Phase I/Ib Study of Pembrolizumab With Vorinostat for Patients With Advanced Renal or Urothelial Cell Carcinoma

NCT02619253 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: IUSCC-0551
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 4

Brief Summary

Primary objective: To assess the early signals for anti-tumor activity (i.e. objective response rate, progression-free survival) of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma. Secondary objectives: (1) To evaluate the overall safety profile of pembrolizumab in combination with vorinostat; (2) To assess the safety and tolerability of pembrolizumab in combination with vorinostat in patients with advanced prostate, renal or urothelial cell carcinoma in order to select the recommended Phase 2 Dose (RP2D)

Conditions

Renal Cell Carcinoma; Urinary Bladder Neoplasms

Keywords

Immunotherapy; Safety; Pharmacodynamics; Efficacy

Outcome Measures

Primary Outcomes (2)

• Objective Response Rate (Percentage of Patients With Complete Response or Partial Response)

  Measured by RECIST v1.1 Complete response: Disappearance of all target lesions Partial response: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter The percentage of patients with objective response and its 95% confidence interval will be provided.

  Up to 4.5 years

• Progression Free Survival

  Progression free survival was determined from start date of treatment to date of progression for patients who progressed or date of death for patients who died without progressing. The observations of patients remaining alive and progression free were censored at the date of last disease evaluation. The Kaplan-Meier method was used to determine the median and 95% confidence interval.

  Up to 4.5 years

Secondary Outcomes (2)

• Safety and Tolerablity: Number of Patients Who Experienced Grade 3 or 4 Adverse Events

  Up to 4.5 years

• Number of Patients Experiencing a Dose Limiting Toxicity

  Up to 21 days

Study Arms (2)

Dose Finding Cohort

EXPERIMENTAL

Estimate the Recommended Phase 2 Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. Patients will be treated with oral vorinostat every day for 14 days, and with pembrolizumab at the fixed dose of 200 mg IV. Each cycle is every 21 days. Two dose levels of vorinostat will be tested in 2 patient cohorts according to the 3 + 3 standard design (100 and 200 mg).

Drug: Pembrolizumab; Drug: Vorinostat

Expansion Cohort

EXPERIMENTAL

Once the Expansion Test Dose is identified, the Dose Expansion Phase will be opened and the combination will be tested in patients with advanced renal cell or urothelial cell carcinoma. Forty-five patients with prior treatments will be enrolled in three expansion cohorts: 15 anti-PD1 naive renal and urothelial patients, 15 anti-PD1 resistant renal and urothelial patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition), and 15 patients with androgen-sensitive or castration-resistant prostate cancer.

Drug: Pembrolizumab; Drug: Vorinostat

Interventions

Pembrolizumab DRUG

Also known as: Keytruda

Dose Finding Cohort; Expansion Cohort

Vorinostat DRUG

Also known as: Zolinza

Dose Finding Cohort; Expansion Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible for participation in this trial, the subject must:
• Have one of the following diagnoses/conditions:
• Renal cell carcinoma - previously treated and progressive disease, locally advanced or metastatic
• Urothelial cell carcinoma - previously treated and progressive disease, locally advanced or metastatic
• Prostate cell carcinoma - progressive disease, locally advanced or metastatic disease (enrolling only at IUSCC and its affiliates). Patients with hormone-sensitive disease where ADT in combination with either docetaxel or abiraterone is indicated will not be eligible (i.e. patients with high burden disease).
• Be willing and able to provide written informed consent for the trial.
• Be 18 years of age or older on day of signing informed consent.
• Have measurable disease based on RECIST 1.1. for patients with solid malignancies or evaluable disease as assessed by bone scan and/or PET scan. Patients with advanced or metastatic prostate cancer can have either androgen-sensitive or castration-resistant disease.
• Have a performance status of 0-2 on the ECOG Performance Scale.
• Demonstrate adequate organ function. All screening labs should be performed within 10 days of treatment initiation.
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Subjects of childbearing potential should be willing to use 2 methods of contraception for the course of the study through 120 days after the last dose of study medication. Acceptable methods of birth control include: abstinence, partner with previous vasectomy, placement of an intrauterine device (IUD), condom with spermicidal foam/gel/film/cream/suppository, diaphragm or cervical vault cap, or hormonal birth control (pills or injections). NOTE: Females are considered of childbearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year).
• Male subjects without a previous vasectomy should agree to use an adequate method of contraception (i.e. abstinence, condom with spermicidal foam/gel/film/cream) starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• Subjects with urothelial carcinoma must have received a prior platinum-based regimen in the metastatic setting or have signed consent for this study within 12 months of receiving a platinum-based regimen in the perioperative setting (neoadjuvant or adjuvant).
• Subjects with a history of diabetes mellitus must have HgbA1c level of \<8.5% upon study entry.

You may not qualify if:

• The subject must be excluded from participating in the trial if the subject:
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1 Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1 Day 1 or who has not recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of, or any evidence of active, non-infectious pneumonitis.
• Has an active infection requiring systemic therapy.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

Sponsors & Collaborators

• Nabil Adra: lead

Study Sites (4)

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Indiana University Hospital

Indianapolis, Indiana, 46202, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21205, United States

Location

Related Publications (1)

• Pili R, Quinn DI, Adra N, Logan T, Colligan S, Burney HN, Hahn NM. A Phase I/IB, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and Efficacy of Pembrolizumab in Combination With Vorinostat in Patients With Advanced Prostate, Renal or Urothelial Carcinoma. Cancer Med. 2025 Apr;14(7):e70725. doi: 10.1002/cam4.70725.

  PMID: 40145367 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell; Urinary Bladder Neoplasms

Interventions

pembrolizumab; Vorinostat

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Urinary Bladder Diseases

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Dr. Nabil Adra
• Organization: IndianaU

nadra@iu.edu

317-278-7728

Study Officials

• Roberto Pili, MD

  Indiana University School of Medicine, Indiana University Simon Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor of Clinical Medicine

Study Record Dates

• First Submitted: November 16, 2015
• First Posted: December 2, 2015
• Study Start: February 23, 2016
• Primary Completion: March 28, 2023
• Study Completion: March 28, 2023
• Last Updated: November 18, 2024
• Results First Posted: November 18, 2024

Record last verified: 2024-09

Locations

US (4)