Sorafenib Combined With Erlotinib, Tipifarnib, or Temsirolimus in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma

NCT00335764 | Completed Phase 1 Results DMC

• 4 other identifiers: NCI-2009-00676CDR0000476286NABTC-05-02U01CA137443
• Study Type: interventional
• Target: 92
• Locations: 1 country
• Sites: 7

Brief Summary

This phase I/II trial is studying the side effects and best dose of erlotinib, tipifarnib, and temsirolimus when given together with sorafenib and to see how well they work in treating patients with recurrent glioblastoma multiforme or gliosarcoma. Sorafenib, erlotinib, tipifarnib, and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib and tipifarnib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with erlotinib, tipifarnib, or temsirolimus may kill more tumor cells.

Conditions

Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Recurrent Adult Brain Tumor

Outcome Measures

Primary Outcomes (15)

• Maximum Tolerated Dose (MTD) of the Each Combination Agent Combined With a Fixed Dose of BAY 43-9006 Determined by Dose-limiting Toxicities (DLT) (Phase I)

  DLT defined as: any grade 4 hematologic toxicity; grade 3 thrombocytopenia \> 7 days, any grade 3/4 non-hematologic toxicity (despite maximal medical therapy), any intolerable grade 2 non-hematological, ro grade 3 hematological toxicity requiring deduction during first 28 days of treatment, any toxicity resulting in delay of \>1week during first 28 days of treatment

  28 days

• Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I)

  Group 2: 13 patients received temsirolimus 25mg IV and 7 patients treated with 200mg Sorafenib and 6 patients treated with 400mg Sorafenib

  cycle 1 ((Day1, Day15, Day28)

• Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I)

  8 samples collected over 24 hours on Day 1, day 15 and day 28 13 total patients treated 100mg Erlotinib and either 200mg or 400mg of Sorafenib

  28days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration)

• Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I)

  8 samples collected over 24 hours on Day 1, day 15 and day 28 16 patients Note that although 16 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference AUC - Area Under Curve

  28Days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) AUC 0-12

• Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I)

  Group 2: 12 patients were analyzed for Day 1 (1 patient not evaluable), 5 patients were analyzed for Day 15 (8 patients not evaluable)

  15 days

• Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I)

  Day 1 = 12 patients (1 sample not evaluable) Day 15 = 5 patients (8 samples not evaluable) AUC - Area Under Curve 8 samples collected over 24 hours - 28 day PKs

  Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)

• Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1)

  Group 3: Only PKs for Dose level 1 and -1 were collected.

  Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)

• Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID

  Group 3: patients were studied for their day 1 Cmax, and day 15 Cmax Tipifanib and Day 15 and Day 28 sorafenib Group 3: Only PKs for Dose level 1 and -1 were collected.

  Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)

• Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1)

  Group 3: PKs for Dose level -1 100mg QD Note that although 9 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference

  Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)

• Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1)

  Group 3: PKs for Dose level 1 Tipifarnib 100mg BID

  Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)

• 12 Month Survival Rate (Phase II)

  number of patients alive at 12 months

  12 months

• Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I)

  CTCAE 3.0

  28 days

• Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2)

  1 year

• Progression-free Survival at 6 Months (Phase II)

  Patients with a scan at 6 months without progressive disease Progressive disease defined as Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.

  6 months

• Objective Response Rate in Patients With Measurable Disease (Phase II)

  Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

  Up to 5 years

Other Outcomes (2)

• Exploratory Correlative Laboratory Studies (Phase II)

  28 days

• Molecular Targeted Combinations Correlative Study Initiative

  28 days

Study Arms (3)

Group 1

EXPERIMENTAL

Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.

Drug: sorafenib tosylate; Drug: erlotinib hydrochloride

Group 2

EXPERIMENTAL

Patients receive sorafenib tosylate as in group 1. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.

Drug: sorafenib tosylate; Drug: temsirolimus

Group 3

EXPERIMENTAL

Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21.

Drug: sorafenib tosylate; Drug: tipifarnib

Interventions

sorafenib tosylate DRUG

given orally

Also known as: BAY 43-9006, BAY 43-9006 Tosylate Salt, BAY 54-9085, Nexavar, SFN

Group 1; Group 2; Group 3

erlotinib hydrochloride DRUG

given orally

Also known as: CP-358,774, erlotinib, OSI-774

Group 1

tipifarnib DRUG

given orally

Also known as: R115777, Zarnestra

Group 3

temsirolimus DRUG

IV administration

Also known as: CCI-779, cell cycle inhibitor 779, Torisel

Group 2

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed intracranial glioblastoma multiforme or gliosarcoma
• Evidence of tumor progression by MRI or CT scan within the past 14 days AND on a steroid dose that has been stable for ≥ 5 days
• Patients who underwent prior therapy that included interstitial brachytherapy or stereotactic radiosurgery must have confirmation of true progressive disease rather than radiation necrosis by either positron emission tomography or thallium scanning, magnetic resonance (MR) spectroscopy, or surgical documentation of disease
• Recent resection of recurrent or progressive tumor allowed
• Residual disease is not required
• Treatment for any number of prior relapses, defined as disease progression after initial therapy (i.e., radiotherapy with or without chemotherapy if used as initial treatment), allowed (phase I)
• No more than 3 prior therapies (initial therapy and therapy for 2 relapses) (phase II)
• Each of the following is considered 1 relapse:
• Disease progression after initial therapy (i.e., radiotherapy with or without chemotherapy if used as initial therapy)
• Underwent a surgical resection for relapsed disease and received no anticancer therapy for up to 12 weeks after surgical resection AND then underwent a subsequent surgical resection
• Received prior therapy for a low-grade glioma, followed by a surgical diagnosis of glioblastoma
• Failed prior radiotherapy
• unstained paraffin slides or 1 tissue block must be available from original surgery, definitive surgery, or surgery closest to the initiation of this study (phase II)
• Karnofsky performance status 60-100%
• White Blood Cell (WBC) ≥ 3,000/mm\^3

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (7)

University of California at Los Angeles

Los Angeles, California, 90095, United States

Location

University of California San Francisco

San Francisco, California, 94115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15232, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Wisconsin Hospital and Clinics

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Glioblastoma; Gliosarcoma; Brain Neoplasms

Interventions

Sorafenib; Erlotinib Hydrochloride; tipifarnib; temsirolimus; Sirolimus

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; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Macrolides; Lactones

Limitations and Caveats

Due to combo toxicities for Sorafenib and Tipifarnib exceeding monotherapy for each, MTD was not determined nor was Phase 2 explored.

Results Point of Contact

• Title: Mark Gilbert, MD
• Organization: Adult Brain Tumor Consortium (ABTC)

jfisher@jhmi.edu

410-955-3657

Study Officials

• Mark Gilbert, MD

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: June 8, 2006
• First Posted: June 12, 2006
• Study Start: April 1, 2006
• Primary Completion: February 1, 2010
• Study Completion: September 1, 2012
• Last Updated: July 2, 2018
• Results First Posted: July 2, 2018

Record last verified: 2018-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)