematologic
malignancy (including chronic lymphocytic leukemia [CLL]) at any time
• Distant metastatic disease (M1), visceral and/or distant nodal
• Prior radiation therapy for CSCC
• Patients with a condition requiring corticosteroid therapy (>10 mg prednisone/day or
equivalent) within 14 days of the first dose of study drug.
• Patients with active, known, or suspected autoimmune disease that has required
systemic therapy within 5 years of the projected enrollment date.
• History of interstitial lung disease (eg, idiopathic pulmonary fibrosis, organizing
pneumonia) or active, noninfectious pneumonitis that required immune-suppressive doses
of glucocorticoids to assist with management.
• Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B or
hepatitis C virus (HBV or HCV) infection; or diagnosis of immunodeficiency
• Active tuberculosis
NOTE: Other protocol-defined Inclusion/Exclusion Criteria apply
Drug: Cemiplimab
Cutaneous Squamous Cell Carcinoma, Melanoma, skin, Other Skin
CSCC, Stage II, Stage III, Stage IV, CSCC of Head/neck, CSCC of Extremity, CSCC of Trunk
HYHOPE: De-intensified Hypofractionated Radiation Therapy for HPV-associated Oropharynx Cancer
This is a single arm Phase I study of de-intensified hypofractionated radiation therapy for
favorable human papilloma virus-associated oropharynx cancer. It will evaluate the
tolerability of a de-intensified hypofractionated radiation therapy regimen completed in 3
weeks (with equivalent biologically effective dose to 60 Gy in 30 fractions) with concurrent
weekly cisplatin.
1. Pathologically-proven diagnosis of T1-3 (up to 6 cm), N0-2 (AJCC 8th edition) p16
positive squamous cell carcinoma of the oropharynx (except T1-2N0 as noted in the
exclusion criteria)
2. ≤10 pack-year smoking history and not actively smoking
3. Age ≥18 years
4. ECOG performance status 0-2
5. Women of child-bearing potential and men 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.
6. Negative serum or urine pregnancy test within 2 weeks before registration for women of
childbearing potential.
7. Ability to understand and the willingness to sign a written informed consent.
Exclusion Criteria:
1. Distant metastasis
2. T1-2N0 (AJCC 8th edition) p16 positive squamous cell carcinoma of the oropharynx
(candidates for definitive RT alone or surgery alone)
3. Inability to receive concurrent weekly cisplatin due to comorbid conditions
4. Synchronous non-skin cancer primaries outside of the oropharynx, oral cavity, larynx,
and hypopharynx except for low- and intermediate-risk prostate cancer and
well-differentiated thyroid cancer. For prostate cancer, patient should not be
receiving active treatment. For thyroid cancer, thyroid surgery may occur before or
after radiation treatment, provided all other eligibility criteria are met.
5. Prior invasive malignancy with an expected disease-free interval of less than 3 years
6. Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation fields
7. Subjects may not be receiving any other investigational agents for the treatment of
the cancer under study.
8. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the chemotherapy agents in this study
9. 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
10. Subjects must not be pregnant or nursing due to the potential for congenital
abnormalities and the potential of this regimen to harm nursing infants.
11. History of severe immunosuppression, including HIV, organ or autologous or allogeneic
stem cell transplant, or active immunosuppressive medication at the time of enrollment
Phase 1 Study of MM-398 Plus Cyclophosphamide in 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, Brainand 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, OralCavityand 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
1. Have histologically confirmed advanced or metastatic castration-resistant prostate
cancer, bladder cancer, melanoma, non-small cell lung cancer, pancreatic cancer,
colorectal cancer, gastric cancer, esophageal cancer, ovarian cancer, and head neck
squamous cell carcinoma.
Or,
Have histologically confirmed metastatic pancreatic adenocarcinoma. Recurrent
unresectable pancreatic cancer is acceptable as long as the treatment is first-line.
2. Have not received any approved chemotherapy, except in the adjuvant setting.
Exclusion Criteria:
1. Subject was using immunosuppressive medications within 14 days before Screening with
the exception of topical (intranasal, inhaled, and local injection), systemic
(prednisone equivalent 10 mg/day or less), or as needed for hypersensitivity reactions
such as computed tomography (CT) scan premedication.
2. Subject has active infections or other serious underlying significant medical illness,
abnormal and clinically significant laboratory findings or psychiatric illness/social
situation.
3. Subject is using a pacemaker, implantable cardiac defibrillator, neurostimulator,
cochlear implants, cochlear implants, or other electronic medical equipment.
4. Subject has documented immunodeficiency or organ transplant.
5. Subject has an untreated central nervous system disease, leptomeningeal disease or
cord compression.
6. Subject has a history, or presence, of significant cardiovascular diseases; including
uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or
myocardial infarction within 6 months before randomization, congestive heart failure >
New York Heart Association Class II, severe peripheral vascular disease, corrected QT
(QTc) prolongation >470 msec, clinically significant pericardial effusion.
7. Subject has a history or presence of documented inflammatory bowel disease.
8. Subject is known to be positive for human immunodeficiency virus infection.
-
A Phase 1 Trial of a Novel XPO1 Inhibitor in Patients With Advanced Solid Tumors
Study SL-801-0115 is a dose-escalation study evaluating multiple doses and schedules of
orally administered SL-801 in patients with Advanced Solid Tumors
• The patient must have histologic or cytologic evidence of a malignant solid tumor and
must have disease that is resistant to or relapsed following available standard
systemic therapy, or for which there is no standard systemic therapy or reasonable
therapy likely to result in clinical benefit.
• The patient must have advanced disease, defined as cancer that is either metastatic,
OR locally advanced and unresectable (and for which additional radiation therapy or
other locoregional therapies are not considered feasible).
• The patient must have disease that is measurable by standard imaging techniques, per
the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), or
evaluable per RECIST 1.1. (For patients with prior radiation therapy, measurable
lesions must be outside of any prior radiation field[s], unless disease progression
has been documented at that disease site subsequent to radiation.)
• The patient is ≥18 years old.
• The patient has an ECOG PS of 0-2.
• The patient has adequate baseline organ function, as demonstrated by the following:
• Serum creatinine ≤1.5 × institutional upper limit of normal (ULN) or calculated
creatinine clearance >30 mL/min.
• Serum albumin ≥2.5 g/dL.
• Bilirubin ≤1.5 × institutional ULN.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 ×
institutional ULN (patients with hepatic metastases must have AST/ALT ≤5 times
ULN).
• International normalized ratio (INR) ≤1.5 or prothrombin time (PT) ≤1.5 × ULN;
and either partial thromboplastin time or activated partial thromboplastin time
(PTT or aPTT) ≤1.5 × ULN.
• The patient has adequate baseline hematologic function, as demonstrated by the
following:
• Absolute neutrophil count (ANC) ≥1.5×10⁹/L
• Hemoglobin ≥8 g/dL, with no red blood cell (RBC) transfusions within the prior 14
days.
• Platelet count ≥100×10⁹/L, with no platelet transfusions within the prior 14
days.
