Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma

NCT03552380 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: HCRN GU17-326
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

This is a Phase II, open-label, safety, pharmacodynamic and efficacy study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic renal cell carcinoma (RCC) who have progressed on ipilimumab + nivolumab regimen. Prior to Phase II, a safety lead-in will be conducted to establish the RP2D of entinostat when used in combination with ipilimumab + nivolumab. Subjects will initially be treated with the combination of oral entinostat and intravenous (IV) nivolumab plus ipilimumab. Entinostat will be dosed weekly, and nivolumab and ipilimumab will be dosed every 3 weeks, for a total of four, 3-week cycles. Following these first four cycles, entinostat will continue to be administered weekly in combination with nivolumab every 4 weeks or every 2 weeks based on subject tolerance (ipilimumab will be discontinued), with treatment continued until disease progression or prohibitive toxicity. Anti-tumor activity will be assessed by radiological tumor assessments conducted at baseline and every 6 weeks thereafter using RECIST version 1.1.

Conditions

Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) Via RECIST 1.1

  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

  From C1D1 until death or up to 31 months.

Secondary Outcomes (5)

• Number of Participants With Adverse Events

  From C1D1 until death or up to 31 months

• Objective Response Rate Via Immune Related Response Criteria (irRC)

  From C1D1 until death up to 31 months

• Progression Free Survival (PFS) Via RECIST 1.1

  Up to 31 months.

• Progression Free Survival (PFS) Via irRC

  Up to 31 months

• Overall Survival (OS)

  Up to a maximum of 59 months

Study Arms (1)

Entinostat, Nivolumab and Ipilimumab

EXPERIMENTAL

Entinostat: 5mg, 3mg, or 2mg orally (PO) on D1, 8, 15 plus Nivolumab: 3 mg/kg IV D1 and Ipilimumab 1 mg/kg IV D1 Each cycle is 21 days

Drug: Entinostat; Drug: Nivolumab; Drug: Ipilimumab

Interventions

Entinostat DRUG

RP2D will be determined with a 6 patient safety lead-in. Entinostat will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles.

Also known as: MS-275, SND-275

Entinostat, Nivolumab and Ipilimumab

Nivolumab DRUG

Nivolumab will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles.

Also known as: Opdivo

Entinostat, Nivolumab and Ipilimumab

Ipilimumab DRUG

Ipilimumab will be administered in combination with entinostat and nivolumab for Cycles 1-4 only.

Also known as: Yervoy

Entinostat, Nivolumab and Ipilimumab

Eligibility Criteria

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

You may qualify if:

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 within 28 days prior to registration.
• Histological or cytological evidence of renal cell carcinoma (initial diagnosis).
• Metastatic disease
• Progressive disease (PD) on nivolumab + ipilimumab regimen. Note: Patients who have completed at least one dose of ipilimumab + nivolumab and progress or have completed the 4 doses of ipilimumab + nivolumab and progress during nivolumab monotherapy maintenance are eligible unless they have received additional treatment(s) for their renal cell carcinoma prior to registration. Patients who discontinue prior ipilimumab + nivolumab or nivolumab monotherapy for toxicity are excluded. Patients who receive nivolumab or other anti-PD-1/PD-L1 agents as subsequent therapy after ipilimumab + nivolumab are excluded.
• Target lesions according to RECIST v1.1 or non-target bone lesions assessed by bone scan or positron emission tomography (PET) scan.
• A subject with prior brain metastasis may be considered if they have completed their treatment for brain metastasis at least 4 weeks prior to study registration, have been off corticosteroids for ≥ 4 weeks, and are asymptomatic.
• Prior cancer treatment (excluding nivo/ipi) must be completed at least 28 days prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia or neuropathy) to ≤Grade 1 or baseline. If subject underwent major surgery or radiation therapy of \>30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
• Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 28 days prior to registration
• Platelets ≥100 x 10\^9/L
• Absolute Neutrophil Count (ANC) ≥1.5 x 10\^9/L
• Hemoglobin (Hgb) ≥9 g/dL or ≥5.6 mmol/L
• Creatinine OR Measured or calculated creatinine clearance (CrCl) (glomerular filtration rate \[GFR\] can also be used in place of CrCl) Creatinine clearance should be calculated per institutional standard ≤1.5 x the upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \>1.5 x institutional ULN
• Bilirubin ≤1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 x ULN

You may not qualify if:

• Subjects meeting any of the criteria below may not participate in the study:
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator, including, but not limited to:
• Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) Class III or IV disease, or a corrected QT interval (QTc) interval \> 470 msec.
• Uncontrolled hypertension or diabetes mellitus.
• Another known malignancy that is progressing or requires active treatment.
• Any prior history of other cancer within the prior 5 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia \[CIN\]/cervical carcinoma in situ or melanoma in situ).
• Active infection requiring systemic therapy.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Pregnant or breastfeeding. Note: breast milk cannot be stored for future use while the mother is being treated on study.
• 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.
• Allergy to benzamide or inactive components of entinostat.
• Hypersensitivity to nivolumab, ipilimumab, or any of their excipients.
• Treatment with any investigational drug or device within 4 weeks prior to registration.
• Treatment with systemic steroids within 4 weeks prior to registration. Note: adrenal replacement doses of steroids (for example prednisone 10mg daily) are permitted while on study.
• Evidence of active autoimmune disease requiring systemic treatment within the past 90 days or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.

Sponsors & Collaborators

• Roberto Pili: lead
• Bristol-Myers Squibb: collaborator
• Syndax Pharmaceuticals: collaborator
• Indiana University School of Medicine: collaborator

Study Sites (2)

Georgetown University

Washington D.C., District of Columbia, 20057, United States

Location

Indiana Univeristy Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

entinostat; Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; 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: Annesha Majumdar
• Organization: Hoosier Cancer Research Network

amajumdar@hoosiercancer.org

3179212050

Study Officials

• Roberto Pili, MD

  Indiana Univervisty Simon Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: May 29, 2018
• First Posted: June 11, 2018
• Study Start: July 31, 2018
• Primary Completion: June 7, 2022
• Study Completion: February 15, 2024
• Last Updated: September 3, 2024
• Results First Posted: September 3, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)