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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00335764
• Collaborator: (none)
• Enrollment: 92
• Locations: 7
• Arms: 3
• Duration (Months): 77
• Patients Per Site: 13.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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

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 Design

• Study Type: Interventional
• 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: Apr 1, 2006
• Actual Primary Completion Date: Feb 1, 2010
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

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

Outcome Measures

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) [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) [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) [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) [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) [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) [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) [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 [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) [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) [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) [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) [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) [1 year]

14. 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.

15. 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).

Other Outcome Measures

1. 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

2. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California at Los Angeles	Los Angeles	California	United States	90095
2	University of California San Francisco	San Francisco	California	United States	94115
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
5	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15232
6	M D Anderson Cancer Center	Houston	Texas	United States	77030
7	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mark Gilbert, MD, National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00335764
• Other Study ID Numbers: NCI-2009-00676; NCI-2009-00676; CDR0000476286; NABTC-05-02; NABTC-05-02; U01CA137443
• First Posted: Jun 12, 2006
• Last Update Posted: Jul 2, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Recurrence; Sirolimus; Erlotinib Hydrochloride; Sorafenib; Tipifarnib

Study Results

Participant Flow

Recruitment Details	patients enrolled from 2006 - 2009 Patients accrued from comprehensive outpatient cancer centers

Arm/Group Title	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
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally Dose Level 0: 200mg BID (fixed) Dose Level 1: 400mg BID (fixed) erlotinib hydrochloride: given orally Dose Level 0: 100mg QD Dose Level 1: 100mg QD Dose Level 2: 150mg QD	Patients receive sorafenib tosylate BID as in group 2. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID temsirolimus: IV administration Dose Level 0: 25mg IV QW Dose Level 1: 25mg IV QW Dose Level 2: 50mg IV QW Dose Level 3: 75mg IV QW Dose Level 4: 125mg IV QW Dose Level 5: 175mg IV QW	Patients receive sorafenib tosylate BID as in group 3. Patients also receive oral tipifarnib twice daily on days 1-21. sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID tipifarnib: given orally Dose Level 0: 100mg BID Dose Level 1: 100mg BID Dose Level 2: 200mg BID Dose Level 3: 300mg BID	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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 400mg BID temsirolimus: IV administration 25mg IV QW
Period Title: Overall Study
STARTED	17	13	24	19	19
COMPLETED	16	13	24	19	18
NOT COMPLETED	1	0	0	0	1

Baseline Characteristics

Arm/Group Title	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
Arm/Group Description	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	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	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	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	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	Total of all reporting groups
Overall Participants	16	13	24	19	18	90
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	53	50	57	52	50	53
Sex: Female, Male (Count of Participants)
Female	7 43.8%	4 30.8%	8 33.3%	10 52.6%	9 50%	38 42.2%
Male	9 56.3%	9 69.2%	16 66.7%	9 47.4%	9 50%	52 57.8%
Karnofsky Performance Status Scale (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	90	80	85	90	90	90

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

3+3 design due to excessive toxicities of Group 3 no DLT was defined for Group 3

Arm/Group Title	Group 1 Phase I Sorafenib and Erlotinib QD	Group 2 Phase I Sorafenib and Temsirolimus QW	Group 3 Phase I Sorafenib and Tipifarnib BID
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally Dose Level 0: 200mg BID (fixed) Dose Level 1: 400mg BID (fixed) erlotinib hydrochloride: given orally Dose Level 0: 100mg QD Dose Level 1: 100mg QD Dose Level 2: 150mg QD	Patients receive sorafenib tosylate BID as in group 2. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID temsirolimus: IV administration Dose Level 0: 25mg IV QW Dose Level 1: 25mg IV QW Dose Level 2: 50mg IV QW Dose Level 3: 75mg IV QW Dose Level 4: 125mg IV QW Dose Level 5: 175mg IV QW	Patients receive sorafenib tosylate BID as in group 3. Patients also receive oral tipifarnib twice daily on days 1-21. sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID tipifarnib: given orally Dose Level 0: 100mg BID Dose Level 1: 100mg BID Dose Level 2: 200mg BID Dose Level 3: 300mg BID
Measure Participants	16	13	24
Number [mg]	100	25	NA

