Cabozantinib and Durvalumab with or without Tremelimumab in Treating Patients with Stage III-IV Gastroesophageal Cancer and Other Gastrointestinal Malignancies

Inclusion Criteria

• Male or female, (all races and ethnicities are eligible)
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Histologically confirmed diagnosis of any of the following: * Gastric or gastroesophageal junction adenocarcinoma * Esophageal adenocarcinoma * Colorectal adenocarcinoma (CRC) * Hepatocellular carcinoma (HCC)
• Patients should have advanced (stage 4) or locally unresectable (stage III) disease
• Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Previously irradiated lesion cannot be considered as target lesion (TL) except in cases of documented progression of the lesion since the completion of radiation therapy
• Patients must consent to undergo a required screening/baseline biopsy procedure (and potentially another tumor biopsy at time of disease response and progression) for correlative testing. If the patient has only one target lesion (TL), biopsy from that lesion is allowed. Archival tissue can be accepted in lieu of fresh biopsy if: collected after most recent line of systemic therapy, and/or approval from the principal investigator.
• Patients with gastric, gastroesophageal, or esophageal adenocarcinoma must show evidence of progression or intolerance to at least two previous standard of care systemic therapy (not more than 3 lines of prior therapy). Neoadjuvant or adjuvant chemotherapy would count as one prior line of therapy if progression occurs =< 6 months from the last cycle of chemotherapy. HER2 positive patients should fail or be intolerant to HER2 targeted therapy to be eligible
• Patients with CRC must show evidence of progression or intolerance to at least 2 previous standard of care systemic therapy (not more than 3 lines of prior therapy). Neoadjuvant or adjuvant chemotherapy would count as one prior line of therapy if progression occurs =< 6 months from the last cycle of chemotherapy. RAS wild type patients should fail EGFR monoclonal antibody (panitumumab or cetuximab) to be eligible
• Patients with HCC must be treatment naive or show evidence of disease progression or intolerance to at least 1 previous immunotherapy regimen (not more than 1 line of prior therapy)
• Patients should have known tumor results for microsatellite instability (MSI) or mismatch repair (MMR) proteins. If unknown, analysis will be obtained through University of Kansas (KU) pathology lab using archival tissue if available or the baseline tumor biopsy
• Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 from toxicities related to any prior treatments, unless adverse event (AE)(s) are clinically nonsignificant and/or stable on supportive therapy
• Body weight > 66 pounds (lbs) (30 kg)
• White blood cell count >= 2500/mm^3 (>= 2.5 GI/L), (>= 2000/mm^3 for HCC)
• Absolute neutrophil count (ANC) >= 1.5 x 10(9)/L
• Hemoglobin >= 9.0 g/dl (transfusion assistance acceptable)
• Platelet count >= 100 x 10^9/L (>= 60 x 10^9/L for HCC)
• Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), =< 2.5 x institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be =< 5 x ULN
• Alkaline phosphatase (ALP) =< 3 x ULN. ALP =< 5 x ULN with documented bone metastases, liver metastases or HCC
• Total bilirubin =< 1.5 x ULN (total bilirubin =< 2.0 x ULN for HCC)
• Serum albumin >= 2.8 g/dl
• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3 x ULN. HCC patients are eligible if PT/INR is =< 1.6
• Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine CL > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol)
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply: * Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
• Women of child-bearing potential and men with partners of child-bearing potential must agree to use the highly effective forms of contraception listed below prior to study entry, for the duration of study participation, and for 180 days post completion of therapy. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. Men of child-bearing potential must not donate sperm while on this study and for 180 days after their last study treatment. * The following restrictions apply while the patient is receiving study treatment and for the specified times before and after treatment, as described below: ** Female patient of child-bearing potential *** Females of childbearing potential who are sexually active with a non-sterilized male partner must use at least 1 highly effective method of contraception from the time of screening and must agree to continue using such precautions for 180 days after the last dose of durvalumab + any drug combination therapy *** Non-sterilized male partners of a female patient must use male condom plus spermicide throughout this period. Cessation of birth control after this point should be discussed with a responsible physician *** Not engaging in sexual activity (abstinence) for the total duration of the drug treatment and the drug washout period is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control *** Female patients should also refrain from breastfeeding throughout this period ** Male patients with a female partner of childbearing potential *** Non-sterilized males who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + any drug combination therapy *** Not engaging in sexual activity (abstinence) is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Male patients should refrain from sperm donation throughout this period *** Female partners (of childbearing potential) of male patients must also use a highly effective method of contraception throughout this period *** Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal *** Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause ** Highly effective methods of contraception, defined as one that results in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are described in the table below *** Note that some contraception methods are not considered highly effective (e.g., male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills) ** Highly effective methods of contraception (< 1% failure rate) *** Barrier/Intrauterine methods **** Copper T intrauterine device **** Levonorgestrel-releasing intrauterine system (e.g., Mirena) (this is also considered a hormonal method) *** Hormonal methods **** Implants: Etonogestrel-releasing implants: e.g. Implanon or Norplant **** Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal devices: e.g. NuvaRing **** Injection: Medroxyprogesterone injection: e.g. Depo-Provera **** Combined Pill: Normal and low dose combined oral contraceptive pill **** Patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g. Ortho Evra **** Minipill: Progesterone based oral contraceptive pill using desogestrel: Cerazette is currently the only highly effective progesterone-based
• Ability of participant OR legally authorized representative (LAR) to understand this study, and participant or LAR willingness to sign a written informed consent
• Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Patients should agree to not donate blood while participating in this study and for at least 90 days following the last infusion of durvalumab or tremelimumab