• If the patient is a woman of child bearing potential (WOCBP), she has had a negative
serum or urine pregnancy test within 1 week prior to treatment.
• The patient (male and female) agrees to use acceptable contraceptive methods for the
duration of time on the study, and continue to use acceptable contraceptive methods
for 1 month after the last dose of SL-801.
• The patient has signed informed consent prior to initiation of any study-specific
procedures or treatment.
• The patient is able to adhere to the study visit schedule and other protocol
requirements, including follow-up for survival assessment.
Exclusion Criteria:
• The patient has persistent clinically significant ≥Grade 2 toxicities from previous
anticancer therapy (excluding Grade 2 chemotherapy-related neuropathy which is
permitted, and excluding Grade 2-3 laboratory abnormalities if they are not associated
with symptoms, are not considered clinically significant by the Investigator, and can
be managed with available medical therapies).
• The patient has received treatment with chemotherapy, external-beam radiation, or
other systemic anticancer therapy within 28 days prior to study entry (Patients with
advanced prostate cancer who are receiving luteinizing hormone releasing hormone
[LHRH] agonists are permitted onto the study and should continue use of these agents
during study treatment).
• The patient has received treatment with an investigational systemic anticancer agent
within 28 days prior to C1D1.
• The patient has previously received treatment with SL-801 or another investigational
agent that inhibits the XPO1/CRM1 pathway.
• The patient has an additional active malignancy that may confound the assessment of
the study endpoints. Patients with a past cancer history (active malignancy within 2
years prior to study entry) with substantial potential for recurrence must be
discussed with the Sponsor before study entry. Patients with the following concomitant
neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ
(including transitional cell carcinoma, cervical intraepithelial neoplasia),
organ-confined prostate cancer with no evidence of progressive disease.
• The patient has clinically significant cardiovascular disease (e.g., uncontrolled or
any New York Heart Association Class 3 or 4 congestive heart failure [Appendix 1],
uncontrolled angina, history of myocardial infarction, unstable angina or stroke
within 6 months prior to study entry, uncontrolled hypertension or clinically
significant arrhythmias not controlled by medication).
• The patient has uncontrolled, clinically significant pulmonary disease (e.g., chronic
obstructive pulmonary disease, pulmonary hypertension) that, in the Investigator's
opinion, would put the patient at significant risk for pulmonary complications during
the study.
• The patient has known active or suspected brain or leptomeningeal metastases. (Central
nervous system [CNS] imaging is not required prior to study entry unless there is a
clinical suspicion of CNS involvement). Patients with stable, treated brain metastases
are eligible provided there is no evidence of CNS disease growth on imaging for at
least 3 months following radiation therapy or other locoregional ablative therapy to
the CNS.
• The patient is receiving immunosuppressive therapy for prophylaxis following a prior
organ transplant (solid organ or allogeneic stem cell) or management of
immune-mediated toxicities due to immunotherapy. Low-dose corticosteroid (defined as <
10mg/day of prednisone or equivalent) therapy is permitted.
• The patient has uncontrolled intercurrent illness including, but not limited to,
uncontrolled infection, disseminated intravascular coagulation, or psychiatric
illness/social situations that would limit compliance with study requirements.
• The patient is pregnant or breast feeding.
• The patient has known positive status for human immunodeficiency virus active or
chronic Hepatitis B or Hepatitis C.
• The patient is oxygen-dependent.
• The patient has any medical condition which in the opinion of the Investigator places
the patient at an unacceptably high risk for toxicities.
Drug: SL-801
Lymphoma, Solid Tumors, Brainand Nervous System, Breast - Female, Breast - Male, Colon, Corpus Uteri, Esophagus, Kidney, Lip, OralCavityand Pharynx, Liver, Lung/Thoracic, Other Digestive Organ, Pancreas, Prostate, Stomach, Urinary Bladder, Small Intestine, Unknown Sites
Study of Lenvatinib in Combination With Everolimus in Recurrent and Refractory Pediatric Solid Tumors, Including Central Nervous System Tumors
Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum
tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of
lenvatinib administered in combination with everolimus once daily to pediatric participants
with recurrent/refractory solid tumors. Phase 2, utilizing Simon's optimal 2-stage design,
will be conducted to estimate the antitumor activity of lenvatinib in combination with
everolimus in pediatric participants with selected recurrent/refractory solid tumors
including Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma,
and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome
measure.
Inclusion Criteria
• ≥2 years and <18 years of age for enrolment in Phase 1 or ≥2 years and ≤21 years of
age for enrolment in Phase 2.
• Recurrent or refractory solid tumors
• Phase 1: All solid tumors (measurable or evaluable disease), including primary
central nervous system (CNS) tumors; exclusion of hepatoblastoma and lymphomas.
Participants with diffuse intrinsic pontine glioma, optic pathway glioma, or
pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and beta-human
chorionic gonadotropin [ß-hCG][or human chorionic gonadotropin [hCG])do not
require histological or cytological confirmation of diagnosis
• Phase 2: Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET),
Rhabdomyosarcoma, High Grade Glioma (HGG) (all must have measurable disease);
exclusion of Diffuse Intrinsic Pontine Glioma
• Histologically or cytologically confirmed diagnosis
• Measurable disease that meets the following criteria (Phase 2):
1. RECIST 1.1 (for all tumor types except HGG): At least 1 lesion of ≥1.0 cm in the
longest diameter for a non lymph node or ≥1.5 cm in the short-axis diameter for a
lymph node which is serially measurable according to RECIST 1.1 using computed
tomography /magnetic resonance imaging (CT/MRI)
2. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG): At
least one lesion must be measurable as defined as a bi dimensionally contrast
enhancing lesion with clearly defined margins by CT or MRI scan, with a minimal
diameter of 1 cm, and visible on 2 axial slices which are preferably at most 5 mm
apart with 0 mm skip
Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as
radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1
to be deemed a target lesion
• Karnofsky performance score ≥50 for participants>16 year of age and Lansky play score
≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS
tumors must have been relatively stable for at least 7 days prior to study enrollment.
Participants who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score
• Prior Therapy
• Participants must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy
• Cytotoxic chemotherapy or other chemotherapy known to be myelosuppressive: ≥21
days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days
if prior nitrosourea)
• Anti-cancer agents not known to be myelosuppressive (eg, not associated with
reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of
agent
• Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the
antibody must have elapsed after the last dose of a monoclonal antibody
(including checkpoint inhibitors). Toxicity related to prior antibody therapy
must be recovered to Grade ≤1
• Corticosteroids: If used to modify immune adverse events related to prior
therapy, ≥14 days must have elapsed since last dose of corticosteroid.
Participants receiving corticosteroids, who have not been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment, are
not eligible
• Hematopoietic growth factors: ≥14 days after the last dose of a long-acting
growth factor or 7 days for short-acting growth factor. For agents that have
known adverse events occurring beyond 7 days after administration, this period
must be extended beyond the time during which adverse events are known to occur
• Interleukins, interferons, and cytokines (other than hematopoietic growth
factors): ≥21 days after the completion of interleukins, interferons or cytokines
(other than hematopoietic growth factors)
• Stem cell infusions (with or without total body irradiation): Allogeneic
(non-autologous) bone marrow or stem cell transplant, or any stem cell infusion
including donor leukocytes infusion or boost infusion: ≥84 days after infusion
and no evidence of graft versus host disease; Autologous stem cell infusion
including boost infusion: ≥42 days
• Cellular Therapy: ≥42 days after the completion of any type of cellular therapy
(eg, modified T cells, natural killer cells, dendritic cells, etc)
• Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after
local XRT; ≥150 days after total body irradiation, craniospinal XRT or if
radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow
radiation.
• Radiopharmaceutical therapy: ≥42 days after systemically administered therapy.
• Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or
mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received
prior exposure to lenvatinib; May have previously progressed on an mTOR
inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only);
Must not have received prior VEGF/VEGFR-targeted therapy in combination with an
mTOR inhibitor (For Phase 2 only)
• Adequate bone marrow function for participants with solid tumors without known bone
marrow involvement
• Adequate bone marrow function for participants with known bone marrow metastatic
disease
• Adequate renal function
• Adequate liver function
• Adequate cardiac function
• Adequate neurologic function
• Adequate blood pressure (BP) control with or without antihypertensive medications
• Adequate coagulation
• Adequate pancreatic function
• Adequate metabolic function
• Adequate glycemic control
• Participants must have a minimum body surface area (BSA) of 0.6 m^2 at study entry.
Exclusion Criteria
• Participants who have had or are planning to have the following invasive procedures
• Major surgical procedure, laparoscopic procedure, open biopsy or significant
traumatic injury within 28 days prior to enrolment
• Central line placement or subcutaneous port placement is not considered major
surgery. External central lines must be placed at least 3 days prior to
enrollment and subcutaneous ports must be placed at least 7 days prior to
enrollment
• Fine needle aspirate within 7 days prior to enrolment
• Surgical or other wounds must be adequately healed prior to enrolment
• For purposes of this study, bone marrow aspirate and biopsy are not considered
surgical procedures and therefore are permitted within 14 days prior to start of
protocol therapy
• Participants who have non-healing wound, unhealed or incompletely healed fracture, or
a compound (open) bone fracture at the time of enrolment
• Participants having an active infection requiring systemic therapy.
• Participants with a known history of active hepatitis B (defined as hepatitis B
surface antigen reactive or hepatitis B virus- deoxyribonucleic [DNA] detected) or
known active hepatitis C virus (HCV, defined as HCV- Ribonucleic acid [RNA] detected).
Note: No testing for hepatitis B and hepatitis C is required unless mandated by the
local health authority.
• Known to be human immunodeficiency virus (HIV) positive. Note: HIV testing is required
at screening only when mandated by the local health authority
• Clinical evidence of nephrotic syndrome prior to enrolment
• Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half
teaspoon) within 21 days prior to enrolment
• Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days
prior to enrollment
• Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment
obtained within 28 days prior to study enrollment for Participants with HGG
• Diagnosis of lymphoma
• Radiographic evidence of major blood vessel invasion/infiltration.
• Evidence of untreated CNS metastases (exception: participants with primary CNS tumors
and leptomeningeal disease)
• Participants who are currently receiving enzyme-inducing anticonvulsants
• Participants chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein
(P-gp) inhibitors or inducers within 7 days prior to study enrollment
• Females who are breastfeeding or pregnant. For females of childbearing potential, a
negative screening pregnancy test must be obtained within 72 hours before the first
dose of study drug
Drug: Lenvatinib, Drug: Everolimus
Sarcoma, Recurrent and Refractory Solid Tumors, Brainand 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, OralCavityand 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, Kaposis sarcoma, Small Intestine, Soft Tissue
pediatrics, central nervous system tumors, lenvatinib, E7080, everolimus, Ewing sarcoma/peripheral primitive neuroectodermal tumor, rhabdomyosarcoma, high grade glioma, solid tumors
Testing Docetaxel-Cetuximab or the Addition of an Immunotherapy Drug, Atezolizumab, to the Usual Chemotherapy and Radiation Therapy in High-Risk Head and Neck Cancer
This phase II/III trial studies how well radiation therapy works when given together with
cisplatin, docetaxel, cetuximab, and/or atezolizumab after surgery in treating patients with
high-risk stage III-IV head and neck cancer the begins in the thin, flat cells (squamous
cell). Specialized radiation therapy that delivers a high dose of radiation directly to the
tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in
chemotherapy, such as cisplatin and docetaxel, work in different ways to stop the growth of
tumor cells, either by killing the cells or by stopping them from dividing. Cetuximab is a
monoclonal antibody that may interfere with the ability of tumor cells to grow and spread.
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 compare the usual treatment (radiation therapy with
cisplatin chemotherapy) to using radiation therapy with docetaxel and cetuximab chemotherapy,
and using the usual treatment plus an immunotherapy drug, atezolizumab.
• PHASE II INCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
• Pathologically (histologically or cytologically) proven diagnosis of head and neck
squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips), oropharynx
(p16 negative), larynx, or hypopharynx
• Patients must have undergone gross total surgical resection of high-risk oral cavity,
oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to
registration; Note: patients may have biopsy under general anesthesia in an operating
room followed by definitive ablative cancer surgery representing gross total
resection; the gross total resection has to be done within 63 days prior to
registration; if, however, patients have ablative resection but shortly recur or are
determined to have persisting disease requiring re-resection to achieve gross total
resection, then the patient is not eligible
• Patients must have at least 1 of the following high-risk pathologic features:
extracapsular nodal extension or invasive cancer at the primary tumor resection margin
(tumor on ink)
• Pathologic stage III or IV HNSCC, including no distant metastases, based upon the
following minimum diagnostic workup:
• General history and physical examination by a radiation oncologist and/or medical
oncologist within 84 days prior to registration;
• Examination by an ear nose throat (ENT) or head & neck surgeon prior to surgery;
a laryngopharyngoscopy (mirror and/or fiber optic and/or direct procedure), if
appropriate, is recommended but not required; intra-operative examination is
acceptable documentation
• Pre-operative (op) Imaging of the head and neck: A neck computed tomography (CT)
(with contrast) or CT/positron emission tomography (PET) (with contrast) and/or
an magnetic resonance imaging (MRI) of the neck (T1 with gadolinium and T2)
within 84 days prior to surgery; Note: this imaging data (diagnostic
pre-operative scan showing gross disease) is to be submitted in Digital Imaging
and Communications in Medicine (DICOM) format via TRIAD; the report is to be
