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

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ClinicalTrials.gov Identifier: NCT02238496
Recruitment Status : Active, not recruiting
First Posted : September 12, 2014
Last Update Posted : April 23, 2019
Sponsor:
Collaborators:
Pfizer
AEterna Zentaris
Information provided by (Responsible Party):
Andrew B Lassman, MD, Columbia University

Tracking Information
First Submitted Date  ICMJE August 29, 2014
First Posted Date  ICMJE September 12, 2014
Last Update Posted Date April 23, 2019
Actual Study Start Date  ICMJE December 8, 2014
Actual Primary Completion Date October 27, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
Clinical Benefit Rate [ Time Frame: Up to 6 months from the start of treatment ]
Clinical Benefit Rate is defined as the radiographic response rate plus 6-month progression-free survival (PFS) rate.
Original Primary Outcome Measures  ICMJE
 (submitted: September 11, 2014)
  • Radiographic Response [ Time Frame: Every 8 weeks, starting at 8 weeks after Day 1 of treatment, and up to 48 months ]
    Tumor measurements will be calculated and compared to baseline measurements to determine if the regimen induces radiographic response (tumor shrinkage or stabilization) and/or delay in disease progression. These statuses will be categorized as Complete Response (CR), Partial Response (PR), Minor Response (MR), Stable Disease (SD), Progressive Disease (PD), and Unknown (UNK).
  • 6 month progression free survival [ Time Frame: Up to 6 months from drug administration ]
    Subjects' disease status will be evaluated for progression at 6 months: 6 months from first day of study drug administration (Arm A) and 6 months from first day of study drug administration following surgery (Arm B). This will be accomplished via radiographic measurement comparisons between follow-up on-study scans, compared to the baseline scan tumor measurements.
Change History Complete list of historical versions of study NCT02238496 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2019)
Median Overall Survival Rate [ Time Frame: Up to 48 months from start of treatment ]
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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 11, 2014)
Median Overall Survival [ Time Frame: From time of first study drug administration until expiration, (approximately 48 months) ]
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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Perifosine and Torisel (Temsirolimus) for Recurrent/Progressive Malignant Gliomas
Official Title  ICMJE Pilot Trial of Temsirolimus and Perifosine in Recurrent/Progressive Malignant Gliomas
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
No Masking
Primary Purpose: Treatment
Condition  ICMJE
  • Brain Tumor, Recurrent
  • Glioblastoma
  • Anaplastic Astrocytoma
  • Anaplastic Oligodendroglioma
  • Mixed Glioma
Intervention  ICMJE
  • Procedure: Cytoreductive surgery
    Standard of care/routine cytoreductive glioma resection surgery. Arm B only.
    Other Name: 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:
    • AEZS-104/D-21266
    • KRX-0401
  • 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 Name: Torisel
Study Arms  ICMJE
  • 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).
    Interventions:
    • Procedure: Cytoreductive surgery
    • Drug: Perifosine
    • Drug: Temsirolimus
  • 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).
    Interventions:
    • Drug: Perifosine
    • Drug: Temsirolimus
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 7, 2016)
10
Original Estimated Enrollment  ICMJE
 (submitted: September 11, 2014)
17
Estimated Study Completion Date  ICMJE August 31, 2019
Actual Primary Completion Date October 27, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02238496
Other Study ID Numbers  ICMJE AAAM3801
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Andrew B Lassman, MD, Columbia University
Study Sponsor  ICMJE Andrew B Lassman, MD
Collaborators  ICMJE
  • Pfizer
  • AEterna Zentaris
Investigators  ICMJE
Principal Investigator: Andrew B. Lassman, MD Columbia University
PRS Account Columbia University
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP