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
Overview
- Phase
- Phase 2
- Intervention
- Nivolumab
- Conditions
- Renal Cell Carcinoma
- Sponsor
- Roberto Pili
- Enrollment
- 18
- Locations
- 2
- Primary Endpoint
- Objective Response Rate (ORR) Via RECIST 1.1
- Status
- Active, not recruiting
- Last Updated
- 4 years ago
Overview
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.
Investigators
Roberto Pili
Sponsor-Investigator
Hoosier Cancer Research Network
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
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.
Arms & Interventions
Entinostat, Nivolumab and Ipilimumab
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: Nivolumab
Entinostat, Nivolumab and Ipilimumab
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: Entinostat
Entinostat, Nivolumab and Ipilimumab
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: Ipilimumab
Outcomes
Primary Outcomes
Objective Response Rate (ORR) Via RECIST 1.1
Time Frame: From C1D1 until death or up to 31 months.
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.
Secondary Outcomes
- Objective Response Rate Via Immune Related Response Criteria (irRC)(From C1D1 until death up to 31 months)
- Number of Participants With Adverse Events(From C1D1 until death or 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)