PH I Addition of Farnesyl Transferase Inhibitor to Temozolomide for Pts w Gr 3 & 4 Malignant Gliomas - Full Text View

Sponsor:	Duke University
Collaborator:	Schering-Plough
Information provided by:	Duke University
ClinicalTrials.gov Identifier:	NCT00612651

Purpose

Objectives:

To determine maxi tolerated dose of farnesyl transferase inhibitor, SCH 66336, when administered w TEMODAR®.

To characterize any toxicity associated w combo of farnesyl transferase inhibitor, SCH 66336, & TEMODAR®.

To observe pts for clinical antitumor response when treated w combo of farnesyl transferase inhibitor, SCH 66336, & TEMODAR®.

To assess pharmacokinetics of SCH 66336 for pt on & not on enzyme inducing antiepileptic drugs.

Condition	Intervention	Phase
Gliosarcoma Glioblastoma Anaplastic Astrocytoma	Drug: Temodar and SCH 66336	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Safety/Efficacy Study
Official Title:	A Phase I Trial of the Addition of the Farnesyl Transferase Inhibitor, SCH 66336, to Temodar for Patients With Grade 3 and 4 Malignant Gliomas

Resource links provided by NLM:

Drug Information available for: Temozolomide Lonafarnib

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:

Dose-limiting toxicity [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Progression-free survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	48
Study Start Date:	October 2005
Estimated Study Completion Date:	January 2011
Estimated Primary Completion Date:	January 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Pts receiving EIAEDs	Drug: Temodar and SCH 66336 2 separate strata accrued independently: Stratum 1-pts receiving CYP3A4-inducing anticonvulsants. Stratum 2-pts on non CYP3A4-inducing anticonvulsants or pts not on any anti-convulsants. Each strata treated & escalated independent of each other. Temozolomide administered orally at dose of 150 mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200 mg/m2 daily for 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice daily, approximately every 12hrs. Except as specifically noted, pts advised to take capsules wh morning & evening meals, with approximately 240ml of non-carbonated water. Initial doses will be 125mg BID for stratum 1 & 75mg BID for stratum2. Treatment cycles repeated every 4 wks following dose of Temozolomide from previous cycle.
2: Experimental Pts not receiving EIAEDs	Drug: Temodar and SCH 66336 2 separate strata accrued independently: Stratum 1-pts receiving CYP3A4-inducing anticonvulsants. Stratum 2-pts on non CYP3A4-inducing anticonvulsants or pts not on any anti-convulsants. Each strata treated & escalated independent of each other. Temozolomide administered orally at dose of 150 mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200 mg/m2 daily for 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice daily, approximately every 12hrs. Except as specifically noted, pts advised to take capsules wh morning & evening meals, with approximately 240ml of non-carbonated water. Initial doses will be 125mg BID for stratum 1 & 75mg BID for stratum2. Treatment cycles repeated every 4 wks following dose of Temozolomide from previous cycle.

Arms

Assigned Interventions

1: Experimental

Pts receiving EIAEDs

Drug: Temodar and SCH 66336

2 separate strata accrued independently: Stratum 1-pts receiving CYP3A4-inducing anticonvulsants. Stratum 2-pts on non CYP3A4-inducing anticonvulsants or pts not on any anti-convulsants. Each strata treated & escalated independent of each other. Temozolomide administered orally at dose of 150 mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200 mg/m2 daily for 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice daily, approximately every 12hrs. Except as specifically noted, pts advised to take capsules wh morning & evening meals, with approximately 240ml of non-carbonated water. Initial doses will be 125mg BID for stratum 1 & 75mg BID for stratum2. Treatment cycles repeated every 4 wks following dose of Temozolomide from previous cycle.

2: Experimental

Pts not receiving EIAEDs

Drug: Temodar and SCH 66336

2 separate strata accrued independently: Stratum 1-pts receiving CYP3A4-inducing anticonvulsants. Stratum 2-pts on non CYP3A4-inducing anticonvulsants or pts not on any anti-convulsants. Each strata treated & escalated independent of each other. Temozolomide administered orally at dose of 150 mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200 mg/m2 daily for 5 days, at bedtime during subsequent cycles if tolerated. Treatment cycles repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice daily, approximately every 12hrs. Except as specifically noted, pts advised to take capsules wh morning & evening meals, with approximately 240ml of non-carbonated water. Initial doses will be 125mg BID for stratum 1 & 75mg BID for stratum2. Treatment cycles repeated every 4 wks following dose of Temozolomide from previous cycle.

Detailed Description:

2 separate strata accrued independently of each other: Stratum1-pts receiving Dilantin, Tegretol / phenobarbital. Stratum2-pts on anti-convulsants other than Dilantin, Tegretol / phenobarbital / pts not on any anti-convulsants. Each stratum treated & escalated independent of each other.Temozolomide administered orally at dose of 150mg/m2 daily for 5 days, at bedtime, for 1st cycle & escalated to 200mg/m2 daily for 5days, at bedtime during subsequent cycles if tolerated. Treatment cycles may be repeated every 4wks following doses of Temozolomide from previous cycle. SCH 66336 administered orally twice day, approximately every 12hrs. Initial doses will be 125mg BID for stratum 1 & 75mg for stratum 2. Treatment cycles may be repeated every 4 wks following dose of Temozolomide from previous cycle.

