Phase I / II Vorinostat, Erlotinib and Temozolomide for Recurrent Glioblastoma Multiforme (GBM)

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01110876
First received: April 22, 2010
Last updated: March 20, 2014
Last verified: March 2014
  Purpose

Objectives:

  1. Phase I

    To determine the maximum tolerated dose (MTD) of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas.

  2. Phase II

Primary:

To determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + temozolomide in patients with recurrent glioblastoma multiforme as progression free survival using a two arm adaptive randomization phase II trial design.

Secondary:

To determine the radiological response, progression free survival (PFS) at 6 months, overall survival and unexpected toxicity in the two treatment arms.

To obtain exploratory data regarding histone 3 and 4 acetylation, treatment related changes in the epidermal growth factor receptor (EGFR) pathway proteins, and changes in e-cadherin and vimentin expression (mRNA /protein) levels in tumor tissue and peripheral monocytes in a subset of surgical patients.


Condition Intervention Phase
Brain Cancer
Glioblastoma Multiforme
Drug: Vorinostat
Drug: Erlotinib
Drug: Temozolomide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I / II Adaptive Randomized Trial of Vorinostat, Erlotinib and Temozolomide in Adults With Recurrent Glioblastoma Multiforme

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: Evaulated with each 28 day (+2 days) cycle ] [ Designated as safety issue: No ]
    Arm 1 of the phase I component will assess the MTD vorinostat in combination with escalating doses of erlotinib and Temozolomide. A conventional phase I design will be used with 3 patients enrolled into the first dose level and monitored for 3 weeks. If no DLT is seen, the next 3 patients will be enrolled at the next dosage level. A maximum of 4 dosage levels will be utilized with deescalation by 2 dose levels if DLT is seen at the starting dose level. If no DLT is noted after dose escalation to Level 4, these doses will be utilized for the phase II components of the study. If 1/3 patients experience DLT, the cohort will be expanded to 3 more patients, If 2/6 patients experience DLT, the previous (lower) dosage level will be declared as the MTD of vorinostat in combination with erlotinib and Temozolomide.


Secondary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    This is an adaptive randomized phase II trial to Vorinostat + Erlotinib to Vorinostat + Erlotinib + Temozolomide in patients with recurrent GBM. The primary outcome is progression free survival (PFS). Patients will be randomized between the two arms using a Bayesian adaptive algorithm. Participants randomized equally between the two arms at the start of the trial (for the first 20 patients). Thereafter, as the trial progresses and data accrue, the randomization will become unbalanced in favor of the treatment that, on average, has better results in terms of failure time. Therefore, each successive patient is more likely to receive the treatment with better results, on average. A minimum of 20 and a maximum of 90 patients will be accrued and there will be 6 months follow up after the last patient is accrued. Based on an anticipated accrual rate between 3 and 5 patients per month, the maximum trial accrual period will be between 30 and 18 months.


Estimated Enrollment: 182
Study Start Date: June 2011
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Vorinostat + Erlotinib + Temozolomide
Phase I Vorinostat with Erlotinib + Temozolomide
Drug: Vorinostat

Phase I Starting Dose: 200 mg twice daily by mouth on Days 1-7, 15-21 of each 28 day cycle.

Phase II Dose: MTD from Phase I.

Other Names:
  • SAHA
  • Suberoylanilide Hydroxamic Acid
  • MSK-390
  • Zolinza
Drug: Erlotinib

Phase I Starting Dose: 200 mg by mouth daily on Days 1-21 of 28 day cycle. For patients on enzyme inducing anticonvulsants (EIACs), starting dose of 400 mg.

Phase II Dose: MTD from Phase I.

Other Names:
  • Erlotinib Hydrochloride
  • OSI-774
  • Tarceva
Drug: Temozolomide
125 mg/m2 by mouth daily on days 1-7, 15-21 of each 28 day cycle.
Other Name: Temodar
Experimental: Vorinostat + Erlotinib
Drug dosing based on the MTD identified in the phase I portion of the study.
Drug: Vorinostat

Phase I Starting Dose: 200 mg twice daily by mouth on Days 1-7, 15-21 of each 28 day cycle.

Phase II Dose: MTD from Phase I.

Other Names:
  • SAHA
  • Suberoylanilide Hydroxamic Acid
  • MSK-390
  • Zolinza
Drug: Erlotinib

Phase I Starting Dose: 200 mg by mouth daily on Days 1-21 of 28 day cycle. For patients on enzyme inducing anticonvulsants (EIACs), starting dose of 400 mg.

Phase II Dose: MTD from Phase I.

