PRIMARY OBJECTIVE:
I. To determine whether cabozantinib alone, or the combination of nivolumab and cabozantinib,
as compared to standard chemotherapy alone, extends progression-free survival (PFS) for this
patient population with non squamous NSCLC.
SECONDARY OBJECTIVES:
I. To evaluate the progression free survival (PFS) and best overall radiographic response
rate of the targeted therapy arm of the trial.
II. To determine the overall survival for each arm of the trial. III. To evaluate the best
overall radiographic response rate for each arm of the trial.
IV. To evaluate and describe the toxicity profile of monotherapy with cabozantinib, and the
combination of nivolumab and cabozantinib in this patient population with non-squamous NSCLC.
EXPLORATORY IMAGING OBJECTIVES:
I. To describe time point tumor response assessment, overall best response, progression-free
survival and overall survival using the conventional Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 criteria and the exploratory revised CHOI criteria with all measurements
performed by the central review.
II. To compare the progression-free survival using the RECIST1.1 imaging response assessment
measurements by site study personnel to those performed by central review.
EXPLORATORY CORRELATIVE OBJECTIVE:
I. To perform correlative biomarker research on tissue and blood biospecimens collected
within this trial.
OUTLINE: Patients without known molecular alterations are randomly assigned to 1 of 3 arms.
Patients with known molecular alterations are assigned to Arm B.
ARM A: Patients receive cabozantinib S-malate orally (PO) once daily (QD). Cycles repeat
every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients may
continue to receive therapy after investigator-assessed RECIST 1.1 defined progression,
including stable clinical and performance status and have potential for continued clinical
benefit.
ARM B: Patients receive cabozantinib S-malate PO QD and nivolumab intravenously (IV) over 30
minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or
unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed
RECIST 1.1 defined progression, including stable clinical and performance status and have
potential for continued clinical benefit.
ARM C:
STEP 1: Patients receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on
day 1, or docetaxel IV over 1 hour on day 1 or on days 1 and 8, or gemcitabine hydrochloride
IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30
minutes on days 1, 8, and 15. Cycles repeat every 3 weeks in the absence of disease
progression or unacceptable toxicity and at the discretion of the treating physician.
Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined
progression, including stable clinical and performance status and have potential for
continued clinical benefit.
STEP 2: Patients receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day
1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable
toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1
defined progression, including stable clinical and performance status and have potential for
continued clinical benefit.
After the completion of study treatment, patients are followed up every 3 months for up to 3
years.
Inclusion Criteria:
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have pathologically
confirmed non-squamous non-small cell lung carcinoma (NSCLC)
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have stage IV disease
(includes M1a, M1b, or recurrent earlier stage disease), according to the 8th edition
of the lung cancer Tumor Node Metastasis (TNM) classification system
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have predominant
non-squamous histology (patients with NSCLC no otherwise specified [NOS] are
eligible). Mixed tumors will be categorized by the predominant cell type. If small
cell elements are present the patient is ineligible
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient's tumor(s) must be tested
and known negative for EGFR tyrosinase kinase inhibitor (TKI) sensitizing mutations
(EGFR Exon 19 deletions, L858R, L861Q, G719X) and ALK gene rearrangements (by
fluorescence in situ hybridization [FISH], next generation sequencing [NGS], or
immunohistochemistry [IHC]) by routine Clinical Laboratory Improvement Act
(CLIA)-certified clinical testing methods. Negative circulating tumor deoxyribonucleic
acid (DNA) results alone are not acceptable. Prior testing for tumor PD-L1 status is
not required
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients WITHOUT tumors with known
molecular alterations in ROS1, MET, RET, or must have progressed radiographically (per
local investigator assessment) following one, but only one, line of platinum-based
chemotherapy AND one, but only one, line of prior immunotherapy. Lines of therapy are
defined by clinical or radiographic progression. Patients may have received
chemotherapy and immunotherapy either concurrently or sequentially in either order.
