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Testing the Addition of the Pill Chemotherapy, Cabozantinib, to the Standard Immune Therapy Nivolumab Compared to Standard Chemotherapy for Non-small Cell Lung Cancer
Not Recruiting
Trial ID: NCT04310007
Purpose
This phase II trial compares cabozantinib alone and the combination of cabozantinib and
nivolumab to standard chemotherapy in the treatment of patients with non-squamous non-small
cell lung cancer (NSCLC). Cabozantinib may stop the growth of tumor cells by blocking some of
the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as
nivolumab, may help the body's immune system attack the cancer, and may interfere with the
ability of tumor cells to grow and spread. Ramucirumab is a monoclonal antibody that may
interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs, such as
docetaxel, gemcitabine hydrochloride, paclitaxel, and nab-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. Giving cabozantinib alone or in combination
with nivolumab may be more effective than standard chemotherapy in treating patients with
non-small cell lung cancer.
Official Title
A Randomized Phase II Trial of Cabozantinib and Cabozantinib Plus Nivolumab Versus Standard Chemotherapy in Patients With Previously Treated Non-Squamous NSCLC
Stanford Investigator(s)
Joel Neal, MD, PhD
Associate Professor of Medicine (Oncology)
Eligibility
Inclusion Criteria:
- RANDOMIZATION (STEP 1): Patient must be >= 18 years of age
- RANDOMIZATION (STEP 1): Patient must have pathologically confirmed non-squamous
non-small cell lung carcinoma (NSCLC). Patients with NSCLC not otherwise specified
(NOS) are eligible. Mixed tumors will be categorized by predominant cell type. If
small cell elements are present, the patient is ineligible
- RANDOMIZATION (STEP 1): Patient must have metastatic Stage IVA or IVB disease
(includes M1a, M1b, and M1c), according to the 8th edition of the lung cancer TNM
classification system. Recurrent metastatic NSCLC ineligible for curative therapy (in
the treating investigator's opinion) is also allowed
- RANDOMIZATION (STEP 1): Patient's tumor must be known negative for EGFR tyrosine
kinase inhibitor (TKI) sensitizing mutations (for example at a minimum, negative for
EGFR Exon 19 deletions, EGFR exon 20 insertions, and Exon 21 L858R, L861Q mutations )
AND negative for ALK gene rearrangements (by fluorescence in situ hybridization
[FISH], next generation sequencing [NGS], or immunohistochemistry [IHC]) by routine
Clinical Laboratory Improvement Act (CLIA)- or Food and Drug Administration
(FDA)-certified clinical testing methods. CLIA or FDA approved circulating tumor
deoxyribonucleic acid (DNA) testing is acceptable as an alternative to tissue testing
- RANDOMIZATION (STEP 1): Patient must have radiographic and/or clinical progression
(per local investigator assessment) following one, but only one, line of
platinum-based chemotherapy AND one, but only one, line of prior checkpoint inhibitor
(anti-PD-1 or PD-L1) immunotherapy, either concurrently or sequentially in either
order. A minimum of two doses of prior immunotherapy is required. Only one prior line
of therapy is allowed if patients received chemotherapy and immunotherapy together
(patients may not receive subsequent single agent chemotherapy), and greater than two
prior lines of therapy are not allowed.
- NOTE: Lines of therapy are defined by clinical or radiographic progression. For
patients with recurrent metastatic NSCLC following treatment for stage 1-3 NSCLC,
platinum-based chemotherapy received within 12 months of recurrence and/or
immunotherapy received within 6 months of recurrence will meet the requirement
for prior chemotherapy and/or immunotherapy but subsequent receipt of more
immunotherapy and/or platinum-based chemotherapy is also allowed.
- NOTE: Prior anti-VEGF antibody therapy (ie bevacizumab) is allowed. Prior
ipilimumab, or investigational agents not excluded below, in combination with the
required prior therapies above are allowed.
