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Atezolizumab, Entinostat, and Bevacizumab in Treating Patients with Metastatic Kidney Cancer

Trial Status: Closed to Accrual and Intervention

This phase I / II trial studies the side effects and best dose of entinostat when given together with atezolizumab and bevacizumab and how well they work in treating patients with kidney cancer that has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Entinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Bevacizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving atezolizumab, entinostat, and bevacizumab may work better in treating patients with kidney cancer.

Inclusion Criteria

  • Signed informed consent form (ICF)
  • Ability and willingness to comply with the requirements of the study protocol
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 for patients with solid malignancies or patients with bone disease must have disease evaluated by bone scan and/or positron emission tomography (PET) scan
  • Metastatic renal cell carcinoma * During Phase I - All prior treatments or none are allowed * During Phase II/Cohort A - No prior treatments with PD1 or PDL1 inhibitors are allowed * During Phase II/Cohort B - Must have at least one prior treatment with a PD1 or PDL1 inhibitor for metastatic disease for at least 3 months and have progressed by either clinical or radiographic assessment
  • Life expectancy of at least 6 months
  • Absolute neutrophil count (ANC) >= 1500 cells/uL (within 14 days prior to the first study treatment [cycle 1, day 1])
  • White blood cell (WBC) counts > 2500/uL (within 14 days prior to the first study treatment [cycle 1, day 1])
  • Lymphocyte count >= 300/uL (within 14 days prior to the first study treatment [cycle 1, day 1])
  • Platelet count >= 100,000/uL; for patients with hematologic malignancies, platelet count >= 75,000/uL (within 14 days prior to the first study treatment [cycle 1, day 1])
  • Hemoglobin >= 9.0 g/dL (within 14 days prior to the first study treatment [cycle 1, day 1])
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to the first study treatment [cycle 1, day 1]) with the following exception: * Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled * Direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days prior to the first study treatment [cycle 1, day 1]) with the following exception: * Patients with liver involvement: AST and/or ALT =< 5 x ULN
  • Alkaline phosphatase (ALP) =< 2.0 x ULN (within 14 days prior to the first study treatment [cycle 1, day 1]) with the following exception: * Patients with documented liver involvement or bone metastases: ALP =< 5 x ULN
  • Serum creatinine =< 1.25 x ULN or creatinine clearance >= 60 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (within 14 days prior to the first study treatment [cycle 1, day 1])
  • Urine dipstick for proteinuria < 2+ or 24-hour urine protein < 1 g of protein is demonstrated (within 14 days prior to the first study treatment [cycle 1, day 1])
  • International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (within 14 days prior to the first study treatment [cycle 1, day 1]) * This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose
  • If a female of childbearing potential, negative serum blood pregnancy test during screening and a negative urine pregnancy test =< 3 days prior to receiving the first dose of study drug; if the screening serum test is done =< 3 days prior to receiving the first dose of study drug, a urine test is not required * Non-childbearing potential is defined as (by other than medical reasons): ** >= 45 years of age and has not had menses for > 2 years ** Amenorrhoeic for < 2 years without a hysterectomy and/or oophorectomy and a follicle stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation ** Post hysterectomy or oophorectomy; documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound
  • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two forms of highly effective contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 150 days after the last dose of all study drugs (atezolizumab, entinostat, and bevacizumab)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria

  • Any approved anti-cancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, =< 3 weeks prior to first dose of study drug; however, the following are allowed: * Hormone-replacement therapy or oral contraceptives * Herbal therapy > 1 week prior to cycle 1, day 1 (herbal therapy intended as anti-cancer therapy must be discontinued at least 1 week prior to cycle 1, day 1) * Palliative radiotherapy for bone metastases > 2 weeks prior to cycle 1, day 1
  • Currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device =< 4 weeks of the first dose of study drug
  • Adverse events (AEs) from prior anti-cancer therapy that have not resolved to grade =< 1 except for alopecia and neuropathy
  • Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption
  • Bisphosphonate therapy for symptomatic hypercalcemia * Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is allowed
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease
  • Patients with acute leukemias, accelerated/blast-phase chronic myelogenous leukemia, chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory myeloma
  • Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases * Patients with asymptomatic untreated CNS disease may be enrolled, provided all of the following criteria are met: ** Evaluable or measurable disease outside the CNS ** No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm of the optic apparatus (optic nerves and chiasm) ** No history of intracranial hemorrhage or spinal cord hemorrhage ** No ongoing requirement for dexamethasone for CNS disease; patients on a stable dose of anticonvulsants are permitted ** No neurosurgical resection or brain biopsy =< 28 days prior to cycle 1, day 1 * Patients with asymptomatic treated CNS metastases may be enrolled, provided all the criteria listed above are met as well as the following: ** Radiographic demonstration of improvement upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study ** No stereotactic radiation or whole-brain radiation =< 28 days prior to cycle 1, day 1 ** Screening CNS radiographic study >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
  • Pregnancy, lactation, or breastfeeding
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
  • Known hypersensitivity to any component of bevacizumab
  • Allergy to benzamide or inactive components of entinostat
  • Inability to comply with study and follow-up procedures
  • Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
  • Uncontrolled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg) that persists over 3 weeks and 3 consecutive measurements (each 1 week apart) despite medication
  • Prior history of hypertensive crisis or hypertensive encephalopathy
  • Uncontrolled diabetes mellitus
  • History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis * Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible * Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions: ** Rash must cover less than 10% of body surface area (BSA) ** Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) ** No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
  • History of human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies) or active hepatitis B (chronic or acute) or hepatitis C infection * Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible; hepatitis B virus (HBV) deoxyribonucleic acid (DNA) test must be performed in these patients prior to study treatment * Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA)
  • Active tuberculosis
  • Clinically significant (i.e. active) cardiovascular disease (e.g., myocardial infarction or arterial thromboembolic events =< 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, grade II or greater congestive heart failure, or serious cardiac arrhythmia, or a corrected QT (QTc) interval > 470 msec)
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis =< 6 months of study enrollment
  • Any previous venous thromboembolism > National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 3
  • History of hemoptysis (>= 1/2 teaspoon of bright red blood per episode) =< 28 days of study enrollment
  • Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  • Current or recent (=< 10 days of study enrollment) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or therapeutic oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes * The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to medical standard of the institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks at the time of study enrollment; prophylactic use of anticoagulants is allowed
  • Severe infections =< 4 weeks prior to cycle 1, day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Signs or symptoms of infection =< 2 weeks prior to cycle 1, day 1
  • Received oral or IV antibiotics =< 2 weeks prior to cycle 1, day 1 * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
  • Major surgical procedure =< 28 days prior to cycle 1, day 1 or anticipation of need for a major surgical procedure during the course of the study
  • Administration of a live, attenuated vaccine =< 4 weeks before cycle 1, day 1 or anticipation that such a live, attenuated vaccine will be required during the study * Influenza vaccination should be given during influenza season only (approximately October to March); patients must not receive live, attenuated influenza vaccine (e.g., FluMist) =< 4 weeks prior to cycle 1, day 1 or at any time during the study
  • History of abdominal fistula or gastrointestinal perforation =< 6 months before cycle 1, day 1; serious non-healing wound, active ulcer, or untreated bone fracture (adjuvant trials: bone fractures must be healed)
  • Proteinuria as demonstrated by a urine protein creatinine (UPC) ratio >= 1.0 at screening
  • Malignancies other than the disease under study =< 5 years prior to cycle 1, day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai stage 0, prostate cancer with Gleason score =< 6, and prostate-specific antigen [PSA] =< 10 mg/mL, etc.)
  • MEDICATION-RELATED EXCLUSION CRITERIA:
  • Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN] alpha or interleukin [IL]-2) =< 6 weeks or five half-lives of the drug (whichever is shorter) prior to cycle 1, day 1
  • Treatment with investigational agent =< 4 weeks prior to cycle 1, day 1 (or within five half lives of the investigational product, whichever is longer)
  • Treatment with systemic immunosuppressive medications (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) =< 2 weeks prior to cycle 1, day 1 * Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled * The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation

Indiana

Indianapolis
Indiana University / Melvin and Bren Simon Cancer Center
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION
Contact: Nabil Adra
Phone: 317-944-5349
Email: nadra@iu.edu

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION
Contact: J. Paul Monk
Phone: 614-293-9863

Pennsylvania

Philadelphia
University of Pennsylvania / Abramson Cancer Center
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION
Contact: Vivek K. Narayan
Phone: 215-360-0928

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of atezolizumab in combination with entinostat and bevacizumab in patients with advanced renal cell carcinoma. (Phase I)

II. To assess the objective response rate of atezolizumab in combination with entinostat and bevacizumab in anti-PD 1 naive patients and atezolizumab in combination with entinostat in anti-PD 1 resistant patients with advanced renal cell carcinoma. (Phase II)

SECONDARY OBJECTIVE:

I. To assess the objective response rate (Phase I only), progression-free survival and overall survival.

CORRELATIVE OBJECTIVE:

I. To characterize PD-L1/2, immune cell subsets, and micro ribonucleic acid (RNA) (miRs) in tumor and/or blood in correlation with response.

OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II study.

Patients receive atezolizumab intravenously (IV) over 30-60 minutes on day 1, bevacizumab IV over 30-90 minutes on day 1, and entinostat orally (PO) every 7 days. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 6 months thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Indiana University / Melvin and Bren Simon Cancer Center

Principal Investigator
Nabil Adra

  • Primary ID IUSCC-0574
  • Secondary IDs NCI-2018-00085
  • Clinicaltrials.gov ID NCT03024437