Sorafenib Tosylate and Temsirolimus in Treating Patients With Recurrent Glioblastoma

Study Overview
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Brief Summary
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This phase I/II trial studies the side effects and best dose of temsirolimus when given together with sorafenib tosylate and to see how well they work in treating patients with glioblastoma that has come back. Sorafenib tosylate may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temsirolimus, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib tosylate and temsirolimus may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sorafenib tosylate with temsirolimus may kill more tumor cells.

Detailed Description
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Primary Objective - Phase I (closed to accrual as of 01/11/2008): To establish a maximum tolerable dose of temsirolimus in combination with sorafenib in patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs). Phase II (closed to accrual as of 12/07/2012): To assess the efficacy of temsirolimus and sorafenib in the treatment of recurrent glioblastoma in non-EIAC patients as measured by progression-free survival status at six months (PFS6). Secondary Objectives - Phase I (closed to accrual as of 01/11/2008): I. To define the safety profile of temsirolimus and sorafenib in non-EIAC patients. II. To assess the evidence of antitumor activity. Phase II (closed to accrual as of 12/07/2012): I. To assess the safety and toxicities of temsirolimus and sorafenib in the above-noted patient populations. Outline: This is a multicenter, phase I, dose-escalation study followed by a phase II study. Phase I (Arm A): Patients receive sorafenib orally (PO) twice daily (BID) on days 1-28 and temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of temsirolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients are assigned to 1 of 3 treatment groups. Group 1 (Arm B): Patients receive sorafenib and temsirolimus as in phase I at the MTD. (patients not undergoing surgery) Group 2 (Arm C): Patients receive sorafenib PO BID on days 1-8 (15 doses) and temsirolimus IV at the MTD on day 1. Patients undergo surgery on day 8. (patients undergoing surgery) After recovering from surgery, patients receive sorafenib and temsirolimus as in phase I at the MTD. Group 3 (Arm D): Patient receive sorafenib and temsirolimus as in phase I at the MTD. (patients who have received prior anti-vascular endothelial growth factor [VEGF] therapy and are not undergoing surgery) Biopsy or resected tissue and blood are collected prior to treatment (usually at diagnosis) and analyzed for biomarkers. After completion of study treatment, patients are followed every 6 months for 5 years and then annually thereafter.

Official Title
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A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma

Conditions
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Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Neoplasm