2. Primary Outcome

Title	Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 2 Phase I Temsirolimus 25mg QW	Group 2 Phase I Sorafenib 200mg BID	Group 2 Phase I Sorafenib 400mg BID
Arm/Group Description	Pt receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients receive sorafenib tosylate BID. sorafenib tosylate: given orally temsirolimus: IV administration 25mg	Patients receive sorafenib tosylate BID 200mg. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally 200mg temsirolimus: IV administration 25mg	Patients receive sorafenib tosylate BID 400mg. Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally 400mg temsirolimus: IV administration 25mg
Measure Participants	13	7	6
Day 1 Cmax	530 (101)	NA (NA)	NA (NA)
Day 15 Cmax	616 (209)	4.04 (1.68)	7.49 (3.46)
Day 28 Cmax	NA (NA)	3.26 (1.34)	6.24 (4.03)

3. Primary Outcome

Title	Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 Phase I Erlotinib 100mg QD	Group 1 Phase I Sorafenib 200mg BID	Group 1 Phase I Sorafenib 400mg BID
Arm/Group Description	Patients receive oral oral erlotinib hydrochloride 100 mg once daily on days 1-28. Pts also receive Sorafenib tosylate BID sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive oral sorafenib tosylate BID 200mg oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally 200mg erlotinib hydrochloride: given orally	Patients receive oral sorafenib tosylate BID 400mg and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally 400mg erlotinib hydrochloride: given orally
Measure Participants	16	9	6
cMax Day 1	443 (155)	NA (NA)	NA (NA)
cMax Day 15	662 (373)	5.51 (2.68)	8.4 (5.18)
cMax Day 28	653 (469)	4.67 (2.10)	4.10 (0.56)

4. Primary Outcome

Title	Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 Phase I Erlotinib 100mg QD	Group 1 Phase I Sorafenib 200mg	Group 1 Phase I Sorafenib 400mg
Arm/Group Description	Patients receive oral erlotinib hydrochloride 100 mg once daily on days 1-28.And also oral sorafenib tosylate BID sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive oral sorafenib tosylate BID 200mg and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally 200mg erlotinib hydrochloride: given orally	Patients receive oral sorafenib tosylate BID 400mg and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally 400mg erlotinib hydrochloride: given orally
Measure Participants	16	9	6
AUC0-12 Day1	6.3 (2.61)	NA (NA)	NA (NA)
AUC0-12 Day 15	6.9 (4.59)	45.85 (21.5)	62.4 (38)
AUC0-12 Day 28	7.7 (4.05)	40.29 (18.6)	38.7 (9.61)

5. Primary Outcome

Title	Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 2 Phase I Sorafenib and Temsirolimus QW
Arm/Group Description	Patients receive sorafenib tosylate BID Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally temsirolimus: IV administration
Measure Participants	13
Trough Day 1	24 (6.92)
Trough Day 15	20 (7.05)

6. Primary Outcome

Title	Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 2 Phase I Temsirolimus 25mg QW	Group 2 Phase I Sorafenib 200mg	Group 2 Phase I Sorafenib 400mg
Arm/Group Description	Patients receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Patients also receive sorafenib tosylate BID sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID temsirolimus: IV administration Dose Level 0: 25mg IV QW Dose Level 1: 25mg IV QW	Patients receive sorafenib tosylate BID Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally Dose Level 0: 200mg BID temsirolimus: IV administration Dose Level 0: 25mg IV QW Dose Level 1: 25mg IV QW	Patients receive sorafenib tosylate BID Patients also receive temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. sorafenib tosylate: given orally Dose Level 1: 400mg BID temsirolimus: IV administration Dose Level 0: 25mg IV QW Dose Level 1: 25mg IV QW
Measure Participants	13	13	13
AUC 0-12 Day 1	1.53 (0.27)	NA (NA)	NA (NA)
AUC 0-12 Day 15	1.35 (0.28)	35.45 (18.10)	42.32
AUC 0-12 Day 28	NA (NA)	29.0 (12.32)	32.98 (0.318)

7. Primary Outcome

Title	Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1)
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 3 Phase I Tipifarnib 100mg QD	Group 3 Phase I Sorafenib 200mg BID
Arm/Group Description	Patients receive oral tipifarnib every day on days 1-21. Patients also receive sorafenib tosylate BID sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose level -1: 100mg QD	Patients receive sorafenib tosylate BID Patients also receive oral tipifarnib every day on days 1-21. sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose level -1: 100mg QD
Measure Participants	6	6
Cmax Day 1	209.5 (135.85)	NA (NA)
Cmax Day 15	169.5 (186)	3.34 (1.31)
Cmax Day 28	NA (NA)	3.43 (1.46)

8. Primary Outcome

Title	Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID
Description	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)

