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

Primary Purpose

Brain Tumor, Recurrent, Glioblastoma, Anaplastic Astrocytoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cytoreductive surgery
Perifosine
Temsirolimus
Sponsored by
Andrew B Lassman, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Brain Tumor, Recurrent focused on measuring Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma, akt-Oncogene Protein, mTOR Protein, Glioma, Brain Neoplasms, Brain Tumor, Recurrent

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Columbia University Irving Medical Center
  • Memorial Sloan-Kettering Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Surgical Cohort - cytoreductive surgery

Medical Cohort - no cytoreductive surgery

Arm Description

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).

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).

Outcomes

Primary Outcome Measures

Clinical Benefit Rate
Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.

Secondary Outcome Measures

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.

Full Information

First Posted
August 29, 2014
Last Updated
May 23, 2023
Sponsor
Andrew B Lassman, MD
Collaborators
Pfizer, AEterna Zentaris
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1. Study Identification

Unique Protocol Identification Number
NCT02238496
Brief Title
Perifosine and Torisel (Temsirolimus) for Recurrent/Progressive Malignant Gliomas
Official Title
Pilot Trial of Temsirolimus and Perifosine in Recurrent/Progressive Malignant Gliomas
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Completed
Study Start Date
December 8, 2014 (Actual)
Primary Completion Date
October 27, 2017 (Actual)
Study Completion Date
February 14, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Andrew B Lassman, MD
Collaborators
Pfizer, AEterna Zentaris

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Brain Tumor, Recurrent, Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma
Keywords
Glioblastoma, Anaplastic Astrocytoma, Anaplastic Oligodendroglioma, Mixed Glioma, akt-Oncogene Protein, mTOR Protein, Glioma, Brain Neoplasms, Brain Tumor, Recurrent

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Masking Description
No Masking
Allocation
Non-Randomized
Enrollment
10 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Surgical Cohort - cytoreductive surgery
Arm Type
Other
Arm Description
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).
Arm Title
Medical Cohort - no cytoreductive surgery
Arm Type
Other
Arm Description
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).
Intervention Type
Procedure
Intervention Name(s)
Cytoreductive surgery
Other Intervention Name(s)
Resection
Intervention Description
Standard of care/routine cytoreductive glioma resection surgery. Arm B only.
Intervention Type
Drug
Intervention Name(s)
Perifosine
Other Intervention Name(s)
AEZS-104/D-21266, KRX-0401
Intervention Description
Perifosine is a pill that has not been approved by the FDA which blocks a messenger that tells cancer cells to grow.
Intervention Type
Drug
Intervention Name(s)
Temsirolimus
Other Intervention Name(s)
Torisel
Intervention Description
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.
Primary Outcome Measure Information:
Title
Clinical Benefit Rate
Description
Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.
Time Frame
Up to 6 months from the start of treatment
Secondary Outcome Measure Information:
Title
Median Overall Survival Rate
Description
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.
Time Frame
Up to 48 months from start of treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: convection enhanced delivery, catheter based intra-tumoral treatment, or carmustine (BCNU)/Gliadel® wafers stereotactic radiosurgery, or re-irradiation of any type agent designed to inhibit mTOR or PI3K/AKT 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew B. Lassman, MD
Organizational Affiliation
Columbia University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Columbia University Irving Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
http://hiccc.columbia.edu/clinicaltrials
Description
Herbert Irving Comprehensive Cancer Center (HICCC) Clinical Trials Page

Learn more about this trial

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

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