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

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ClinicalTrials.gov Identifier: NCT02619253
Recruitment Status : Recruiting
First Posted : December 2, 2015
Last Update Posted : March 22, 2018
Sponsor:
Information provided by (Responsible Party):
Roberto Pili, Indiana University School of Medicine

Brief Summary:

Primary objective: To assess the safety and tolerability of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma in order to select the recommended Phase 2 dose (RP2D).

Secondary objectives: (1) To evaluate the overall safety profile of pembrolizumab in combination with vorinostat; (2) To assess the anti-tumor activity (i.e. objective response rate, progression-free survival) of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma; (3) To characterize PD-L1/2, immune cell subsets, and miRs in tumor and/or blood.


Condition or disease Intervention/treatment Phase
Renal Cell Carcinoma Urinary Bladder Neoplasms Drug: Pembrolizumab Drug: Vorinostat Phase 1

Detailed Description:

This is a Phase I/Ib, open-label, safety, and pharmacodynamics study of pembrolizumab in combination with vorinostat in patients with advanced renal or urothelial cell carcinoma. This clinical study will be composed of a Dose Finding Phase and an Expansion Phase. The Dose Finding Phase will estimate the Recommended Phase II Dose (RP2D) in patients with advanced renal and urothelial cell carcinoma patients. The Dose Finding Phase will lead to the identification of an Expansion Test Dose for pembrolizumab in combination with vorinostat. The Expansion Test Dose will be the Recommended Phase II Dose (RP2D) (i.e. the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor). 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 mg and 200 mg). 200 mg dose represents 50% of the recommended vorinostat dose as single agent.

For the Dose Finding Phase (Combination Phase), the starting dose level of vorinostat will be 100 mg by mouth (PO) every day for 14 days, with 7 days break. The first dose level will have a minimum of 3 patients treated (unless the first 2 patients experience dose-limiting toxicities (DLTs) before the 3rd patient is enrolled).

Once the RP2D is identified, the Dose Expansion Phase will be opened. During the Dose Expansion Phase, the study will have a run-in phase with sequential single-agents and then the combination phase. The reason for the run-in phase during dose expansion is to obtain data on the immunomodulatory effects of vorinostat separately from pembrolizumab. Thirty patients with prior treatments will be enrolled in two expansion cohorts: 15 anti-PD1 naive patients and 15 anti-PD1 resistant patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition).


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/Ib, Open Label, Dose Finding Study to Evaluate Safety, Pharmacodynamics and Efficacy of Pembrolizumab (MK-3475) in Combination With Vorinostat in Patients With Advanced Renal or Urothelial Cell Carcinoma
Actual Study Start Date : January 14, 2016
Estimated Primary Completion Date : May 31, 2019
Estimated Study Completion Date : May 31, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Finding Cohort
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
Other Name: Keytruda

Drug: Vorinostat
Other Name: Zolinza

Experimental: Expansion Cohort
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. Thirty patients with prior treatments will be enrolled in two expansion cohorts: 15 anti-PD1 naive patients and 15 anti-PD1 resistant patients (defined as patients with transient clinical response or without clinical response to prior immune-checkpoint inhibition).
Drug: Pembrolizumab
Other Name: Keytruda

Drug: Vorinostat
Other Name: Zolinza




Primary Outcome Measures :
  1. Find Recommended Phase 2 Dose (RP2D) of pembrolizumab in combination with vorinostat [ Time Frame: 18 months ]
    Measurements of MTD (i.e. the highest dose of vorinostat associated with the occurrence of Dose Limiting Toxicities (DLTs) in <33% of patients) or the RP2D (i.e. the highest tested dose that is declared safe and tolerable by the Investigators and Sponsor)


Secondary Outcome Measures :
  1. Serious adverse events, adverse events (AEs) and discontinuations due to AEs will be summarized according to CTCAE 4.0 [ Time Frame: 18 months ]
    Safety of pembrolizumab in combination with vorinostat

  2. Objective response rate [ Time Frame: 18 months ]
    Efficacy (i.e., anti-tumor activity) of pembrolizumab in combination with vorinostat

  3. Progression free survival [ Time Frame: 18 months ]
    Efficacy (i.e., anti-tumor activity) of pembrolizumab in combination with vorinostat



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

All subjects must have previously treated either locally advanced or metastatic renal or urothelial cell carcinoma to be eligible for participation.

Subject Inclusion Criteria

In order to be eligible for participation in this trial, the subject must:

  1. Be willing and able to provide written informed consent for the trial.
  2. Be 18 years of age jor older on day of signing informed consent.
  3. Have measurable disease based on RECIST 1.1.
  4. Have a performance status of 0-2 on the ECOG Performance Scale.
  5. Demonstrate adequate organ function. All screening labs should be performed within 10 days of treatment initiation.
  6. 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.
  7. 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).
  8. 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.
  9. Subjects have archival tumor tissue available or are willing to undergo a baseline biopsy prior to treatment.
  10. Subjects with urothelial carcinoma must be platinum-resistant (i.e., treatment-free interval 6< months)
  11. Subjects with a history of diabetes mellitus must have HgbA1c level of _<7% upon study entry.

Subject Exclusion Criteria

The subject must be excluded from participating in the trial if the subject:

  1. 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.
  2. 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.
  3. Has active TB (Bacillus Tuberculosis)
  4. Hypersensitivity to pembrolizumab or any of its excipients.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Has known history of, or any evidence of active, non-infectious pneumonitis.
  11. Has an active infection requiring systemic therapy.
  12. 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.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (only Cohort A).
  16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  17. Has known active Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g. HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days of planned start of study therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02619253


Contacts
Contact: Marietta Moore, RN 317-274-7477

Locations
United States, California
USC/Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Charis Barg, RN    323-865-0845    charis.barg@med.usc.edu   
Principal Investigator: David Quinn, MD         
United States, Indiana
Indiana University Hospital Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Marietta Moore, RN    317-274-7477    marlmoor@iu.edu   
Principal Investigator: Roberto Pili, MD         
Indiana University Melvin and Bren Simon Cancer Center Recruiting
Indianapolis, Indiana, United States, 46202
Contact: Marietta Moore, RN    317-274-7477    marlmoor@iu.edu   
Principal Investigator: Roberto Pili, MD         
IU Health Central Indiana Cancer Centers (CICC) Recruiting
Indianapolis, Indiana, United States, 46219
Contact: Deb Racster, RN    317-727-6549    dracster@iuhealth.org   
Principal Investigator: Andrew Greenspan, MD         
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Recruiting
Baltimore, Maryland, United States, 21205
Contact: Connie Collins    410-955-1017    ccolli23@jhmi.edu   
Principal Investigator: Noah Hahn, MD         
Sponsors and Collaborators
Roberto Pili
Investigators
Principal Investigator: Roberto Pili, MD Indiana University School of Medicine, Indiana University Simon Cancer Center

Responsible Party: Roberto Pili, Professor of Medicine, Robert Wallace Miller Professor of Oncology, Indiana University School of Medicine
ClinicalTrials.gov Identifier: NCT02619253     History of Changes
Other Study ID Numbers: IUSCC-0551
First Posted: December 2, 2015    Key Record Dates
Last Update Posted: March 22, 2018
Last Verified: March 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Roberto Pili, Indiana University School of Medicine:
Immunotherapy
Safety
Pharmacodynamics
Efficacy

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Renal Cell
Urinary Bladder Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Urinary Bladder Diseases
Pembrolizumab
Vorinostat
Antineoplastic Agents
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action