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Adult Anaplastic AstrocytomaPhase 1/2NCT01051557

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

A Phase 1/2 study testing Laboratory Biomarker Analysis, Perifosine and Temsirolimus in people with Adult Anaplastic Astrocytoma and Adult Anaplastic Oligodendroglioma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Perifosine and Temsirolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
1 siteUnited States
Study dates
27 Jan 2010to 30 Sep 2020
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelet count of >= 100,000/mm^3
  • Platelet count of at least 100,000/mm^3 on at least 2 consecutive blood draws, at least 1 week apart, with results stable/trending upward; any question regarding the definition of stable/trending upward must be discussed with the PI
  • Hemoglobin >= 10 gm/dl; eligibility level for hemoglobin may be reached by transfusion
  • Serum glutamic oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) < 2 times upper limit of normal (ULN)
  • Bilirubin < 2 times ULN
  • Creatinine < 1.5 mg/dL
  • Calcium levels at or above the lower limit of normal
  • Phosphorus levels at or above the lower limit of normal
  • Cholesterol level =< 350 mg/dl
  • Triglycerides level =< 400 mg/dl
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • 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
  • Patients must have the ability to understand and the willingness to sign a written informed consent document
  • Measurable disease is not required for eligibility in 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 + perifosine pre-operatively and then re-initiating such therapy after recovering from the effects of surgery
  • PHASE I: Patients must have a EITHER
  • Histologically confirmed intracranial malignant glioma of the following types: glioblastoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligo-astrocytoma (AOA) also called anaplastic mixed gliomas, malignant glioma NOS (not otherwise specified); patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) glioma is made; OR
  • Histologically confirmed low grade (World Health Organization [WHO] grade II) gliomas (such as low grade astrocytoma, low grade oligodendroglioma, low grade oligo-astrocytoma (mixed gliomas), or low grade glioma NOS) IF there is radiographic evidence by MRI or CT of malignant transformation but histologic confirmation of high grade (malignant) transformation would not be otherwise undertaken for routine clinical care; inclusion of patients in this group will allow increased accrual rapidity by enrolling patients who are otherwise ineligible for almost all malignant glioma trials yet whom are treated presumptively for malignant glioma
  • PHASE II: Patients must have a histologically confirmed intracranial malignant glioma of the following types: glioblastoma, anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligo-astrocytoma (AOA) also called anaplastic mixed gliomas, malignant glioma NOS (not otherwise specified); patients will be eligible if the original histology was low-grade glioma and a subsequent histological diagnosis of a high grade (malignant) glioma is made
  • PHASE II (patients enrolling on the surgical substudy to evaluate tissue correlates): Patients eligible for the surgical subset have been identified as candidates for cytoreductive surgery by the treating physician and/or based on discussion in a multidisciplinary tumor board, with the input of other surgeons as well as that of the neuro-oncologists involved in the trial; for the patients in the preoperative component, a scan showing progression is required but stable corticosteroids are not required; following surgery, a scan should be done less than 96 hours after surgery; if this is not performed, then a new baseline scan should be performed at least 4 weeks after surgery to avoid misinterpretation of post-operative changes as enhancing disease; this scan will serve as the new baseline before restarting treatment post-operative, and it must be performed on a stable or decreasing dose of corticosteroids; (as above, regarding the baseline MRI or CT scan prior to registration, patients in the Phase II component who are NOT participating in the pre-operative component of the study should be on a steroid dose that has been stable for at least 5 days prior to the scan; if the corticosteroid dose is increased between the date of imaging and registration a new baseline MR/CT is required)
  • PHASE II (patients enrolling on the surgical substudy to evaluate tissue correlates): Post-operatively, treatment with temsirolimus and perifosine must re-start no later than the 14th day after the scan; if the 96-hour scan is more than 14 days old before treatment is initiated, the scan needs to be repeated on a stable or decreasing steroid dose; treatment must start no later than 56 days after surgery
  • PHASE II (patients previously treated with bevacizumab or other direct inhibitors of VEGF/VEGFR including Aflibercept (VEGF-Trap) and cediranib and XL-184 (BMS 907351): There is no limit on such therapy for patients accrued to phase I; for phase II, historical controls for this group of patients is poorly defined; therefore, we will accrue up to 15 patients who received prior treatment with direct VEGF/VEGFR inhibitors in order to gain preliminary data for use as a comparison group in a follow up study; all other inclusion/exclusion criteria also apply to this cohort

Who cannot join

  • 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
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  • 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
  • PHASE II: Patients with a 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 are ineligible for the phase II study but are eligible for the phase I component

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

Other trials in United States

About this study

Official title: Phase I/II Trial of Temsirolimus and Perifosine for Recurrent or Progressive Malignant Gliomas

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Being tested
Laboratory Biomarker Analysis, Perifosine, Temsirolimus, Therapeutic Conventional Surgery
Medical subject headings
Astrocytoma, Oligodendroglioma, Glioblastoma, Gliosarcoma, Glioma, Brain Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • PerifosineDrug

    Also called 4-[[Hydroxy(octadecyloxy)phosphinyl]oxy]-1,1-dimethylpiperidinium, Inner Salt, D21266, Octadecylphosphopiperidine

    Given PO

  • TemsirolimusDrug

    Also called CCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog

    Given IV

  • Therapeutic Conventional SurgeryProcedure or surgery

    Undergo cytoreductive surgery

Study groups in NCT01051557
Study groupRoleWhat they receive
Treatment (temsirolimus and perifosine)ExperimentalPHASE 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.
Receives: Other: Laboratory Biomarker Analysis; Drug: Perifosine; Drug: Temsirolimus; Procedure: Therapeutic Conventional Surgery

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose of Temsirolimus

    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)

    Measured: 28 days

  2. 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)

    Measured: 5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Jan 2010 (estimated)
  2. Study start27 Jan 2010
  3. Primary completion16 Nov 2018
  4. Study completion30 Sep 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01051557
Sponsor's protocol ID
NCI-2011-01409
Other IDs
NCI-2011-01409, 09-058, MSKCC-09058, CDR0000663573, 09-058, 8249, P30CA008748, U01CA069856
Status last verified
Jun 2021
First submitted
15 Jan 2010
Last updated
19 Jul 2021

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Laboratory Biomarker Analysis, Perifosine and Temsirolimus in people with Adult Anaplastic Astrocytoma and Adult Anaplastic Oligodendroglioma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 34 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 19 Jul 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 18 Apr 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose of Temsirolimus (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01051557.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Jul 2021.

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