Lonafarnib and Temozolomide in Treating Patients With Glioblastoma Multiforme That Is Recurrent or Did Not Respond to Previous Treatment With Temozolomide

Phase I/Ib Study of Sarasar and Temodar in Patients With Recurrent or Temodar-Refractory Glioblastoma Multiforme

This phase I trial studies the side effects and best dose of lonafarnib when given together with temozolomide and to see how well they work in treating patients with glioblastoma multiforme that is has come back or did not respond to previous treatment with temozolomide. Lonafarnib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving lonafarnib together with temozolomide may kill more tumor cells.

Study Overview

• Status: Active, not recruiting
• Conditions: Recurrent Glioblastoma; Recurrent Gliosarcoma; Malignant Supratentorial Neoplasm
• Intervention / Treatment: Drug: Temozolomide; Drug: Lonafarnib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose Sarasar (SCH66336, lonafarnib) when combined with Temodar (temozolomide) in an alternating week schedule.

II. To describe the toxicities of the Sarasar and Temodar combination treatment using this dosing schedule.

III. To evaluate response as measured by 6-month progression-free survival and objective tumor response.

OUTLINE: This is a dose-escalation study of lonafarnib.

Patients receive temozolomide orally (PO) once daily (QD) on days 1-7 and 15-21 and lonafarnib PO twice daily (BID) on days 8-14 and 22-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with histologically proven supratentorial glioblastoma multiforme (GBM) or gliosarcoma
• Patients must have shown unequivocal evidence for tumor recurrence or progression by magnetic resonance imaging (MRI) scan after radiation therapy; the scan done prior to study entry documenting progression will be reviewed by the treating physician to document tumor volume changes to provide a gross assessment of growth rate
• Patients may have had as many as 2 prior chemotherapy regimens for recurrent or progressive tumor; patients must have had prior treatment with Temodar but may not have had prior treatment with farnesyl transferase inhibitors (Sarasar or Zarnestra); patients in phase 1b expansion are required to have received a minimum of two cycles of adjuvant temozolomide (TMZ)
• All patients must sign an informed consent indicating that they are aware of the investigational nature of this study in keeping with the policies of this hospital
• Patients must have shown unequivocal evidence for tumor progression by MRI or computed tomography (CT) scan; a scan should be performed within 14 days prior to registration and on a steroid dose that has been stable or decreasing for at least 5 days; if the steroid dose is increased between the date of imaging and registration a new baseline magnetic resonance (MR)/CT is required; the same type of scan, i.e., MRI or CT must be used throughout the period of protocol treatment for tumor measurement

• Patients (pts) having had recent resection of recurrent or progressive tumor are eligible as long as:

  • Patients must be status post surgical resection at least 2 weeks prior to study enrollment, have recovered from surgery, have adequate early wound healing and a Karnofsky performance status of > or = 60
  • Residual disease following resection of recurrent tumor is not mandated for eligibility into the study; a CT/MRI should be done within 96 hours (hrs) post-op or at least 4 weeks (wks) post-op (within 14 days of registration); if the steroid dose is increased between the scan date and registration, a new baseline MRI/CT is required on a stable steroid dose for 5 days
• Patients must have a Karnofsky performance status of >= 60
• Patients must have recovered from the toxic effects of prior therapy: 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, thalidomide, cis-retinoic acid, etc. (radiosensitizer does not count); any questions related to the definition of non-cytotoxic agents should be directed to the study chair
• Absolute neutrophil count (ANC) >= 1,500/mm^3
• Platelet count of >= 100,000/mm^3
• Serum glutamic pyruvate transaminase (SGPT) < 2.5 times normal
• Alkaline phosphatase < 2.5 times normal
• Bilirubin < 1.5 mg
• Blood urea nitrogen (BUN) < 1.5 times institutional normal
• Creatinine < 1.5 times institutional normal

Exclusion Criteria:

• Patients must not be taking primidone, carbamazepine, phenobarbital or phenytoin anticonvulsants; patients changing from these anticonvulsants to other allowable drugs that are not enzyme inducing antiepileptic drugs (EIAEDs) must be off the drugs listed above for at least 72 hours prior the initiation of treatment
• Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), are ineligible unless in complete remission and off of all therapy for that disease for a minimum of 3 years

• Patients must not have:

  • Uncontrolled active infection
  • Disease that will obscure toxicity or dangerously alter drug metabolism
  • Serious intercurrent medical illness
  • Prior recurrence with a farnesyl transferase inhibitor
  • Oral contraceptives and other hormonal methods (Depo-Provera) of birth control

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (temozolomide and lonafarnib); Patients receive temozolomide PO QD on days 1-7 and 15-21 and lonafarnib PO BID on days 8-14 and 22-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Drug: Temozolomide; Given PO; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Drug: Lonafarnib; Given PO; Other Names: SCH66336; Sarasar; 4-[2-[4-[(11R)-3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide; SCH 66336; SCH-66336

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose (MTD) of lonafarnib when given with temozolomide, defined as the dose at which fewer than one-third of patients experience dose-limiting toxicity (DLT)	28 days
Tolerability of regimen in patients with disease progression or recurrence during or after recent completion of treatment with temozolomide	Up to 11 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	In the historical dataset, the proportion of patients remaining alive and free from progression at 6 months was 15% (95% confidence interval for ranged from 10% to 19%). We will set p0 to 15% and we will set p1 to 30% (looking for a doubling of the 6-month PFS rate). Based on these design parameters, a two-stage design would require that at least 4 of the initial 19 patients are without progression at 6 months.	6 months
Objective response		Up to 11 years
Overall survival		Up to 11 years
Treatment-related toxicities	Treatment-related toxicity data will be collected and described.	Up to 11 years

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vinay Puduvalli, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• MD Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): December 21, 2004
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): December 1, 2022

Study Registration Dates

• First Submitted: January 31, 2005
• First Submitted That Met QC Criteria: January 31, 2005
• First Posted (Estimate): February 1, 2005

Study Record Updates

• Last Update Posted (Actual): January 3, 2022
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Glioblastoma; Recurrence; Gliosarcoma; Supratentorial Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide; Lonafarnib
• Other Study ID Numbers: 2004-0424 (Other Identifier: M D Anderson Cancer Center); NCI-2012-01311 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); NCI-2010-00417

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No