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

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

1. 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.

2. 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

1. 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.

2. 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

1. 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.

2. 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.

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)