Patient must have received at least 2 prior doses of checkpoint inhibitor therapy in
an every 2, 3, or 4 week schedule. No submission of molecular testing is required and
patients may be registered for Step 0 then proceed directly to Step 1 screening OR
Patients with tumors with known molecular alterations in ROS1, MET, and RET must have
progressed radiographically (per local investigator clinical assessment) on at least
one line of prior chemotherapy or targeted therapy, but there is no limit on number of
prior number. Reciept of prior immunotherapy is allowed but not required.
- Known molecular alterations in ROS1 , MET, and RET are defined as below ROS1 gene
rearrangement by FISH or DNA analysis. In addition to above requirements, these
patients must have progressed on at least one prior ROS1 TKI therapy
- MET exon 14 splice mutations on DNA analysis. In addition to above requirements,
prior MET directed TKI therapy is optional
- MET mutations predicted to be sensitive to MET inhibitor. In addition to above
requirements, prior MET directed TKI therapy is optional
- High MET amplification by FISH (characterized by a fluorescence in situ
hybridization MET/CEP7 ratio of 5 or greater); OR MET amplification by DNA NGS
CLIA certified assay. In addition to above requirements, prior MET directed TKI
therapy is optional
- RET gene rearrangement by FISH or DNA analysis. In addition to above
requirements, prior RET directed TKI therapy is optional
- During Step 0 screening, CLIA reports of the testing results must be
submitted via Medidata Rave for central review for instructions. The central
review will be performed by the study chair, co-chair, biology co-chair,
and/or a delegate to determine that the results indicate a patient's
eligibility for targeted therapy. CLIA reports that contain information
pertaining to any of the above mutations will be uploaded to Medidata Rave
for central review of documentation for determination of patient eligibility
for targeted therapy (Arm T). Central testing of tissue will not be
performed. Institutions will be notified of the patient's eligibility status
for Arm T within two (2) business days of submission of the molecular
testing reports. Patients with tumors with the above known molecular
alterations are eligible for cohort Arm Z following Step 1 eligibility
review. Patients without tumors with the above known molecular alterations
for randomization to Arm A, B or C following Step 1 eligibility review
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): NOTE: 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
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patients with known history or
current symptoms of cardiac disease, or history of treatment with cardiotoxic agents
(such as anthracycline or human epidermal growth factor receptor (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
- ELIGIBILITY CRITERIA FOR STEP 0 (PRE-REGISTRATION): Patient must have Eastern
Cooperative Oncology Group (ECOG) performance status 0-1
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must have met the eligibility criteria outlined above
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must have measurable disease as defined by RECIST version (v) 1.1 criteria.
Measurements must be obtained within 4 weeks prior to randomization/registration
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must have an anticipated life expectancy greater than 3 months
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Any prior chemotherapy (based on administration schedule) must have been completed in
greater than or equal to the following times prior to randomization/registration:
- Chemotherapy/targeted oral therapy administered in a daily or weekly schedule
must be completed >= 1 week prior to randomization/registration
- Any chemotherapy administered in an every 2 week or greater schedule must be
completed >= 2 weeks prior to randomization/registration
- Additionally, patient should be recovered to equal to or less than grade 1
toxicities related to any prior treatment, unless adverse events (AE[s]) are
clinically non significant and/or stable on supportive therapy (as determined by
the treating physician)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Leukocytes >= 3,000/mcL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Absolute neutrophil count >= 1,500/mcL (obtained within 2 weeks prior to
randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Platelets >= 100,000/mcL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Hemoglobin >= 9 g/dL (obtained within 2 weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained within 2
weeks prior to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR 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/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Creatinine =< 1.5 x ULN OR calculated (Cockcroft-Gault formula) or measured creatinine
clearance >= 50 mL/min/1.73 m^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 >= 50 ml/min/1.73 m^2 (obtained within 2 weeks prior
to randomization/registration)
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must have corrected QT interval calculated by the Fridericia formula QTc
corrected by Fridericia (QTcF) =< 500 ms within 28 days prior to
randomization/registration
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must be able to swallow tablets
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patients with new or progressive brain metastases (active brain metastases) are
eligible if the treating physician determines that immediate CNS specific treatment is
not required and is unlikely to be required during the first cycle of study treatment.
