| Eligibility |
Inclusion Criteria:
1. The subject has a histologic or cytologic diagnosis of colorectal adenocarcinoma that
is metastatic or unresectable;
- The patient either did not tolerate, is refractory to or progressed (or relapsed)
following treatment with a fluoropyrimidine, irinotecan, oxaliplatin, and
bevacizumab;
- Prior epidermal growth factor inhibitor therapy is required for patients with
left-sided, RAS wild-type tumors;
- Patients must be microsatellite stable (MSS), microsatellite-low (MSI-L) or have
proficient mismatch repair (pMMR;
- Prior TAS-102 (Lonsurf) treatment is not required;
- Patients must have known extended RAS and BRAF status as per local standard of
practice;
2. Measurable disease per RECIST v.1.1 as determined by the investigator;
3. The subject has had an assessment of all known disease sites e.g. by computerized
tomography (CT) scan and/or magnetic resonance imaging (MRI) within 28 days before the
first dose of cabozantinib;
4. The subject is = 18 years old on the day of consent;
5. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0
or 1;
6. Recovery to baseline or = Grade 1 CTCAE v.5.0 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy;
7. Adequate archival tissue available from primary or metastatic site for biomarker
analysis (20 unstained FFPE slides and/or tumor block with minimum of 15 slides needed
for eligibility). Tissue from the primary site is preferable for analysis, but if
unavailable, tissue from a metastatic site may be utilized;
8. 1. Subjects enrolled in Part 2 of this study must have a site of disease that is
amenable to biopsy and be a candidate for tumor biopsy prior to the first dose of
study drug to be considered for this study;
1. 20 subjects enrolled in Part 2 of the study will be required to undergo mandatory
pre- and on-treatment tumor biopsies.
2. 12 subjects enrolled in Part 2 of the study will not be required to undergo a
mandatory tumor biopsy and thus not required to have disease amenable to biopsy;
9. The subject has organ and marrow function and laboratory values as follows within 7
days before the first dose of study treatment:
1. The ANC = 1.5 x 109/L without colony stimulating factor support;
2. White blood cell count = 2.5 x 109/L;
3. Platelets = 100 x 109/L without transfusion;
4. Hemoglobin = 9 g/dL;
5. Total bilirubin = 1.5 x ULN. For subjects with known Gilbert's disease, bilirubin
= 3.0 mg/dL;
6. Serum albumin = 2.8 g/dl;
7. Serum creatinine = 1.5 x ULN or creatinine clearance (CrCl) = 40 mL/min. For
creatinine clearance estimation, the Cockcroft and Gault equation should be used:
i. Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); ii. Female:
Multiply above result by 0.85; h. ALT and AST = 3.0 x ULN in patients without hepatic
metastases; ALT and AST = 5.0 x ULN in patients with hepatic metastases; i. Lipase <
2.0 x the upper limit of normal and no radiologic or clinical evidence of
pancreatitis; j. UPCR = 1 mg/mg (= 113.2 mg/mmol), or 24-h urine protein = 1 g; k.
Serum phosphorus, calcium, magnesium and potassium = LLN.
10. The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document;
11. Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and 5
months after the last dose of study treatment (i.e., 30 days (duration of ovulatory
cycle) plus the time required for the investigational drug to undergo approximately
five half-lives);
12. Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and 7
months after the last dose of study treatment (i.e., 90 days (duration of sperm
turnover) plus the time required for the investigational drug to undergo approximately
five half-lives);
Exclusion Criteria:
1. Known microsatellite-high (MSI-H) or deficient mismatch repair (dMMR) colorectal
cancer.
2. The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g. cytokines or antibodies) within 3 weeks, or
nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment;
3. Prior treatment with cabozantinib or other small molecule kinase inhibitors;
4. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody or any
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways;
5. Radiation therapy for bone metastasis within 2 weeks, any other external radiation
therapy within 4 weeks before the first dose of study treatment. Systemic treatment
with radionuclides within 6 weeks before the first dose of study treatment. Subjects
with clinically relevant ongoing complications from prior radiation therapy are not
eligible;
6. The subject has received any other type of investigational agent within 28 days before
the first dose of study treatment;
7. Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before the first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of the start of study
treatment;
8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test =
1.3 x the laboratory ULN within 7 days before the first dose of study treatment;
9. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran). Direct factor Xa inhibitor betrixaban, or platelet
inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
guidelines) and low-dose low molecular weight heparins (LMWH).
