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Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03426891
Recruitment Status : Recruiting
First Posted : February 8, 2018
Last Update Posted : September 30, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
H. Lee Moffitt Cancer Center and Research Institute

Tracking Information
First Submitted Date  ICMJE February 2, 2018
First Posted Date  ICMJE February 8, 2018
Last Update Posted Date September 30, 2019
Actual Study Start Date  ICMJE March 16, 2018
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2018)
Maximum Tolerated Dose (MTD) [ Time Frame: 12 weeks ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03426891 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2018)
Overall Survival (OS) [ Time Frame: Up to 24 months ]
Median overall survival time, 95% confidence survival. OS: Time from randomization until death from any cause.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma
Official Title  ICMJE A Phase I Trial of Pembrolizumab and Vorinostat Combined With Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma
Brief Summary 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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Glioblastoma
  • Brain Tumor
  • GBM
Intervention  ICMJE
  • Drug: Pembrolizumab
    200 mg intravenously (IV) every 3 weeks. The dose of pembrolizumab will remain the same throughout study treatment. During the maintenance phase, participants will receive pembrolizumab (for 12 months).
    Other Names:
    • Keytruda
    • immunotherapy
  • Drug: Vorinostat
    Dose Escalation Level -1 vorinostat 100 mg/day by mouth on days 1-5 every week during radiotherapy starting on first day of radiotherapy and 300 mg/day 1 week on 1 week off after radiotherapy. Level 1:vorinostat 200 mg/day by mouth on day 1-5 every week during radiotherapy, starting on first day of radiotherapy; and 300 mg/day 1 week on 1 week off after radiotherapy. Dose Escalation Level 2: vorinostat 300 mg/day by mouth on days 1-5 every week during radiotherapy, starting on first day of radiotherapy; and 400 mg/day 1 week on 1 week off after radiotherapy. Dose Expansion:all participants will receive the same dose of vorinostat that was determined to be most tolerated dose. During the maintenance phase, participants will receive vorinostat (for 12 months).
    Other Names:
    • Zolinza™
    • chemotherapy
    • histone deacetylase inhibitor
  • Drug: Temozolomide
    All participants will receive standard Temozolomide: Temozolomide (chemotherapy) 75 mg/m^2/day by mouth administered during the course of radiotherapy. Temozolomide will be administered continuously from Day 1 of radiotherapy to the last day of radiation. Maintenance Phase: temozolomide will start 4 weeks (+/- 3 days) after last dose of radiotherapy and will continue for 6 cycles post radiotherapy (150-200 mg/m^2/day, days 1-5 every 4 weeks) as per standard of care. During the maintenance phase, participants will receive Temozolomide (for the first 6 months).
    Other Names:
    • chemotherapy
    • Temodar
    • TMZ
  • Radiation: Radiotherapy
    All participants will receive standard radiotherapy: a total dose of 60 Gy administered in daily doses of 2 Gy, typically on a 5 days on / 2 days off schedule over 6 - 7 weeks.
    Other Name: radiation therapy
Study Arms  ICMJE Experimental: Combination Therapy
Pembrolizumab 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).
Interventions:
  • Drug: Pembrolizumab
  • Drug: Vorinostat
  • Drug: Temozolomide
  • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2018)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2022
Estimated Primary Completion Date April 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03426891
Other Study ID Numbers  ICMJE MCC-19342
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party H. Lee Moffitt Cancer Center and Research Institute
Study Sponsor  ICMJE H. Lee Moffitt Cancer Center and Research Institute
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Solmaz Sahebjam, M.D. H. Lee Moffitt Cancer Center and Research Institute
PRS Account H. Lee Moffitt Cancer Center and Research Institute
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP