Brain Tumor, GBM, Glioblastoma
Conditions
Keywords
Immunotherapy, Radiotherapy, 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.
Interventions
DRUGPembrolizumab
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).
DRUGVorinostat
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.
DRUGTemozolomide
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).
RADIATIONRadiotherapy
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.
Sponsors
Merck Sharp & Dohme LLC
H. Lee Moffitt Cancer Center and Research Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 lesion \< 4 cm in longest diameter (diameter of enhancing lesion) * 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 serious 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Up to 24 months | Median overall survival rate, 95% confidence survival. OS: Time from randomization until death from any cause. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Level -1 Level -1: Vorinostat 100 mg/day PO during RTX; 300 mg/day PO after RTX | 6 |
| Level 1 Level 1: Vorinostat 200 mg/day PO during RTX; 300 mg/day PO after RTX | 8 |
| Radiotherapy and Maintenance Phase 100 mg/day Vorinostat (+200 mg Pembro) with radiotherapy and 400 mg/day Vorinostat (+200 mg Pembro) maintenance. | 7 |
| Total | 21 |
Baseline characteristics
| Characteristic | Level -1 | Total | Radiotherapy and Maintenance Phase | Level 1 |
|---|---|---|---|---|
| Age, Continuous | 56.33 years | 57.62 years | 55.57 years | 60.38 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 17 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 5 Participants | 17 Participants | 5 Participants | 7 Participants |
| Region of Enrollment United States | 6 participants | 21 participants | 7 participants | 8 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 4 Participants | 13 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 6 | 5 / 8 | 1 / 7 |
| other Total, other adverse events | 6 / 6 | 8 / 8 | 7 / 7 |
| serious Total, serious adverse events | 2 / 6 | 6 / 8 | 3 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
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.
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation Phase | Maximum Tolerated Dose (MTD) | MTD during RTX | 100 mg/day Vorinostat |
| Dose Escalation Phase | Maximum Tolerated Dose (MTD) | MTD after RTX | 300 mg/day Vorinostat |
Secondary
Overall Survival (OS)
Median overall survival rate, 95% confidence survival. OS: Time from randomization until death from any cause.
Time frame: Up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase | Overall Survival (OS) | NA Months |
| Level 1 | Overall Survival (OS) | 12.2 Months |
| Radiotherapy and Maintenance Phase | Overall Survival (OS) | NA Months |