FORWARD Optune and Adjuvant TMZ in Grade II/III Astrocytoma

• Sponsor: University of Florida (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03906448
• Collaborator: NovoCure Ltd. (Industry)
• Enrollment: 1
• Locations: 5
• Arms: 2
• Actual Duration (Months): 12.6
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Astrocytoma, Grade II; Astrocytoma, Grade III	Combination Product: TTFields with adjuvant temozolomide	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: May 20, 2019
• Actual Primary Completion Date: Jun 8, 2020
• Actual Study Completion Date: Jun 8, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Astrocytoma Patients Patients newly diagnosed with Grade II and III astrocytoma.	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 Names: Optune
No Intervention: Control Arm Data collection from medical record only

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Up to 2 years]

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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UF Health at the University of Florida	Gainesville	Florida	United States	32610
2	USF Health Morsani College of Medicine-Moffitt Cancer Center	Tampa	Florida	United States	33612
3	Henry Ford Health System	Detroit	Michigan	United States	48202
4	Brown University-Rhode Island Hospital	Providence	Rhode Island	United States	02903
5	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• University of Florida
• NovoCure Ltd.

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 24, 2020
• Informed Consent Form - Apr 1, 2020

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT03906448
• Other Study ID Numbers: IRB201800600; OCR17711
• First Posted: Apr 8, 2019
• Last Update Posted: Sep 23, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Astrocytoma; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Astrocytoma Patients	Control Arm
Arm/Group Description	Patients newly diagnosed with Grade II and III astrocytoma. 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.	Data collection from medical record only
Period Title: Overall Study
STARTED	1	0
COMPLETED	1	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Astrocytoma Patients	Control Arm	Total
Arm/Group Description	Patients newly diagnosed with Grade II and III astrocytoma. 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.	Data collection from medical record only	Total of all reporting groups
Overall Participants	1	0	1
Age (Count of Participants)
<=18 years	0 0%	0 NaN	0 0%
Between 18 and 65 years	1 100%	0 NaN	1 100%
>=65 years	0 0%	0 NaN	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 NaN	0 0%
Male	1 100%	0 NaN	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 NaN	0 0%
Not Hispanic or Latino	1 100%	0 NaN	1 100%
Unknown or Not Reported	0 0%	0 NaN	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 NaN	0 0%
Asian	0 0%	0 NaN	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 NaN	0 0%
Black or African American	0 0%	0 NaN	0 0%
White	1 100%	0 NaN	1 100%
More than one race	0 0%	0 NaN	0 0%
Unknown or Not Reported	0 0%	0 NaN	0 0%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Frequency of overall survival in study participants. 2 years of active treatment, lifelong survival follow-up.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

This multicenter center study was terminated early by mutual decision between the Study Chair/IDE Sponsor and Novocure; therefore, statistical analysis of the 1 participant in the intervention arm was not done.

Arm/Group Title	Astrocytoma Patients	Control Arm
Arm/Group Description	Patients newly diagnosed with Grade II and III astrocytoma. 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.	Data collection from medical record only
Measure Participants	0	0

Adverse Events

Time Frame	after the start of study treatment for 30 days after the After Treatment Stop Visit
Adverse Event Reporting Description	The control arm was a historical control.
Arm/Group Title	Astrocytoma Patients		Control Arm
Arm/Group Description	Patients newly diagnosed with Grade II and III astrocytoma. 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.		Data collection from medical record only
All Cause Mortality
	Astrocytoma Patients		Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Serious Adverse Events
	Astrocytoma Patients		Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Gastrointestinal disorders
Vomiting	1/1 (100%)	1	0/0 (NaN)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Disease progression	1/1 (100%)	1	0/0 (NaN)	0
Death	1/1 (100%)	1	0/0 (NaN)	0
Other (Not Including Serious) Adverse Events
	Astrocytoma Patients		Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1 (100%)		0/0 (NaN)
Blood and lymphatic system disorders
Platelet Count Decreased	1/1 (100%)	1	0/0 (NaN)	0
Cardiac disorders
Syncope	1/1 (100%)	2	0/0 (NaN)	0
Gastrointestinal disorders
Nausea	1/1 (100%)	1	0/0 (NaN)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
metastatic disease	1/1 (100%)	1	0/0 (NaN)	0
Skin and subcutaneous tissue disorders
Rash	1/1 (100%)	1	0/0 (NaN)	0
Reactive Dermatitis	1/1 (100%)	1	0/0 (NaN)	0

Limitations/Caveats

This multicenter center study was terminated early by mutual decision between the Study Chair/IDE Sponsor and Novocure; therefore, statistical analysis of the 1 participant in the intervention arm was not done.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.