NCT03552380

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

Terminated Phase 2 Results posted Last updated 3 September 2024

What this trial tests

Phase 2 trial testing Entinostat in Renal Cell Carcinoma in 12 participants. Terminated before completion.

Timeline

31 July 2018

Primary endpoint
7 June 2022

15 February 2024

Quick facts

Lead sponsor	Roberto Pili
Phase	Phase 2
Status	Terminated
Study type	INTERVENTIONAL
Allocation	na
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	12
Start date	31 July 2018
Primary completion	7 June 2022
Estimated completion	15 February 2024
Sites	2 locations across United States

Drugs / interventions tested

• Entinostat — full drug profile →
• Nivolumab (nivolumab) — full drug profile →
• Ipilimumab — full drug profile →

Conditions studied

• Renal Cell Carcinoma — all drugs for Renal Cell Carcinoma →

Sponsor

Roberto Pili

Who can join

18 and older, any sex, with Renal Cell Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Objective Response Rate (ORR) Via RECIST 1.1 Primary · 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.

Group	Value	95% CI
Phase II, Dose Level 1:Entinostat 5 mg With Nivolumab and Ipilimumab	20	5.1 – 71.6
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	42.9	9.9 – 81.6

Number of Participants With Adverse Events Secondary · From C1D1 until death or up to 31 months

Assess adverse events according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4

Number of patients had at least one adverse event of any grade.

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	5
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	7

Number of patients had at least one grade 3 or greater adverse event.

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	5
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	3

Number of patients had at least one grade 3 or greater treatment related adverse event

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	5
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	2

Number of patients having serious adverse event.

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	3
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	3

Objective Response Rate Via Immune Related Response Criteria (irRC) Secondary · From C1D1 until death up to 31 months

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

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	20	5.1 – 71.6
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	28.6	3.7 – 71

Progression Free Survival (PFS) Via RECIST 1.1 Secondary · 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; 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.

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	4.3	1.3 – NA
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	11.7	1.9 – NA

Progression Free Survival (PFS) Via irRC Secondary · Up to 31 months

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.

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	4.3	1.3 – NA
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	11.7	5.9 – NA

Overall Survival (OS) Secondary · Up to a maximum of 59 months

OS is defined from Day 1 of treatment until death as a result of any cause

Group	Value	95% CI
Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab	49.9	6.7 – NA
Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab	36	5.9 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: All-Cause Mortality was monitored up to a maximum of 59 months. Serious Adverse Events and Other (Not Including Serious) Adverse Events were monitored up to 31 months.. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Phase II, Dose Level 1: Entinostat 5 mg With Nivolumab and Ipilimumab

Serious: 3/5 (60%)

Deaths: 3/5

Phase II, Dose Level 2: Entinostat 3 mg With Nivolumab and Ipilimumab

Serious: 3/7 (43%)

Deaths: 4/7

Serious adverse events (8 terms)

Reaction	System	Phase II, Dose Level 1: En…	Phase II, Dose Level 2: En…
Platelet count decreased	Investigations	—	—
Skin infection	Infections and infestations	—	—
Vomiting	Gastrointestinal disorders	—	—
Adrenal insufficiency	Endocrine disorders	—	—
Gastrointestinal disorders - Other, specify	Gastrointestinal disorders	—	—
Heart failure	Cardiac disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Lower gastrointestinal hemorrhage	Gastrointestinal disorders	—	—

Other adverse events (70 terms — click to expand)

Reaction	System	Phase II, Dose Level 1: En…	Phase II, Dose Level 2: En…
Fatigue	General disorders	—	—
Hypophosphatemia	Metabolism and nutrition disorders	—	—
Neutrophil count decreased	Investigations	—	—
Platelet count decreased	Investigations	—	—
Rash maculo-papular	Skin and subcutaneous tissue disorders	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—
Anemia	Blood and lymphatic system disorders	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Hyponatremia	Metabolism and nutrition disorders	—	—
Insomnia	Psychiatric disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Weight loss	Investigations	—	—
Gastrointestinal disorders - Other, specify	Gastrointestinal disorders	—	—
Headache	Nervous system disorders	—	—
Hyperglycemia	Metabolism and nutrition disorders	—	—
Lymphocyte count decreased	Investigations	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—
Skin and subcutaneous tissue disorders - Other, specify	Skin and subcutaneous tissue disorders	—	—
Sore throat	Respiratory, thoracic and mediastinal disorders	—	—
Adrenal insufficiency	Endocrine disorders	—	—
Alopecia	Skin and subcutaneous tissue disorders	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—
Creatinine increased	Investigations	—	—
Dehydration	Metabolism and nutrition disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Edema limbs	General disorders	—	—
Eye infection	Infections and infestations	—	—
Hypertension	Vascular disorders	—	—
Hypokalemia	Metabolism and nutrition disorders	—	—
Hypomagnesemia	Metabolism and nutrition disorders	—	—
Hypotension	Vascular disorders	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—
Pneumonitis	Respiratory, thoracic and mediastinal disorders	—	—
Skin induration	Skin and subcutaneous tissue disorders	—	—
Skin infection	Infections and infestations	—	—
Upper respiratory infection	Infections and infestations	—	—
Vertigo	Ear and labyrinth disorders	—	—
Weight gain	Investigations	—	—

Most-reported serious reactions: Platelet count decreased, Skin infection, Vomiting, Adrenal insufficiency, Gastrointestinal disorders - Other, specify, Heart failure, Hyperglycemia, Lower gastrointestinal hemorrhage.

Data from ClinicalTrials.gov NCT03552380 adverse events section.

Sponsor's own 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 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.
   Cheng Y, He C, Wang M, Ma X, et al · · 2019 · cited 760× · PMID 31871779 · DOI 10.1038/s41392-019-0095-0
2. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets.
   Yang J, Xu J, Wang W, Zhang B, et al · · 2023 · cited 251× · PMID 37217462 · DOI 10.1038/s41392-023-01480-x
3. Immunotherapy in Renal Cell Carcinoma: The Future Is Now.
   Deleuze A, Saout J, Dugay F, Peyronnet B, et al · · 2020 · cited 178× · PMID 32260578 · DOI 10.3390/ijms21072532
4. Epigenetics-targeted drugs: current paradigms and future challenges.
   Dai W, Qiao X, Fang Y, Guo R, et al · · 2024 · cited 131× · PMID 39592582 · DOI 10.1038/s41392-024-02039-0
5. Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma.
   Sharma R, Kadife E, Myers M, Kannourakis G, et al · · 2021 · cited 120× · PMID 34099013 · DOI 10.1186/s13046-021-01961-3
6. Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials.
   Kooshkaki O, Derakhshani A, Hosseinkhani N, Torabi M, et al · · 2020 · cited 95× · PMID 32580338 · DOI 10.3390/ijms21124427
7. Advances in epigenetic therapeutics with focus on solid tumors.
   Jin N, George TL, Otterson GA, Verschraegen C, et al · · 2021 · cited 87× · PMID 33879235 · DOI 10.1186/s13148-021-01069-7
8. Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases.
   Gatla HR, Muniraj N, Thevkar P, Yavvari S, et al · · 2019 · cited 68× · PMID 30841513 · DOI 10.3390/ijms20051110