Vorinostat, Isotretinoin and Temozolomide in Adults With Recurrent Glioblastoma Multiforme (GBM)

NCT00555399 | Terminated Phase 1 Results DMC FDA Drug

• 4 other identifiers: 2006-0709NCI-2010-007824808704BTTC09-02
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to learn if vorinostat when given with isotretinoin and temozolomide can help to control glioblastoma or gliosarcoma. The safety of these drug combinations will also be studied.

Conditions

Glioblastoma Multiforme; Anaplastic Glioma

Keywords

Glioblastoma Multiforme; Anaplastic Glioma; Vorinostat; Suberoylanilide Hydroxamic Acid; SAHA; MSK-390; Zolinza; Isotretinoin; Accutane; 13-cis-Retinoic Acid; Carboplatin; Paraplatin; CBT; Temozolomide; Temodar

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose (MTD)

  To determine the maximum tolerated dose (MTD) of vorinostat + isotretinoin (cRA), carboplatin (CBT) + cRA, and vorinostat + cRA + CBT combinations in adult patients with recurrent glioblastoma multiforme (GBM) and anaplastic gliomas. The units of measurement for the drug dose were either mg/day \[VOR and cRA\] or AUC \[CBT\]. In the outcome measure data table below we have provided the cohort number for each arm at which MTD was declared.

  62 months

• Phase II: To Determine the Efficacy of Vorinostat + cRA, Versus CBT + cRA, Versus Vorinostat + cRA + CBT in Patients With Recurrent Glioblastoma Multiforme as Determined by Time to Progression (TTP) Using an Adaptive Randomization Phase II Trial Design.

  Phase II of the trial has never opened d/t Sponsor's withdrawal of the funding

  two patients withdrew consents and one pt chose not to proceed with treatment

Study Arms (5)

Ph I: Arm 1

EXPERIMENTAL

Vorinostat plus isotretinoin

Drug: Vorinostat; Drug: Isotretinoin

Ph I: Arm 2

EXPERIMENTAL

Temozolomide plus isotretinoin

Drug: Isotretinoin; Drug: Temozolomide

Ph I: Arm 3

EXPERIMENTAL

Vorinostat plus isotretinoin plus temozolomide

Drug: Vorinostat; Drug: Isotretinoin; Drug: Temozolomide

Ph II: Arm 1

NO INTERVENTION

Non-Surgical

Ph II: Arm 2

OTHER

Surgical Arm

Procedure: Surgical Resection

Interventions

Vorinostat DRUG

Phase I/Arm 1: Level 0 = 300 mg PO x 14 days; Level I = 400 mg PO x 14 days; Level II = 500 mg PO x 14 days. Phase I/Arm 3: Level -II = 300 mg PO x 14 days; Level -I = 400 mg PO x 14 days; Level 0 = 400 mg PO x 14 days; Level I = 500 mg PO x 14 days.

Also known as: SAHA, Suberoylanilide Hydroxamic Acid, MSK-390, Zolinza

Ph I: Arm 1; Ph I: Arm 3

Isotretinoin DRUG

Phase I/Arm 1: Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days. Phase I/Arm 2: Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days. Phase I/Arm 3: Level -II = 100 mg/m\^2/day PO x 21 days; Level -I = 100 mg/m\^2/day PO x 21 days; Level 0 = 100 mg/m\^2/day PO x 21 days; Level I = 100 mg/m\^2/day PO x 21 days; Level II = 100 mg/m\^2/day PO x 21 days.

Also known as: cRA, Accutane, 13-cis-Retinoic Acid

Ph I: Arm 1; Ph I: Arm 2; Ph I: Arm 3

Surgical Resection PROCEDURE

Surgical Resection for recurrent Glioblastoma Multiforme

Ph II: Arm 2

Temozolomide DRUG

Phase I/Arm 2: All Levels = 150 mg/m2/day PO X 14 days. Phase I/Arm 3: Level 0 = 150 mg/m2/day PO X 14 days; Level I = 150 mg/m2/day PO X 14 days; Level -I = 125 mg/m2/day PO X 14 days; Level -II = 125 mg/m2/day PO X 14 days; Level -III = 100 mg/m2/day PO X 14 days.

