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Pembrolizumab, Vorinostat, Temozolomide and Radiation Therapy in Treating Patients with Newly Diagnosed Glioblastoma

Trial Status: Active

This phase I trial studies the side effects and best dose of vorinostat when given together with pembrolizumab, temozolomide and radiation therapy in treating patients with newly diagnosed glioblastoma. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as vorinostat and temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab, vorinostat and temozolomide with radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started.

Inclusion Criteria

  • 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
  • Absolute neutrophil count (ANC) >= 1,500 /mcL (within 21 days of treatment initiation)
  • Platelets >= 100,000 / mcL (within 21 days of treatment initiation)
  • Hemoglobin >= 9 g/dL or >= 5.6 mmol/L within 21 days of treatment initiation without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) (within 21 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 21 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases within 21 days of treatment initiation
  • Albumin > 2.5 mg/dL (within 21 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 21 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 21 days of treatment initiation)
  • Resting baseline oxygen (O2) saturation by pulse oximetry of >= 92% at rest
  • Be 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 measurable lesion < 4 cm in longest diameter
  • Patient shouldn’t have received any anti-cancer therapy for glioblastoma in past
  • Female subject of childbearing potential 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
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception 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 the subject
  • Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
  • Use of Optune device is allowed

Exclusion Criteria

  • Had prior treatment of glioblastomas (GBM) with radiation and temozolomide
  • Has evidence of leptomeningeal disease
  • Had prior treatment with Gliadel
  • Is unable (due to existent medical condition) or unwilling to have a contrast enhanced magnetic resonance imaging (MRI) of brain
  • 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
  • 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 TB (bacillus tuberculosis)
  • 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: 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
  • 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren’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 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
  • 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., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy * 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

Florida

Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Solmaz Sahebjam
Phone: 813-745-4251

PRIMARY OBJECTIVES:

I. To evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) of vorinostat given in combination with pembrolizumab, temozolomide, and radiotherapy in patients with newly diagnosed glioblastoma.

SECONDARY OBJECTIVES:

I. To evaluate the 12 months and 24 months survival rate in patients with newly diagnosed glioblastoma who are treated with pembrolizumab in combination with vorinostat and standard treatment with radiotherapy and temozolomide.

EXPLORATORY OBJECTIVES:

I. To explore tissue and blood biomarkers that may predict tumor response to pembrolizumab in combination with vorinostat and standard treatment with radiotherapy and temozolomide in patients with newly diagnosed glioblastoma.

OUTLINE: This is a dose-escalation study of vorinostat.

CONCURRENT RADIOTHERAPY PHASE: Patients undergo radiation therapy 5 days per week for a total of 30 fractions over 6-7 weeks, and temozolomide orally (PO) daily from the first day to the last day of radiation therapy. Patients also receive vorinostat PO on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, 43-47, 50-54, 57-61, 64-68, 71-75, and 78-82, and pembrolizumab intravenously (IV) over 30 minutes on days 1, 22, 43, and 64.

MAINTENANCE PHASE: Beginning 4 weeks after last dose of radiation therapy, patients receive temozolomide PO on days 1-5 every 4 weeks. Patients also receive vorinostat PO for 1 week on (7 days) and 1 week off (7 days), and pembrolizumab IV every 3 weeks. Courses repeat every 12 weeks for 12 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Moffitt Cancer Center

Principal Investigator
Solmaz Sahebjam

  • Primary ID MCC-19342
  • Secondary IDs NCI-2018-00503, Merck Sharp & Dohme Corp. 55584
  • Clinicaltrials.gov ID NCT03426891