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 3 Phase I Tipifarnib 100mg BID	Group 3 Phase I Sorafenib 200mg BID
Arm/Group Description	Patients receive oral tipifarnib 100mg twice daily on days 2-21. Patients also sorafenib tosylate BID 200mg sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level 1: 100mg BID	Patients receive oral tipifarnib 100mg twice daily on days 2-21. Patients also sorafenib tosylate BID 200mg sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level 1: 100mg BID
Measure Participants	10	10
Day 1 Cmax	132.17 (65.96)	NA (NA)
Day 15 Cmax	233.60 (84.83)	4.17 (2.99)
Day 28 Cmax	NA (NA)	4.53 (2.38)

9. Primary Outcome

Title	Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1)
Description	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)

Outcome Measure Data

Analysis Population Description

Group 3: PKs for Dose level -1 Tipifarnib 100mg QD Sorafenib started day 2

Arm/Group Title	Group 3 Phase I Tipifarnib 100mg QD	Group 3 Phase I Sorafenib 200mg BID
Arm/Group Description	Patients receive oral tipifarnib 100mg twice daily on days 1-21. also receive sorafenib tosylate BID100mg sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level -1: 100mg QD	Patients receive sorafenib tosylate BID100mgal and also tipifarnib 100mg QD on days 1-21.sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level -1: 100mg QD
Measure Participants	9	9
AUC 0-12 Day 1	814.5 (347.57)	NA (NA)
AUC 0-12 Day 15	706 (644.88)	30.59 (14.59)
AUC 0-12 Day 28	NA (NA)	41.43 (28.82)

10. Primary Outcome

Title	Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1)
Description	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)

Outcome Measure Data

Analysis Population Description

Group 3: PKs for Dose level 1 Tipifarnib 100mg BID

Arm/Group Title	Group 3 Phase I Tipifarnib 100mg QD	Group 3 Phase I Sorefenib 200mg BID
Arm/Group Description	Patients receive oral tipifarnib twice daily on days 1-21. Patients also receive sorafenib tosylate BID 200 mg starting on day 2 sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level 1: 100mg BID	Patients also receive sorafenib tosylate BID 200 mg starting on day 2. Patients receive oral tipifarnib twice daily on days 1-21. sorafenib tosylate: given orally Dose Level 0: 200mg BID tipifarnib: given orally Dose Level 1: 100mg BID
Measure Participants	10	10
AUC 0-12 Day 1	631.67 (431.12)	NA (NA)
AUC 0-12 Day 15	390.25 (758.07)	12.17 (16.33)
AUC 0-12 Day 28	NA (NA)	36.45 (17.21)

11. Primary Outcome

Title	12 Month Survival Rate (Phase II)
Description	number of patients alive at 12 months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Group 3 did not reach an MTD Hence, did not complete the Phase 2 portion of study, combination treatment too toxic.

Arm/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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
Measure Participants	19	18
Patients Alive at 12 Months	8 50%	10 76.9%
Patients Dead at 12 Months	11 68.8%	8 61.5%

12. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 Phase I Sorafenib and Erlotinib QD	Group 2 Phase I Sorafenib and Temsirolimus QW	Group 3 Phase I Sorafenib and Tipifarnib BID
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate BID 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	Patients receive sorafenib tosylate BID as in group 3. Patients also receive oral tipifarnib twice daily on days 1-21. sorafenib tosylate: given orally tipifarnib: given orally
Measure Participants	16	13	24
Leukopenia Grade 3	0	0	0
Lymphopenia Grade 3	0	2	3
Neutropenia Grade 3	0	0	0
Thrombocytopenia Grade 3	0	1	0
AST, SGOT Grade 3	1	1	0
Cholesterol Grade 3	0	1	0
Diarrhea Grade 3	0	1	2
Hemmorrhoids Grade 3	0	1	0
Hypertriglyceridemia Grade 3	0	1	0
Hypophosphatemia Grade 3	3	2	4
Fatigue Grade 3	0	0	1
Vomiting Grade 3	0	0	1
Lipase Grade 4	0	0	3
Joint - Knee Pain Grade 3	0	0	1
Thrombosis/thrombus/embolism Grade 4	0	0	1
Fever Grade 3	0	0	1
Dysphasia Grade 3	0	0	1
Pain - Head/Headache Grade 3	0	0	1
Encephalopathy Grade 3	0	0	1
Lipase Grade 3	1	0	0
ALT, SGPT Grade 3	2	0	0
Hypertension Grade 3	1	0	0

