Clinical Trials /

Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma

NCT03426891

Description:

The purpose of this research study is to test the safety and tolerability of the combination treatment of the investigational drugs vorinostat and pembrolizumab, in combination with chemotherapy (temozolomide), and radiotherapy. The U.S. Food and Drug Administration (FDA) has approved pembrolizumab for use to treat a deadly skin cancer called melanoma and lung cancer and vorinostat to treat some forms of blood and lymph node cancers. However, both vorinostat and pembrolizumab are considered investigational drugs in this study because they are not approved for treatment of glioblastoma.

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma
  • Official Title: A Phase I Trial of Pembrolizumab and Vorinostat Combined With Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma

Clinical Trial IDs

  • ORG STUDY ID: MCC-19342
  • NCT ID: NCT03426891

Conditions

  • Glioblastoma
  • Brain Tumor
  • GBM

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, immunotherapyCombination Therapy
VorinostatZolinza™, chemotherapy, histone deacetylase inhibitorCombination Therapy
Temozolomidechemotherapy, Temodar, TMZCombination Therapy

Purpose

The purpose of this research study is to test the safety and tolerability of the combination treatment of the investigational drugs vorinostat and pembrolizumab, in combination with chemotherapy (temozolomide), and radiotherapy. The U.S. Food and Drug Administration (FDA) has approved pembrolizumab for use to treat a deadly skin cancer called melanoma and lung cancer and vorinostat to treat some forms of blood and lymph node cancers. However, both vorinostat and pembrolizumab are considered investigational drugs in this study because they are not approved for treatment of glioblastoma.

Detailed Description

      There are 2 parts to this study:

      Part 1 (dose escalation) and Part 2 (dose expansion). The main purpose of Part 1 is
      Dose-Escalation. "Dose-Escalation" means that different dose levels will be tested at
      different times during the study to find the best dose level that is safe and well tolerated
      in participants. In this study investigators will determine the best dose of Vorinostat that
      can be given with pembrolizumab, chemotherapy and radiotherapy. The dose of temozolomide and
      radiotherapy will be the same as standard treatment.

      Part 2 (Dose Expansion), all participants will receive the same dose of vorinostat with
      pembrolizumab, chemotherapy and radiotherapy.

      Maintenance Phase: During the maintenance phase, participants will receive Temozolomide (for
      the first 6 months), vorinostat (for 12 months), and pembrolizumab (for 12 months).
    

Trial Arms

NameTypeDescriptionInterventions
Combination TherapyExperimentalPembrolizumab and Vorinostat Combined with Temozolomide and Radiotherapy. There are two parts to this study: Part 1 (dose escalation) and Part 2 (dose expansion). Dose Expansion: Twenty participants will be treated with vorinostat at the maximum tolerated dose (MTD) from dose escalation phase, pembrolizumab, temozolomide and radiation. During the maintenance phase, participants will receive Temozolomide (for the first 6 months), vorinostat (for 12 months), and pembrolizumab (for 12 months).
  • Pembrolizumab
  • Vorinostat
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Newly diagnosed glioblastoma or gliosarcoma

          -  Histologically confirmed diagnosis of World Health Organization Grade IV malignant
             glioma

          -  An interval of ≥ 21 days since surgical resection prior to treatment on the trial

          -  Karnofsky performance status of 70 or higher

          -  Adequate organ function laboratory values

          -  Resting baseline O2 saturation by pulse oximetry of ≥ 92% at rest

          -  Willing and able to provide written informed consent/assent for the trial.

          -  Life expectancy ≥ 12 weeks

          -  Willingness to discontinue medications known to be associated with risk of Torsades de
             Pointes such as quinidine, procainamide, disopyramide, amiodarone, erythromycin,
             clarithromycin, chlorpromazine and haloperidol

          -  Single measureable lesion < 4 cm in longest diameter

          -  Patient shouldn't have received any anti-cancer therapy for glioblastoma in past

          -  Females of childbearing potential (FOCBP) should have a negative urine or serum
             pregnancy 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.

          -  Females and males of childbearing potential must be willing to use an adequate method
             of contraception per protocol for the course of the study through 120 days after the
             last dose of study medication. Note: Abstinence is acceptable if this is the usual
             lifestyle and preferred contraception for participant.

          -  Use of Optune device is allowed.

        Exclusion Criteria:

          -  Had prior treatment of glioblastoma (GBM) with radiation and temozolomide

          -  Has evidence of leptomeningeal disease

          -  Had prior treatment with Gliadel

          -  Unable (due to existent medical condition) or unwilling to have a contrast enhanced
             MRI of brain

          -  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. Physiologic doses of steroid therapy (≤ 2 mg/day dexamethasone equivalents)
             by the time of first dose of treatment are allowed.

          -  Has a known history of active Bacillus Tuberculosis (TB)

          -  Hypersensitivity to pembrolizumab or any of its excipients

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             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 study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent. Note: Potential
             participants with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the study. Note: If patient 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 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. Patients with vitiligo or resolved childhood asthma/atopy
             would be an exception to this rule. Patients that require intermittent use of
             bronchodilators or local steroid injections would not be excluded from the study.
             Patients with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will
             not be excluded from the study.

          -  Has known history of, or any evidence of active, interstitial lung disease or
             non-infectious pneumonitis requiring corticosteroid therapy

          -  Has an active infection requiring systemic therapy

          -  Had major surgical procedure, open biopsy, or significant traumatic injury within 21
             days prior to day 1 of treatment on study

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the patient's
             participation for the full duration of the trial, or is not in the best interest of
             the patient to participate

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

          -  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.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Has received a live vaccine within 30 days of 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD)
Time Frame:12 weeks
Safety Issue:
Description:The maximum tolerated dose (MTD)/recommended dose expansion dose of vorinostat given in combination with pembrolizumab, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma. Toxicities will be graded in severity according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for toxicity categories as outlined in the study protocol.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to 24 months
Safety Issue:
Description:Median overall survival time, 95% confidence survival. OS: Time from randomization until death from any cause.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:H. Lee Moffitt Cancer Center and Research Institute

Trial Keywords

  • Immunotherapy
  • Radiotherapy
  • Glioblastoma

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