Overview

This trial is active, not recruiting.

Conditions adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, recurrent adult brain tumor
Treatments sorafenib tosylate, temsirolimus, conventional surgery
Phase phase 1/phase 2
Targets mTOR, RAF, FLT-3, KIT, PDGF, VEGF
Sponsor National Cancer Institute (NCI)
Start date March 2006
End date February 2013
Trial size 115 participants
Trial identifier NCT00329719, CDR0000472240, N0572, NCCTG-N0572, NCI-2009-00652, U10CA025224

Summary

This phase I/II trial is studying the side effects and best dose of temsirolimus when given together with sorafenib and to see how well they work in treating patients with recurrent glioblastoma. Sorafenib 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 and temsirolimus may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving sorafenib together with temsirolimus may kill more tumor cells.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Endpoint classification safety/efficacy study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Phase I, Arm A, Dose Escalation 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.
sorafenib tosylate BAY 43-9006
Given PO
temsirolimus CCI-779
Given IV
(Experimental)
Phase II, Arm B, Group I (patients not undergoing surgery) Patients receive sorafenib and temsirolimus at the MTD (25mg temsirolimus and 200mg sorafenib).
sorafenib tosylate BAY 43-9006
Given PO
temsirolimus CCI-779
Given IV
(Experimental)
Phase II, Arm C, Group II (patients undergoing surgery) 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. After recovering from surgery, patients receive sorafenib and temsirolimus as in phase I at the MTD (25mg temsirolimus and 200mg sorafenib).
sorafenib tosylate BAY 43-9006
Given PO
temsirolimus CCI-779
Given IV
conventional surgery surgery, conventional
Undergo surgery
(Experimental)
Phase II, Arm D, Group III (patients who received prior anti-VEGF therapy) Patients receive sorafenib and temsirolimus as in phase I at the MTD (25mg temsirolimus and 200mg sorafenib).
sorafenib tosylate BAY 43-9006
Given PO
temsirolimus CCI-779
Given IV

Primary Outcomes

Measure
Progression-free Survival
time frame: At 6 months

Secondary Outcomes

Measure
Overall Survival
time frame: 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
time frame: Up to 5 years
Progression-free Survival
time frame: Time from study registration to date of disease progression or last follow-up, assessed up to 5 years

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Central pathology review submission prior to registration to confirm eligibility. It should be initiated as soon after surgery as possible. - ≤2 prior systemic chemotherapy regimens. - ≥18 years of age. - 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 Computerized 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. - ≥4 weeks from prior cytotoxic chemotherapy (≥6 weeks for nitrosoureas). - ≥2 weeks from cytostatic chemotherapy such as tamoxifen, cis-retinoic acid, or thalidomide. - The following laboratory values obtained ≤7 days prior to registration: - WBC ≥3000/mm3 - ANC ≥1500/mm3 - PLT ≥100,000/mm3 - Hgb ≥10 gm/dL - Total bilirubin ≤1.5 x ULN - SGOT (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 mTOR or raf. Patients receiving prior agents inhibiting VEGF or VEGFR (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 (INR; International Normalized Ratio 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). - 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 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. - Any of the following because temsirolimus and sorafenib are investigational agents whose genotoxic effects on the developing fetus and newborn are unknown: - Pregnant women - Nursing women - Men or women of childbearing potential who are unwilling to employ adequate contraception - Known hypersensitivity to any of the components of temsirolimus 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, or psychiatric illness/social situations that would limit compliance with study requirements. - Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be HIV positive. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with temsirolimus and sorafenib. - Receiving any investigational agents other than temsirolimus and sorafenib. - Significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or CT, or other history of significant intratumoral, intracerebral, or subarachnoid hemorrhage.

Additional Information

Official title A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma
Principal investigator Kurt Jaeckle
Description 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.
Trial information was received from ClinicalTrials.gov and was last updated in May 2016.
Information provided to ClinicalTrials.gov by National Cancer Institute (NCI).