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

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ClinicalTrials.gov Identifier: NCT03405792
Recruitment Status : Recruiting
First Posted : January 23, 2018
Last Update Posted : July 9, 2018
Sponsor:
Collaborator:
NovoCure Ltd.
Information provided by (Responsible Party):
University of Florida

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Glioblastoma Glioblastoma, WHO Grade IV Drug: Temozolomide (TMZ) Device: Optune System Drug: Pembrolizumab Phase 2

Detailed Description:

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.


Study Type : Interventional
Estimated Enrollment : 29 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : February 23, 2018
Estimated Primary Completion Date : February 2023
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 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.
Drug: Temozolomide (TMZ)
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.

Device: Optune System
Patients will undergo 24-months of planned treatment with Optune therapy.
Other Name: NovoTTF Therapy

Drug: Pembrolizumab
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.
Other Name: Keytruda

Historical Control
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)
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.

Device: Optune System
Patients will undergo 24-months of planned treatment with Optune therapy.
Other Name: NovoTTF Therapy




Primary Outcome Measures :
  1. Progression-free survival between the groups [ Time Frame: Assessed up to 24 months ]
    The study team will use the log-rank test to compare Kaplan-Meier PFS curves and Cox proportional hazards regression to estimate a hazard ratio (HR) for the risk of progression in the triple combination arm relative to the historical control arm.


Secondary Outcome Measures :
  1. Number of adverse events [ Time Frame: Change from baseline and every month up to 24 months ]
    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

  2. Overall Survival (OS) [ Time Frame: Assessed up to 5 years ]
    Days of OS

  3. Augmentation of TTFields-initiated glioma-specific immune reaction by pembrolizumab [ Time Frame: Assessed up to 24 months ]
    We will use mixed effect regression models to assess changes in response variables related to glioma-specific immune reaction before, during, and after treatment with pembrolizumab.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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:

    1. Gliadel wafers placement at the time of surgical resection is allowed.
    2. Any additional treatment directed at GBM will be considered exclusionary.
    3. 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:

    1. ANC ≥ 1,500/mcL
    2. Platelets ≥ 100,000/mcL
    3. Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (transfusion is allowed)
    4. Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine > 1.5 x IULN
    5. Serum total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN
    6. 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 malignancy (other than glioblastoma) during the last two years except non-melanoma skin cancer, in situ cervical cancer, indolent neoplasm not requiring active treatment, or cured, early-stage prostate cancer not requiring active treatment or treated with local treatment only.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03405792


Contacts
Contact: Sonisha Warren, PhD 352-294-8737 sonisha.warren@neurosurgery.ufl.edu

Locations
United States, Florida
University of Florida Health Recruiting
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
NovoCure Ltd.
Investigators
Principal Investigator: David Tran, MD, PhD University of Florida

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT03405792     History of Changes
Other Study ID Numbers: IRB201702270
First Posted: January 23, 2018    Key Record Dates
Last Update Posted: July 9, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by University of Florida:
Tumor Treating Electric Fields (TTFields)

Additional relevant MeSH terms:
Glioma
Glioblastoma
Astrocytoma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pembrolizumab
Temozolomide
Dacarbazine
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action