Clinical Trials /

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

NCT03405792

Description:

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.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: IRB201702270
  • SECONDARY ID: OCR16397
  • NCT ID: NCT03405792

Conditions

  • Glioblastoma
  • Glioblastoma, WHO Grade IV

Interventions

DrugSynonymsArms
Temozolomide (TMZ)Historical Control
PembrolizumabKeytrudaOptune System combined with Temozolomide (TMZ) + Pembrolizumab

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Optune System combined with Temozolomide (TMZ) + PembrolizumabExperimentalPatients 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.
  • Temozolomide (TMZ)
  • Pembrolizumab
Historical ControlOtherHistorical 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.
  • Temozolomide (TMZ)

Eligibility 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.

          -  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).
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival between the groups
Time Frame:Assessed up to 24 months
Safety Issue:
Description: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

Measure:Number of adverse events
Time Frame:Change from baseline and every month up to 24 months
Safety Issue:
Description: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
Measure:Overall Survival (OS)
Time Frame:Assessed up to 5 years
Safety Issue:
Description:Days of OS
Measure:Augmentation of TTFields-initiated glioma-specific immune reaction by pembrolizumab
Time Frame:Assessed up to 24 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Florida

Trial Keywords

  • Tumor Treating Electric Fields (TTFields)

Last Updated

February 10, 2020