uploaded into Rave
• Chest CT scan (with or without contrast) or CT/PET that includes the chest (with
or without contrast) either within 84 days prior to surgery or within 120 days
prior to registration; Note: if the CT/PET with or without contrast is done
within 84 days prior to surgery, it fulfills the chest imaging requirement
• Zubrod performance status of 0-1 within 14 days prior to registration
• Absolute granulocyte count (AGC) >= 1,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
• Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to registration on
study)
• Hemoglobin >= 8.0 g/dl (Note: the use of transfusion or other intervention to achieve
hemoglobin [Hgb] >= 8.0 g/dl is acceptable)
• Total bilirubin < 2 x institutional upper limit of normal (ULN) within 14 days prior
to registration
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x institutional
ULN within 14 days prior to registration
• Serum creatinine institutional ULN within 14 days prior to registration or; creatinine
clearance (CC) >= 50 ml/min within 14 days prior to registration determined by 24-hour
collection or estimated by Cockcroft-Gault formula
• Negative urine or serum pregnancy test within 14 days prior to registration for women
of childbearing potential
• The following assessments are required within 14 days prior to registration: sodium
(Na), potassium (K), chloride (Cl), glucose, calcium (Ca), magnesium (Mg), and
albumin; Note: patients with an initial magnesium < 0.5 mmol/L (1.2 mg/dl) may receive
corrective magnesium supplementation but should continue to receive either
prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (e.g.,
magnesium oxide) at the investigator's discretion
• Patients with feeding tubes are eligible for the study
• Women of childbearing potential and male participants who are sexually active must
agree to use a medically effective means of birth control
• Patient must provide study specific informed consent prior to study entry, including
consent for mandatory tissue submission for epidermal growth factor receptor (EGFR)
analysis and for oropharyngeal cancer patients, human papilloma virus (HPV) analysis
• PHASE III: Pathologically (histologically or cytologically) proven diagnosis of head
and neck squamous cell carcinoma (HNSCC) involving the oral cavity (excluding lips),
oropharynx (p16 negative), larynx, or hypopharynx
• PHASE III: Patients with oropharyngeal cancer must have p16-negative based on central
review prior to Step 2 registration; all patients with oropharyngeal primary must
consent for mandatory tissue submission for central p16 confirmation
• PHASE III: Patients must have undergone gross total surgical resection of high-risk
oral cavity, oropharynx (p16 negative), larynx, or hypopharynx within 63 days prior to
registration; note: patients may have biopsy under general anesthesia in an operating
room followed by definitive ablative cancer surgery representing gross total
resection; the gross total resection has to be done within 63 days prior to
registration; if, however, patients have ablative resection but shortly recur or are
determined to have persisting disease requiring re-resection to achieve gross total
resection, then the patient is not eligible
• PHASE III: Patients must have at least 1 of the following high-risk pathologic
features: extracapsular nodal extension or invasive cancer at the primary tumor
resection margin (tumor on ink or tumor in a final separately submitted margin)
• PHASE III: Pathologic stage III or IV HNSCC (American Joint Committee on Cancer [AJCC]
7th edition), including no distant metastases, based upon the following minimum
diagnostic workup:
• General history and physical examination by a radiation oncologist or medical
oncologist within 84 days prior to registration;
• Examination by an ENT or head & neck surgeon prior to surgery; a
laryngopharyngoscopy (mirror or fiberoptic or direct procedure), if appropriate,
is recommended but not required. Intra-operative examination is acceptable
documentation.
• Pre-op Imaging of the head and neck: A neck CT (with contrast and of diagnostic
quality) or PET/CT (with contrast and of diagnostic quality) and/or an MRI of the
neck of diagnostic quality (T1 with gadolinium and T2) within 84 days prior to
surgery; Note: this imaging data (diagnostic pre-operative scan showing gross
disease) is to be submitted in DICOM format via TRIAD. The report is to be
uploaded into Rave.
• Chest CT scan (with or without contrast) or PET/CT that includes the chest (with
or without contrast) either within 84 days prior to surgery or within 120 days
prior to registration; Note: If the PET/CT with or without contrast is done
within 84 days prior to surgery, it fulfills the chest imaging requirement
• PHASE III: Zubrod performance status of 0-1 within 14 days prior to registration
• PHASE III: Leukocytes >= 2,500 cells/mm^3 (obtained within 14 days prior to
registration on study)
• PHASE III: Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (obtained within 14
days prior to registration on study)
• PHASE III: Platelets >= 100,000 cells/mm^3 (obtained within 14 days prior to
registration on study)
• PHASE III: Hemoglobin >= 8.0 g/dL (Note: The use of transfusion or other intervention
to achieve Hgb >= 8.0 g/dL is acceptable) (obtained within 14 days prior to
registration on study)
• PHASE III: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
(however, patients with known Gilbert disease who have serum bilirubin level =< 3 x
institutional ULN may be enrolled) (within 14 days prior to registration)
• PHASE III: AST or ALT =< 3 x institutional ULN (within 14 days prior to registration)
• PHASE III: Alkaline phosphatase =< 2.5 x institutional ULN (within 14 days prior to
registration)
• PHASE III: Creatinine clearance (CrCl) >= 50 mL/min within 14 days prior to
registration determined by 24-hour collection or estimated by Cockcroft-Gault formula
• PHASE III: Patients with feeding tubes are eligible for the study
• PHASE III: Negative urine or serum pregnancy test within 14 days prior to registration
for women of childbearing potential
• PHASE III: All patients must provide study specific informed consent prior to study
entry
• PHASE III: Patients positive for human immunodeficiency virus (HIV) are allowed on
study, but HIV-positive patients must have:
• A stable regimen of highly active anti-retroviral therapy (HAART);
• No requirement for concurrent antibiotics or antifungal agents for the prevention
of opportunistic infections;
• A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
polymerase chain reaction (PCR)-based tests
Exclusion Criteria:
• PHASE II EXCLUSION CRITERIA (COMPLETE AS OF 20-MAR-2020)
• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 1095 days (3 years); noninvasive cancers (for example, carcinoma in
situ of the breast, oral cavity, or cervix are all permissible) are permitted even if
diagnosed and treated < 3 years ago
• Patients with simultaneous primaries or bilateral tumors are excluded, with the
exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
• Prior systemic chemotherapy or anti-epidermal growth factor (EGF) therapy for the
study cancer; note that prior chemotherapy for a different cancer is allowable
• Prior radiotherapy to the region of the study cancer that would result in overlap of
radiation therapy fields
• Severe, active co-morbidity, defined as follows:
• Unstable angina and/or congestive heart failure requiring hospitalization within
6 months prior to registration
• Transmural myocardial infarction within 6 months prior to registration
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of registration
• Idiopathic pulmonary fibrosis or other severe interstitial lung disease that
requires oxygen therapy or is thought to require oxygen therapy within 1
year prior to registration
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects;
note, however, that laboratory tests for coagulation parameters are not required
for entry into this protocol
• Acquired immune deficiency syndrome (AIDS) based upon current Centers for
Disease and Control and Prevention (CDC) definition; note: human
immunodeficiency virus (HIV) testing is not required for entry into this
protocol; the need to exclude patients with AIDS from this protocol is
necessary because the treatments involved in this protocol may be
significantly immunosuppressive; protocol-specific requirements may also
exclude immuno-compromised patients.
• Grade 3-4 electrolyte abnormalities (Common Terminology Criteria for Adverse Events
[CTCAE], version [v.] 4):
• Serum calcium (ionized or adjusted for albumin) < 7 mg/dl (1.75 mmol/L) or > 12.5
mg/dl (> 3.1 mmol/L) despite intervention to normalize levels
• Glucose < 40 mg/dl (< 2.2 mmol/L) or > 250 mg/dl (> 14 mmol/L)
• Magnesium < 0.9 mg/dl (< 0.4 mmol/L) or > 3 mg/dl (> 1.23 mmol/L) despite intervention
to normalize levels
• Potassium < 3.0 mmol/L or > 6 mmol/L despite intervention to normalize levels
• Sodium < 130 mmol/L or > 155 mmol/L despite intervention to normalize levels
• Pregnancy or women of childbearing potential and men who are sexually active and not
willing/able to use medically acceptable forms of contraception; this exclusion is
necessary because the treatment involved in this study may be significantly
teratogenic
• Prior allergic reaction to cetuximab
• PHASE III: Prior invasive malignancy (except non-melanomatous skin cancer) unless
disease free for a minimum of 1095 days (3 years) with the following exceptions: T1-2,
N0, M0 resected differentiated thyroid carcinoma; Note that noninvasive cancers (For
example, carcinoma in situ of the breast, oral cavity, or cervix) are permitted even
if diagnosed and treated < 3 years ago
• PHASE III: Patients with simultaneous primaries or bilateral tumors are excluded, with
the exception of patients with bilateral tonsil cancers or patients with T1-2, N0, M0
resected differentiated thyroid carcinoma, who are eligible
• PHASE III: Prior systemic therapy, including cytotoxic chemotherapy, biologic/targeted
therapy (such as anti-EGF therapy), or immune therapy for the study cancer; note that
prior chemotherapy for a different cancer is allowable, however, a prior anti-PD-1,
anti-PD-L1, or anti-PD-L2 agent is not permitted
• PHASE III: Prior radiotherapy to the region of the study cancer that would result in
overlap of radiation therapy fields
• PHASE III: Severe, active co-morbidity, defined as follows:
• 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 within 6
months prior to registration
• Transmural myocardial infarction within 6 months prior to registration;
• Severe infections within 4 weeks prior to registration including, but not limited
to, hospitalization for complications of infection, bacteremia, or severe
pneumonia;
• Acute bacterial or fungal infection requiring intravenous antibiotics at the time
of registration; Note: Patients receiving prophylactic antibiotics (e.g., for
prevention of a urinary tract infection or chronic obstructive pulmonary disease
exacerbation) are eligible.
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness
requiring hospitalization or precluding study therapy at the time of
registration;
• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan. History of radiation pneumonitis in a prior radiation field
(fibrosis) is permitted, provided that field does not overlap with the planned
radiation field for the study cancer;
• Patients with active tuberculosis (TB) are excluded;
• Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease;
• Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface ant
A Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) and With Bempegaldesleukin Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies (REVEAL)
Patients will receive intra-tumoral (IT) NKTR-262 in 3-week treatment cycles. During the
Phase 1 dose escalation portion of the trial, NKTR-262 will be combined with systemic
administration of bempegaldesleukin. After determination of the recommended Phase 2 dose
(RP2D) of NKTR-262, between 6 and 18 patients may be enrolled at the RP2D to further
characterize the safety and tolerability profile of the combination of NKTR 262 plus
bempegaldesleukin (doublet) or NKTR 262 plus bempegaldesleukin in combination with nivolumab
(triplet) in Cohorts A and B, respectively. In the Phase 2 dose expansion portion, patients
will be treated with doublet or triplet in the relapsed/refractory setting and earlier lines
of therapy.
• Histologically confirmed diagnosis of a locally advanced (not amenable to curative
therapy such as surgical resection) metastatic cancer of the following histologies:
melanoma (MEL), Merkel cell carcinoma (MCC), triple-negative breast cancer (TNBC),
renal cell carcinoma (RCC), colorectal cancer, head and neck squamous cell carcinoma
(HNSCC), or sarcoma.
• Life expectancy > 12 weeks as determined by the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Measurable disease per RECIST 1.1.
• Patients enrolled in Cohorts 1-10, Cohort A, Cohort B and Phase 2 Doublet must be
refractory to all therapies known to confer clinical benefit to their disease.
• Fresh tumor tissue available for cellular characterization and programmed cell death
protein 1 (PD-L1) status.
• Injected lesions (up to two) must be between 20 mm and 90 mm in diameter for IT
injection; lesions must be accessible for baseline and on-treatment biopsies. Any
liver lesion targeted for injection must not exceed 50 mm at the time of injection.
• Demonstrated adequate organ function within 14 days of Cycle 1 Day 1 (C1D1).
Key
Exclusion Criteria:
• Use of an investigational agent or an investigational device within 21 days before
administration of first dose of study drug(s).
• Patients treated with prior interleukin-2 (IL-2).
• Patients who have been previously treated with a toll-like receptor (TLR) agonist
(excluding topical agents) and patients who have received experimental cancer
vaccines.
• Patients who have received systemic interferon (IFN)α within the previous 6 months
prior to enrollment to the study.
• Other active malignancy, except non-melanomic skin cancer
• Evidence of clinically significant interstitial lung disease or active, noninfectious
pneumonitis.
• Prior surgery or radiotherapy within 14 days of initiating study drug(s). Patients
must have recovered from all radiation-related toxicities, not required
corticosteroids and have not had radiation pneumonitis.
• Prolonged Fridericia's corrected QT interval (QTcF) > 450 ms for men and > 470 ms for
women at Screening.
History of unstable or deteriorating cardiac disease within the previous 6 months prior to
screening including but not limited to the following:
• Unstable angina or myocardial infarction.
• Congestive heart failure (NYHA Class III or IV).
• Uncontrolled clinically significant arrhythmias.
• Patients with a history of any retinal disorders (e.g., retinal detachment, diabetic
retinopathy, retinal hemorrhage, macular degeneration).
• Uveal melanoma will be excluded
• Patients with tumor that invade the superior vena cava or other major blood vessels.
Additional general and tumor specific inclusion and exclusion criteria will apply.
Study of Cabozantinib in Combination With Atezolizumab to Subjects With Locally Advanced or Metastatic Solid Tumors
This is a multicenter Phase 1b, open-label study to assess safety, tolerability, preliminary
efficacy, and pharmacokinetics (PK) of cabozantinib taken in combination with atezolizumab in
subjects with multiple tumor types, including advanced urothelial carcinoma (UC) (including
bladder, renal pelvis, ureter, urethra), renal cell carcinoma (RCC), castration-resistant
prostate cancer (CRPC), non-small-cell lung cancer (NSCLC), triple negative breast cancer
(TNBC), ovarian cancer (OC), endometrial cancer (EC), hepatocellular cancer (HCC), gastric
cancer and gastroesophageal junction cancer (GC/GEJC), colorectal cancer (CRC), head and neck
(H&N) cancer, and differentiated thyroid cancer (DTC). The study consists of two stages: in
the Dose Escalation Stage, an appropriate recommended cabozantinib dose for the combination
with standard dosing regimen of atezolizumab will be established; in the Expansion Stage,
tumor-specific cohorts will be enrolled in order to further evaluate the safety and efficacy
of the combination treatment in these tumor indications. Two exploratory single-agent
cabozantinib (SAC) cohorts will also be enrolled with UC or NSCLC subjects.
