Sorafenib and Temsirolimus in Treating Patients With Recurrent Glioblastoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00329719
First received: May 23, 2006
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Adult Giant Cell Glioblastoma
Adult Glioblastoma
Adult Gliosarcoma
Recurrent Adult Brain Tumor
Drug: sorafenib tosylate
Drug: temsirolimus
Procedure: conventional surgery
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Sorafenib and CCI-779 in Patients With Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: At 6 months ] [ Designated as safety issue: No ]
    The âsuccessâ 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 percent confidence intervals for the âsuccessâ probability will be calculated according to the approach of Duffy and Santner.


Secondary Outcome Measures:
  • Time to disease progression [ Time Frame: From start of study therapy to documentation of disease progression, up to 5 years ] [ Designated as safety issue: No ]
    The time-to-progression distribution will be estimated using the Kaplan-Meier method.

  • Overall survival [ Time Frame: From start of study therapy to death due to any cause or until last follow-up, up to 5 years ] [ Designated as safety issue: No ]
    The overall survival distribution will be estimated using the method of Kaplan-Meier.

  • Objective response, as determined by a neurological exam, MRI, and/or CT measurement [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Adverse events as assessed by NCI CTCAE v4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Correlation of biomarkers with antitumor activity/patient outcomes [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 144
Study Start Date: March 2006
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group I (patients not undergoing surgery)
Patients receive sorafenib and temsirolimus at the MTD.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Experimental: 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.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel
Procedure: conventional surgery
Undergo surgery
Other Name: surgery, conventional
Experimental: Group III (patients who received prior anti-VEGF therapy)
Patients receive sorafenib and temsirolimus as in phase I at the MTD.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Drug: temsirolimus
Given IV
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel

Detailed Description:

PRIMARY OBJECTIVES:

I. Establish a maximum tolerable dose of temsirolimus in combination with sorafenib in patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs). (Phase I [closed to accrual as of 11/21/07]) II. Define the safety profile of temsirolimus and sorafenib in these patients. (Phase I [closed to accrual as of 11/21/07]) III. Assess the evidence of antitumor activity. (Phase I [closed to accrual as of 11/21/07])Assess the efficacy, as measured by progression-free survival, of temsirolimus and sorafenib in patients with recurrent glioblastoma not receiving EIACs. (Phase II) IV. Assess the safety and toxicities of this regimen in these patients. (Phase II)

SECONDARY OBJECTIVES:

I. Correlate tumor and blood biomarkers with clinical outcome of patients treated with temsirolimus and sorafenib.

II. Evaluate tumor tissue specimens for evidence of bioactivity of these agents.

OUTLINE: This is a multicenter, phase I (closed to accrual as of 11/21/07), dose-escalation study of temsirolimus followed by a phase II open-label study.

PHASE I: 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. (closed to accrual as of 11/21/07) 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: Patients receive sorafenib and temsirolimus as in phase I (closed to accrual as of 11/21/07) at the MTD. (patients not undergoing surgery)

GROUP 2: 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 (closed to accrual as of 11/21/07) at the MTD.

GROUP 3: Patient receive sorafenib and temsirolimus as in phase I (closed to accrual as of 11/21/07) 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed grade IV astrocytoma (glioblastoma) or gliosarcoma
  • Evidence of tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan after prior radiotherapy or most recent antitumor therapy
  • Bidimensionally measurable or evaluable disease by MRI or CT scan
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
  • White blood cells (WBC) >= 3,000/mm^3
  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count >= 100,000/mm^3
  • Hemoglobin >= 10 g/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
  • International normalized ration (INR) > 1.5 (unless on full-dose warfarin)
  • Not pregnant or nursing
  • Fertile patients must use effective contraception during and for 6 months after completion of study therapy
  • No human immunodeficiency virus (HIV) positivity
  • No evidence of bleeding diathesis or coagulopathy
  • No condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for IV alimentation, or active peptic ulcer disease) that would impair the ability to swallow pills
  • No uncontrolled hypertension with systolic blood pressure (BP) > 140 mm Hg or diastolic BP pressure> 90 mm Hg
  • No uncontrolled infection
  • No known hypersensitivity to any of the components of temsirolimus or sorafenib
  • No immunocompromised patients (other than that related to the use of corticosteroids)
  • No other active malignancy
  • No uncontrolled intercurrent illness, including, but not limited to, any of the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situation that would preclude study compliance
  • No significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or CT scan
  • No other history of significant intratumoral, intracerebral, or subarachnoid hemorrhage
  • Concurrent full-dose anticoagulants (e.g., warfarin) allowed provided all of the following criteria are met:

    • In-range INR(between 2 and 3) on a stable dose of oral anticoagulant or on a stabledose of low molecular weight heparin
    • No active bleedingor pathological condition that carries a high risk of bleeding (e.g., tumorinvolving major vessels or known varices)
  • At least 12 weeks since prior radiotherapy
  • At least 4 weeks since prior temsirolimus, sorafenib, or other agents specifically targeting mTOR, raf, or vascular endothelial growth factor (VEGF)/VEGF receptors and recovered
  • At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas)
  • At least 2 weeks since prior cytostatic chemotherapy (e.g., tamoxifen, isotretinoin, or thalidomide)
  • At least 1 week since prior fixed or decreasing dose of corticosteroids (or no corticosteroids)
  • At least 1 week since prior minor surgery other than venous line placement (3 weeks for major surgery)
  • No more than 2 prior systemic chemotherapy regimens
  • No prior surgical procedures affecting absorption
  • No prior intratumoral chemotherapy (e.g., polifeprosan 20 with carmustine implant or cintredekin besudotox), stereotactic radiosurgery, or interstitial brachytherapy unless there is a separate lesion on MRI that is not part of the previous treatment field or there is proof of recurrent disease based on biopsy, MRI spectroscopy, or positron emission tomography scan
  • No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin,fosphenytoin, carbamazepine, phenobarbital, or primidone) or any other potent CYP3A4 inducer, such as rifampin or Hypericum perforatum (St. John's wort)
  • No other concurrent investigational agents
  • No concurrent prophylactic hematopoietic colony-stimulating factors
  • No other concurrent anticancer agents or therapies
  • Concurrent prophylactic anticoagulation therapy (e.g., low-dosewarfarin) allowed provided coagulation parameter levels (prothrombin time [INR]) < 1.1 times upper limit of normal (ULN)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00329719

  Show 176 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Kurt Jaeckle North Central Cancer Treatment Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00329719     History of Changes
Other Study ID Numbers: NCI-2009-00652, N0572, CDR0000472240, NCCTG-N0572, U10CA025224
Study First Received: May 23, 2006
Last Updated: June 11, 2013
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Brain Neoplasms
Glioblastoma
Gliosarcoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Sirolimus
Everolimus
Sorafenib
Niacinamide
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents

ClinicalTrials.gov processed this record on August 28, 2014