Temsirolimus and Perifosine in Treating Patients With Recurrent or Progressive Malignant Glioma

Temsirolimus and Perifosine in Treating Patients With Recurrent or Progressive Malignant Glioma
This study is currently recruiting participants.
Verified January 2011 by National Cancer Institute (NCI)

First Received on January 15, 2010.  
Last Updated on June 12, 2012  
History of Changes
Sponsor: Memorial Sloan-Kettering Cancer Center
Collaborator: National Cancer Institute (NCI)
Information provided by: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01051557
  Purpose

RATIONALE: Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as perifosine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving temsirolimus together with perifosine may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of temsirolimus when given together with perifosine and to see how well they work in treating patients with recurrent or progressive malignant glioma.

Condition Intervention Phase
Brain and Central Nervous System Tumors Drug: perifosine
Drug: temsirolimus
Genetic: fluorescence in situ hybridization
Genetic: western blotting
Other: immunohistochemistry staining method
Other: laboratory biomarker analysis
Procedure: therapeutic conventional surgery
Phase 1
Phase 2

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Glioma

Resource links provided by NLM:

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

Primary Outcome Measures:

  • Maximum tolerated dose of temsirolimus in combination with perifosine (Phase I) [ Designated as safety issue: Yes ]
  • Progression-free survival at 6 months (Phase II) [ Designated as safety issue: No ]
  • Radiographic response rate (Phase II) [ Designated as safety issue: No ]

Secondary Outcome Measures:

  • Toxicity [ Designated as safety issue: Yes ]
  • Overall survival [ Designated as safety issue: No ]
  • Progression-free survival [ Designated as safety issue: No ]
  • Molecular effects during treatment [ Designated as safety issue: No ]
  • Molecular predictors of response [ Designated as safety issue: No ]

Estimated Enrollment: 92
Study Start Date: January 2010
Estimated Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)

Detailed Description:

OBJECTIVES:

Primary

  • Define the maximum tolerated dose of temsirolimus in combination with perifosine in patients with recurrent or progressive malignant glioma who are not taking enzyme-inducing anti-epileptic drugs. (Phase I)
  • Determine the efficacy of this regimen, as measured by 6-month progression-free survival and radiographic response rates, in these patients. (Phase II)

Secondary

  • Characterize the safety profile of this regimen in these patients.
  • Estimate the median overall and progression-free survival of patients treated with this regimen.
  • Explore the association of pre-treatment molecular phenotype with response to treatment.
  • Explore molecular effects during treatment, including PI3K/AKT/mTOR/S6K and RAS/MEK/ERK signaling, proliferation, and apoptosis.

OUTLINE: This is a phase I dose-escalation study of temsirolimus, followed by a phase II study. Patients are stratified according to study phase (I vs II), prior treatment with direct VEGF/VEGFR inhibitor (yes vs no), histologically documented malignant glioma (yes vs no), histology at study registration (glioblastoma [GBM] [GBM, gliosarcoma, GBM with oligodendroglioma features, giant cell GBM] vs anaplastic glioma [anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, or high-grade glioma not otherwise specified]), enrollment in phase II surgical substudy (yes vs no), presence of measurable disease (yes vs no), and molecular profile of baseline tissue (enriched [PDGF] vs non-enriched [EGFR, NF1, or undetermined/other]).

  • Phase I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and oral perifosine once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Phase II: Patients receive temsirolimus (at the maximum-tolerated dose determined in phase I) and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.

Archived and resected tumor tissue samples are collected for correlative laboratory studies, including molecular analysis of PI3K/AKT/mTOR/S6K and RAS/MEK/ERK signaling, proliferation, and apoptosis by IHC, western blot, FISH, and TUNEL, and other molecular studies.

After completion of study therapy, patients are followed up every 3 months.

