Adult Giant Cell Glioblastoma, Adult Glioblastoma, Adult Gliosarcoma, Recurrent Adult Brain Tumor
Conditions
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.
Interventions
DRUGsorafenib tosylate
given orally
DRUGerlotinib hydrochloride
given orally
DRUGtipifarnib
given orally
DRUGtemsirolimus
IV administration
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate in Patients With Measurable Disease (Phase II) | 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). |
| 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) | 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. |
| 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) | 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) | 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) | 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) | 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) | 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) | 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) | 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 | 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) | 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) | 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) | 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) | 28 days | CTCAE 3.0 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Molecular Targeted Combinations Correlative Study Initiative | 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 |
| Exploratory Correlative Laboratory Studies (Phase II) | 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 |
Countries
United States
Participant flow
Recruitment details
patients enrolled from 2006 - 2009 Patients accrued from comprehensive outpatient cancer centers
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Phase I Sorafenib and Erlotinib Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
sorafenib tosylate: given orally
erlotinib hydrochloride: given orally | 16 |
| Group 2 Phase I Sorafenib and Temsirolimus Patients receive sorafenib tosylate as in group 2. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.
sorafenib tosylate: given orally
temsirolimus: IV administration | 13 |
| Group 3 Phase I Sorafenib and Tipifarnib Patients receive sorafenib tosylate as in group 3. Patients also receive oral tipifarnib twice daily on days 1-21.
sorafenib tosylate: given orally
tipifarnib: given orally | 24 |
| Group 1 Phase II Sorafenib and Erlotinib Patients receive oral sorafenib tosylate twice daily and oral erlotinib hydrochloride once daily on days 1-28.
sorafenib tosylate: given orally
erlotinib hydrochloride: given orally | 19 |
| Group 2 Phase II Sorafenib and Temsirolimus Patients receive sorafenib tosylate 400 mg BID as in group 2. Patients also receive temsirolimus IV 25 mg over 30 minutes on days 1, 8, 15, and 22.
sorafenib tosylate: given orally
temsirolimus: IV administration | 18 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | wrong histology | 1 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Group 1 Phase I Sorafenib and Erlotinib | Group 2 Phase I Sorafenib and Temsirolimus | Group 3 Phase I Sorafenib and Tipifarnib | Group 1 Phase II Sorafenib and Erlotinib | Group 2 Phase II Sorafenib and Temsirolimus | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 53 years | 50 years | 57 years | 52 years | 50 years | 53 years |
| Karnofsky Performance Status Scale | 90 units on a scale | 80 units on a scale | 85 units on a scale | 90 units on a scale | 90 units on a scale | 90 units on a scale |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 8 Participants | 10 Participants | 9 Participants | 38 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 16 Participants | 9 Participants | 9 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 16 | 13 / 13 | 24 / 24 | 19 / 19 | 18 / 18 |
| other Total, other adverse events | 13 / 16 | 8 / 13 | 15 / 24 | 11 / 19 | 12 / 18 |
| serious Total, serious adverse events | 0 / 16 | 0 / 13 | 4 / 24 | 1 / 19 | 2 / 18 |
Outcome results
Primary
12 Month Survival Rate (Phase II)
number of patients alive at 12 months
Time frame: 12 months
Population: Group 3 did not reach an MTD Hence, did not complete the Phase 2 portion of study, combination treatment too toxic.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | 12 Month Survival Rate (Phase II) | Patients Alive at 12 Months | 8 Participants |
| Group 1 Phase I Sorafenib and Erlotinib QD | 12 Month Survival Rate (Phase II) | Patients Dead at 12 Months | 11 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | 12 Month Survival Rate (Phase II) | Patients Alive at 12 Months | 10 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | 12 Month Survival Rate (Phase II) | Patients Dead at 12 Months | 8 Participants |
Primary
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
Time frame: 28 days
Population: 3+3 design due to excessive toxicities of Group 3 no DLT was defined for Group 3
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | 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) | 100 mg |
| Group 2 Phase I Sorafenib and Temsirolimus QW | 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) | 25 mg |
| Group 3 Phase I Sorafenib and Tipifarnib BID | 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) | NA mg |
Primary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Cholesterol (high) Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hyponatremia Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Lymphopenia Grade 3 | 2 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypophosphatemia Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Diarrhea Grade 3 | 1 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Lipase (high) Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Thrombocytopenia Grade 4 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Pharyngeal mucositis Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Fatigue Grade 3 | 3 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Pruritis Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Thrombocytopenia Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Rash Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypokalemia Grade 3 | 0 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypertension Grade 3 | 1 events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Seizures Grade 3 | 0 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypertension Grade 3 | 0 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Seizures Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Lymphopenia Grade 3 | 2 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Thrombocytopenia Grade 3 | 5 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Thrombocytopenia Grade 4 | 2 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Cholesterol (high) Grade 3 | 2 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Diarrhea Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Fatigue Grade 3 | 2 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypokalemia Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hyponatremia Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Hypophosphatemia Grade 3 | 3 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Lipase (high) Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Pharyngeal mucositis Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Pruritis Grade 3 | 1 events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2) | Rash Grade 3 | 1 events |
Primary
Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I)
CTCAE 3.0
