Clinical Trials /

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

NCT03552380

Description:

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.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU17-326
  • NCT ID: NCT03552380

Conditions

  • Renal Cell Carcinoma

Interventions

DrugSynonymsArms
EntinostatMS-275, SND-275Entinostat, Nivolumab and Ipilimumab
NivolumabOpdivoEntinostat, Nivolumab and Ipilimumab
IpilimumabYervoyEntinostat, Nivolumab and Ipilimumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Entinostat, Nivolumab and IpilimumabExperimentalEntinostat: 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
  • Entinostat
  • Nivolumab
  • Ipilimumab

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 activity
             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 7
             months after the last dose of study drug.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Establish the recommended Phase II dose (RP2D)
Time Frame:6 months
Safety Issue:
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.

Secondary Outcome Measures

Measure:Assess Adverse Events
Time Frame:24 months
Safety Issue:
Description:Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
Measure:ORR via irRC
Time Frame:24 months
Safety Issue:
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).
Measure:Progression Free Survival (PFS) via RECIST 1.1
Time Frame:24 months
Safety Issue:
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
Measure:Progression Free Survival (PFS) via irRC
Time Frame:24 months
Safety Issue:
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.
Measure:Overall Survival (OS)
Time Frame:24
Safety Issue:
Description:OS is defined from Day 1 of treatment until death as a result of any cause

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roberto Pili

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