Protocol No.: OCR16397
Sponsor Protocol No.: 2-THE-TOP
Phase 2, Single Arm, Historically Controlled Study Testing The Safety and Efficacy Adjuvant Temozolomide Plus Optune Plus Pembrolizumab in Patients with Newly Diagnosed Glioblastoma (2-THE-TOP)
Glioblastoma multiforme (GBM) is the most common and deadliest primary malignant neoplasm of the central nervous system in adults. Despite an aggressive multimodality treatment approach including surgery, radiation therapy and chemotherapy, overall survival remains poor. Pembrolizumab has recently been approved in the United States for the treatment of patients with advanced and metastatic non-small cell lung cancer, recurrent or metastatic head and neck squamous cell carcinoma, locally advanced urothelial carcinoma, classical Hodgkin lymphoma, unresectable or metastatic melanoma
This study is being performed to determine whether the triple combination of pembrolizumab when added to TTFields (Optune®) and adjuvant temozolomide increases progression-free survival (PFS) in patients with newly diagnosed GBM as compared to historical control data.
Patients with newly-diagnosed GBM who undergo maximal safe resection (biopsy alone is eligible) followed by standard chemoradiation will be eligible for this trial.
Four weeks after completing chemoradiation, patients will undergo baseline standard of care MRI. Four to six weeks after finishing chemoradiation, patients will start monthly cycles of adjuvant TMZ. A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given. Treatment with Optune will start at approximately the same time as the first cycle of adjuvant TMZ and continue until second disease progression or a maximum of 2 years. Within one week after starting Cycle 2 of adjuvant TMZ and Optune therapy, patients will begin open-label treatment with pembrolizumab every 3 weeks until first disease progression or unacceptable toxicities or 2 years, whichever comes first.
At first progression, patients will be allowed to continue with Optune therapy combined with any other therapy, which may include pembrolizumab, per standard of care at the discretion of the treating physician. Surgical resection or biopsy of first recurrent tumor for confirmation of recurrence is allowed within the protocol.
All patients will be seen before Cycle 1 of TMZ, before cycle 2 of TMZ, before starting the second dose of pembrolizumab, and every 3 weeks before each subsequent pembrolizumab dose at an outpatient clinic until they complete all 12 cycles of adjuvant TMZ or discontinue TMZ due to toxicity or first progression.
Medical follow-up will continue for 30 days after treatment termination. After this visit, mortality will be assessed based on telephone interviews with the patients or the patients' caregivers every 3 months.
Phase: Phase II
Age Group: Adult
Optune System combined with Temozolomide (TMZ) + Pembrolizumab:
Patients with newly-diagnosed GBM who undergo maximal safe resection (biopsy alone is eligible) followed by chemoradiation consisting of concomitant TMZ daily and radiation therapy (RT) with minimal RT will be eligible for this trial. Four to six weeks after finishing chemoradiation, patients will start monthly cycles of adjuvant TMZ. Treatment with Optune will start at approximately the same time as the first cycle of adjuvant TMZ and continue until second disease progression or a maximum of 2 years. Within one week after starting Cycle 2 of adjuvant TMZ and Optune therapy, patients will begin open-label treatment with pembrolizumab every 3 weeks until first disease progression or unacceptable toxicities or 2 years, whichever comes first.
1. Ages 18 - 80 years of age
2. Histologic confirmation of glioblastoma, WHO Grade IV (GBM variants are allowed).
3. MGMT methylation status if available (indeterminate methylation status will be considered unmethylated).
4. Karnofsky performance status (KPS) >= 70%.
5. Received maximal safe resection (biopsy only allowed) and radiotherapy concomitant with temozolomide:
- Gliadel wafers placement at the time of surgical resection is allowed.
- Any additional treatment directed at GBM will be considered exclusionary.
- Minimum dose for concomitant radiotherapy is 40 Gy.
6. Candidate for adjuvant high dose temozolomide and Optune therapy.
7. Life expectancy of at least 3 months.
8. Adequate bone marrow and organ function as defined below:
- ANC >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (transfusion is allowed)
- Serum creatinine == 60 mL/min for patients with serum creatinine > 1.5 x IULN
- Serum total bilirubin = 1.5 x IULN
- AST (SGOT) and ALT (SGPT) =9. Participants of childbearing age must use effective contraception:
- Women of childbearing potential (WOCBP) must be using a highly effective method of contraception to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug to minimize the risk of pregnancy. Prior to study enrollment, women of childbearing potential must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Refer to Appendix D for guidance on highly effective contraceptive methods.
- WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
- Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or
- For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
- Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
10. Ability of the patient or their legally authorized representative (LAR) to understand and willingness to sign an IRB approved written informed consent document
11. Steroid dose equivalent to dexamethasone dose of ≤ 4mg daily at the time of starting adjuvant treatment
12. Optune and temozolomide treatment start date will be at least 4 weeks but not more than 6 weeks from the later of last dose of concomitant temozolomide or radiotherapy. Although Optune and temozolomide should be started simultaneously, it is not required as long as both are started within this time frame
1. Prior treatment with anti-angiogenic agents including bevacizumab.
2. History of malignancy (other than glioblastoma) during the last two years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer not requiring active treatment or treated with local treatment only.
3. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
**Contact study team for complete eligibility details.
Applicable Disease Sites
Brain and Nervous System
UF Gainesville : Sarah Andrews
Sarah Andrews, RN
View study listing on ClinicialTrials.gov