Also known as: Temodar

Ph I: Arm 2; Ph I: Arm 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically proven supratentorial WHO grade IV glioma (glioblastoma or gliosarcoma) will be eligible for the study.
• Patients must have shown unequivocal evidence for tumor recurrence or progression by MRI scan and should have failed radiation therapy. 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. Patients with prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis.
• (2. continued) Patients with prior therapy that included interstitial brachytherapy, Gliadel wafers or stereotactic radiosurgical procedures must have confirmation of true progressive disease rather than radiation necrosis. Such confirmation may be using advanced imaging studies (e.g. PET scans, diffusion-perfusion MRI, SPECT etc) or if available, surgical sampling and histological confirmation (surgery is not required).
• Patients may have had up to 2 prior relapses.
• All patients must sign an IRB approved informed consent indicating their awareness of the investigational nature of this study. Patients must have signed an authorization for the release of their protected health information.
• The baseline on-study MRI should be performed within 14 days (+ 3 working 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.
• Patients who have undergone recent resection of recurrent or progressive tumor will be eligible as long as they have recovered from the effects of surgery. Evaluable or measurable disease following resection of recurrent tumor is not mandated for eligibility into the study. 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.
• Patients must be 18 years old or older.
• Patients must have a Karnofsky performance status equal or greater than 60.
• Patients must have recovered from the toxic effects of prior therapy to \< grade 2 non hematological or grade 2 or lesser hematological toxicity per CTC ver 4 (except deep vein thrombosis): 4 weeks from prior cytotoxic therapy 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). Patients who receive anticancer agents for non-therapeutic purposes unrelated to this study
• (10. continued) (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.
• Patients must have adequate bone marrow function (ANC = or \> 1,500/mm\^3 and platelet count of = or \> 100,000/mm\^3), adequate liver function (SGPT = or \< 3 times upper limit of normal and alkaline phosphatase = or \< 2 times upper limit of normal, bilirubin = or \<1.5 mg/dl), adequate renal function (BUN and creatinine = or \<1.5 times upper limit of normal) and normal serum amylase and lipase prior to starting therapy. Elevated cholesterol and triglycerides are not a contraindication to study enrollment, but should be managed as clinically appropriate by the treating physician.
• Patients must be willing and able to comply with the FDA mandated iPLEDGE program for treatment with isotretinoin (cRA). Patients must sign specific informed consents for treatment with cRA, as mandated by iPLEDGE guidelines. Women of childbearing potential must not be pregnant, must not be breast-feeding and must practice adequate contraception during and one month after participation in the study. Male and Female 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.
• Prior treatment with dose dense regimens of temozolomide is not allowed (e.g, 7 days on/7 days off, 21 day/28 day and daily low dose continuous dosing). However, prior treatment with standard day 1-5 dosing in the adjuvant setting and low dose daily dosing as part of chemoradiation therapy are allowed
• Prior treatment with isotretinoin is allowed because the trial is based on the hypothesis that HDAC inhibition will potentially overcome resistance to retinoids.

You may not qualify if:

• 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.
• Patients must not have: a) active infection; b) disease that will obscure toxicity or dangerously alter drug metabolism, especially liver disease; c) serious intercurrent medical illness; d) prior treatment with HDAC inhibitors. However, patients who have received anticancer agents for non-therapeutic purposes (for eg., as part of a pharmacology study without therapeutic intent) will remain eligible for enrollment into the study.
• Prior treatment with bevacizumab is not allowed.
• 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. No wash out period is required.
• Patients on previous treatment with carboplatin.
• Patients with a known allergy to any component of vorinostat, or a known allergy to temozolomide and/or isotretinoin.
• Patients receiving treatment with other antiepileptic medications will not be excluded. Vorinostat is not metabolized by cytochrome P450 3A4 (CYP 3A4). However, vorinostat may potentially suppress CYP 3A4 activity. Therefore, patients should preferably be treated with non-enzyme inducing anti-epileptic medications to avoid any potential interactions with vorinostat.
• (8. continued) However, the use of non-enzyme inducing anti-epileptic medications is not mandatory. If enzyme-inducing antiepileptic drugs are used, monitoring of drug levels should be considered, as considered clinically appropriate by the treating physician.

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• The University of Texas M.D Anderson Cancer Center Official Website

MeSH Terms

Conditions

Glioblastoma

Interventions

Vorinostat; Isotretinoin; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Pigments, Biological; Biological Factors; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Vinay K. Puduvalli
• Organization: University of Texas M D Anderson Cancer Center

vpuduval@mdanderson.org

(713) 745-2343

Study Officials

• Marta Penas-Prado, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

• Vinay Puduvalli, MD

  Brain Tumor Trials Collaborative (BTTC), and Ohio State University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 6, 2007
• First Posted: November 8, 2007
• Study Start: November 28, 2007
• Primary Completion: January 24, 2020
• Study Completion: January 24, 2020
• Last Updated: August 22, 2024
• Results First Posted: August 22, 2024

Record last verified: 2024-07

Locations

US (1)