Exclusion Criteria

• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment (HCC patients fulfilling this criterion are eligible)
• Prior treatment with a PD1 or PD-L1 inhibitor, including durvalumab, or anti PD-L2 (HCC and gastric or esophageal patients with prior exposure to these agents are eligible)
• Prior treatment with cabozantinib or other MET or dual MET/HGF monoclonal antibodies or MET/HGF tyrosine kinase inhibitors (TKIs), including crizotinib, foretinib, tivantinib, rilotumumab, and onartuzumab
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies) =< 28 days prior to the first dose of study drug. If sufficient wash-out time has not occurred due to the schedule or pharmacokinetic (PK) properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune, Exelixis and the principal investigator
• Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable
• Abdominal fistula, gastrointestinal (GI) perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. Note: complete healing of an intra-abdominal abscess must be confirmed before first dose
• Gastric or esophageal varices that are untreated or incompletely treated with bleeding or high risk for bleeding. Subjects treated with adequate endoscopic therapy (according to institutional standards) without any episodes of recurrent GI bleeding requiring transfusion or hospitalization for at least 6 months prior to study entry are eligible
• Evidence of tumor invading the GI tract
• Evidence of active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
• Inability to swallow tablets
• Uncontrollable ascites or pleural effusion
• Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
• Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 tsp (2.5 ml) of red blood, or other history of significant bleeding within 12 weeks
• Any sign indicative of pulmonary hemorrhage within 3 months
• Lesions invading any major blood vessels. HCC subjects with lesions invading the hepatic portal vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible
• Any unresolved toxicity National Cancer Institute (NCI) v 5.0 grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
• Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after consultation with the principal investigator
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab with or without tremelimumab may be included only after consultation with the study physician
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
• Patients with clinically relevant ongoing complications from prior chemoradiation or radiation therapy are not eligible
• Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries (e.g., simple excision, tooth extraction) within 7 days before first dose. 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
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid * The following are exceptions to this criterion: ** Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) ** Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent ** Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• History of allogenic organ transplantation
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician * Patients with celiac disease controlled by diet alone
• History of active primary immunodeficiency
• Active infection requiring systemic treatment including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis (TB) testing in line with local practice), known history or suspected human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) or acquired immunodeficiency syndrome (AIDS) related illness, known history or suspected acute or chronic hepatitis B (positive HBV surface antigen (HBsAg) result) or hepatitis C infection in non-HCC tumor cohorts. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA). HCC patients with hepatitis B or C infection are allowed if meeting the following criteria: * Patients with HBV infection, characterized by positive hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV deoxyribonucleic acid (DNA) (>= 10 IU/ml or above the limit of detection per local lab standard), must be treated with antiviral therapy, as per institutional practice, to ensure adequate viral suppression (HBV DNA =< 2000 IU/mL) prior to enrollment. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication. Patients who test positive for antihepatitis B core (HBc) with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require anti-viral therapy prior to enrollment. These subjects will be tested at every cycle to monitor HBV DNA levels and initiate antiviral therapy if HBV DNA is detected (>= 10 IU/ml or above the limit of detection per local lab standard). HBV DNA detectable subjects must initiate and remain on antiviral therapy for the study duration and for 6 months after the last dose of study medication * Patients with HCV infection must have confirmed diagnosis of HCV characterized by the presence of detectable HCV RNA or anti-HCV antibody upon enrollment (management of this disease is per local institutional practice)
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
• Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
• Other clinically significant disorders that would preclude safe study participation * Serious non-healing wound/ulcer/bone fracture * Uncompensated/symptomatic hypothyroidism * Moderate to severe hepatic impairment (Child-Pugh B or C)
• Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
• Mean QT interval corrected for heart rate (Fridericia's correction formula [QTcF]) > 470 ms calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart) using Fridericia’s correction
• Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of deep venous thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with low molecular weight heparin (LMWH) for at least 2 weeks before first dose
• Brain metastases or spinal cord compression. Patients with suspected brain metastases at screening should have a magnetic resonance imaging (MRI) (preferred) or CT each preferably with IV contrast of the brain prior to study entry * Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of =< 10 mg/day of prednisone or its equivalent for at least 14 days prior to the start of treatment
• Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on the baseline brain imaging or identified prior to signing the informed consent form (ICF)
• History of another primary malignancy except for: * Malignancy treated with curative intent/ resection and with no known active disease before the first dose of IP and of low potential risk for recurrence * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease
• 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: * Prophylactic use of low‐dose aspirin for cardio‐protection (per local applicable guidelines) and low‐dose low molecular weight heparins (LMWH) * 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. (For the HCC cohort oral anticoagulants are not permitted in this population. HCC subjects must have a screening platelet count > 100,000/uL in order to use therapeutic doses of LMWH)
• Concomitant use of strong inhibitors or inducers of CYP3A4 family
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab and/or tremelimumab.