13. Primary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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
Measure Participants	19	18
Lymphopenia Grade 3	2	2
Thrombocytopenia Grade 3	0	5
Thrombocytopenia Grade 4	0	2
Cholesterol (high) Grade 3	0	2
Diarrhea Grade 3	1	1
Fatigue Grade 3	3	2
Hypokalemia Grade 3	0	1
Hyponatremia Grade 3	0	1
Hypophosphatemia Grade 3	0	3
Lipase (high) Grade 3	0	1
Pharyngeal mucositis Grade 3	0	1
Pruritis Grade 3	0	1
Rash Grade 3	0	1
Seizures Grade 3	0	1
Hypertension Grade 3	1	0

14. Primary Outcome

Title	Progression-free Survival at 6 Months (Phase II)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus	Group 3 Phase I Sorafenib and Tipifarnib BID
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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	Patients receive sorafenib tosylate BID as in group 3. Patients also receive oral tipifarnib twice daily on days 1-21. sorafenib tosylate: given orally Dose Level 0: 200mg BID Dose Level 1: 400mg BID tipifarnib: given orally Dose Level 0: 100mg BID Dose Level 1: 100mg BID Dose Level 2: 200mg BID Dose Level 3: 300mg BID
Measure Participants	19	18	24
Mean (95% Confidence Interval) [weeks]	15.8	8	4.2

15. Primary Outcome

Title	Objective Response Rate in Patients With Measurable Disease (Phase II)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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
Measure Participants	19	18
Partial Response	0 0%	2 15.4%
Complete Response	0 0%	0 0%
Stable Response	7 43.8%	3 23.1%
Progressive Disease	10 62.5%	13 100%
Unevaluable	2 12.5%	0 0%

16. Other Pre-specified Outcome

Title	Exploratory Correlative Laboratory Studies (Phase II)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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
Measure Participants	0	0

17. Other Pre-specified Outcome

Title	Molecular Targeted Combinations Correlative Study Initiative
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Group 1 Phase II Sorafenib and Erlotinib	Group 2 Phase II Sorafenib and Temsirolimus
Arm/Group Description	Patients receive oral sorafenib tosylate BID and oral erlotinib hydrochloride once daily on days 1-28. sorafenib tosylate: given orally erlotinib hydrochloride: given orally	Patients receive sorafenib tosylate 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
Measure Participants	0	0