1. Cytologically or histologically and radiologically confirmed solid tumor that is
inoperable, locally advanced, metastatic, or recurrent:
• Dose-Escalation Stage:
• Subjects with UC (including renal pelvis, ureter, bladder, urethra) after
prior platinum-based therapy, or
• Subjects with RCC (clear cell, non-clear cell histology) with or without
prior systemic anticancer therapy
• Expansion Stage:
• Inoperable locally advanced or metastatic solid tumor (UC, RCC, CRPC, NSCLC,
TNBC, OC, EC, HCC, GC/GEJC, CRC, H&N cancer, and DTC as outlined above)
2. Measurable disease per RECIST 1.1 as determined by the investigator.
3. Tumor tissue material available (archival or recent tumor biopsy)
4. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
5. Age eighteen years or older on the day of consent.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
7. Adequate organ and marrow function.
8. Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception.
9. Female subjects of childbearing potential must not be pregnant at screening.
Exclusion Criteria:
1. Prior treatment with cabozantinib or immune checkpoint inhibitors including
anti-CTLA-4, anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy except in Expansion Cohorts
5, 7,19 and 20. Other restrictions regarding prior therapy may apply.
2. Known brain metastases or cranial epidural disease unless adequately treated and
stable for at least 4 weeks before first dose of study treatment.
3. Concomitant anticoagulation with oral anticoagulants.
4. Subject is receiving systemic steroid therapy or any other form of immunosuppressive
therapy within 2 weeks prior to first dose of study treatment.
5. Administration of a live, attenuated vaccine within 30 days before first dose of study
treatment.
6. The subject has uncontrolled, significant intercurrent or recent illness, including,
but not limited to, an active or history of autoimmune disease or immune deficiency;
idiopathic pulmonary fibrosis, organizing pneumonia, pneumonitis; active infection
requiring systemic treatment, infection with human immunodeficiency virus (HIV),
AIDS-related illness, acute or chronic hepatitis B or C infection, positive test for
tuberculosis, moderate to severe hepatic impairment (Child-Pugh B or C).
7. Pregnant or lactating females.
8. Previously identified allergy or hypersensitivity to components of the study treatment
formulations.
9. Diagnosis of another malignancy within 2 years before first dose of study treatment.
A Study of Oral LOXO-292 (Selpercatinib) in Pediatric Participants With Advanced Solid or Primary Central Nervous System (CNS) Tumors (LIBRETTO-121)
This is an open-label, multi-center Phase 1/2 study of oral LOXO-292 in pediatric
participants with an activating rearranged during transfection (RET) alteration and an
advanced solid or primary CNS tumor.
• Advanced or metastatic solid or primary CNS tumor which has failed standard of care
therapies
• Evidence of an activating RET gene alteration in the tumor and/or blood
• Measurable or non-measurable disease
• Karnofsky (participants 16 years and older) or Lansky (participants younger than 16)
performance score of at least 50
• Participant with primary CNS tumors or cerebral metastases must be neurologically
stable for 7 days prior and must not have required increasing doses of steroids within
the last 7 days
• Adequate hematologic, hepatic and renal function.
• Ability to receive study drug therapy orally or via gastric access
• Willingness of men and women of reproductive potential to observe conventional and
effective birth control
Exclusion Criteria:
• Major surgery within two weeks prior to planned start of LOXO-292
• Clinically significant, uncontrolled cardiac, cardiovascular disease or history of
myocardial infarction within 6 months prior to planned start of LOXO-292
• Active uncontrolled systemic bacterial, viral, fungal or parasitic infection
• Clinically significant active malabsorption syndrome
• Pregnancy or lactation
• Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the participant
required a modification to current thyroid medication in the 7 days before start of
LOXO-292)
• Uncontrolled symptomatic hypercalcemia or hypocalcemia
• Known hypersensitivity to any of the components of the investigational agent, LOXO-292
or Ora-Sweet® SF and OraPlus®, for participants who will receive LOXO-292 suspension
• Prior treatment with a selective RET inhibitor(s) (including investigational selective
RET inhibitor[s])
Pembrolizumab Compared to Standard of Care Observation in Treating Patients With Completely Resected Stage I-III Merkel Cell Cancer, STAMP Study
This phase III trial studies how well pembrolizumab works compared to standard of care
observation in treating patients with stage I-III Merkel cell cancer that has been completely
removed by surgery (resected). 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.
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status: 0,
1, or 2 (However, those patients with a performance state of 3 because they are wheel
chair bound due to congenital or traumatic events more than one year before the
diagnosis of Merkel cell carcinoma are eligible).
• Women must not be pregnant or breast-feeding due to the unknown effects of the study
drug in this setting. All women of childbearing potential must have a blood test or
urine study within 2 weeks 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: 1) has achieved
menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy;
or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does
not rule out childbearing potential) for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months).
• Women of childbearing potential, and sexually active males, on Arm A MK-3475
(pembrolizumab must use accepted and effective method(s) of contraception or abstain
from sex from time of registration, while on study treatment, and continue for 120
days after the last dose of study treatment. For patients on Arm B only receiving
radiation therapy, contraception use should be per institutional standard.
• Patient must have a histological confirmation of diagnosis of Merkel cell carcinoma
(MCC), pathologic stages (American Joint Committee on Cancer [AJCC] version 8) I-IIIb.
• Stage I patients with negative sentinel lymph node biopsy are ineligible.
Patients who have a positive biopsy or for whom no biopsy was done are eligible.
• Patients with distant metastatic disease (stage IV) are not eligible.
• The primary tumor must have grossly negative margins. (Microscopically positive
margins are allowed).
• Cancers of unknown primary that have regional disease only can be included.
• Complete nodal dissection is not required for eligibility.
• Patients with all macroscopic Merkel cell carcinoma (either identified by physical
exam or imaging) have been completely resected by surgery within 16 weeks before
registration.
• All patients must have disease-free status documented by a complete physical
examination and conventional imaging studies within 8 weeks prior to registration.
• Patient may not have a history of distant metastatic disease.
• NOTE: Loco-regional recurrent disease is acceptable, as long as this is not
metastatic (prior surgery with or without radiation therapy is acceptable).
• For patients with initial presentation of Merkel cell carcinoma, patient must have no
previous systemic therapy or radiation therapy prior to surgery for Merkel cell
carcinoma and cannot have completed adjuvant radiation therapy for Merkel cell
carcinoma more than 6 weeks prior to registration. Patients actively undergoing
radiation therapy or having completed adjuvant radiation therapy within 6 weeks of
registration are eligible, as long as resection date is within 16 weeks of
registration.
• White blood count >= 2000/uL (within 4 weeks prior to randomization).
• Absolute neutrophil count (ANC) >= 1000/uL (within 4 weeks prior to randomization).
• Platelets >= 75 x 10^3/uL (within 4 weeks prior to randomization).
• Hemoglobin >= 8 g/dL (>= 80 g/L; may be transfused) (within 4 weeks prior to
randomization).
• Creatinine =< 2.0 x upper limit of normal (ULN) (within 4 weeks prior to
randomization).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
(within 4 weeks prior to randomization).
• Total bilirubin =< 2.0 x ULN, (except patients with Gilbert's syndrome, who must have
a total bilirubin less than 3.0 mg/dL) (within 4 weeks prior to randomization).
• Patients who are human immunodeficiency virus (HIV)+ with undetectable HIV viral load
are eligible provided they meet all other protocol criteria for participation.
• Patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are
eligible provided viral loads are undetectable. Patients on suppressive therapy are
eligible.
• Patients must not be on active immunosuppression, have a history of life threatening
virus, have had other (beside non-melanoma skin cancers, or recent indolent cancers
e.g.: resected low grade prostate cancer) invasive cancer diagnoses in the last two
years, or have had immunotherapy of any kind within the last 2 years.
• Patients must not have a history of (non-infectious) pneumonitis that required
steroids or has current pneumonitis.
• Operative notes from patient's surgical resection must be accessible.
Other: Best Practice, Biological: Pembrolizumab, Radiation: Radiation Therapy
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1)
Phase 1 dose escalation will determine the first cycle dose-limiting toxicities (DLTs), the
maximum tolerated dose (MTD), the biologically effective dose and recommended Phase 2 dose
(RP2D) of repotrectinib given to adult subjects with advanced solid malignancies harboring an
ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
Midazolam DDI substudy will examine effect of of repotrectinib on CYP3A induction.
Phase 2 will determine the confirmed Overall Response Rate (ORR) as assessed by Blinded
Independent Central Review (BICR) of repotrectinib in each subject population expansion
cohort of advanced solid tumors that harbor a ROS1, NTRK1, NTRK2, or NTRK3 gene
rearrangement. The secondary objective will include the duration of response (DOR), time to
response (TTR), progression-free survival (PFS), overall survival (OS) and clinical benefit
rate (CBR) of repotrectinib in each expansion cohort of advanced solid tumors that harbor a
ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement.
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) (Stage IV, American Joint Committee on
Cancer v.7) that harbors an ALK, ROS1, NTRK1, NTRK2, or NTRK3 gene rearrangement by
protocol specified tests.
2. ECOG PS 0-1.
3. Age ≥18 (or age ≥ 20 of age as required by local regulation).
4. Capability to swallow capsules intact (without chewing, crushing, or opening).
5. At least 1 measurable target lesion according to RECIST version 1.1. CNS-only
measurable disease as defined by RECIST version 1.1 is allowed.
6. Prior cytotoxic chemotherapy is allowed.
7. Prior immunotherapy is allowed.
8. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
9. Patients with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
10. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance Within normal limits or > 40 mL/min; Total serum bilirubin < 1.5 × ULN;
Liver transaminases (ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present
Alkaline phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are
present; Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or
without supplementation
11. Life expectancy ≥ 3 months.
PHASE 2 Key Inclusion Criteria
1. Histologically or cytologically confirmed diagnosis of locally advanced, or metastatic
solid tumor (including primary CNS tumors) that harbors a ROS1, or NTRK1-3 gene
fusion.
2. Subject must have a documented ROS1 or NTRK1-3 gene fusion determined by tissue-based
local testing using either:
1. a next-generation sequencing (NGS) or quantitative polymerase chain reaction
(qPCR) test will be accepted to determine molecular eligibility.
• Adequate tumor tissue needs to be sent to the Sponsor designated central
diagnostic laboratory for retrospective confirmation by a central diagnostic
laboratory test selected by the Sponsor.
OR
2. a fluorescence in situ hybridization (FISH) test AND prospective confirmation of
fusion status by a central diagnostic laboratory test selected by the Sponsor
PRIOR to enrollment will be accepted to determine molecular eligibility.
• Adequate tumor tissue must be sent to the Sponsor designated central
diagnostic laboratory for prospective confirmation by a central diagnostic
laboratory test selected by the Sponsor PRIOR to enrollment.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
4. Age ≥12 (or age ≥ 20 as required by local regulation).
5. Willing and able to provide written institutional review board (IRB)/institutional
ethics committee-approved Informed Consent or an Assent signed by a parent or legal
guardian for subjects age 12 to 17.
6. At least 1 measurable target lesion according to RECIST (v1.1) prospectively confirmed
by Blinded Independent Central Radiology Review (BICR), selected by Sponsor, PRIOR to
enrollment. Subjects with CNS-only measurable disease ≥10 mm as defined by RECIST
(v1.1) are eligible.
7. Subjects with advanced solid tumors harboring ROS1, NTRK1, NTRK2, or NTRK3
rearrangement will be assigned into 6 distinct expansion (EXP) cohorts provided all
inclusion and exclusion criteria are met.
i. EXP-1: ROS1 TKI-naïve ROS1+ NSCLC ii. EXP-2: 1 Prior ROS1 TKI and 1 Platinum based
chemo ROS1+ NSCLC iii. EXP-3: 2 Prior ROS1 TKIs ROS1+ NSCLC (No Chemo or IO) iv.
EXP-4: 1 Prior ROS1 TKI ROS1+ NSCLC (No Chemo or IO) v. EXP-5: TRK TKI-naïve NTRK+
solid tumors vi. EXP-6: TRK TKI-pretreated NTRK+ solid tumors
8. Subjects with asymptomatic CNS metastases (treated or untreated) and/or asymptomatic
leptomeningeal carcinomatosis are eligible to enroll if they satisfy the protocol
specified criteria.
9. Baseline laboratory values fulfilling the following requirements:Absolute neutrophils
count (ANC) ≥1500/mm3 (1.5 × 109/L); Platelets (PLTs) ≥100,000/mm3 (100 × 109/L);
Hemoglobin ≥ 9.0 g/dL transfusions are allowed; Serum creatinine or creatinine
clearance > 40 mL/min; Total serum bilirubin < 1.5 × ULN; Liver transaminases
(ASTs/ALTs) < 2.5 × ULN; < 5 × ULN if liver metastases are present Alkaline
phosphatase (ALP); < 2.5 × ULN; < 5 × ULN if liver and/or bone metastasis are present;
Serum calcium, magnesium, and potassium Normal or CTCAE grade ≤ 1 with or without
supplementation
10. Life expectancy ≥ 3 months.
Key Exclusion Criteria PHASE 1 and PHASE 2
1. Concurrent participation in another therapeutic clinical trial.
2. Symptomatic brain metastases or leptomeningeal involvement.
3. History of previous cancer, except for squamous cell or basal-cell carcinoma of the
skin, or any in situ carcinoma that has been completely resected, requiring therapy
within the previous 2 years.