Time frame: 28 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 3 | 1 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fever Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertriglyceridemia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombocytopenia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombosis/thrombus/embolism Grade 4 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypophosphatemia Grade 3 | 3 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertension Grade 3 | 1 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Joint - Knee Pain Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fatigue Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Encephalopathy Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 4 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Vomiting Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | AST, SGOT Grade 3 | 1 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | ALT, SGPT Grade 3 | 2 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Pain - Head/Headache Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Cholesterol Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Neutropenia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Leukopenia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Diarrhea Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lymphopenia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Dysphasia Grade 3 | 0 Events |
| Group 1 Phase I Sorafenib and Erlotinib QD | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hemmorrhoids Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Dysphasia Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Leukopenia Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lymphopenia Grade 3 | 2 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Neutropenia Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombocytopenia Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | AST, SGOT Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Cholesterol Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Diarrhea Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hemmorrhoids Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertriglyceridemia Grade 3 | 1 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypophosphatemia Grade 3 | 2 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fatigue Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Vomiting Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 4 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Joint - Knee Pain Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombosis/thrombus/embolism Grade 4 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fever Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Pain - Head/Headache Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Encephalopathy Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | ALT, SGPT Grade 3 | 0 Events |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertension Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombosis/thrombus/embolism Grade 4 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hemmorrhoids Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lymphopenia Grade 3 | 3 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fever Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Diarrhea Grade 3 | 2 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Cholesterol Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Dysphasia Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | AST, SGOT Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertension Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Pain - Head/Headache Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Thrombocytopenia Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | ALT, SGPT Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Encephalopathy Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Vomiting Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Fatigue Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Neutropenia Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 4 | 3 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypophosphatemia Grade 3 | 4 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Leukopenia Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Joint - Knee Pain Grade 3 | 1 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Hypertriglyceridemia Grade 3 | 0 Events |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I) | Lipase Grade 3 | 0 Events |
Primary
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).
Time frame: Up to 5 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Objective Response Rate in Patients With Measurable Disease (Phase II) | Complete Response | 0 Participants |
| Group 1 Phase I Sorafenib and Erlotinib QD | Objective Response Rate in Patients With Measurable Disease (Phase II) | Progressive Disease | 10 Participants |
| Group 1 Phase I Sorafenib and Erlotinib QD | Objective Response Rate in Patients With Measurable Disease (Phase II) | Stable Response | 7 Participants |
| Group 1 Phase I Sorafenib and Erlotinib QD | Objective Response Rate in Patients With Measurable Disease (Phase II) | Unevaluable | 2 Participants |
| Group 1 Phase I Sorafenib and Erlotinib QD | Objective Response Rate in Patients With Measurable Disease (Phase II) | Partial Response | 0 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Objective Response Rate in Patients With Measurable Disease (Phase II) | Unevaluable | 0 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Objective Response Rate in Patients With Measurable Disease (Phase II) | Partial Response | 2 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Objective Response Rate in Patients With Measurable Disease (Phase II) | Complete Response | 0 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Objective Response Rate in Patients With Measurable Disease (Phase II) | Stable Response | 3 Participants |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Objective Response Rate in Patients With Measurable Disease (Phase II) | Progressive Disease | 13 Participants |
Primary
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
Time frame: 28Days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) AUC 0-12
Population: 8 samples collected over 24 hours on Day 1, day 15 and day 28 AUC 0-12 16 patients treated at 100mg erlotinib,and Sorafenib at either 200 or 400mg Note that although 16 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 15 | 6.9 ug xhr/mL | Standard Deviation 4.59 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day1 | 6.3 ug xhr/mL | Standard Deviation 2.61 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 28 | 7.7 ug xhr/mL | Standard Deviation 4.05 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 15 | 45.85 ug xhr/mL | Standard Deviation 21.5 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day1 | NA ug xhr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 28 | 40.29 ug xhr/mL | Standard Deviation 18.6 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day1 | NA ug xhr/mL | — |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 28 | 38.7 ug xhr/mL | Standard Deviation 9.61 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I) | AUC0-12 Day 15 | 62.4 ug xhr/mL | Standard Deviation 38 |
Primary
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
Time frame: 28days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration)
Population: 8 samples collected over 24 hours on Day 1, day 15 and day 28 (0,1,2,4,6,8,12hr, \& 24hr post administration). Note that although 16 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 15 | 662 ng/mL | Standard Deviation 373 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 1 | 443 ng/mL | Standard Deviation 155 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 28 | 653 ng/mL | Standard Deviation 469 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 15 | 5.51 ng/mL | Standard Deviation 2.68 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 1 | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 28 | 4.67 ng/mL | Standard Deviation 2.1 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 1 | NA ng/mL | — |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 28 | 4.10 ng/mL | Standard Deviation 0.56 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I) | cMax Day 15 | 8.4 ng/mL | Standard Deviation 5.18 |
Primary
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.
