Clinical trial NCT00335764 (phase 1/phase 2, status: completed)
Conditions: adult giant cell glioblastoma, adult glioblastoma, adult gliosarcoma, recurrent adult brain tumor
ICD codes: G47.13, J01.41, K11.22, K12.0, N96, F33.8, G03.2
Drugs: sorafenib tosylate, erlotinib hydrochloride, tipifarnib, temsirolimus
SMILES: CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1, COCCOC1=CC2=C(C=C1OCCOC)C(NC1=CC(=CC=C1)C#C)=NC=N2, CN1C=NC=C1[C@@](N)(C1=CC=C(Cl)C=C1)C1=CC2=C(C=C1)N(C)C(=O)C=C2C1=CC(Cl)=CC=C1, CN1N=NC2=C(N=CN2C1=O)C(N)=O
Eligibility criteria:

        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)