  Eligibility

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

DISEASE CHARACTERISTICS:

  • Phase I and II: Histologically confirmed intracranial malignant glioma*, including one of the following cell types:

    • Glioblastoma
    • Anaplastic astrocytoma
    • Anaplastic oligodendroglioma
    • Anaplastic oligoastrocytoma (also called anaplastic mixed gliomas)
    • Malignant glioma not otherwise specified (NOS) NOTE: *Patients with original histology of low-grade glioma are eligible provided subsequent histological diagnosis of high-grade (malignant) glioma is made
  • Phase I: Histologically confirmed low-grade (WHO grade II) gliomas (e.g., low-grade astrocytoma, low-grade oligodendroglioma, low-grade oligoastrocytoma [mixed gliomas], or low-grade glioma NOS) allowed provided there is radiographic evidence of malignant transformation by MRI or CT scan but histologic confirmation of high-grade (malignant) transformation would not be otherwise undertaken for routine clinical care (phase I)
  • Unstained slides or tissue blocks available from ≥ 1 prior surgery

    • Frozen tissue requested if available
    • Mandatory for phase II
  • Must have received prior radiotherapy and temozolomide
  • Must have unequivocal evidence of tumor progression by baseline MRI or CT scan (in comparison to a prior scan) OR have recently undergone resection for recurrent/progressive disease

    • Must be on a stable or decreasing dose of corticosteroids for ≥ 5 days before baseline MRI/CT scan (and PET scan for patients enrolled in the phase II portion of the study)

      • Stable corticosteroids are not required for patients undergoing surgery on the surgical substudy portion of the phase II study
  • Measurable disease not required for patients who recently underwent resection as long as progressive disease led to the surgery and the histology of the most recent surgery documented recurrent/progressive/persistent malignant glioma

    • If cytoreductive surgery is planned for tumor recurrence at the time of enrollment, such patients may be eligible for the surgical substudy (Phase II only), taking temsirolimus and perifosine pre-operatively and then re-initiating such therapy after recovering from the effects of surgery

PATIENT CHARACTERISTICS:

  • Karnofsky performance status 60-100%
  • Life expectancy > 8 weeks
  • WBC ≥ 2,000/mm^3
  • ANC ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 10 g/dL (transfusion allowed)
  • Bilirubin < 2 times upper limit of normal (ULN)
  • SGOT and/or SGPT < 2 times ULN
  • Calcium normal
  • Phosphorus normal
  • Creatinine < 1.5 mg/dL
  • Cholesterol ≤ 350 mg/dL
  • Triglycerides ≤ 400 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must agree to use effective contraception
  • No history of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years (phase II)
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus or perifosine
  • No concurrent uncontrolled 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 and/or social situation that would limit compliance with study requirements

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • Recovered from prior therapy
  • At least 6 weeks since prior radiotherapy or nitrosoureas
  • At least 4 weeks since prior temozolomide
  • At least 4 weeks since prior direct inhibitors of VEGF/VEGFR (e.g., bevacizumab [Avastin], aflibercept [VEGF Trap], cediranib [AZD2171], or XL-184 [BMS 907351])
  • At least 4 weeks since prior investigational agents or cytotoxic therapy
  • At least 3 weeks since prior procarbazine
  • At least 2 weeks since prior vincristine
  • At least 2 weeks since prior and no concurrent enzyme-inducing anti-epileptic drugs
  • At least 1 week since prior non-cytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or cis-retinoic acid)
  • No prior mTOR inhibitors (e.g., temsirolimus, sirolimus, or everolimus) (phase II)
  • No prior perifosine or other AKT-targeting agents (phase II)
  • No prior treatment with convection-enhanced delivery, other catheter-based intra-tumoral treatment, or carmustine/Gliadel wafers (phase II)
  • Prior stereotactic radiosurgery (including gamma-knife or cyber-knife) for newly diagnosed or recurrent disease, or re-irradiation of any type allowed provided there is confirmation of true progressive disease (rather than radiation necrosis) by surgical documentation of recurrent/progressive disease (phase II)
  • No other concurrent investigational agents
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent anticancer therapy (including chemotherapy, radiotherapy, hormonal therapy, or immunotherapy)
  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01051557

Locations
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Thomas Kaley, MD     212-639-5122        
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Investigators
Principal Investigator: Thomas Kaley, MD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:

No publications provided

Responsible Party: Andrew B. Lassman, Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01051557    
History of Changes
Other Study ID Numbers: CDR0000663573, MSKCC-09058
Study First Received: January 15, 2010
Last Updated: June 12, 2012
Health Authority: Unspecified

Keywords provided by National Cancer Institute (NCI):

adult giant cell glioblastoma
adult anaplastic astrocytoma
adult diffuse astrocytoma
adult anaplastic oligodendroglioma
adult oligodendroglioma
adult glioblastoma
adult gliosarcoma
adult mixed glioma
recurrent adult brain tumor

Additional relevant MeSH terms:

Glioma
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Sirolimus
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antifungal Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on August 21, 2012

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