Subjects are pts w MG histologically confirmed at diagnosis, who were treated previously w conventional external beam XRT & w/without chemo, & have stable disease, recurrence/relapse at time of enrollment. Approximately 48 subjects will be enrolled.

Temozolomide has been well tolerated by both adults & children w most common toxicity being mild myelosuppression. Other, less likely, potential toxicities include nausea & vomiting, constipation, headache, alopecia, rash, burning sensation of skin, esophagitis, pain, diarrhea, lethargy, & hepatotoxicity. Hypersensitivity reactions have not yet been noted w Temozolomide. As is case w many anti-cancer drugs,Temozolomide may be carcinogenic. Rats given Temozolomide have developed breast cancer. Significance of this finding for humans is not presently known.

Significant adverse events observed included vomiting, diarrhea, anorexia, headaches, reversible renal toxicities, & hematological toxicities. SCH 66336, although not genotoxic, inhibits rapidly proliferating cells & at high doses inhibits spermatogenesis in male rats. It is not clear that inhibition of spermatogenesis is reversible,& pts advised of possibility of irreversible sterility.

Eligibility

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

Criteria

Inclusion Criteria:

Pts with MG histologically confirmed at diagnosis, who were treated previously with conventional external beam radiation & with or without chemotherapy, & have stable disease, recurrence or relapse at the time of enrollment.
Age > 18 years.
Pts who have had previous surgical resection are eligible:

Interval of at least 3 weeks between prior surgical resection, 2 weeks between prior radiotherapy, or 4 weeks between prior chemotherapy, unless there is unequivocal evidence of tumor progression after surgery, radiotherapy, or chemotherapy.

Karnofsky performance score >60%.
Adequate hematologic, renal & liver function as demonstrated by lab values performed within 14 days, inclusive, prior to administration of chemotherapy:
ANC >1500/mm3
Platelet count >100,000/mm3
Hemoglobin >10 gm/dL
BUN and serum creatinine <1.5 times upper limit of lab normal
Total serum bilirubin <1.5 times upper limit of lab normal
SGOT <2.5 times upper limit of lab normal
Pts must have recovered from any effects of major surgery.
Pts must have life expectancy of greater than 12 weeks.
Pts or legal guardian must give written, informed consent.

Exclusion Criteria:

Pts requiring immediate radiation therapy.
Pts who have not recovered from surgery.
Pts who are not neurologically stable for 2 weeks prior to study entry.
Pts who are poor medical risks because of non-malignant systemic disease as well as those with acute infection treated with intravenous antibiotics.
Frequent vomiting or medical condition that could interfere with oral medication intake.
Pt is < 5 years free of another primary malignancy except: if the other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
Known HIV positivity or AIDS-related illness.
Pregnant or nursing women.
Women of childbearing potential who are not using an effective method of contraception. Women of childbearing potential must have a negative serum pregnancy test 72 hours prior to administration of study drug and be practicing medically approved contraceptive precautions.
Men who are not advised to use an effective method of contraception.
Pts taking immuno-suppressive agents other than prescribed corticosteroids.
Pts previously treated with farnesyl transferase inhibitors.
Pts with significant QTc prolongation (>500 msec)as evaluated by an EKG.
Pt having presented prior disease progression on TEMODAR.
Pt having presented any grade 4 hematologic toxicity or grade 3 or 4 non-hematologic toxicity on TEMODAR in the past.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00612651

Locations

United States, North Carolina
Duke University Health System
Durham, North Carolina, United States, 27710

Sponsors and Collaborators

Duke University

Schering-Plough

Investigators

Principal Investigator:

Annick Desjardins, MD

Duke University Health System

More Information

Additional Information:

The Preston Robert Tisch Brain Tumor Center at DUKE This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Duke University Health System ( Annick Desjardins )
Study ID Numbers:	00005027, 7009
Study First Received:	January 29, 2008
Last Updated:	December 26, 2008
ClinicalTrials.gov Identifier:	NCT00612651 History of Changes
Health Authority:	United States: Food and Drug Administration

Keywords provided by Duke University:

GBM
Malignant glioma
Brain tumor
Temodar
Temozolomide
SCH 66336

Farnesyl transferase inhibitor
Glioblastoma multiforme
Gliosarcoma
Anaplastic astrocytoma
Anaplastic oligodendroglioma
Anaplastic oligoastrocytoma

Additional relevant MeSH terms:

Glioblastoma
Neoplasms by Histologic Type
Molecular Mechanisms of Pharmacological Action
Astrocytoma
Antineoplastic Agents
Neoplasms, Nerve Tissue
Temozolomide
Pharmacologic Actions
Neuroectodermal Tumors

Neoplasms
Therapeutic Uses
Neoplasms, Germ Cell and Embryonal
Glioma
Antineoplastic Agents, Alkylating
Gliosarcoma
Neoplasms, Neuroepithelial
Alkylating Agents
Neoplasms, Glandular and Epithelial

ClinicalTrials.gov processed this record on November 27, 2009