CBM588 in Combination With Nivolumab and Cabozantinib for the Treatment of Advanced or Metastatic Kidney Cancer

Inclusion Criteria:

• Histological confirmation of renal cell carcinoma (RCC) with a clear-cell, papillaryor sarcomatoid component

• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) RCC

• No prior systemic therapy for RCC with the following exception:

• One prior adjuvant or neoadjuvant therapy for completely resectable RCC ifrecurrence occurred at least 6 months after the last dose of adjuvant orneoadjuvant therapy

• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Recovery to baseline or =< grade 1 CTCAE v5 from toxicities related to any priortreatments unless adverse events (AE[s]) are clinically nonsignificant and/or stableon supportive therapy

• Karnofsky performance status >= 70%

• Males and females, ages >= 18

• Any ethnicity or race

• Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulatingfactor support (within 14 days before first dose of study treatment)

• White blood cell count >= 2500/uL (within 14 days before first dose of studytreatment)

• Platelets >= 100,000/uL without transfusion (within 14 days before first dose ofstudy treatment)

• Hemoglobin >= 9 g/dL (>= 90 g/L) (within 14 days before first dose of studytreatment)

• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documentedbone metastases (within 14 days before first dose of study treatment)

• Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 x ULN) (within 14 days before first dose of study treatment)

• Serum albumin >= 2.8 g/dl (within 14 days before first dose of study treatment)

• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastintime (PTT) test < 1.3 x the laboratory ULN (within 14 days before first dose ofstudy treatment)

• Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 40mL/min (>= 0.675 mL/sec) using the Cockcroft-Gault equation (within 14 days before first doseof study treatment)

• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)urine protein =< 1 g (within 14 days before first dose of study treatment)

• Capable of understanding and complying with the protocol requirements and must havesigned the informed consent document

• Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 4 months after the last dose of cabozantinib, 5 months after the last dose ofnivolumab for women with childbearing potential, and 7 months after the last dose ofnivolumab for men

• Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria is met: documented permanent sterilization (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence ofother biological or physiological causes. In addition, females < 55 years-of-agemust have a serum follicle stimulating [FSH] level > 40 mIU/mL to confirmmenopause). Note: Documentation may include review of medical records, medicalexaminations, or medical history interview by study site

Exclusion Criteria:

• Prior treatment with cabozantinib

• Current use, or intent to use, probiotics, yogurt, or bacterial fortified foodsduring the period of treatment

• Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitisrequiring treatment with systemic steroids

• Known medical condition (e.g., a condition associated with diarrhea or acutediverticulitis) that, in the investigator's opinion, would increase the riskassociated with study participation or study drug administration or interfere withthe interpretation of safety results

• Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks before first dose of study treatment

• Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment

• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible

• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks priorto first dose of study treatment after major surgery (e.g., removal or biopsy ofbrain metastasis). Subjects must have complete wound healing from major surgery orminor surgery before first dose of study treatment. Eligible subjects must beneurologically asymptomatic and without corticosteroid treatment at the time offirst dose of study treatment

• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

• Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines) and low-dose low molecular weight heparins (LMWH)

• Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen or the tumor

• Administration of a live, attenuated vaccine within 30 days before first dose ofstudy treatment

• The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

• Cardiovascular disorders:

• Congestive heart failure New York Heart Association class 3 or 4, unstableangina pectoris, serious cardiac arrhythmias

• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensivetreatment

• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venousthrombosis, pulmonary embolism) within 6 months before first dose of studytreatment

• Subjects with a diagnosis of incidental, subsegmental pulmonaryembolism (PE) or deep vein thrombosis (DVT) within 6 months areallowed if stable, asymptomatic, and treated with a stable dose ofpermitted anticoagulation for at least 1 week before first dose ofstudy treatment

• Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation:

• The subject has evidence of tumor invading the GI tract, active pepticulcer disease, inflammatory bowel disease (e.g., Crohn's disease),diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or commonbile duct, or gastric outlet obstruction.

• Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominalabscess within 6 months before first dose of study treatment. Note:Complete healing of an intra-abdominal abscess must be confirmed beforefirst dose of study treatment

• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5ml) of red blood, or other history of significant bleeding (e.g., pulmonaryhemorrhage) within 12 weeks before first dose of study treatment

• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation

• Lesions invading or encasing any major blood vessels

• Other clinically significant disorders that would preclude safe study participation:

• Any active, known, or suspected autoimmune disease will be excluded, with thefollowing exceptions:

• Type 1 diabetes mellitus.

• Hypothyroidism only requiring hormone replacement.

• Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiringsystemic treatment.

• Conditions not expected to recur in the absence of an external trigger.

• Any condition requiring systemic treatment with either corticosteroids (> 10 mgdaily prednisone equivalent) or other immunosuppressive medications within 14days before first dose of study treatment.

• Note: Inhaled, intranasal, intra-articular, or topical steroids arepermitted. Adrenal replacement steroid doses > 10 mg daily prednisoneequivalent are permitted. Transient short-term use of systemiccorticosteroids for allergic conditions (e.g., contrast allergy) is alsoallowed.

• Active infection requiring systemic treatment. Acute or chronic hepatitis B orC infection, known human immunodeficiency virus (HIV) or acquiredimmunodeficiency syndrome (AIDS)-related illness, or known positive test fortuberculosis infection where there is clinical or radiographic evidence ofactive mycobacterial infection.

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis onscreening chest CT scan.

• Serious non-healing wound/ulcer/bone fracture.

• Malabsorption syndrome.

• Uncompensated/symptomatic hypothyroidism.

• Moderate to severe hepatic impairment (Child-Pugh B or C).

• Requirement for hemodialysis or peritoneal dialysis.

• History of solid organ or allogenic stem cell transplant.

• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal, or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment. Minorsurgeries within 10 days before first dose of study treatment. Subjects must havecomplete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible.

• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment.Furthermore, subjects with a history of additional risk factors for torsades depointes (e.g., long QT syndrome) are also excluded.

• Note: If a single ECG shows a QTcF with an absolute value > 500 ms, twoadditional ECGs at intervals of approximately 3 min must be performed within 30min after the initial ECG, and the average of these three consecutive resultsfor QTcF will be used to determine eligibility.

• Pregnant or lactating females

• Inability to swallow tablets or unwillingness or inability to receive IVadministration

• Previously identified allergy or hypersensitivity to components of the studytreatment formulations or history of severe infusion-related reactions to monoclonalantibodies. Subjects with rare hereditary problems of galactose intolerance, theLapp lactase deficiency or glucose-galactose malabsorption are also excluded.

• Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 3 years prior to first dose of study treatment thatrequires active treatment, except for locally curable cancers that have beenapparently cured, such as basal or squamous cell skin cancer, superficial bladdercancer, or carcinoma in situ of the prostate, cervix, or breast.