Renal Cell CarcinomaPhase 2NCT03552380
Study of Entinostat With Nivolumab Plus Ipilimumab in Previously Treated Renal Cell Carcinoma
A Phase 2 study testing Entinostat, Nivolumab and Ipilimumab in people with Renal Cell Carcinoma, run by Roberto Pili at 2 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Renal Cell Carcinoma
- What is being tested?
- Entinostat, Nivolumab and Ipilimumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 2 sitesUnited States
- Study dates
- 31 Jul 2018to 15 Feb 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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
- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Indiana Univeristy Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
Georgetown University
Washington D.C., District of Columbia, 20057
About this study
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
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
- Being tested
- Entinostat, Nivolumab, Ipilimumab
- Medical subject headings
- Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
EntinostatDrug
Also called MS-275, SND-275
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.
NivolumabDrug
Also called Opdivo
Nivolumab will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles.
IpilimumabDrug
Also called Yervoy
Ipilimumab will be administered in combination with entinostat and nivolumab for Cycles 1-4 only.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Drug: Entinostat; Drug: Nivolumab; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From C1D1 until death or up to 31 months.
Secondary outcomes (5)
Number of Participants With Adverse Events
Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4
Measured: From C1D1 until death or up to 31 months
Objective Response Rate Via Immune Related Response Criteria (irRC)
Per immune-related response criteria (irRC): Complete Response(irCR), Disappearance of all target and nontarget lesions; Partial Reponse (irPR), ≥ 50% decrease in tumor burden compared with baseline; Progressive Disease (irPD), >= 25% increase in tumour burden relative to nadir or the appearance new lesions; Stable Disease (irSD), not meeting criteria for irCR or irPR, in absence of irPD. Overall Response (OR) = irCR + irPR
Measured: From C1D1 until death up to 31 months
Progression Free Survival (PFS) 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; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD.
PFS is defined as time from starting treatment to disease progression met by RECIST 1.1 or death as a result of any cause.
Measured: Up to 31 months.
Progression Free Survival (PFS) Via irRC
Per immune-related response criteria (irRC): Complete Response(irCR), Disappearance of all target and nontarget lesions; Partial Reponse (irPR), ≥ 50% decrease in tumor burden compared with baseline; Progressive Disease (irPD), >= 25% increase in tumour burden relative to nadir or the appearance new lesions; Stable Disease (irSD), not meeting criteria for irCR or irPR or irPD.
PFS is defined as time from starting treatment to disease progression met by irRC or death as a result of any cause.
Measured: Up to 31 months
Overall Survival (OS)
OS is defined from Day 1 of treatment until death as a result of any cause
Measured: Up to a maximum of 59 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jun 2018
- Study start31 Jul 2018
- Primary completion7 Jun 2022
- Study completion15 Feb 2024
Why it stopped: Funder halted development of compound in this disease
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Renal Cell CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Roberto Pili
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb, Syndax Pharmaceuticals, Indiana University
- Responsible party
- Sponsor-investigator, Roberto Pili, Hoosier Cancer Research Network
- Investigators
- Roberto Pili, MD, Principal investigator, Indiana Univervisty Simon Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03552380
- Sponsor's protocol ID
- HCRN GU17-326
- Status last verified
- Aug 2024
- First submitted
- 29 May 2018
- Last updated
- 3 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 3 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03552380
- Acronym / sponsor ID
- HCRN GU17-326
- Conditions
- Renal Cell Carcinoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Funder halted development of compound in this disease
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Roberto PiliUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb, Syndax Pharmaceuticals, Indiana University
- Study start
- 31 Jul 2018 (actual)
- Primary completion
- 7 Jun 2022 (actual)
- Study completion
- 15 Feb 2024 (actual)
- First posted
- 11 Jun 2018 (actual)
- Results
- Posted 3 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Entinostat, Nivolumab and Ipilimumab | Experimental | Drug: Entinostat, Drug: Nivolumab, Drug: IpilimumabEntinostat: 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- 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
Key exclusion criteria (20 listed)
- Subjects meeting any of the criteria below may not participate in the study:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| EntinostatAlso: MS-275, SND-275RP2D 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. | Drug | Entinostat, Nivolumab and Ipilimumab |
| NivolumabAlso: OpdivoNivolumab will continue until disease progression or prohibitive toxicity. Cycles 1-4 are 21 day cycles. Cycles 5 and subsequent are 28 day cycles. | Drug | Entinostat, Nivolumab and Ipilimumab |
| IpilimumabAlso: YervoyIpilimumab will be administered in combination with entinostat and nivolumab for Cycles 1-4 only. | Drug | Entinostat, Nivolumab and Ipilimumab |
Primary outcome
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.
5 secondary outcomes
Number of Participants With Adverse Events
Time frame: From C1D1 until death or up to 31 months
Objective Response Rate Via Immune Related Response Criteria (irRC)
Time frame: From C1D1 until death up to 31 months
Progression Free Survival (PFS) Via RECIST 1.1
Time frame: Up to 31 months.
Progression Free Survival (PFS) Via irRC
Time frame: Up to 31 months
Overall Survival (OS)
Time frame: Up to a maximum of 59 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Pucotenlimab, Lenvatinib, and SBRT Before Surgery for Localized Clear Cell Renal Cell Carcinoma
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roberto Pili, MD principal investigator
Indiana Univervisty Simon Cancer Center
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Entinostat, Nivolumab and Ipilimumab in people with Renal Cell Carcinoma, run by Roberto Pili at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 3 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) Via RECIST 1.1 (time frame: From C1D1 until death or up to 31 months.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Sep 2024.