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.
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).
- Newly diagnosed glioblastoma or gliosarcoma
- Histologically confirmed diagnosis of World Health Organization Grade IV malignant
- 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.
- 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.