4. Major surgery within 4 weeks of start of repotrectinib treatment. Radiation therapy
(except palliative to relieve bone pain) within 2 weeks of study entry. Palliative
radiation (≤10 fractions) must have been completed at least 48 hours prior to study
entry
5. Clinically significant cardiovascular disease (either active or within 6 months prior
to enrollment): myocardial infarction, unstable angina, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure (New York Heart Association
Classification Class ≥ II), cerebrovascular accident or transient ischemic attack,
symptomatic bradycardia, requirement for anti-arrhythmic medication. Ongoing cardiac
dysrhythmias of NCI CTCAE grade ≥2
6. Any of the following cardiac criteria:
Mean resting corrected QT interval (ECG interval measured from the onset of the QRS
complex to the end of the T wave) for heart rate (QTcF) > 470 msec obtained from 3
ECGs, using the screening clinic ECG machine-derived QTc value Any clinically
important abnormalities in rhythm, conduction or morphology of resting ECG (e.g.,
complete left bundle branch block, third degree heart block, second degree heart
block, PR interval > 250 msec) Any factors that increase the risk of QTc prolongation
or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT
syndrome, family history of long QT syndrome, or any concomitant medication known to
prolong the QT interval.
7. Known active infections (bacterial, fungal, viral including HIV positivity).
8. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
9. Peripheral neuropathy of CTCAE ≥grade 2.
10. History of extensive, disseminated, bilateral, or presence of CTCAE grade 3 or 4
interstitial fibrosis or interstitial lung disease including a history of pneumonitis,
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease,
obliterative bronchiolitis, and pulmonary fibrosis. Subjects with history of prior
radiation pneumonitis are not excluded.
A Study to Evaluate ONM-100, an Intraoperative Fluorescence Imaging Agent for the Detection of Cancer
This study is to evaluate diagnostic performance, safety and timing of post-dose imaging of
ONM-100, an intraoperative fluorescence imaging agent for the detection of cancer in patients
with solid tumors undergoing routine surgery.
• Biopsy-confirmed diagnosis of primary or recurrent respective tumor type and scheduled
to undergo surgical resection
• Part 1: Biopsy-confirmed diagnosis of head and neck squamous cell carcinoma (HNSCC) or
breast cancer
• Part 2: Biopsy-confirmed diagnosis of HNSCC, breast cancer, colorectal cancer,
prostate cancer, ovarian cancer, urothelial carcinoma and non-small cell lung cancer.
• Part 3: Stage 2 to 4 HNSCC Including T0 or Tx unknown Primary cancers
Exclusion Criteria:
• Histologically diagnosed by an excisional biopsy procedure
• Tumors at sites of which the surgeon would assess that in vivo intraoperative imaging
would not be feasible
• Life expectancy <12 weeks
• Hepatic impairment (Child-Pugh score >5) or significant liver disease including active
hepatitis or cirrhosis
Drug: ONM-100
Prostate Cancer, Non-Small Cell Lung Cancer, Breast Cancer, Colorectal Cancer, Ovarian Cancer, Head and Neck Squamous Cell Carcinoma, Urothelial Carcinoma, Breast - Female, Colon, Ovary, Prostate
AcceleRET Lung Study of Pralsetinib for 1L RET Fusion-positive, Metastatic NSCLC
This is an international, randomized, open-label, Phase 3 study designed to evaluate whether
the potent and selective RET inhibitor, pralsetinib, improves outcome when compared to a
platinum chemotherapy-based regimen chosen by the Investigator from a list of standard of
care treatments, as measured primarily by progression free survival (PFS), for patients with
RET fusion-positive metastatic NSCLC who have not previously received systemic anticancer
therapy for metastatic disease. Patients who have centrally confirmed progressive disease on
the control arm have the option to crossover to pralsetinib.
Main inclusion criteria:
• Patient is ≥18 years of age
• Patient has pathologically confirmed, definitively diagnosed, advanced (not able to be
treated with surgery or radiotherapy) or metastatic NSCLC and has not been treated
with systemic anticancer therapy for metastatic disease.
• Patient must have a documented RET-fusion
• Patient has measurable disease based on RECIST 1.1 as determined by the local site
Investigator/radiology assessment.
• Patient has an ECOG PS of 0-1.
• Patient should not have received any prior anticancer therapy for metastatic disease.
• Patients can have received previous anticancer therapy (except a selective RET
inhibitor) in the neoadjuvant or adjuvant setting but must have experienced an
interval of at least ≥ 6 months from completion of therapy to recurrence.
• Patients that received previous immune checkpoint inhibitors in the adjuvant or
consolidation following chemoradiation are not allowed to receive pembrolizumab
if randomized in Arm B
• Patient is an appropriate candidate for and agrees to receive 1 of the Investigator
choice platinum-based chemotherapy regimens if randomized to Arm B.
• Patient provides signed informed consent to participate in the study.
Main exclusion criteria:
• Patient's tumor has any additional known primary driver alterations other than RET,
such as targetable mutations of EGFR, ALK, ROS1, MET, and BRAF. Investigators should
discuss enrollment with Sponsor designee regarding co-mutations.
• Patient previously received treatment with a selective RET inhibitor.
• Patient received radiotherapy or radiosurgery to any site within 14 days before
randomization or more than 30 Gy of radiotherapy to the lung in the 6 months before
randomization.
• Patient has a presence of Grade 2 or worse interstitial lung disease or interstitial
pneumonitis, including radiation pneumonitis within 28 days before randomization.
• Patient has CNS metastases or a primary CNS tumor that is associated with progressive
neurological symptoms or requires increasing doses of corticosteroids to control the
CNS disease. If a patient requires corticosteroids for management of CNS disease, the
dose must have been stable for the 2 weeks before Cycle 1 Day 1.
Carcinoma, Non-Small-Cell Lung, Carcinoma, Neoplasms by Site, Neoplasms, Head and Neck Neoplasms, Carcinoma, Bronchogenic, Respiratory Tract Neoplasms, Thoracic Neoplasms, Neoplasms, Nerve Tissue, Lung Diseases, Respiratory Tract Disease, Lung/Thoracic, RET-fusion Non Small Cell Lung Cancer, Lung Neoplasm, Bronchial Diseases, Adenocarcinoma, Neoplasms by Histologic Type, Neoplasms, Germ Cell and Embryonal
Advanced Non-Small Cell Lung Cancer, RET Lung, RET Mutation, RET Alteration, RET Positive, RET Inhibitor, RET Altered, RET Rearrangement, RET NSCLC, RET-Rearranged NSCLC, RET Fusion, RET Fusion Lung Cancer, M918T, TRIM33-RET, Lung Cancer Mutation, BLU 667, Pralsetinib, RET Tyrosine Kinase, RET Gene Mutation, RET Kinase, Advanced Lung Cancer, Metastatic Lung Cancer, KIF5B-RET, CCDC6-RET
A Study of LOXO-292 in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRETTO-001)
This is a Phase 1/2, 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:
• Without measurable disease but otherwise meet criteria for Cohorts 1 and 2;
• 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 due to intolerance may be eligible with prior
Sponsor approval
• Cohort 7: Participants must have a histologically confirmed stage IB-IIIA NSCLC by
AJCC (The American Joint Committee on Cancer) version 8. The tumor must have been
deemed resectable by a thoracic surgeon, the participant must be determined to be
medically operable based on the determination of a thoracic surgeon, and the
participant must not have received prior systemic therapy, including prior radiation
therapy, 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 4 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)
• Required treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or
inducers and certain prohibited concomitant medications