- NOTE: Prior receipt of one or two lines of targeted therapy for ROS1, RET, MET,
BRAF, ERBB2/HER2, or KRAS G12C positive NSCLC is allowed and will not count
toward the line of therapy limit. However, progression is still required after
chemotherapy and immunotherapy as above. Patients with ROS1, RET, MET positive
NSCLC are strongly encouraged to get appropriate targeted therapy (such as
crizotinib, entrectinib, lorlatinib, selpercatinib, pralsetinib, capmatinib,
tepotinib, or another investigational, off-label, or approved agent directed
against ROS1, RET, or MET positive NSCLC) prior to participation and will be
stratified.
- NOTE: No prior predominantly VEGFR directed TKI therapy (such as cabozantinib,
lenvatinib, or sitravantinib) is allowed, except for the agents named above.
- RANDOMIZATION (STEP 1): The investigator must document the intended chemotherapy
regimen should their patient be randomized to Arm C (docetaxel and ramucirumab, OR
single agent chemotherapy - docetaxel, gemcitabine, paclitaxel, nab-paclitaxel). The
patient must not have received the selected chemotherapy agent previously for
metastatic disease
- RANDOMIZATION (STEP 1): Any prior chemotherapy (based on administration schedule) must
have been completed in greater than or equal to the following times prior to
randomization:
- FDA approved targeted oral therapy must be completed >= 1 week prior
- Chemotherapy and/or immunotherapy must be completed >= 2 weeks prior
- Prior investigational agents must be completed >= 4 weeks prior.
- RANDOMIZATION (STEP 1): Prior radiation therapy is allowed with a 2 week washout prior
to randomization. Patient must not receive any systemic treatment with radionuclides
within 6 weeks prior to randomization. Patient must have no clinically relevant
ongoing complication from prior radiation therapy
- RANDOMIZATION (STEP 1): Patients with a prior or concurrent malignancy whose natural
history or treatment does not have the potential to interfere with the safety or
efficacy assessment of the investigational regimen (in the opinion of the treating
physician) are eligible for this trial
- RANDOMIZATION (STEP 1): Patients with known history or current symptoms of cardiac
disease, or history of treatment with cardiotoxic agents (such as anthracycline or
HER2-directed antibody therapy, but not prior checkpoint inhibitor therapy), must have
a clinical risk assessment of cardiac function using the New York Heart Association
Functional Classification. To be eligible for this trial, patients must be class 2B or
better
- RANDOMIZATION (STEP 1): Patient must have Eastern Cooperative Oncology Group (ECOG)
performance status 0-1
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have met the eligibility
criteria outlined above
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have measurable disease as
defined by RECIST v1.1. Measurements must be obtained within 4 weeks prior to
randomization/registration
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have recovered to equal to
or less than grade 1 toxicities related to prior treatment, unless toxicities are
clinically non significant and/or stable on supportive therapy (as determined by the
treating physician)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Absolute neutrophil count >= 1,500/mcL
(obtained within 2 weeks prior to randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Platelets >= 100,000/mcL (obtained within
2 weeks prior to randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Hemoglobin >= 9 g/dL (obtained within 2
weeks prior to randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Total bilirubin =< 1.5 x institutional
upper limit of normal (ULN) (for patients with Gilbert's disease total bilirubin must
be =< 3 x ULN) (obtained within 2 weeks prior to randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Aspartate aminotransferase (AST)(serum
glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT)(serum
glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained within 2 weeks prior to
randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Creatinine =< 1.5 x ULN OR calculated
(Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73m^2
(normalized to body surface area [BSA]) for patients with creatinine levels greater
than 1.5 times the institutional normal creatinine =< 1.5 X ULN or creatinine
clearance >= 50ml/min/1.73m^2 (obtained within 2 weeks prior to randomization)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must have corrected QT interval
calculated by the Fridericia formula (QTcF) =< 500 msec within 28 days prior to Step 1
randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must be able to swallow tablets
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with brain metastases are
eligible as follows:
- Previously treated brain metastases must have been treated with radiation > 2
weeks prior to randomization or surgery > 3 months prior to randomization OR
- Untreated (active) brain metastases are allowed if they are clinically
asymptomatic, < 1 cm, non-hemorrhagic, the patient is not on systemic
anticoagulation, and the investigator believes that central nervous system (CNS)
specific treatment is unlikely to be required during the first 3 months of study
treatment.
