Phase 1-2 of Temozolomide and Hypofractionated Radiotherapy in Tx of Supratentorial Glioblastoma Multiform

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety and effectiveness of a combination treatment for glioblastoma multiforme utilizing radiotherapy plus the FDA-approved chemotherapy drug temozolomide

Detailed Description
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Primary Objective: To determine the maximum tolerated dose (MTD), based on acute CNS toxicity at 30 days, of hypofractionated radiotherapy given in 5 fractions with temozolomide for the treatment of glioblastoma multiforme. Secondary Objectives: Assess the short- and long-term adverse effects. Determine the radiographic response rate. Determine the overall survival rate. Assess quality of life during treatment To determine the maximum tolerated dose (MTD) of hypofractionated (5 fractions) radiotherapy with temozolomide for the treatment of glioblastoma multiforme, patients will be evaluated by a multi-disciplinary team composed of radiation oncologists, neurosurgeons, and neuro-oncologists to assess for their eligibility. Patient's oncologic history, presenting symptoms, physical examination, pathology, and imaging studies will be reviewed. Patients will be evaluated for surgical candidacy and resectability. Patients who are surgical candidates will undergo a surgical resection prior to radiotherapy. Patients whose tumors are unresectable or are not good surgical candidates will undergo a biopsy for tissue diagnosis. Radiation will be delivered in five fractions.

Official Title
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A Phase 1-2 Trial of Temozolomide and Hypofractionated Radiotherapy in Treatment of Supratentorial Glioblastoma Multiforme

Conditions
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Glioblastoma, Cancer of Brain and Nervous System, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Temozolomide
* Procedure: Stereotactic Radiosurgery (SRS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed newly diagnosed glioblastoma multiforme. Diagnosis must be made by surgical biopsy or excision The tumor must be supratentorial in location The planning target volume (tumor plus margin) must measure ≤ 150 cm^3 in volume Age ≥ 18 years Life expectancy of at least 12 weeks Patient must have adequate organ function to tolerate temozolomide (details in the protocol) Exclusion Criteria: Patients who have previously been treated with brain irradiation to the region that would result in overlap of the radiation fields Tumor foci detected below the tentorium Multifocal disease or leptomeningeal spread Prior allergic reaction to the study drugs involved in this protocol Patients with pacemaker will be allowed to undergo CT instead of MRI Pediatric patients (age < 18), pregnant women, and nursing patients will be excluded