Other Names:
  • Erlotinib Hydrochloride
  • OSI-774
  • Tarceva

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with histologically proven glioblastoma multiforme, gliosarcoma or anaplastic glioma will be eligible for the Phase I component. Anaplastic gliomas include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic oligoastrocytoma (AOA), or 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 malignant glioma is made. Only patients with histologically proven supratentorial glioblastoma multiforme or gliosarcoma will be eligible for the Phase II component.
  2. Patients must have shown unequivocal evidence for tumor recurrence or progression by MRI scan and should have failed radiation therapy. Patients should have completed radiation therapy at least 3 months prior to entry into the study. The scan done prior to study entry documenting progression will be reviewed by the treating physician to document changes in tumor dimension to confirm recurrence.
  3. (2. continued) Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have reasonable confirmation of true progressive disease rather than radiation necrosis as determined by the treating physician and neuro-radiologist; for example, through MRI, MR spectroscopy, or PET scan of the brain.
  4. For the Phase I component, any number of prior relapses is allowed, provided the patient fulfills all other eligibility criteria particularly that of the functional status. For the phase II component, patients may have had up to 2 prior relapses
  5. All patients must sign an informed consent indicating their awareness of the investigational nature of this study in keeping with the policies of this hospital.
  6. The baseline on-study MRI should be performed within 14 days (+/- 3 days) prior to registration and on a steroid dosage that has been stable or decreasing for at least 5 days. If the steroid dose is increased between the date of imaging and the initiation of therapy (or at that time), a new baseline MRI is required. The same type of scan, i.e., MRI, must be used throughout the period of protocol treatment for tumor measurement.
  7. Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: a) They have recovered from the effects of surgery. b) Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. c) To best assess the extent of residual measurable disease post-operatively, a MRI should be done no later than 96 hours in the immediate post-operative period or 4-6 weeks post-operatively.
  8. Patients must be 18 years old or older.
  9. Patients must have a Karnofsky performance status (KPS) equal or greater than 60
  10. Patients must have recovered from the toxic effects of prior therapy to grade 1 non hematological or </= grade 2 hematological toxicity (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy or bevacizumab and/or at least two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and 1 week for non-cytotoxic agents, e.g., interferon, tamoxifen, cis-retinoic acid, etc. (radiosensitizer does not count).
  11. (10. continued) Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study (such as presurgically for obtaining pharmacology data for the agent) will be eligible to enter the study provided they have recovered from the toxic effects of the agent if any. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.
  12. Patients must have adequate bone marrow function (ANC>/= 1,500/mm^3 and platelet count of >/= 100,000/mm^3), adequate liver function (SGPT </= 3 times normal and alkaline phosphatase </= 2 times normal, bilirubin </= 1.5 mg/dl), adequate renal function (BUN and creatinine </= 1.5 times institutional normal) prior to registration.
  13. Women of childbearing potential on treatment must not be pregnant, must not be breast-feeding and must practice adequate contraception. Male patients on treatment with vorinostat must agree to use an adequate method of contraception for the duration of the study, and for 30 days after the last dose of study medication.

Exclusion Criteria:

  1. Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or bladder), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible.
  2. Patients must not have: a) active infection b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease including cirrhosis or hepatic dysfunction c) serious intercurrent medical illness
  3. Patients who are currently on active treatment for AIDS or hepatitis will be excluded due to the potential for adverse interaction with ongoing treatment agents and for unknown toxicity.
  4. Patients receiving valproic acid (VPA), an anticonvulsant drug with HDAC inhibitor properties, will be excluded, unless they are switched to an alternative agent prior to treatment initiation. A 5 day wash out period is required.
  5. Prior treatment with EGFR inhibitors or temozolomide on a standard day 1-5 dosing and low dose daily dosing as part of chemoradiation therapy is allowed because the trial is based on the hypothesis that the combination of agents used will be synergistic in their effects, and that HDAC inhibition will potentially overcome resistance to EGFR inhibitors and temozolomide. However, prior treatment with dose dense regimens of temozolomide (7 days on/ 7 days off, 21 days/28 days or continuous low dose daily dosing not with chemoradiation) and HDAC inhibitors other than valproic acid (such as depsipeptide, LBH-589 or vorinostat) are not permitted.
  6. Patients with a known allergy to any component of vorinostat, or a known allergy to Temozolomide or erlotinib will be excluded.
  7. Patient must be able to tolerate the procedures required in this study including periodic blood sampling, study related assessments, and management at the treating institution for the duration of the study. Inability to comply with protocol or study procedures (for example, an inability to swallow tablets) will be an exclusion criteria.
  8. This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender.
  9. No exclusion to this study will be based on race. The malignant glioma patient population treated at MDACC over the past year is as follows: American Indian or Alaskan Native - 0; Asian or Pacific Islander - <2%; Black, not of Hispanic Origin - 3%; Hispanic - 6%; White, not of Hispanic Origin - 88%; Other or Unknown - 2%; Total-100%.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01110876

Contacts
Contact: John DeGroot, MD 713-792-2883

Locations
United States, Texas
UT MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Vinay K. Puduvalli, MD         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: John DeGroot, MD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01110876     History of Changes
Other Study ID Numbers: 2009-0651, NCI-2011-00469
Study First Received: April 22, 2010
Last Updated: March 20, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by M.D. Anderson Cancer Center:
Recurrent Glioblastoma Multiforme
GBM
Brain
Central Nervous Center
Malignant glioma
Glioblastoma multiforme
Gliosarcoma
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Anaplastic oligoastrocytoma
Vorinostat
SAHA
Suberoylanilide Hydroxamic Acid
MSK-390
Zolinza
Erlotinib
Erlotinib Hydrochloride
OSI-774
Tarceva
Temozolomide
Temodar

Additional relevant MeSH terms:
Brain Neoplasms
Glioblastoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Temozolomide
Dacarbazine
Vorinostat
Erlotinib
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 20, 2014