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Population: Group 3: patients were studied for their day 1 Cmax, day 15 Cmax. and Day 28 Cmax PKs for 100mg BID Tipifarnib Note that although 10 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference~Level 1 (n=10): Day 1 n=6 (4 samples not evaluable) and D15 n=5 (5 samples not evaluable)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 1 Cmax | 132.17 ng/mL | Standard Deviation 65.96 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 15 Cmax | 233.60 ng/mL | Standard Deviation 84.83 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 28 Cmax | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 1 Cmax | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 15 Cmax | 4.17 ng/mL | Standard Deviation 2.99 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID | Day 28 Cmax | 4.53 ng/mL | Standard Deviation 2.38 |
Primary
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.
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Population: Group 3: Only PKs for Dose level 1 and -1 were collected. Note that although 6 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 1 | 209.5 ng/mL | Standard Deviation 135.85 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 15 | 169.5 ng/mL | Standard Deviation 186 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 28 | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 1 | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 15 | 3.34 ng/mL | Standard Deviation 1.31 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1) | Cmax Day 28 | 3.43 ng/mL | Standard Deviation 1.46 |
Primary
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
Time frame: cycle 1 ((Day1, Day15, Day28)
Population: Group 2: total 13 patients were studied for their day 1 Cmax ,day 15 Cmax and day 28 Cmax Note that although 13 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 15 Cmax | 616 ng/mL | Standard Deviation 209 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 1 Cmax | 530 ng/mL | Standard Deviation 101 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 28 Cmax | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 15 Cmax | 4.04 ng/mL | Standard Deviation 1.68 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 1 Cmax | NA ng/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 28 Cmax | 3.26 ng/mL | Standard Deviation 1.34 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 1 Cmax | NA ng/mL | — |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 28 Cmax | 6.24 ng/mL | Standard Deviation 4.03 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I) | Day 15 Cmax | 7.49 ng/mL | Standard Deviation 3.46 |
Primary
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
Time frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Population: 13 patients temsirolimus 25mg and Sorafenib at either 200mg or 400mg. 1 patient withdrew early hence specimens not analyzed in other cases samples were either missing or not enough to analyze if numbers are not 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 15 | 1.35 mcg*hr/mL | Standard Deviation 0.28 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 1 | 1.53 mcg*hr/mL | Standard Deviation 0.27 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 28 | NA mcg*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 15 | 35.45 mcg*hr/mL | Standard Deviation 18.1 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 1 | NA mcg*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 28 | 29.0 mcg*hr/mL | Standard Deviation 12.32 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 1 | NA mcg*hr/mL | — |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 28 | 32.98 mcg*hr/mL | Standard Deviation 0.318 |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I) | AUC 0-12 Day 15 | 42.32 mcg*hr/mL | — |
Primary
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
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Population: Group 3: PKs for Dose level 1 Tipifarnib 100mg BID
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 1 | 631.67 ng*hr/mL | Standard Deviation 431.12 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 15 | 390.25 ng*hr/mL | Standard Deviation 758.07 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 28 | NA ng*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 1 | NA ng*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 15 | 12.17 ng*hr/mL | Standard Deviation 16.33 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1) | AUC 0-12 Day 28 | 36.45 ng*hr/mL | Standard Deviation 17.21 |
Primary
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
Time frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Population: Group 3: PKs for Dose level -1 Tipifarnib 100mg QD Sorafenib started day 2
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 1 | 814.5 ng*hr/mL | Standard Deviation 347.57 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 15 | 706 ng*hr/mL | Standard Deviation 644.88 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 28 | NA ng*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 1 | NA ng*hr/mL | — |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 15 | 30.59 ng*hr/mL | Standard Deviation 14.59 |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1) | AUC 0-12 Day 28 | 41.43 ng*hr/mL | Standard Deviation 28.82 |
Primary
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.
Time frame: 6 months
Population: Group 3 did not reach an MTD not complete the Phase 2 portion of study, combination treatment too toxic. End points not followed for group 3 Phase 2
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Progression-free Survival at 6 Months (Phase II) | 15.8 weeks |
| Group 2 Phase I Sorafenib and Temsirolimus QW | Progression-free Survival at 6 Months (Phase II) | 8 weeks |
| Group 3 Phase I Sorafenib and Tipifarnib BID | Progression-free Survival at 6 Months (Phase II) | 4.2 weeks |
Primary
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)
Time frame: 15 days
Population: Group 2: 12 patients were analyzed for Day 1, 5 patients were analyzed for Day 15. In both cases samples were either missing or not enough to analyze.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 Phase I Sorafenib and Erlotinib QD | Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I) | Trough Day 1 | 24 ng/mL | Standard Deviation 6.92 |
| Group 1 Phase I Sorafenib and Erlotinib QD | Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I) | Trough Day 15 | 20 ng/mL | Standard Deviation 7.05 |
Other Pre-specified
Exploratory Correlative Laboratory Studies (Phase II)
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
Time frame: 28 days
Population: this was more an exploratory correlative and as per the pre-specified protocol, was only to be performed if the outcome of other parts of the study indicated positive results.
Other Pre-specified
Molecular Targeted Combinations Correlative Study Initiative
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
Time frame: 28 days
Population: This was more an exploratory correlative and as per the pre-specified protocol, was only to be performed if the outcome of other parts of the study indicated positive results.