Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Gliomas
Overview
- Phase
- Phase 1
- Intervention
- Laboratory Biomarker Analysis
- Conditions
- Adult Anaplastic Astrocytoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 36
- Locations
- 1
- Primary Endpoint
- Determine the Efficacy of Temsirolimus in Combination With Perifosine in Patients With Recurrent/Progressive Glioblastomas (GBMs) Not Taking EIAEDs as Measured by 6 Month Progression-free Survival (6mPFS) and Radiographic Response Rates. (Phase II)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
This phase I/II trial studies the side effects and best dose of temsirolimus when given together with perifosine and to see how well it works in treating patients with recurrent or progressive malignant glioma. 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 with perifosine may be an effective treatment for malignant glioma.
Detailed Description
PRIMARY OBJECTIVES: I. Define the maximum tolerated dose (MTD) of temsirolimus in combination with perifosine in patients with recurrent or progressive malignant glioma who are not taking enzyme-inducing anti-epileptic drugs (EIAEDs). (Phase I) II. Determine the efficacy of temsirolimus in combination with perifosine in patients with recurrent/progressive glioblastomas (GBMs) not taking EIAEDs as measured by 6 month progression-free survival (6mPFS) and radiographic response rates. (Phase II) SECONDARY OBJECTIVES: I. Characterize the safety profile of perifosine and temsirolimus. II. Estimate median overall and progression-free survival. III. Explore the association of pre-treatment molecular phenotype with response to treatment. IV. Explore molecular effects during treatment including phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) and rat sarcoma (RAS)/mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (ERK) signaling, proliferation, and apoptosis. OUTLINE: This is a phase I dose-escalation study of temsirolimus, followed by a phase II study. PHASE I: Patients receive temsirolimus intravenously (IV) over 30 minutes on days 1, 8, 15, and 22 and perifosine orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery. After completion of study therapy, patients are followed up every 3 months.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have unstained slides or tissue blocks available from at least one prior surgery; frozen tissue is also requested if available
- •Patients must have received prior radiotherapy and temozolomide; there is otherwise no limit on the number of prior recurrences/therapies
- •At least 6 weeks (42 days) must have elapsed since completion of radiation therapy to initiation of study treatment
- •At least 4 weeks (28 days) must have elapsed since most recent temozolomide and initiation of study treatment
- •Patients must have recovered from the toxic effects of other prior direct inhibitors of vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR): 4 weeks from prior therapy with agents such as bevacizumab (Avastin), aflibercept (VEGF-Trap), cediranib (AZD2171), or XL-184 (BMS 907351); any questions regarding the definition of a direct anti-VEGF/VEGFR therapy must be discussed with the principal investigator (PI) or co-PI; patients must have recovered from the toxic effects of other prior therapy including: 4 weeks (28 days) from any investigational agent, two weeks (14 days) from vincristine, 6 weeks (42 days) from nitrosoureas, 3 weeks (21 days) from procarbazine administration, and 1 week (7 days) for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count), and 4 weeks (28 days) from any other prior cytotoxic therapy; any questions related to the definition of non-cytotoxic agents should be directed to the co-PI
- •Patients must have shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI)/computed tomography (CT) on the baseline MRI/CT in comparison to a prior scan OR have recently undergone resection for recurrent/progressive disease; the baseline brain MRI/CT must be performed 14 days or fewer prior to treatment; the same type of scan, i.e., MRI (or CT for patients who cannot undergo MRI) must be used throughout the period of protocol treatment for tumor measurement; criteria for progression on this study are not mandatory if the disease progression is obvious in the opinion of the investigator; any questions should be addressed to the PI
- •Patients must be on a stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT (and positron emission tomography \[PET\] scans for patients on the phase II study) except patients undergoing surgery on the surgical substudy of phase II; if the corticosteroid dose is increased between the date of imaging and registration a new baseline MR/CT is required
- •Karnofsky performance status \>= 60%
- •Life expectancy of greater than 8 weeks
- •White blood cell (WBC) \>= 2,000/ul
Exclusion Criteria
- •Patients may not be receiving any other investigational agents
- •Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus or perifosine
- •Patients must not be taking EIAED; if previously on an EIAED, the patient must be off of it for at least two weeks prior to treatment on study
- •Patients must not have 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
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with temsirolimus and perifosine
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- •PHASE II: Patients may not have received prior treatment with mTOR inhibitors such as temsirolimus, rapamycin (sirolimus), or RAD001 (everolimus); any question regarding the definition of mTOR inhibiting therapy must be discussed with the PI; such prior therapy is allowed for the phase I component
- •PHASE II: Patients may not have previously received perifosine or other AKT targeting agents; any question regarding the definition of AKT targeting therapy must be discussed with the PI; such prior therapy is allowed for the phase I component
- •PHASE II: Patients must not have received prior treatment with convection enhanced delivery, other catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel wafers; such prior therapy is allowed for the phase I component
- •PHASE II: Patients with prior therapy that included stereotactic radiosurgery (including gamma-knife or cyber-knife) during therapy for newly diagnosed or recurrent disease, or re-irradiation of any type, must have confirmation of true progressive disease rather than radiation necrosis based upon surgical documentation of recurrent/progressive disease; imaging with magnetic resonance (MR) spectroscopy, PET, or other techniques is not adequate to exclude radiation necrosis for this study; such prior therapy is allowed for the phase I component and does not require surgical documentation of disease
Arms & Interventions
Treatment (temsirolimus and perifosine)
PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and perifosine PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.
Intervention: Laboratory Biomarker Analysis
Treatment (temsirolimus and perifosine)
PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and perifosine PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.
Intervention: Perifosine
Treatment (temsirolimus and perifosine)
PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and perifosine PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.
Intervention: Temsirolimus
Treatment (temsirolimus and perifosine)
PHASE I: Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22 and perifosine PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients receive temsirolimus and perifosine as in phase I. Some patients may also undergo cytoreductive surgery.
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
Determine the Efficacy of Temsirolimus in Combination With Perifosine in Patients With Recurrent/Progressive Glioblastomas (GBMs) Not Taking EIAEDs as Measured by 6 Month Progression-free Survival (6mPFS) and Radiographic Response Rates. (Phase II)
Time Frame: 5 years
Maximum Tolerated Dose of Temsirolimus
Time Frame: 28 days
MTD defined as the dose at which fewer than one-third of patients experience a dose limiting toxicity (DLT) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (Phase I)