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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)

Tracking Information
First Submitted Date  ICMJE June 8, 2006
First Posted Date  ICMJE June 12, 2006
Results First Submitted Date August 16, 2017
Results First Posted Date July 2, 2018
Last Update Posted Date July 2, 2018
Study Start Date  ICMJE April 2006
Actual Primary Completion Date February 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 31, 2018)
  • 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
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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.
  • 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.
  • 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
  • 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
  • 12 Month Survival Rate (Phase II) [ Time Frame: 12 months ]
    number of patients alive at 12 months
  • 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
  • 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 ]
  • 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.
  • 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).
Original Primary Outcome Measures  ICMJE Not Provided
Change History Complete list of historical versions of study NCT00335764 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Outcome Measures  ICMJE
 (submitted: May 31, 2018)
  • 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
  • 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
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Sorafenib Combined With Erlotinib, Tipifarnib, or Temsirolimus in Treating Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma
Official Title  ICMJE 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
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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Adult Giant Cell Glioblastoma
  • Adult Glioblastoma
  • Adult Gliosarcoma
  • Recurrent Adult Brain Tumor
Intervention  ICMJE
  • 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
  • Drug: tipifarnib
    given orally
    Other Names:
    • R115777
    • Zarnestra
  • Drug: temsirolimus
    IV administration
    Other Names:
    • CCI-779
    • cell cycle inhibitor 779
    • Torisel
Study Arms
  • Experimental: Group 1
    Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
    Interventions:
    • Drug: sorafenib tosylate
    • Drug: erlotinib hydrochloride
  • 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.
    Interventions:
    • Drug: sorafenib tosylate
    • Drug: temsirolimus
  • Experimental: Group 3
    Patients receive sorafenib tosylate as in group 1. Patients also receive oral tipifarnib twice daily on days 1-21.
    Interventions:
    • Drug: sorafenib tosylate
    • Drug: tipifarnib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 31, 2018)
92
Original Enrollment  ICMJE Not Provided
Actual Study Completion Date September 2012
Actual Primary Completion Date February 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00335764
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mark Gilbert, MD National Cancer Institute (NCI)
PRS Account National Cancer Institute (NCI)
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP