Perifosine and Torisel (Temsirolimus) for Recurrent/Progressive Malignant Gliomas

Pilot Trial of Temsirolimus and Perifosine in Recurrent/Progressive Malignant Gliomas

The purpose of this study is to test the effectiveness of a drug called temsirolimus in combination with a drug called perifosine in treating brain tumors that have continued to grow after previous treatment. Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors. Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow. Research suggests that combined treatment with both drugs is better than either alone, and that it is reasonably safe.

Study Overview

• Status: Completed
• Conditions: Glioblastoma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Brain Tumor, Recurrent; Mixed Glioma
• Intervention / Treatment: Procedure: Cytoreductive surgery; Drug: Perifosine; Drug: Temsirolimus

Detailed Description

Malignant gliomas are the most common primary brain tumors, and glioblastoma (GBM) is the most common subtype in adults, representing more than 50% of gliomas. Standard initial treatment for newly diagnosed GBM consists of maximal surgical resection followed by radiotherapy to the tumor bed and chemotherapy with an oral DNA alkylator, temozolomide. However, recurrence is nearly universal despite standard therapy. There is no standard treatment at recurrence. Median survival is about 15 months from diagnosis and 6 months from recurrence. Once patients develop tumor progression, conventional chemotherapy is generally ineffective.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed intracranial glioblastoma (GBM), including sub variants
• At least 15 unstained slides or at least 1 tissue blocks must be collected from at least one prior surgery.
• Received prior radiotherapy and prior temozolomide as treatment for the malignant glioma
• Recovered from toxic effects of prior therapies and at least 2 weeks must have elapsed since any prior signaling pathway modulators; in general, at least 4 weeks must have elapsed from any other anticancer therapy
• Able to undergo contrast enhanced magnetic resonance imaging (MRI) scans or CT scans
• Shown unequivocal evidence for contrast enhancing tumor progression by MRI or CT in comparison to a prior scan
• Age > or = 18 years
• Karnofsky Performance Status > or = 70
• Life expectancy of > 8 weeks
• Normal organ and marrow function, adequate liver function, and adequate renal function before starting therapy
• Platelet count of at least 100,000/mm3 on at least 2 consecutive blood draws at least 1 week apart with results stable or trending upward
• Normal coagulation
• Cholesterol level < or = 350 mg/dl and triglycerides level < or = 400 mg/dl
• Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation
• Women of childbearing potential must have a negative beta-human chorionic gonadotropin (B-hCG) pregnancy test documented within 7 days prior to treatment
• Women must agree not to breast feed
• Ability to understand and the willingness to sign a written informed consent document
• Ability to swallow tablets

Group A (medical) specific inclusion criteria:

• Fulfill all of the general inclusion criteria
• At least 3 months between any prior brain radiotherapy and initiation of study therapy
• MRI/CT must demonstrate measurable enhancing tumor of at least 1cm squared in cross-sectional area to allow assessment of radiographic response
• On stable or decreasing dose of corticosteroids for a minimum of 5 days before the baseline MRI/CT
• The baseline brain MRI/CT must be performed less than 15 days prior to initiation of study treatment. Otherwise it must be repeated

Group B (surgical) specific inclusion criteria:

• Fulfill all of the general inclusion criteria
• Have cytoreductive surgery as part of their routine care for recurrent tumor
• Have cytoreductive surgery as part of their routine care for recurrent tumor
• A brain MRI/CT must be performed less than 15 days prior to initiation of study treatment. Otherwise it must be repeated

Exclusion Criteria:

• There is no limit on the number or type of prior chemotherapies except:

  1. convection enhanced delivery, catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel® wafers
  2. stereotactic radiosurgery, or re-irradiation of any type
  3. agent designed to inhibit mTOR or PI3K/AKT
  4. direct Vascular Endothelial Growth Factor (VEGF)/Vascular Endothelial Growth Factor Receptors (VEGFR) inhibitors
• Smoking or plan to smoke tobacco or marijuana during study therapy
• Plan to eat grapefruit or drink grapefruit juice during study therapy
• Receiving any other investigational agents concurrently with study treatment
• Taking hepatic Enzyme Inducing Anti-Epileptic Drug (EIAED)
• Taking medications that are inducers or inhibitors of Cytochrome P450 3A4 (CYP3A4) for at least two weeks prior to study treatment
• Uncontrolled intercurrent illness
• HIV-positive patients on combination antiretroviral therapy
• Other active concurrent malignancy
• History of gout which can be exacerbated by perifosine
• Known history of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus or perifosine
• Therapeutic anticoagulation
• History of hemorrhagic or ischemic stroke
• Prior intratumoral bleeding must be evaluated with a non-contrast head CT to exclude acute blood prior to start of treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Surgical Cohort - cytoreductive surgery; Cytoreductive surgery planned (surgical cohort). After post-operative standard evaluations, patients will resume therapy. After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose after recovery from surgery. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).	Procedure: Cytoreductive surgery; Standard of care/routine cytoreductive glioma resection surgery. Arm B only.; Other Names: Resection; Drug: Perifosine; Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow.; Other Names: KRX-0401; AEZS-104/D-21266; Drug: Temsirolimus; Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors.; Other Names: Torisel
Other: Medical Cohort - no cytoreductive surgery; No-Cytoreductive surgery planned (medical cohort). After anti-emetic prophylaxis, patients will receive the first divided dose of the perifosine loading dose. Patients will be observed for at least 30 minutes to ensure there has been adequate anti-emetic prophylaxis, and then patients will receive temsirolimus administered over 30-60 minutes IV. The remaining divided doses of the perifosine loading dose will then be administered. Patients will then return weekly for infusion of temsirolimus over 30-60 minutes IV. Dosing will be continuous although for the purposes of evaluation, a cycle will be defined as 4 weeks (28 days).	Drug: Perifosine; Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow.; Other Names: KRX-0401; AEZS-104/D-21266; Drug: Temsirolimus; Temsirolimus is an intravenous drug approved by the FDA for treatment of other cancers (kidney cancer, certain types of lymphoma) but not for brain tumors.; Other Names: Torisel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Benefit Rate	Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.	Up to 6 months from the start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Overall Survival Rate	Overall survival will be calculated by using the interval between the date in which the first study drug administration took place (Arm A), and first day of study drug administration following surgery (Arm B), until the date of subject expiration.	Up to 48 months from start of treatment

Collaborators and Investigators

• Sponsor: Andrew B Lassman, MD
• Collaborators: Pfizer; AEterna Zentaris
• Investigators: Principal Investigator: Andrew B. Lassman, MD, Columbia University

Publications and helpful links

Helpful Links

• Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2014
• Primary Completion (Actual): October 27, 2017
• Study Completion (Actual): February 14, 2021

Study Registration Dates

• First Submitted: August 29, 2014
• First Submitted That Met QC Criteria: September 11, 2014
• First Posted (Estimated): September 12, 2014

Study Record Updates

• Last Update Posted (Actual): May 25, 2023
• Last Update Submitted That Met QC Criteria: May 23, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Glioma; Glioblastoma; Brain Tumor, Recurrent; Anaplastic Astrocytoma; Mixed Glioma; Brain Neoplasms; Anaplastic Oligodendroglioma; akt-Oncogene Protein; mTOR Protein
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Glioblastoma; Recurrence; Glioma; Brain Neoplasms; Astrocytoma; Oligodendroglioma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Protein Kinase Inhibitors; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus; Temsirolimus; MTOR Inhibitors
• Other Study ID Numbers: AAAM3801

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No