2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
are on a stable dose of the anticoagulant for at least 1 week before first dose
of study treatment without clinically significant hemorrhagic complications from
the anticoagulation regimen or the tumor;
10. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment;
11. The subject has radiographic evidence of cavitating pulmonary lesion(s) or known
endobronchial disease manifestation;
12. The subject has tumor invading or encasing any major blood vessels;
13. The subject has evidence of clinically significant bleeding from tumor invading the GI
tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of
endotracheal or endobronchial tumor within 28 days before the first dose of study
treatment;
14. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York
Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of
screening; ii. Concurrent uncontrolled hypertension defined as sustained blood
pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study treatment; iii.
Any history of congenital long QT syndrome; iv. Any of the following within 6 months
before the first dose of study treatment:
- unstable angina pectoris;
- clinically-significant cardiac arrhythmias;
- stroke (including transient ischemic attack (TIA), or other ischemic event);
- myocardial infarction;
- thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a
venous filter (e.g. vena cava filter) are not eligible for this study);
- Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6
months are allowed if stable, asymptomatic, and treated with a stable dose
of permitted anticoagulation (see exclusion criterion #8) for at least 1
week before first dose of study treatment; b. GI disorders particularly
those associated with a high risk of perforation or fistula formation
including: i. The subject has evidence of tumor invading the GI tract,
active peptic ulcer disease, inflammatory bowel disease (e.g. Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct
or common bile duct, or gastric outlet obstruction ii. Abdominal fistula, GI
perforation, bowel obstruction, intra-abdominal abscess within 6 months
before randomization, Note: Complete healing of an intra-abdominal abscess
must be confirmed prior to randomization c. Other clinically significant
disorders that would preclude safe study participation: i. Serious
non-healing wound/ulcer/bone fracture; ii. Uncompensated/symptomatic
hypothyroidism; iii. Moderate to severe hepatic impairment (Child-Pugh B or
C);
15. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
within 10 days before first dose of study treatment. Subjects must have complete wound
healing from major surgery or minor surgery before first dose of study treatment.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible;
16. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
a. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional
ECGs at intervals of approximately 3 min must be performed within 30 min after the
initial ECG, and the average of these three consecutive results for QTcF will be used
to determine eligibility.
17. Pregnant or lactating females;
18. Inability to swallow intact tablets;
19. Previously identified allergy or hypersensitivity to components of the study treatment
formulations;
20. History of severe hypersensitivity reaction to any monoclonal antibody;
21. Diagnosis of another malignancy within 2 years before the first dose of study
treatment, except for superficial skin cancers, or localized, low-grade tumors deemed
cured and not treated with systemic therapy;
22. Active, known or suspected autoimmune disease (patients with type I diabetes mellitus,
hypothyroidism only requiring hormone replacement, skin disorders not requiring
systemic treatment or conditions not expected to recur in the absence of an external
trigger are permitted);
23. Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14
days of first dose of study treatment. Inhaled or topical steroids and adrenal
replacement steroids >10 mg daily prednisone equivalent, are permitted in the absence
of active autoimmune disease. The use of corticosteroids for premedication for
patients with documented contrast allergy prior to imaging is permitted;
24. Subjects with interstitial lung disease that is symptomatic or may interfere with the
detection or management of suspected drug-related pulmonary toxicity;
25. Prior stem cell transplant or solid organ transplant;
26. Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS);
27. Any positive test result for hepatitis B virus (HBV) or hepatitis C virus (HCV)
indicating acute or chronic infection, and/or detectable virus;
28. Subjects that have received a live/attenuated vaccine within 30 days of first dose of
study treatment.
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