- NOTE: Symptomatic leptomeningeal disease is NOT allowed
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of human
immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy
with undetectable viral load within 6 months of randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with known history of chronic
hepatitis B virus (HBV) infection must have undetectable HBV viral at time of
randomization (suppressive therapy is allowed, if indicated)
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients with a known history of
hepatitis C virus (HCV) infection must have been treated and cured. For patients with
HCV infection who are currently on treatment, they are eligible if they have an
undetectable HCV viral load at time of randomization
- STEP 2 (CROSSOVER ARM Z): Patient must have met all eligibility requirements for Step
1 at time of registration to Step 1 to be eligible for Step 2
- STEP 2 (CROSSOVER ARM Z): Patient must have radiographic progressive disease per
RECIST criteria after >= 2 cycles of therapy on Arm C. The scan showing progression
must be completed within 6 weeks prior to Step 2 registration
- STEP 2 (CROSSOVER ARM Z): Patient must have an ECOG performance status 0-2
- STEP 2 (CROSSOVER ARM Z): Patient must have recovered to equal to or less than grade 1
toxicities related to prior treatment, unless the adverse event(s) are clinically non
significant and/or stable on supportive therapy (as determined by the treating
physician)
- STEP 2 (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL (obtained within 2
weeks prior to registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained within 2 weeks prior to
registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to
registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): Total bilirubin =< 1.5 x institutional ULN (for patients
with Gilbert's disease total bilirubin must be =< 3 x ULN) (obtained within 2 weeks
prior to registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): AST(SGOT) and ALT(SGPT) =< 2.5 x ULN (obtained within 2
weeks prior to registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault
formula) or measured creatinine clearance >= 50 mL/min/1.73m^2 (normalized to BSA) for
patients with creatinine levels greater than 1.5 times the institutional normal
creatinine =< 1.5 X ULN or creatinine clearance >= 50ml/min/1.73m^2 (obtained within 2
weeks prior to registration to Step 2)
- STEP 2 (CROSSOVER ARM Z): Patient must have corrected QT interval calculated by the
Fridericia formula (QTcF) =< 500 ms within 28 days prior to Step 2 registration
Exclusion Criteria:
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not be pregnant or
breast-feeding due to the unknown effects of cabozantinib and nivolumab on human
development and for the potential risk for adverse events in nursing infants with the
treatment regimens being used.
- All patients of childbearing potential must have a blood test or urine study
within 14 days prior to randomization/registration to rule out pregnancy.
- A patient of childbearing potential is anyone, 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).
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not expect to conceive or
father children by using accepted and effective method(s) of contraception or by
abstaining from sexual intercourse for the duration of their participation in the
study and for 6 months after completion of treatment on the study
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have clinically
significant gastrointestinal bleeding within 6 months prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have pulmonary
hemorrhage or hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months
prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have active drug
induced pneumonitis within 3 months prior to randomization. Prior immune mediated
pneumonitis of grade 3 or 4 are not eligible regardless of time window
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have current
radiographic evidence of tumor invading major blood vessel, evidence of tumor
cavitation > 1 cm, evidence of tumor invading the gastrointestinal (GI) tract
(esophagus, stomach, small or large bowel, rectum or anus), or evidence of
endotracheal or mainstem endobronchial tumor
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have peptic ulcer
disease, known malabsorption syndrome, bowel obstruction or gastric outlet obstruction
within 3 months prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have abdominal fistula,
GI perforation, or intra-abdominal abscess within 6 months prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have grade 3 or greater
infection, or infection requiring intravenous systemic treatment within 14 days prior
to randomization. Patients must be off antibiotics at the time of randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have serious
non-healing wound/ulcer/bone fracture within 28 days prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of organ
transplant
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent
symptomatic untreated hypothyroidism
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have history of major
surgery within 3 months prior to randomization, minor surgery within 28 days prior to
randomization, other minor procedures within 7 days prior to randomization, or
clinically relevant ongoing complications from prior procedures
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have concurrent
uncontrolled hypertension defined as sustained blood pressure (BP) > 160 mm Hg
systolic, or > 100 mm Hg diastolic despite optimal antihypertensive treatment
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have unstable angina
pectoris, clinically-significant cardiac arrhythmias, stroke (including transient
ischemic attack [TIA]), or myocardial infarction within 6 months prior to
randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patients must not have a diagnosis of
deep vein thrombosis/pulmonary embolism (DVT/PE) within 6 months of randomization
unless stable, asymptomatic, and treated with low-molecular-weight heparin (LMWH) or a
permitted oral anticoagulant for at least 7 days before randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be receiving
anticoagulants (i.e., warfarin, aspirin, clopidogrel) except:
- Prophylactic use of low-dose aspirin (100 mg po daily or less) and/or low dose
molecular weight heparin (LMWH) is permitted.
