Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 2, Single Arm, Historically Controlled Study Testing The Safety and Efficacy of Adjuvant Temozolomide Plus TTFields (Optune®) Plus Pembrolizumab in Patients With Newly Diagnosed Glioblastoma (2-THE-TOP)

Conditions
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Glioblastoma, Glioblastoma, WHO Grade IV

Intervention / Treatment
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* Drug: Temozolomide (TMZ)
* Device: Optune System
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic confirmation of glioblastoma, WHO Grade IV (GBM variants are allowed; Lower grade gliomas that have been transformed to GBM will be considered newly diagnosed GBM if the lower-grade tumor was not previously treated, and the standard treatment for GBM including radiation and temozolomide is now planned). MGMT methylation status if available (indeterminate methylation status will be considered unmethylated). Karnofsky performance status (KPS) ≥70%. Patients must be at least 18 years of age. 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. Candidate for adjuvant high dose temozolomide and Optune therapy. Life expectancy of at least 3 months. 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 ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN AST (SGOT) and ALT (SGPT) ≤ 3 x IULN 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. Ability of the patient or their legally authorized representative (LAR) to understand and willingness to sign an IRB approved written informed consent document Steroid dose equivalent to dexamethasone dose of ≤ 4mg daily at the time of starting adjuvant treatment 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 Exclusion Criteria: Prior treatment with anti-angiogenic agents including bevacizumab. History of other malignancy that, in the primary oncologist's estimation, has a higher risk of recurrence or death than the study-related cancer at the time of study participation. 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). Progressive disease (according to RANO criteria). Advanced imaging is allowed to further investigate suspected pseudoprogression if deemed necessary. Actively participating in another clinical treatment trial intended to treat GBM. Multifocal gliomas defined as distinct tumors that do not have overlapping T2/FLAIR signal. Presence of leptomeningeal metastases. Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias. Tumor is entirely located in the infra-tentorial region. History of hypersensitivity reactions or allergies to hydrogels and/or compounds of similar chemical or biologic composition to Temozolomide and Pembrolizumab. Steroid dose equivalent to > 4 mg dexamethasone at the time of starting adjuvant therapy. History of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (with the exception of daily dexamethasone ≤ 4 mg). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements. History of active autoimmune disease requiring systemic treatment within 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. History of (non-infectious) pneumonitis that required steroids or current pneumonitis. Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancy test within 72 hours of study entry. Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 24 weeks after the last dose of study drug. Known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected) infection. Known history of active TB (bacillus tuberculosis). Known history of HIV (HIV 1/2 antibodies).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Optune System combined with Temozolomide (TMZ) + Pembrolizumab<br>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. | Drug: Temozolomide (TMZ)<br>* Patients will begin treatment with adjuvant TMZ at least 4 weeks but no more than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given depending on tolerability and toxicity.<br>Device: Optune System<br>* Patients will undergo 24-months of planned treatment with Optune therapy.<br>* Other names: NovoTTF Therapy;Drug: Pembrolizumab<br>* Pembrolizumab will be given intravenously every 3 weeks beginning on Day 1 of Cycle 2 of adjuvant TMZ. Treatment with pembrolizumab every 3 weeks until first disease progression or unacceptable toxicities or 2 years, whichever comes first.<br>* Other names: Keytruda;|
| Other: Historical Control<br>Historical control data of patients treated with Optune System combined with Temozolomide alone will be compared with the Optune System combined with Temozolomide (TMZ) + Pembrolizumab arm. | Drug: Temozolomide (TMZ)<br>* Patients will begin treatment with adjuvant TMZ at least 4 weeks but no more than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and maximum of 12 cycles of adjuvant TMZ will be given depending on tolerability and toxicity.<br>Device: Optune System<br>* Patients will undergo 24-months of planned treatment with Optune therapy.<br>* Other names: NovoTTF Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival between the groups | Time from enrollment to progression or death or censoring, whichever occurs first. The study team will use the one-sample log-rank test to compare PFS progression in the triple combination arm relative to the historical control arm. | Assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity and tolerability | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting for grade 3 or higher. We will estimate proportions and 95% confidence intervals for patients in the triple combination arm who experience toxicities and other types of AEs and serious AEs. | Assessed up to 24 months | 
| Overall Survival (OS) | Time from enrollment to death or censoring, whichever occurs first. We will use the log-rank test to compare OS between the triple combination arm relative to the historical control arm. | Assessed up to 5 years | 
| Augmentation of TTFields-initiated glioma-specific immune reaction by pembrolizumab | We will use mixed effect regression to assess changes in response variables related to glioma-specific immune reaction before, during, and after treatment with pembrolizumab. | Assessed up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumor Treating Electric Fields (TTFields)