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

Primary Purpose

Renal Cell Carcinoma

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Entinostat
Nivolumab
Ipilimumab
Sponsored by
Roberto Pili
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Renal Cell Carcinoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 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 109/L
    • Absolute Neutrophil Count (ANC) ≥1.5 x 109/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
    • Aspartate aminotransferase (AST) ≤3 x ULN
    • Alanine aminotransferase (ALT) ≤3 x ULN
    • International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT/INR/PTT is within therapeutic range of intended use of anticoagulants
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and a negative urine pregnancy test within 3 days prior to first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required.
  • Women of childbearing potential must be willing to abstain from heterosexual intercourse or to use an effective method of contraception from the time of informed consent until 5 months after the last dose of study drug.
  • Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving study drugs and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 3 months after the last dose of entinostat.
  • As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.
  • Life expectancy of at least 6 months per investigator discretion.

Exclusion Criteria:

  • 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.
    • Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids.
    • Diagnosis of immunodeficiency; or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 4 weeks prior to registration.
    • Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Testing during screening is not required.
    • Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Subjects with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these subjects prior to study treatment, and results must be negative to be eligible. Subjects with a history of hepatitis C must be tested for presence of hepatitis C virus (HCV) antibody. If HCV antibody positive, subjects will only be eligible if polymerase chain reaction is negative for HCV RNA.
    • Has received a live vaccine within 30 days prior to planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Sites / Locations

  • Georgetown University
  • Indiana Univeristy Melvin and Bren Simon Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Entinostat, Nivolumab and Ipilimumab

Arm Description

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

Outcomes

Primary Outcome Measures

Establish the recommended Phase II dose (RP2D)
The Safety Lead-In will be Entinostat tested in 6-subject cohorts with a dose de-escalation design (5 mg, 3 mg and 2 mg) in combination with fixed dose nivolumab and ipilimumab.
Objective Response Rate (ORR) via RECIST 1.1
Assess ORR via RECIST 1.1 during the Phase II study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic RCC who have progressed on nivolumab + ipilimumab regimen. ORR is defined as the rate of complete response (CR) + partial response (PR).

Secondary Outcome Measures

Assess Adverse Events
Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
ORR via irRC
Assess ORR via immune related response criteria (irRC) during the Phase II study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic RCC who have progressed on nivolumab + ipilimumab regimen. ORR is defined as the rate of complete response (irCR) + partial response (irPR).
Progression Free Survival (PFS) via RECIST 1.1
PFS per RECIST 1.1 is defined from day 1 of treatment until disease progression or death as a result of any cause, with progression defined per RECIST 1.1
Progression Free Survival (PFS) via irRC
PFS per irRC is defined from day 1 of treatment until disease progression or death as a result of any cause, with progression defined per irRC.
Overall Survival (OS)
OS is defined from Day 1 of treatment until death as a result of any cause

Full Information

First Posted
May 29, 2018
Last Updated
January 10, 2022
Sponsor
Roberto Pili
Collaborators
Bristol-Myers Squibb, Syndax Pharmaceuticals, Indiana University School of Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT03552380
Brief Title
Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma
Official Title
A Phase II Study to Evaluate the Safety, Pharmacodynamics, and Efficacy of Entinostat in Combination With Nivolumab Plus Ipilimumab in Patients With Renal Cell Carcinoma Previously Treated With Nivolumab Plus Ipilimumab
Study Type
Interventional

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 31, 2018 (Actual)
Primary Completion Date
August 2022 (Anticipated)
Study Completion Date
August 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Roberto Pili
Collaborators
Bristol-Myers Squibb, Syndax Pharmaceuticals, Indiana University School of Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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 2 weeks (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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Renal Cell Carcinoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Entinostat, Nivolumab and Ipilimumab
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Entinostat
Other Intervention Name(s)
MS-275, SND-275
Intervention Description
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 14 day cycles.
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Other Intervention Name(s)
Opdivo
Intervention Description
Nivolumab will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 14 day cycles.
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Other Intervention Name(s)
Yervoy
Intervention Description
Ipilimumab will be administered in combination with entinostat and nivolumab for Cycles 1-4 only.
Primary Outcome Measure Information:
Title
Establish the recommended Phase II dose (RP2D)
Description
The Safety Lead-In will be Entinostat tested in 6-subject cohorts with a dose de-escalation design (5 mg, 3 mg and 2 mg) in combination with fixed dose nivolumab and ipilimumab.
Time Frame
6 months
Title
Objective Response Rate (ORR) via RECIST 1.1
Description
Assess ORR via RECIST 1.1 during the Phase II study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic RCC who have progressed on nivolumab + ipilimumab regimen. ORR is defined as the rate of complete response (CR) + partial response (PR).
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Assess Adverse Events
Description
Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
Time Frame
24 months
Title
ORR via irRC
Description
Assess ORR via immune related response criteria (irRC) during the Phase II study of entinostat in combination with nivolumab and ipilimumab in subjects with metastatic RCC who have progressed on nivolumab + ipilimumab regimen. ORR is defined as the rate of complete response (irCR) + partial response (irPR).
Time Frame
24 months
Title
Progression Free Survival (PFS) via RECIST 1.1
Description
PFS per RECIST 1.1 is defined from day 1 of treatment until disease progression or death as a result of any cause, with progression defined per RECIST 1.1
Time Frame
24 months
Title
Progression Free Survival (PFS) via irRC
Description
PFS per irRC is defined from day 1 of treatment until disease progression or death as a result of any cause, with progression defined per irRC.
Time Frame
24 months
Title
Overall Survival (OS)
Description
OS is defined from Day 1 of treatment until death as a result of any cause
Time Frame
24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 109/L Absolute Neutrophil Count (ANC) ≥1.5 x 109/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 Aspartate aminotransferase (AST) ≤3 x ULN Alanine aminotransferase (ALT) ≤3 x ULN International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT/INR/PTT is within therapeutic range of intended use of anticoagulants Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and a negative urine pregnancy test within 3 days prior to first dose of study drug. If the screening serum test is done within 3 days prior to receiving the first dose of study drug, a urine test is not required. Women of childbearing potential must be willing to abstain from heterosexual intercourse or to use an effective method of contraception from the time of informed consent until 5 months after the last dose of study drug. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving study drugs and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 3 months after the last dose of entinostat. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Life expectancy of at least 6 months per investigator discretion. Exclusion Criteria: 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. Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids. Diagnosis of immunodeficiency; or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 4 weeks prior to registration. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Testing during screening is not required. Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Subjects with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these subjects prior to study treatment, and results must be negative to be eligible. Subjects with a history of hepatitis C must be tested for presence of hepatitis C virus (HCV) antibody. If HCV antibody positive, subjects will only be eligible if polymerase chain reaction is negative for HCV RNA. Has received a live vaccine within 30 days prior to planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roberto Pili, MD
Organizational Affiliation
Indiana Univervisty Simon Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Georgetown University
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20057
Country
United States
Facility Name
Indiana Univeristy Melvin and Bren Simon Cancer Center
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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