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	CTCAE
Arm/Group Title	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
Arm/Group Description	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		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		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		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		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
All Cause Mortality
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)		13/13 (100%)		24/24 (100%)		19/19 (100%)		18/18 (100%)
Serious Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/13 (0%)		4/24 (16.7%)		1/19 (5.3%)		2/18 (11.1%)
Gastrointestinal disorders
Abdominal pain	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Diarrhea	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	1/18 (5.6%)	1
Infections and infestations
Pancrease infection	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Investigations
Lipase increased	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Serum amylase increased	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Metabolism and nutrition disorders
Hypertriglyceridemia	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Encephalopathy	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Headache	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Seizure	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Psychiatric disorders
Confusion	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	1/19 (5.3%)	1	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Rash acneiform	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Vascular disorders
Hypertension	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Thromboembolic event	0/16 (0%)	0	0/13 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/16 (81.3%)		8/13 (61.5%)		15/24 (62.5%)		11/19 (57.9%)		12/18 (66.7%)
Blood and lymphatic system disorders
Anemia	0/16 (0%)	0	4/13 (30.8%)	4	3/24 (12.5%)	3	1/19 (5.3%)	1	4/18 (22.2%)	4
Ear and labyrinth disorders
Ear and labyrinth disorders - Other, specify	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Eye disorders
Watering eyes	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Gastrointestinal disorders
Acidosis	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Constipation	0/16 (0%)	0	2/13 (15.4%)	2	3/24 (12.5%)	3	1/19 (5.3%)	1	0/18 (0%)	0
Diarrhea	4/16 (25%)	4	4/13 (30.8%)	4	0/24 (0%)	0	2/19 (10.5%)	2	2/18 (11.1%)	2
Dyspepsia	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Muscositis oral	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	3/18 (16.7%)	3
Nausea	2/16 (12.5%)	2	0/13 (0%)	0	2/24 (8.3%)	2	2/19 (10.5%)	2	2/18 (11.1%)	2
Oral pain	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Vomiting	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
General disorders
Chills	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Fatigue	3/16 (18.8%)	3	2/13 (15.4%)	2	7/24 (29.2%)	7	6/19 (31.6%)	6	3/18 (16.7%)	3
Infections and infestations
Lung infection	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Nail infection	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Investigations
Alanine aminotransferase increased	3/16 (18.8%)	3	2/13 (15.4%)	2	2/24 (8.3%)	2	3/19 (15.8%)	3	3/18 (16.7%)	3
Alkaline phosphatase increased	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Aspartate aminotransferase increased	4/16 (25%)	4	2/13 (15.4%)	2	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Blood bilirubin increased	0/16 (0%)	0	2/13 (15.4%)	2	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Cholesterol high	0/16 (0%)	0	3/13 (23.1%)	3	0/24 (0%)	0	0/19 (0%)	0	5/18 (27.8%)	5
Lipase increased	5/16 (31.3%)	5	1/13 (7.7%)	1	4/24 (16.7%)	4	1/19 (5.3%)	1	0/18 (0%)	0
Lymphocyte count decreased	2/16 (12.5%)	2	0/13 (0%)	0	4/24 (16.7%)	4	3/19 (15.8%)	3	5/18 (27.8%)	5
Neutrophil count decreased	2/16 (12.5%)	2	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Platelet count decreased	3/16 (18.8%)	3	5/13 (38.5%)	5	0/24 (0%)	0	2/19 (10.5%)	2	7/18 (38.9%)	7
Serum amylase increased	2/16 (12.5%)	2	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Weight loss	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	0/18 (0%)	0
White blood cell count decreased	6/16 (37.5%)	6	3/13 (23.1%)	3	3/24 (12.5%)	3	1/19 (5.3%)	1	1/18 (5.6%)	1
Metabolism and nutrition disorders
Anorexia	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	0/18 (0%)	0
Hypercalcemia	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Hyperglycemia	2/16 (12.5%)	2	1/13 (7.7%)	1	5/24 (20.8%)	5	1/19 (5.3%)	1	3/18 (16.7%)	3
Hyperkalemia	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Hypermagnesemia	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Hypernatremia	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Hypertriglyceridemia	0/16 (0%)	0	4/13 (30.8%)	4	0/24 (0%)	0	0/19 (0%)	0	4/18 (22.2%)	4
Hypoalbuminemia	2/16 (12.5%)	2	1/13 (7.7%)	1	2/24 (8.3%)	2	1/19 (5.3%)	1	0/18 (0%)	0
Hypocalcemia	1/16 (6.3%)	1	1/13 (7.7%)	1	5/24 (20.8%)	5	0/19 (0%)	0	3/18 (16.7%)	3
Hypokalemia	3/16 (18.8%)	3	1/13 (7.7%)	1	0/24 (0%)	0	1/19 (5.3%)	1	2/18 (11.1%)	2
Hypomagnesemia	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	2/18 (11.1%)	2
Hyponatremia	0/16 (0%)	0	1/13 (7.7%)	1	2/24 (8.3%)	2	0/19 (0%)	0	1/18 (5.6%)	1
Hypophosphatemia	4/16 (25%)	4	3/13 (23.1%)	3	2/24 (8.3%)	2	3/19 (15.8%)	3	4/18 (22.2%)	4
Metabolism and nutrition disorders - Other, specify	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Chest wall pain	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Generalized Muscle Weakness	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Myalgia	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Nervous system disorders
Dizziness	1/16 (6.3%)	1	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Headache	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Peripheral sensory neuropathy	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	1/18 (5.6%)	1
Psychiatric disorders
Confusion	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Depression	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	1/18 (5.6%)	1
Renal and urinary disorders
Hemoglobinuria	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/16 (0%)	0	1/13 (7.7%)	1	0/24 (0%)	0	0/19 (0%)	0	0/18 (0%)	0
Pharyngeal mucositis	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Skin and subcutaneous tissue disorders
Alopecia	2/16 (12.5%)	2	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Bruising	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Dry Skin	1/16 (6.3%)	1	2/13 (15.4%)	2	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Nail loss	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Palmar-plantar erythrodysesthesia syndrome	2/16 (12.5%)	2	0/13 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	1/18 (5.6%)	1
Pruritus	2/16 (12.5%)	2	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Purpura	0/16 (0%)	0	0/13 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	1/18 (5.6%)	1
Rash acneiform	2/16 (12.5%)	2	0/13 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/18 (0%)	0
Rash maculo-papular	4/16 (25%)	4	2/13 (15.4%)	2	2/24 (8.3%)	2	5/19 (26.3%)	5	3/18 (16.7%)	3
Vascular disorders
Hypertension	2/16 (12.5%)	2	1/13 (7.7%)	1	0/24 (0%)	0	1/19 (5.3%)	1	1/18 (5.6%)	1

Limitations/Caveats

Due to combo toxicities for Sorafenib and Tipifarnib exceeding monotherapy for each, MTD was not determined nor was Phase 2 explored.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.