- Patient must meet one of the following criteria with respect to brain metastases:
Patients with no known brain metastasis must have baseline brain imaging within
12 weeks prior to study randomization/registration not demonstrating brain
metastases OR patients with known brain metastases must have baseline brain
imaging and completed treatment to all symptomatic brain metastases (with whole
brain radiation or radiosurgery; or complete neurosurgical resection >= 3 months
prior to randomization/registration) >= 4 weeks prior to
randomization/registration. They must be clinically stable. Known leptomeningeal
disease is not allowed
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Known human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy with undetectable viral load within 6 months of registration
are eligible for this trial
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
For patients with known history of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy at time of
registration/randomization, if indicated
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR 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
registration/randomization
- ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient was
registered to step 0, targeted arm and central review results report the patient is
eligible for arm T
- ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patients
with ROS1 gene rearrangements must have progressed on at least one prior ROS1 targeted
therapy such as crizotinib
- ADDITIONAL ELIGIBILITY CRITERIA FOR STEP 1 (REGISTRATION) TARGETED ARM T: Patient must
have progressed radiographically (per local investigator clinical assessment) on at
least one line of prior chemotherapy or targeted therapy, but there is no limit on
number of prior number. Prior immunotherapy is allowed but not required. Prior
bevacizumab with chemo is allowed.
- NOTE: The requirement for prior chemotherapy will be met if patients have
recurrence within 6 months after prior adjuvant platinum based chemotherapy for
early stage disease, or recurrence within 6 months after prior radiotherapy plus
platinum based chemotherapy for locally advanced disease
- NOTE: Patients with unresectable stage III NSCLC who have received chemo and
radiation then consolidation durvalumab, followed by progression are eligible if
progression happens after > 2 doses of durvalumab. Prior bevacizumab with chemo
is also allowed
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have met all eligibility
requirements for Step 1 at time of registration to Step 1 to be eligible for Step 2
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have radiographic
progressive disease per RECIST criteria after >= 2 cycles of therapy on arm C
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must be registered to step 2
within 4 weeks of the last dose of treatment administration from step 1
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have an ECOG performance
status between 0-2
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have recovered to
baseline (pre-step 1) or Common Terminology Criteria for Adverse Events (CTCAE) v.5.0
=< grade 1 from toxicity due to all prior therapies except alopecia and other
non-clinically significant adverse events (AEs)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Leukocytes >= 3,000/mcL (obtained
within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Absolute neutrophil count >= 1,500/mcL
(obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Platelets >= 100,000/mcL (obtained
within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Hemoglobin >= 9 g/dL (obtained within 2
weeks prior to randomization/registration)
- Total bilirubin =< 1.5 x institutional ULN (obtained within 2 weeks prior to
randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): 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/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Creatinine =< 1.5 x ULN OR calculated
(Cockcroft-Gault formula) or measured creatinine clearance >= 50 mL/min/1.73 m^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 >= 50 ml/min/1.73
m^2 (obtained within 2 weeks prior to randomization/registration)
- STEP 2 ELIGIBILITY CRITERIA (CROSSOVER ARM Z): Patients must have corrected QT
interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before
registration
Exclusion Criteria:
- ELIGIBILITY CRITERIA FOR STEP 1 (RANDOMIZATION/REGISTRATION) FOR ALL TREATMENT ARMS:
Patient must not have had any prior radiation therapy for bone metastasis within 2
weeks, or any other radiation therapy within 4 weeks prior to
randomization/registration
- ELIGIBILITY CRITERIA FOR STEP