- Therapeutic doses of low dose molecular weight heparin (LMWH) or specified direct
factor Xa inhibitors rivaroxaban, edoxaban, or apixaban are allowed in patients
without untreated brain metastases who are on a stable dose 7 days prior to study
randomization, and without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not receive strong CYP3A4
inducers (e.g., dexamethasone (> 1 mg daily dosing), phenytoin, carbamazepine,
rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort) within 7 days
prior to randomization
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not be on continuous
systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or
other immunosuppressive medications within 7 days prior to randomization, with the
following exceptions:
- Inhaled or topical steroids and adrenal replacement doses =< 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune disease.
- Patients are permitted to use topical, ocular, intra-articular, intranasal, and
inhalational corticosteroids (with minimal systemic absorption).
- Physiologic replacement doses of systemic corticosteroids are permitted, if < 10
mg/day prednisone equivalents. A brief course of corticosteroids for prophylaxis
(e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
delayed-type hypersensitivity reaction caused by contact allergen) is permitted
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have known active
autoimmune disease or known history of autoimmune disease for which recurrence may
affect vital organ function or require immune suppressive treatment including systemic
corticosteroids (e.g., immune-related neurologic disease, multiple sclerosis,
autoimmune neuropathy, Guillain-Barre syndrome, etc.).
- RANDOMIZATION (STEP 1 - ALL TREATMENT ARMS): Patient must not have had any prior
allergic reaction or hypersensitivity to study drug components or related drugs
(multitargeted small molecule tyrosine kinase inhibitors or checkpoint inhibitor
monoclonal antibodies)
- STEP 2 (CROSSOVER ARM Z): Patient must not have intervening anticancer treatment or
major surgical procedure(s) between Step 1 and Step 2, except palliative radiation
which was completed >= 1 week prior to registration to Step 2
- STEP 2 (CROSSOVER ARM Z): Patient may not have central nervous system progression, but
patients with stable CNS disease are allowed
- STEP 2 (CROSSOVER ARM Z): Patient must not have any intercurrent illness or disease
complication that the investigator believes would limit the ability to safely tolerate
the combination of cabozantinib and nivolumab
- STEP 2 (CROSSOVER ARM Z): Patient must not be pregnant or breast-feeding due to the
unknown effects of cabozantinib and nivolumab on human development and for the
potential risk for adverse events in nursing infants with the treatment regimens being
used.
- All patients of childbearing potential must have a blood test or urine study
within 14 days prior to registration to Step 2 to rule out pregnancy.
- A patient of childbearing potential is anyone, 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).
- STEP 2 (CROSSOVER ARM Z): Patients must not expect to conceive or father children by
using accepted and effective method(s) of contraception or by abstaining from sexual
intercourse for the duration of their participation in the study and for 6 months
after completion of treatment on the study
Intervention(s):
drug: Cabozantinib S-malate
drug: Docetaxel
drug: Gemcitabine Hydrochloride
drug: Nab-paclitaxel
biological: Nivolumab
drug: Paclitaxel
biological: Ramucirumab
procedure: Biospecimen Collection
procedure: Computed Tomography
procedure: Echocardiography
Not Recruiting
Contact Information
Stanford University
School of Medicine
300 Pasteur Drive
Stanford,
CA
94305
Martina Steffen
650.721.3572