Temozolomide Chronotherapy for High Grade Glioma

Study Overview
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Brief Summary
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Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas (HGG). The short half-life of this drug and known oscillations in DNA damage repair make it an ideal candidate for chronotherapy. Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity and maximizing efficacy through delivery of a medication according to the timing of biological rhythms within a patient. Chronotherapy has improved outcomes through the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but has never been applied to the treatment of gliomas. Based on the preliminary preclinical data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the success of chronotherapy in the treatment of other cancers, the invesitgators hypothesize that the timing of TMZ treatment will alter its efficacy and toxicity.

Official Title
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A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade Glioma

Conditions
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Glioma, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Temozolomide
* Other: Functional Assessment of Cancer Therapy - Brain
* Other: ActTrust Condor Instrument Watch


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed and recurrent high grade gliomas (WHO grades III & IV) and high risk WHO grade II gliomas who are to begin treatment with monthly high dose temozolomide therapy. Scheduled to receive adjuvant temozolomide therapy after having completed concurrent temozolomide and radiation therapy. At least 18 years of age. Karnofsky performance status ≥ 60% Ability to understand and willingness to sign an IRB approved written informed consent document Exclusion Criteria:. -Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: Temozolomide morning<br>Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00). FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment | Drug: Temozolomide<br>* -Given standard of care<br>* Other names: Temodar;Other: Functional Assessment of Cancer Therapy - Brain<br>* 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items. Patients rate all 5 items using a five-point Likert scale ranging from 0 not at all to 4 very much. Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items) The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.<br>* Other names: FACT-Br;Other: ActTrust Condor Instrument Watch<br>* -Will be required to wear 24 hours per day and will only be removed at specified data collection time points<br>|
| Experimental: Arm 2: Temozolomide evening<br>Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00). FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment | Drug: Temozolomide<br>* -Given standard of care<br>* Other names: Temodar;Other: Functional Assessment of Cancer Therapy - Brain<br>* 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items. Patients rate all 5 items using a five-point Likert scale ranging from 0 not at all to 4 very much. Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items) The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.<br>* Other names: FACT-Br;Other: ActTrust Condor Instrument Watch<br>* -Will be required to wear 24 hours per day and will only be removed at specified data collection time points<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of patient treatment compliance as measured by at least 80% compliance with assigned administration time | Compliance is defined as no more than one of five doses of temozolomide per cycle taken outside of the assigned administration time. | Completion of treatment (estimated to be 6 months) | 
| Duration of response | Response and progression will be evaluated in this study using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline [JCO 28(11): 1963-1972, 2010]. The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). | Through completion of follow-up (estimated to be 30 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients experiencing grade 3 or 4 lymphopenia, thrombocytopenia, neutropenia and anemia in each group as measured by standard blood draws | Lymphopenia grade 3 is <500-200/mm3 and grade 4 is <200/mm3 Leukopenia grade 3 is <2000-1000/mm3 and grade 4 is <1000/mm3 Neutropenia grade 3 is <1000-500/mm3 and grade 4 is <500/mm3 Thrombocytopenia grade 3 is <50,000-25,000/mm3 and grade 4 is <25,000/mm3 Anemia grade 3 is <8.0-6.5 g/dL and grade 4 is <6.5 g/dL | Completion of treatment (estimated to be 6 months) | 
| Quality of life as measured by FACT-Br score |  | 1 month after completion of treatment (estimated to be 7 months) | 
| Progression-free survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | Through completion of follow-up (estimated to be 30 months) | 
| Overall survival |  | Through completion of follow-up (estimated to be 30 months) | 
| Comparison of the level of sleep disruption in sleep-wake cycles of participants receiving temozolomide in the morning versus participants receiving temozolomide in the evening | The data will be collected through the ActTrust Condor Instrument Watch and the Sleep Questionniare. The qualitative data (sleep questionnaire) will be used with quantitative data (collected via the ActTrust watch) to assess the level of sleep disruption in sleep/wake cycles | Through 1 month after completion of treatment (estimated to be 7 months) |