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: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose-escalation with 2-level stratification
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stereotactic Radiosurgery (25 Gray x 5 fractions)+Temozolomide<br>Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) < 60 cm³ vs 60 to 150 cm³. | Drug: Temozolomide<br>* 75 mg/m²/day oral, administered concurrently with radiotherapy and as adjuvant therapy.<br>* Other names: Temodal;Procedure: Stereotactic Radiosurgery (SRS)<br>* Standard of care therapeutic radiotherapy administrated at 25, 30, 35, or 40 Gray (Gy)<br>* Other names: Cyberknife surgery;|
| Experimental: Stereotactic Radiosurgery (30 Gray x 5 fractions)+Temozolomide<br>Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) < 60 cm³ vs 60 to 150 cm³. | Drug: Temozolomide<br>* 75 mg/m²/day oral, administered concurrently with radiotherapy and as adjuvant therapy.<br>* Other names: Temodal;Procedure: Stereotactic Radiosurgery (SRS)<br>* Standard of care therapeutic radiotherapy administrated at 25, 30, 35, or 40 Gray (Gy)<br>* Other names: Cyberknife surgery;|
| Experimental: Stereotactic Radiosurgery (35 Gray x 5 fractions)+Temozolomide<br>Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) < 60 cm³ vs 60 to 150 cm³. | Drug: Temozolomide<br>* 75 mg/m²/day oral, administered concurrently with radiotherapy and as adjuvant therapy.<br>* Other names: Temodal;Procedure: Stereotactic Radiosurgery (SRS)<br>* Standard of care therapeutic radiotherapy administrated at 25, 30, 35, or 40 Gray (Gy)<br>* Other names: Cyberknife surgery;|
| Experimental: Stereotactic Radiosurgery (40 Gray x 5 fractions)+Temozolomide<br>Hypofractionated stereotactic radiosurgery with concurrent temozolomide, stratified by Planning Target Volume (PTV) < 60 cm³ vs 60 to 150 cm³. | Drug: Temozolomide<br>* 75 mg/m²/day oral, administered concurrently with radiotherapy and as adjuvant therapy.<br>* Other names: Temodal;Procedure: Stereotactic Radiosurgery (SRS)<br>* Standard of care therapeutic radiotherapy administrated at 25, 30, 35, or 40 Gray (Gy)<br>* Other names: Cyberknife surgery;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose-limiting Toxicities (DLTs) | The maximum-tolerated dose (MTD) of study treatment (temozolomid plus hypofractionated radiotherapy administered as 5 fractions) is defined as either: The highest radiation dose per protocol, or The radiation dose at which dose-limiting toxicities (DLTs) occurred in ≥ 2 of 3 participants at a dose level, and/or ≥ 2 of 6 participants, at a dose level. Dose-limiting toxicity (DLT) was defined as a treatment-related (with possible, probable or definite attribution) Grade 3 to 5 CNS toxicity [Common Terminology Criteria for Adverse Events (CTCAE) v4] occurring within 30 days of stereotactic radiosurgery (SRS). The non-stratified outcome is reported as the number of DLTs observed in by radiation dose and by strata (Planning Target Volume (PTV) < 60 cm³ and from 60 to 150 cm³). | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Acute Toxicity Within 30 Days | Acute toxicity is defined as treatment-related adverse events that occur within 30 days of receiving radiotherapy. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is used to grade adverse events. The non-stratified outcome is reported as number of treatment-related adverse events observed for each radiotherapy dose level. Acute toxicity is based on radiotherapy dose level not tumor volume, and is reported by radiotherapy dose level only. | 30 days | 
| Long-term Toxicity After More Than 30 Days | Long-term toxicity is defined as treatment-related adverse events (any grade or any Body System) that occur ≥ 30 days after receiving radiotherapy. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 is used to grade adverse events. The non-stratified outcome is reported as number of treatment-related adverse events observed for each dose level. Long-term toxicity is based on radiotherapy dose level not tumor volume, and is reported by radiotherapy dose level only. | 12 months | 
| Percent of Participants With Radiographic Response | Radiographic response rate was assessed following radiotherapy until disease progression. Response is considered to be the sum and proportion participants that achieved a complete response (CR); partial response (PR); or minor response (MR). The outcome is expressed as a number without dispersion for each cohort. CR: Tumor is no longer detected by computed tomography (CT) or magnetic resonance imaging (MRI). PR: Decrease in the product of the two greatest diameters > 50%, as determined by CT or MRI, with no new lesions, and the same or lower dose of dexamethasone. MR: Decrease in the product of the two greatest diameters < 50%, as determined by CT or MRI, and neither PR nor PD. PD: New tumor lesion, or > 25% increase in the product of the two greatest diameters of target lesion, as determined by CT or MRI, provided that within 2 months of completion of radiotherapy, the participant has not had a decrease in steroid dose since the last evaluation. | 6 months | 
| Progression-free Survival | Progression-free survival (PFS) following radiotherapy, measured in months. Progressive disease (PD) is defined as: New tumor lesion, or > 25% increase in the product of the 2 greatest diameters of target lesion, as determined by computed tomography (CT) or magnetic resonance imaging (MRI), provided that within 2 months of completion of radiotherapy, the participant has not had a decrease in steroid dose since the last evaluation. The outcome is expressed as the median with 95% confidence interval for each cohort. | 18 Months. | 
| Overall Survival (OS) | Overall survival (OS) was assessed as those participants remaining alive with any tumor status following radiotherapy after 20 months. The outcome is stratified by Planning Target Volume (PTV) < 60 cm³ or 60 to 150 cm³, and expressed as the median value with 95% confidence interval. | 20 Months. | 
| Quality of Life by European Organisation for Research and Treatment of Cancer (EORTC-QLQ C30) Survey | European Organization for Research and Treatment of Cancer (EORTC-QLQ C30) quality of life surveys were administered at study entry and 12 months after treatment initiation to assess health-related quality of life (HR-QOL). The EORTC-QLQ C30 survey has 30 questions and responses are on scale of 1 to 4 with 1 indicating not at all and 4 indicating very much. The total score can range from 30 to 120. The outcome is stratified by Planning Target Volume (PTV) < 60 cm³ or 60 to 150 cm³, and is expressed as the mean of the difference from baseline to 12 months, with 95% confidence interval. | 12 Months | 
| Quality of Life by Brain-20 Survey | Brain-20 (BN-20) quality of life surveys were administered at study entry and 12 months after treatment initiation to assess health-related quality of life (HR-QOL). The Brain-20 (BN-20) quality of life survey has 20 questions and responses are on scale of 1 to 4 with 1 indicating not at all (most favorable) and 4 indicating very much (least favorable). The total score can range from 20 to 80, and the result is expressed as the difference from baseline (study entry) to 12 months after the start of treatment. The outcome is stratified by Planning Target Volume (PTV) < 60 cm³ or 60 to 150 cm³, and expressed as the mean with 95% confidence interval. | 12 months | 
| Quality of Life by MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) Survey | MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) quality of life surveys were administered at study entry and 12 months after treatment initiation to assess health-related quality of life (HR-QOL). MDASI-BT quality of life survey has 23 questions and responses are on scale of 0 to 10 with 0 indicating did not interfere (most favorable) and 10 indicating interfered completely (least favorable). A participant's overall score is computed as the mean of that participant's individual scores, and can range 0 to 10. The outcome is stratified by Planning Target Volume (PTV) < 60 cm³ or 60 to 150 cm³, and expressed as the mean difference from baseline with 95% confidence interval. A positive value for the mean indicates worsening quality of life. | 12 months | 
| Treatment Failure Analysis | Treatment failure in individual participants, ie, tumor recurrence or metastasis, can be described by the location relative to the first treatment failure (ie, infield, marginal, or distal), as further defined below. Failure pattern is defined as tumor recurrence or metastasis relative to the primary lesion that is Infield: at tumor or within 5 mm Marginal: > 5 mm or ≤ 20 mm from tumor Distal: > 20 mm from tumor The outcome will be reported as the number of participants who failed treatment for each type of failure, ie, infield, marginal, or distal failure. | 18 months |