FORWARD Optune and Adjuvant TMZ in Grade II/III Astrocytoma (FORWARD)

• ClinicalTrials.gov Identifier: NCT03906448
• Recruitment Status: Terminated
• First Posted: April 8, 2019
• Results First Posted: September 23, 2021
• Last Update Posted: September 23, 2021
• Sponsor: University of Florida
• Collaborator: NovoCure Ltd.
• Information provided by (Responsible Party): University of Florida

Tracking Information

• First Submitted Date: April 4, 2019
• First Posted Date: April 8, 2019
• Results First Submitted Date: August 26, 2021
• Results First Posted Date: September 23, 2021
• Last Update Posted Date: September 23, 2021
• Actual Study Start Date: May 20, 2019
• Actual Primary Completion Date: June 8, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 4, 2019)

Overall Survival [ Time Frame: Up to 2 years ]

Frequency of overall survival in study participants. 2 years of active treatment, lifelong survival follow-up.

• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: FORWARD Optune and Adjuvant TMZ in Grade II/III Astrocytoma
• Official Title: A Phase 2, Historically Controlled Study Testing the Efficacy of TTFields (Optune®) With Adjuvant Temozolomide in High Risk WHO Grade II and III Astrocytomas (FORWARD)
• Brief Summary: This is a phase 2, multi-institutional, historically-controlled, study of 100 patients with newly diagnosed Grade II and III astrocytoma comparing the combination of TTFields with adjuvant temozolomide versus temozolomide alone in historical controls after the completion of definitive chemoradiotherapy. Study treatment may continue past first tumor recurrence. The primary endpoint will be overall survival.

Detailed Description

Patients with newly diagnosed high-risk Grade II or III astrocytoma must undergo maximal safe resection (biopsy alone may be eligible) and chemoradiotherapy: concomitant 75mg/m2 daily temozolomide with 80% prescribed dose completed and RT with minimal RT dose of 40 Gy delivered.

Within three weeks prior to beginning adjuvant temozolomide, all patients will undergo a Baseline contrast-enhanced MRI of the brain. Within two weeks prior to beginning adjuvant temozolomide, all patients will undergo baseline assessments. Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, and no later than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given. Patients will be seen and examined before each cycle of temozolomide. After a maximum of 12 cycles of adjuvant temozolomide, patients will be seen every 8 weeks. Brain MRI and QoL assessments will be performed every 8 weeks following the baseline MRI for the first 2 years then every 3 months thereafter until second progression (when TTFields treatment will be terminated).

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Astrocytoma, Grade II
• Astrocytoma, Grade III

Intervention

Combination Product: TTFields with adjuvant temozolomide

Patients will begin study treatment with temozolomide and TTFields within 2 weeks of the baseline evaluation, and no later than 6 weeks from last dose of concomitant temozolomide or radiation therapy (the latter of the two). A minimum of 6 and a maximum of 12 cycles of adjuvant temozolomide will be given, depending on tolerability and toxicity.

Other Name: Optune

Study Arms

• Experimental: Astrocytoma Patients
  Patients newly diagnosed with Grade II and III astrocytoma.
  Intervention: Combination Product: TTFields with adjuvant temozolomide
• No Intervention: Control Arm
  Data collection from medical record only

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 26, 2021): 1
• Original Estimated Enrollment (submitted: April 4, 2019): 100
• Actual Study Completion Date: June 8, 2020
• Actual Primary Completion Date: June 8, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Willing and able to provide written informed consent
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Life expectancy of at least 3 months
• Histologic confirmation of WHO Grade II or III astrocytoma---mixed oligoastrocytomas are permitted
• 1p/19q intact per FISH and/or ATRX mutation(s) per immunohistochemistry or next-generation sequencing (e.g. Foundation Medicine, TEMPUS, Caris, or similar CLIA-certified sequencing service)

• Mutational identity determined by CLIA-certified sequencing including:

  1. IDH1/2 wildtype (i.e. lack of detectable mutations on the sequencing report) and
  2. TERT promoter mutation
• Karnofsky performance status ≥70%
• Maximal safe resection---biopsy alone is allowed
• Completed standard chemoradiation with total RT dose of at least 40 Gy and concurrent temozolomide (75mg/m2 daily dose with 80% prescribed dose completed)
• Patients with a tumor that was biopsied or resected in the past followed by observation only without definitive chemoradiation and/or chemotherapy given will be eligible, as long as: repeat maximal surgical resection (biopsy only allowed) has been performed, definitive temozolomide/RT treatment meets the criteria above, and adjuvant temozolomide treatment is planned
• Candidate for adjuvant high dose temozolomide per investigator's clinical judgement
• Adjuvant Temozolomide start date at least 4 weeks, but not more than 6 weeks, from the later of last dose of concomitant temozolomide or radiotherapy
• No evidence of early disease progression per RANO criteria at the time of enrollment

• 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.

  1. 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.
  2. Refer to section 10.2.1 for guidance on highly effective contraceptive methods acceptable in this study.
  3. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral 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 child-bearing 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.

Exclusion Criteria:

• Prior treatment with anti-angiogenic agents including bevacizumab.
• Prior treatment with TTFields.
• Progressive disease (according to RANO criteria) after temozolomide/RT.
• Actively participating in another clinical treatment trial intended to treat the underlying astrocytoma.
• Females who are pregnant or breastfeeding.

• Significant co-morbidities at baseline (within 2 weeks prior to adjuvant temozolomide start) which would prevent adjuvant temozolomide treatment:

  1. Thrombocytopenia (platelet count < 100 x 103/μL)
  2. Neutropenia (absolute neutrophil count < 1.5 x 103/μL)
  3. CTC grade 4 non-hematological toxicity (except for alopecia, nausea, vomiting)
  4. Significant liver function impairment - AST or ALT > 5 times the upper limit of normal
  5. Total bilirubin > 2 times upper limit of normal
  6. Significant renal impairment (GFR ≤ 30 ml/min)
• Implanted pacemaker, programmable shunts, defibrillator, deep brain stimulator, other implanted electronic devices in the brain, or documented clinically significant arrhythmias.
• A skull defect such as missing bone with no replacement
• Bullet fragments embedded the skull
• Tumors located in the brain stem and/or the cerebellum
• History of hypersensitivity reaction to temozolomide, Dacarbazine (DTIC) or hydrogel.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03906448
• Other Study ID Numbers: IRB201800600; OCR17711 ( Other Identifier: UF OnCore )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Florida
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Florida
• Original Study Sponsor: Same as current
• Collaborators: NovoCure Ltd.

Investigators

• Study Chair: David Tran, MD, PhD; University of Florida

• PRS Account: University of Florida
• Verification Date: August 2021