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

Study Overview
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Brief Summary
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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.

Detailed Description
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PRIMARY OBJECTIVES: Phase 1 1. Determine the maximum tolerated dose (MTD) of tipifarnib, erlotinib hydrochloride, or temsirolimus in combination with a fixed dose of sorafenib in patients with recurrent glioblastoma multiforme or gliosarcoma who are not taking enzyme-inducing antiepileptic drugs. SECONDARY OBJECTIVES: Phase 1 and 2 Characterize the safety profile of the doublet combinations of tipifarnib-sorafenib, erlotinib hydrochloride-sorafenib, and temsirolimus-sorafenib in patients with recurrent glioblastoma multiforme or gliosarcoma. Characterize the pharmacokinetics of these doublet combinations, evaluating single-agent pharmacokinetics of each agent and the combination pharmacokinetics to determine drug-drug interactions. Phase 2 Determine the efficacy of each of the doublet combinations, in terms of 6-month progression-free survival, in patients with recurrent glioblastoma multiforme or gliosarcoma. Determine the efficacy of each of the doublet combinations, in terms of 12-month survival and objective tumor response, in patients with recurrent glioblastoma multiforme or gliosarcoma. TERTIARY OBJECTIVES: Phase 2 Perform exploratory correlative laboratory studies by examining tissue markers of signal transduction pathways by immunohistochemical analysis using tissue blocks obtained prior to initiation of protocol therapy, either from the time of diagnosis or subsequent tumor resection. Determine the relationship between tumor and blood biomarkers and clinical outcome of patients treated with the combination of targeted agents. OUTLINE: This is a multicenter, phase I, dose-escalation study of tipifarnib, erlotinib hydrochloride, and temsirolimus followed by a phase II open-label study. PHASE I: Patients are sequentially assigned to 1 of 3 treatment groups. GROUP 1: Patients receive oral sorafenib twice daily and oral erlotinib hydrochloride once daily on days 1-28. GROUP 2: Patients receive sorafenib as in group 1. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. GROUP 3: Patients receive sorafenib as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21. In all groups, treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. In each treatment group, cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride (group 1), temsirolimus (group 2), or tipifarnib (group 3) sequentially until the maximum tolerated dose (MTD) is determined for each group. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course of therapy. PHASE II: Patients receive sorafenib as in phase I. Patients also receive erlotinib hydrochloride, temsirolimus, or tipifarnib as in phase I at the MTD determined in phase I. Tissue that was collected during a prior surgery is examined for biomarkers by immunohistochemistry (in patients enrolled in the phase II portion of the study). Biomarkers examined include epidermal growth factor receptor, Receptor tyrosine-protein kinase (HER-2), Protein kinase B (AKT), S6 ribosomal protein, and Receptor-linked tyrosine kinases (Erk). After completion of study treatment, patients are followed every 3 months.

Official Title
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Phase I/II Studies of BAY 43-9006 (Sorafenib) in Combination With OSI-774 (Erlotinib), R115777 (Tipifarnib) or CCI-779 (Temsirolimus) in Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma

Conditions
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Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor

Intervention / Treatment
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* Drug: sorafenib tosylate
* Drug: erlotinib hydrochloride
* Drug: tipifarnib
* Drug: temsirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 15 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 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10 g/dL (transfusion allowed) Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) ≤ 2.5 times upper limit of normal (ULN) Total bilirubin normal Creatinine < 1.5 mg/dL Prothrombin time (PT)/ international normalized ratio (INR) ≤ 1.5 (INR < 3.0 for patients on anticoagulation therapy) INR < 1.1 times upper limit of normal (ULN) (for patients on prophylactic anticoagulation therapy [low-dose warfarin]) Fasting cholesterol < 350 mg/dL (for patients receiving temsirolimus and sorafenib) Fasting triglycerides < 400 mg/dL (for patients receiving temsirolimus and sorafenib) Well-controlled hypertension (e.g., systolic blood pressure ≤ 140 mm Hg or diastolic pressure ≤ 90 mm Hg) allowed Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for at least 2 weeks (women) or 3 months (men) after completion of study treatment No peripheral neuropathy > grade 1 (for patients receiving sorafenib and tipifarnib) No evidence of bleeding diathesis or coagulopathy No history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission and off all therapy for that disease for ≥ 3 years No significant traumatic injury within the past 21 days No active infection or serious medical illness that would preclude study treatment No condition that would impair ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation or active peptic ulcer disease) No HIV disease No allergies to imidazoles (e.g., clotrimazole, ketoconazole, miconazole or econazole) or a history of allergic reactions attributed to any compound of similar chemical or biological composition to tipifarnib (for patients receiving sorafenib and tipifarnib) No other disease that would obscure toxicity or dangerously alter drug metabolism Recovered from prior therapy At least 7 days since prior noncytotoxic agents (e.g., interferon, tamoxifen, thalidomide, or isotretinoin) (radiosensitizer does not count) At least 14 days since prior vincristine At least 21 days since prior procarbazine or major surgery At least 28 days since prior investigational agent or cytotoxic therapy At least 42 days since prior nitrosoureas or radiotherapy No prior sorafenib, AEE788, or vatalanib No prior surgical procedures affecting absorption No prior tipifarnib, lonafarnib, or other agents targeting farnesyl transferase (for patients receiving sorafenib and tipifarnib) No prior temsirolimus or mechanistic target of rapamycin (mTOR-targeting agent) (phase II), rapamycin or everolimus, or Akt-pathway inhibitors (for patients receiving sorafenib and temsirolimus) No prior erlotinib hydrochloride, multitargeted human epidermal receptor (AEE788), or other epidermal growth factor receptor targeting agents (phase II) (for patients receiving sorafenib and erlotinib hydrochloride) No concurrent enzyme-inducing antiepileptic drugs (e.g., carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, or primidone) Dexamethasone allowed No concurrent hepatic cytochrome p450 enzyme-inducing anticonvulsants No other concurrent investigational agents or anticancer therapies, including chemotherapy, radiotherapy, hormonal therapy, or immunotherapy No concurrent prophylactic filgrastim (G-CSF) or other hematopoietic colony-stimulating factors Full-dose anticoagulants allowed provided both of the following criteria are met: In-range INR (between 2-3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28. | Drug: sorafenib tosylate<br>* given orally<br>* Other names: SFN;Drug: erlotinib hydrochloride<br>* given orally<br>* Other names: OSI-774;|
| Experimental: Group 2<br>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<br>* given orally<br>* Other names: SFN;Drug: temsirolimus<br>* IV administration<br>* Other names: Torisel;|
| Experimental: Group 3<br>Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21. | Drug: sorafenib tosylate<br>* given orally<br>* Other names: SFN;Drug: tipifarnib<br>* given orally<br>* Other names: Zarnestra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |