Atezolizumab in Combination With Entinostat and Bevacizumab in Patients With Advanced Renal Cell Carcinoma

NCT03024437 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: IUSCC-0574
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 4

Brief Summary

This study will assess the immunomodulatory activity of entinostat in patients with advanced renal cell carcinoma receiving the PD-L1 inhibitor atezolizumab. The overall hypothesis is that entinostat will increase the immune response and anti-tumor effect induced by the PD-L1 inhibition by suppressing Treg function. We have chosen renal cell carcinoma that has been reported to respond to PD1/PD-L 1 inhibition. The schedule of entinostat is based on our previous experience with this agent. Based on our working hypothesis that low dose HDAC inhibitors will have a suppressive function on Tregs but not on T effector cells, the starting dose of entinostat will be 1 mg and will be escalated up to 5 mg rather than the 10 mg dose. The combination also with bevacizumab will provide an effective VEGF inhibition that may potentiate the immune response and anti-tumor effect induced by atezolizumab. The proposed dose and schedule for atezolizumab and bevacizumab has been shown to be well tolerated in prior Phase/I/II studies and is currently tested in a Phase III randomized study in patients with renal cell carcinoma with sunitinib as a control arm. The highest proposed dose level for entinostat (5 mg) represents 50% of the recommended Phase II dose for this compound as a single agent.

Conditions

Metastatic Cancer; Renal Cancer

Keywords

PD-L1 inhibitor

Outcome Measures

Primary Outcomes (2)

• Phase I: Recommended Phase II Dose of Entinostat

  Three dose levels of entinostat (1 mg, 3 mg and 5 mg) were tested according to the 3 + 3 standard design. The starting dose level of entinostat was 1 mg orally every 7 days. DLTs attributable to entinostat and/or bevacizumab and/or atezolizumab were evaluated during the first 21 days of the combination treatment. If a DLT occurs in 1 patient treated at the starting dose level, a minimum of 3 additional patients will be treated at this dose level. If DLTs occur in 2 or more of the first 6 patients, the study will be terminated. If a DLT occurs in 1 out of 6 patients, 3 additional patients will be treated at the next dose level (level 2). If no DLTs occur at the starting dose level 1, 3 additional patients will be treated at the next dose level (level 2). The process is repeated for dose level 2. If no DLTs occur at dose level 3 or if 1 DLT occurs out of 6 patients, then this dose level will be recommended for the Phase II portion of the study.

  21 days

• Phase II: Percentage of Patients With Objective Response

  Percentage of patients who achieved a complete response or partial response to treatment as measured per RECIST 1.1. Complete response: Disappearance of all target lesions. Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter.

  Up to 1 year

Secondary Outcomes (3)

• Phase I: Percentage of Patients With Objective Response

  Up to 1 year

• Phase II: Median Progression-free Survival

  Up to 4.5 years

• Phase II: Median Overall Survival

  Up to 5.5 years

Study Arms (3)

Phase I - Dose Escalation

EXPERIMENTAL

Open to patients meeting eligibility criteria with advanced renal cell carcinoma and ANY or NO prior treatments. Three dose levels of entinostat will be tested in 3-patient cohorts according to the 3 + 3 standard design (1 mg, 3 mg and 5 mg). The starting dose level of entinostat will be 1 mg orally every 7 days. The Phase II dose will be recommended phase II dose of entinostat (i.e., the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor).

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Entinostat

Phase II - Cohort A

EXPERIMENTAL

Open to patients meeting eligibility criteria with advanced renal cell carcinoma and NO prior treatments. Patients in Cohort A will be treated with atezolizumab, bevaciuzmab, and the recommended phase II dose of entinostat. During Phase II, the study will have a run-in period with entinostat for one cycle followed by atezolizumab and bevacizumab for the second cycle, and then the combination phase (i.e., atezolizumab + bevacizumab + entinostat for all cycles thereafter).

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Entinostat

Phase II - Cohort B

EXPERIMENTAL

Open to patients meeting eligibility criteria with advanced renal cell carcinoma and at least one prior treatment with a PD1 or PDL1 inhibitor. Patients in Cohort B will be treated with the same combination therapy as in Cohort A.

Drug: Atezolizumab; Drug: Bevacizumab; Drug: Entinostat

Interventions

Atezolizumab DRUG

Atezolizumab will be given intravenously every 3 weeks at 1200 mg.

Also known as: MDPL3280A

Phase I - Dose Escalation; Phase II - Cohort A; Phase II - Cohort B

Bevacizumab DRUG

Bevacizumab will be given intravenously every 3 weeks at 15 mg/kg.

Also known as: Avastin

Phase I - Dose Escalation; Phase II - Cohort A; Phase II - Cohort B

Entinostat DRUG

Entinostat will be given orally every 7 days at 1, 3, or 5 mg depending upon phase. In Phase I, dose levels will be tested in up to 3 cohorts starting at 1 mg. In Phase II, the dose will be the recommended phase II dose that was determined during Phase I (i.e., 1, 3, or 5 mg).

Also known as: SNDX-275

Phase I - Dose Escalation; Phase II - Cohort A; Phase II - Cohort B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must meet the following criteria for study entry:
• Signed Informed Consent Form (ICF)
• Ability and willingness to comply with the requirements of the study protocol
• Age ≥ 18 years
• Measurable disease per RECIST v1.1 (see Appendix 4) for patients with solid malignancies or patients with bone disease must have disease evaluable by bone scan and/or PET scan
• Metastatic renal cell carcinoma
• o During Phase I - All prior treatments or none are allowed
• During Phase II/Cohort A - No prior treatments with PD1 or PDL1 inhibitors 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
• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
• Absolute neutrophil count (ANC) ≥ 1500 cells/microL
• White blood cell (WBC) counts \> 2500/microL
• Lymphocyte count ≥ 300/microL
• Platelet count ≥ 100,000/microL; for patients with hematologic malignancies, platelet count ≥ 75,000/microL

You may not qualify if:

• 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.
• 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

Sponsors & Collaborators

• Roberto Pili: lead
• Genentech, Inc.: collaborator
• Syndax Pharmaceuticals: collaborator

Study Sites (4)

Indiana University Health Hospital

Indianapolis, Indiana, 46202, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Ohio State University

Columbus, Ohio, 43210, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis; Kidney Neoplasms

Interventions

atezolizumab; Bevacizumab; entinostat

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Roberto Pili
• Organization: University at Buffalo

rpili@buffalo.edu

(716) 881-8918

Study Officials

• Nabil Adra, MD

  Indiana University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Oncology

Study Record Dates

• First Submitted: January 16, 2017
• First Posted: January 18, 2017
• Study Start: June 29, 2017
• Primary Completion: June 24, 2024
• Study Completion: June 24, 2024
• Last Updated: March 20, 2025
• Results First Posted: March 20, 2025

Record last verified: 2025-03

Locations

US (4)