Tivozanib and Atezolizumab for the Treatment of Advanced, Unresectable, or Metastatic Immunologically Cold Tumor Types

Inclusion Criteria

• Subjects must have had at least one prior treatment with systemic therapy for advanced and unresectable, or metastatic disease, OR is intolerant to, has refused or for whom there are no standard therapies that impart significant clinical benefit in the opinion of the treating investigator
• An Eastern Cooperative Oncology Group Performance (ECOG) performance status less than or equal to 1 for phase Ib. An ECOG performance status less than or equal to 2 for phase II
• Subjects must not have more than one malignancy at the time of enrollment (Subjects 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 [as determined by the treating physician and approved by the principal investigator (PI)] may be included)
• Adult subjects ≥ eighteen years of age
• A clinical diagnosis consistent with stage IV “immunogenically cold” or otherwise incurable cancer of one of the following histologies: * Bile duct or gallbladder cancer * Metastatic breast cancer, hormone receptor (HR)-negative HER2-positive, who have received at least 3 lines of therapy for disease progression that includes; trastuzumab, pertuzumab/trastuzumab, and ado-trastuzumab emtansine * Neuroendocrine cancer with the following pathological characteristics: ** Grade 2 or 3, ** Well- or moderately- differentiated *** Grades 1, 4, and poorly differentiated neuroendocrine pathologies are not eligible * Federation of Gynecology and Obstetrics (FIGO) stage IV or metastatic (using 2021 FIGO classification) high grade serous or high grade endometrioid (based on local histopathological findings) ovarian cancer, primary peritoneal cancer and / or fallopian-tube cancer that is platinum resistant, with no acceptable standard of care. * Pancreatic adenocarcinoma * Soft tissue sarcoma * Prostate cancer subjects who are castrate-resistant (testosterone =< 50 ng/dL) and have progressed on, declined, or are intolerant to other standard of care therapies. Subjects with prostate cancer must have failed at least one line of treatment with an androgen inhibitor (AI) (i.e. enzalutamide, abiraterone, etc.) or cytotoxic chemotherapy in the advanced or metastatic setting * Vulvar cancer
• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (1500/uL) without granulocyte colony-stimulating factor support (obtained within 14 days prior to initiation of study treatment)
• Lymphocyte count ≥ 0.5 × 10^9/L (500/uL) (obtained within 14 days prior to initiation of study treatment)
• Platelet count ≥ 100 × 10^9/L (100,000/uL) without transfusion (obtained within 14 days prior to initiation of study treatment)
• Hemoglobin ≥ 90 g/L (9 g/dL) (obtained within 14 days prior to initiation of study treatment) * Subjects may be transfused to meet this criterion
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN) (obtained within 14 days prior to initiation of study treatment), with the following exceptions: * Subjects with documented liver metastases: AST and ALT ≤ 5 × ULN * Subjects with documented liver or bone metastases: ALP ≤ 5 × ULN
• Serum bilirubin ≤ 1.5 × ULN (obtained within 14 days prior to initiation of study treatment) with the following exception: * Subjects with known Gilbert disease: serum bilirubin ≤ 3 × ULN
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 30 mL/min (calculated using the Cockcroft-Gault formula) (obtained within 14 days prior to initiation of study treatment)
• Serum albumin ≥ 25 g/L (2.5 g/dL) (obtained within 14 days prior to initiation of study treatment)
• For subjects not receiving therapeutic anticoagulation: International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN (obtained within 14 days prior to initiation of study treatment)
• Subjects receiving therapeutic anticoagulation must be on a stable anticoagulant regimen for ≥ 2 weeks at start of protocol treatment
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Negative human immunodeficiency virus (HIV) test at screening with the following exceptions: Subjects with a positive HIV test at screening are eligible only if they meet the following three conditions: 1) Are stable on anti-retroviral therapy 2) Have a CD4 count ≥ 200 cells/uL AND 3) Have an undetectable viral load
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception (with a failure rate of < 1% per year) to avoid pregnancy throughout the study and for at least 160 days after the last dose of either study drug to minimize the risk of pregnancy. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, copper intrauterine devices, and complete abstinence. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception * WOCBP includes any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, or bilateral oophorectomy) or another cause as determined by the investigator (e.g., Müllerian agenesis),or who is not post-menopausal. Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. Post-menopause is defined as: ** Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or ** For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL
• Males with female partners of child-bearing potential must agree to use physician-approved contraceptive methods, as noted above, throughout the study and should avoid conceiving children for 160 days following the last dose of study drug
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST)
• A life expectancy of greater than or equal to 12 weeks
• Written informed consent obtained from the subject and the subject agrees to comply with all the study-related procedures
• Must have formalin-fixed paraffin embedded (FFPE) tissue or 12 unstained slides available for research purposes. Tissue must have been obtained within the last 3 years. If only cytology is available, this may be allowed with PI approval
• If a new biopsy is needed for diagnostic reasons, the biopsy must be performed from a tumor site that is not the only site of measurable disease
• Subject must be able to swallow capsules