Intervention / Treatment
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* Procedure: Conventional Surgery
* Other: Laboratory Biomarker Analysis
* Drug: Sorafenib Tosylate
* Drug: Temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Central pathology review submission; this review is mandatory prior to registration to confirm eligibility; it should be initiated as soon after surgery as possible =< 2 prior systemic chemotherapy regimens Histological confirmation of a grade 4 astrocytoma (glioblastoma) or gliosarcoma, at primary diagnosis or recurrence by World Health Organization (WHO) criteria; central pathology review is mandatory prior to study entry to confirm eligibility Evidence of tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan following radiation therapy (RT) or following the most recent anti-tumor therapy Bidimensionally measurable or evaluable disease by MRI or CT scan Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 >= 12 weeks since the completion of RT Fixed or decreasing dose of corticosteroids (or no corticosteroids) >= 1 week prior to registration >= 1 week from minor surgery other than venous line placement and > 3 weeks from major surgery (except for patients undergoing tumor tissue acquisition) >= 4 weeks since prior cytotoxic chemotherapy (>= 6 weeks for nitrosoureas) >= 2 weeks from cytostatic chemotherapy such as tamoxifen, cis-retinoic acid, or thalidomide (address questions regarding such agents to study chair) White blood cells (WBC) >= 3,000/mm^3 Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin (Hgb) >= 10 gm/dL Total bilirubin =< 1.5 x upper limit of normal (ULN) Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x ULN Creatinine =< 2.0 x ULN Serum cholesterol =< 350 mg/dL Serum triglycerides =< 400 mg/dL Willingness to provide the biologic specimens as required by the protocol; (please note that the willingness to participate pertains only to the patient and does not factor in the institution?s ability to participate in any part of the translational component) Exclusion Criteria: Prior intratumoral chemotherapy (e.g., Gliadel or IL13-PE38QQR), stereotactic radiosurgery, or interstitial brachytherapy unless there is a separate lesion on MRI which is not part of the previous treatment field or there is proof of recurrent disease based on biopsy, MRI spectroscopy, or positron emission tomography (PET) scan Prior CCI-779, sorafenib, or other agents specifically targeting mammalian target of rapamycin (mTOR) or raf; patients receiving prior agents inhibiting VEGF or VEGF receptor (R) (prior anti-VEGF group) are eligible but: 1) must be at least four weeks from last treatment with the agent(s); and 2) must have recovered from any clinically relevant toxicities attributable to this agent(s) Evidence of bleeding diathesis or coagulopathy Note: Patients on prophylactic anticoagulation therapy (e.g., low-dose warfarin) are eligible provided their coagulation parameter levels are as follows: prothrombin time (International Normalized Ratio [INR] of prothrombin time) < 1.1 x institutional upper limit of normal Note: Patients on full-dose anticoagulants (e.g., warfarin) are eligible provided that both of the following criteria are met: a) the patient has an in-range INR (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin, and b) the patient has no active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) International normalized ration (INR) > 1.5 (unless the patient is on full-dose warfarin) Receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, fosphenytoin, carbamazepine, phenobarbital, or primidone) or any other potent cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer, such as rifampin or St. John?s wort Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow pills Hypertension with systolic blood pressure of > 140 mmHg or diastolic pressure > 90 mmHg; however, patients with well-controlled hypertension are eligible Uncontrolled infection Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately Known hypersensitivity to any of the components of CCI-779 or sorafenib Other active malignancy Uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, psychiatric illness/social situation that would preclude study compliance with study requirements Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive; HIV-positive patients on combination antiretroviral therapy are ineligible Receiving any investigational agents other than CCI-779 and sorafenib Significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or CT, or other history of significant intratumoral, intracerebral, or subarachnoid hemorrhage

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: Group I (sorafenib tosylate, temsirolimus)<br>Patients receive sorafenib tosylate and temsirolimus as in Phase I. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Group II (sorafenib tosylate, temsirolimus, surgery)<br>Patients receive sorafenib tosylate PO BID on days 1-8 and temsirolimus IV over 30 minutes on day 1. Patients undergo surgery on day 8. After recovering from surgery, patients receive sorafenib tosylate and temsirolimus as in Phase I. | Procedure: Conventional Surgery<br>* Undergo surgery<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|
| Experimental: Group III (sorafenib tosylate, temsirolimus, anti-VEGF)<br>Patients who have received prior anti-VEGF therapy and are not undergoing surgery receive sorafenib tosylate and temsirolimus as in Phase I. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Sorafenib Tosylate<br>* Given PO<br>* Other names: sorafenib;Drug: Temsirolimus<br>* Given IV<br>* Other names: Torisel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | The primary endpoint is the proportion of patients alive and progression-free 6 months after study treatment initiation. If more than 41 evaluable patients are accrued in group 1 or group 3, the additional patients will not be used to evaluate the decision rule for that group or otherwise used in any decision-making processes. However, they will be included in the final point and confidence interval estimates for that group. The 'success' probability, i.e., 6-month progression-free survival percentage, for each of group 1 and group 3 will be estimated as the number of evaluable patients still alive at 6 months divided by the total number of evaluable patients followed for at least 6 months. Ninety-five percent confidence intervals for the 'success' probability will be calculated according to the approach of Duffy and Santner. Progression is defined as a 25% increase in product of perpendicular diameters of contrast enhancement or mass or appearance of new lesions. | At 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The overall survival distribution will be estimated using the method of Kaplan-Meier. | From start of study registration to death due to any cause or until last follow-up, up to 5 years | 
| Objective Response, as Determined by a Neurological Exam, MRI, and/or CT Measurement | The proportion of patients in each response category will be summarized and 90% confidence intervals calculated assuming that the incidence of response is binomially distributed. | Up to 5 years | 
| Progression-free Survival | Kaplan-Meier survival curves will be used to estimate progression-time distributions. | Time from study registration to date of disease progression or last follow-up, assessed up to 5 years |