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

NCT02619253

Description:

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); (3) To characterize immune cell subsets, and miRs in tumor and/or blood.

Related Conditions:
  • Prostate Carcinoma
  • Renal Cell Carcinoma
  • Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IUSCC-0551
  • NCT ID: NCT02619253

Conditions

  • Renal Cell Carcinoma
  • Urinary Bladder Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaDose Finding Cohort
VorinostatZolinzaDose Finding Cohort

Purpose

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.

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).
    

Trial Arms

NameTypeDescriptionInterventions
Dose Finding CohortExperimentalEstimate 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).
  • Pembrolizumab
  • Vorinostat
Expansion CohortExperimentalOnce 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).
  • Pembrolizumab
  • Vorinostat

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Find Recommended Phase 2 Dose (RP2D) of pembrolizumab in combination with vorinostat
Time Frame:18 months
Safety Issue:
Description: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

Measure:Serious adverse events, adverse events (AEs) and discontinuations due to AEs will be summarized according to CTCAE 4.0
Time Frame:18 months
Safety Issue:
Description:Safety of pembrolizumab in combination with vorinostat
Measure:Objective response rate
Time Frame:18 months
Safety Issue:
Description:Efficacy (i.e., anti-tumor activity) of pembrolizumab in combination with vorinostat
Measure:Progression free survival
Time Frame:18 months
Safety Issue:
Description:Efficacy (i.e., anti-tumor activity) of pembrolizumab in combination with vorinostat

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roberto Pili

Trial Keywords

  • Immunotherapy
  • Safety
  • Pharmacodynamics
  • Efficacy

Last Updated

January 16, 2017