Exclusion Criteria

• Subjects with known microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR) tumor status
• Subjects with severe uncontrolled hypertension as defined as systolic blood pressure > 150 mmHg or diastolic blood pressure > 100 mmHg
• Subjects who have had prior treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors
• Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 160 days after the last dose of study drug
• Females who are pregnant or breastfeeding
• History of leptomeningeal disease
• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
• Uncontrolled tumor-related pain * Subjects requiring pain medication must be on a stable regimen at study entry * Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. subjects should be recovered from the effects of radiation. There is no required minimum recovery period * Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment * Severe pain directly related to the disease process being treated under study is allowable if in the investigators opinion, initiating the anti-cancer therapy is the best means of reducing and/or controlling ongoing pain
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently, except in the case of ovarian cancer with ascites which may require more frequent drainage). Subjects with indwelling catheters (e.g., PleurX [registered trademark]) are allowed
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: * Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study * Subjects with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study * Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., subjects with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids ** There has been no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
• Active tuberculosis
• Significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• History of malignancy other than the malignancies listed in the inclusion criteria of enrollment within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could impact patient safety
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Note: Subjects receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study
• Prior allogeneic stem cell or solid organ transplantation
• Current treatment with anti-viral therapy for hepatitis B virus (HBV)
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti−CTLA-4, anti−PD-1, and anti−PD-L1 therapeutic antibodies
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor necrosis factor [TNF]-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: * Subjects who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study * Subjects who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician
• Administration of a vaccine containing live virus within 30 days prior to the first dose of trial treatment, during treatment with atezolizumab, and for 160 days after the last dose of atezolizumab. Note: Most flu vaccines are killed viruses, with the exception of the intra-nasal vainer (Flu-Mist) which is an attenuated live virus and therefore prohibited for 30 days prior to first dose. Subjects may receive non-live coronavirus disease 2019 (COVID-19) vaccine
• Prisoners or subjects who are involuntarily incarcerated, or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness
• Subjects with tumor mutation burden (TMB) ≥ 10
• Treatment with any cancer directed therapy (i.e. chemotherapy, radiation therapy, yttrium90 (Y90), microwave ablation, immunotherapy, etc.) within 28 days of study start
• Subjects with treated brain metastases that have remained stable for at least 90 days without steroids are allowed. Subjects with new signs of symptoms of brain metastasis must have a CT or MRI of the brain within 30 days prior to the start of protocol therapy, per routine care. Subjects with a history of brain metastasis must have been clear of metastasis on their most recent scan and report no new signs or symptoms since that scan
• Subjects with autoimmune diseases requiring current treatment and subjects with history of severe autoimmune diseases, subjects with hypothyroidism, adrenal insufficiency, or pituitary insufficiency who are stable on therapy are allowed
• Inability to discontinue use of medications contraindicated by the study treatment
• Proteinuria > 2.5 g/24 hours or 3+ with urine dipstick
• Corrected QT (QTc) interval > 470 at screening or known cardiovascular disease defined as (a) a clinically significant abnormal electrocardiogram (ECG) at screening, or (b) myocardial infarction within 12 weeks prior to start of protocol therapy