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

Primary Purpose

Malignant Supratentorial Neoplasm, Recurrent Glioblastoma, Recurrent Gliosarcoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Lonafarnib
Temozolomide
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Supratentorial Neoplasm

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (temozolomide and lonafarnib)

Arm Description

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.

Outcomes

Primary Outcome Measures

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)
Tolerability of regimen in patients with disease progression or recurrence during or after recent completion of treatment with temozolomide

Secondary Outcome Measures

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.
Objective response
Overall survival
Treatment-related toxicities
Treatment-related toxicity data will be collected and described.

Full Information

First Posted
January 31, 2005
Last Updated
December 13, 2021
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00102648
Brief Title
Lonafarnib and Temozolomide in Treating Patients With Glioblastoma Multiforme That Is Recurrent or Did Not Respond to Previous Treatment With Temozolomide
Official Title
Phase I/Ib Study of Sarasar and Temodar in Patients With Recurrent or Temodar-Refractory Glioblastoma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 21, 2004 (Actual)
Primary Completion Date
December 1, 2022 (Anticipated)
Study Completion Date
December 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Supratentorial Neoplasm, Recurrent Glioblastoma, Recurrent Gliosarcoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
35 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (temozolomide and lonafarnib)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lonafarnib
Other Intervention Name(s)
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, Sarasar, SCH 66336, SCH-66336, SCH66336
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
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, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, Temomedac
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
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)
Time Frame
28 days
Title
Tolerability of regimen in patients with disease progression or recurrence during or after recent completion of treatment with temozolomide
Time Frame
Up to 11 years
Secondary Outcome Measure Information:
Title
Progression free survival (PFS)
Description
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.
Time Frame
6 months
Title
Objective response
Time Frame
Up to 11 years
Title
Overall survival
Time Frame
Up to 11 years
Title
Treatment-related toxicities
Description
Treatment-related toxicity data will be collected and described.
Time Frame
Up to 11 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vinay Puduvalli
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center

Learn more about this trial

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

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