Pembrolizumab and Vorinostat Combined With Temozolomide for Newly Diagnosed Glioblastoma

• ClinicalTrials.gov Identifier: NCT03426891
• Recruitment Status: Recruiting
• First Posted: February 8, 2018
• Last Update Posted: September 30, 2019
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Brain Tumor; GBM	Drug: Pembrolizumab; Drug: Vorinostat; Drug: Temozolomide; Radiation: Radiotherapy	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Trial of Pembrolizumab and Vorinostat Combined With Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma
• Actual Study Start Date: March 16, 2018
• Estimated Primary Completion Date: April 2021
• Estimated Study Completion Date: April 2022

Arms and Interventions

Arm

Intervention/treatment

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).

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

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.

Eligibility Criteria

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

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.

Contacts and Locations

Locations

United States, Florida

H. Lee Moffitt Cancer Center and Research Institute; Recruiting

Tampa, Florida, United States, 33612

Contact: Melissa Wicklund 813-745-3620 melissa.wicklund@moffitt.org

Contact: Solmaz Sahebjam, M.D. 813-745-6101 solmaz.sahebjam@moffitt.org

Sponsors and Collaborators

H. Lee Moffitt Cancer Center and Research Institute

Merck Sharp & Dohme Corp.

Investigators

• Principal Investigator: Solmaz Sahebjam, M.D.; H. Lee Moffitt Cancer Center and Research Institute

More Information

Additional Information:

Moffitt Cancer Center Clinical Trials website 

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT03426891 History of Changes
• Other Study ID Numbers: MCC-19342
• First Posted: February 8, 2018
• Last Update Posted: September 30, 2019
• Last Verified: September 2019

• 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

Keywords provided by H. Lee Moffitt Cancer Center and Research Institute:

Immunotherapy; Radiotherapy; Glioblastoma

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Pembrolizumab; Temozolomide; Vorinostat; Histone Deacetylase Inhibitors; Antineoplastic Agents, Immunological; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors