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

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ClinicalTrials.gov Identifier: NCT00335764
Recruitment Status : Completed
First Posted : June 12, 2006
Results First Posted : July 2, 2018
Last Update Posted : July 2, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

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.

Condition or disease Intervention/treatment Phase
Adult Giant Cell Glioblastoma Adult Glioblastoma Adult Gliosarcoma Recurrent Adult Brain Tumor Drug: sorafenib tosylate Drug: erlotinib hydrochloride Drug: tipifarnib Drug: temsirolimus Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 92 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : April 2006
Actual Primary Completion Date : February 2010
Actual Study Completion Date : September 2012


Arm Intervention/treatment
Experimental: Group 1
Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
Drug: sorafenib tosylate
given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN

Drug: erlotinib hydrochloride
given orally
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774

Experimental: Group 2
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
given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN

Drug: temsirolimus
IV administration
Other Names:
  • CCI-779
  • cell cycle inhibitor 779
  • Torisel

Experimental: Group 3
Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21.
Drug: sorafenib tosylate
given orally
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN

Drug: tipifarnib
given orally
Other Names:
  • R115777
  • Zarnestra




Primary Outcome Measures :
  1. 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) [ Time Frame: 28 days ]
    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

  2. Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) [ Time Frame: cycle 1 ((Day1, Day15, Day28) ]
    Group 2: 13 patients received temsirolimus 25mg IV and 7 patients treated with 200mg Sorafenib and 6 patients treated with 400mg Sorafenib

  3. Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) [ Time Frame: 28days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) ]

    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


  4. Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) [ Time Frame: 28Days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) AUC 0-12 ]

    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


  5. Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I) [ Time Frame: 15 days ]
    Group 2: 12 patients were analyzed for Day 1 (1 patient not evaluable), 5 patients were analyzed for Day 15 (8 patients not evaluable)

  6. Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) [ Time Frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration) ]

    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


  7. Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) [ Time Frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration) ]
    Group 3: Only PKs for Dose level 1 and -1 were collected.

  8. Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID [ Time Frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration) ]

    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.


  9. Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) [ Time Frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration) ]

    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


  10. Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) [ Time Frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration) ]
    Group 3: PKs for Dose level 1 Tipifarnib 100mg BID

  11. 12 Month Survival Rate (Phase II) [ Time Frame: 12 months ]
    number of patients alive at 12 months

  12. Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) [ Time Frame: 28 days ]
    CTCAE 3.0

  13. Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) [ Time Frame: 1 year ]
  14. Progression-free Survival at 6 Months (Phase II) [ Time Frame: 6 months ]
    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.

  15. Objective Response Rate in Patients With Measurable Disease (Phase II) [ Time Frame: Up to 5 years ]

    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).



Other Outcome Measures:
  1. Exploratory Correlative Laboratory Studies (Phase II) [ Time Frame: 28 days ]
    Examination of tissue markers of signal transduction pathways by immunohistochemical analysis this was an exploratory measure and it was not explore due to the negative results of the rest of the study

  2. Molecular Targeted Combinations Correlative Study Initiative [ Time Frame: 28 days ]
    Determine the relationship between tumor and blood biomarkers and clinical outcome of patients this was more an exploratory correlative and was not completed due to the negative outcome of other parts of the study



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00335764


Locations
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United States, California
University of California at Los Angeles
Los Angeles, California, United States, 90095
University of California San Francisco
San Francisco, California, United States, 94115
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15232
United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Mark Gilbert, MD National Cancer Institute (NCI)

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00335764     History of Changes
Other Study ID Numbers: NCI-2009-00676
NCI-2009-00676 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CDR0000476286
NABTC-05-02 ( Other Identifier: Adult Brain Tumor Consortium )
NABTC-05-02 ( Other Identifier: CTEP )
U01CA137443 ( U.S. NIH Grant/Contract )
First Posted: June 12, 2006    Key Record Dates
Results First Posted: July 2, 2018
Last Update Posted: July 2, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Sorafenib
Erlotinib Hydrochloride
Everolimus
Sirolimus
Tipifarnib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents