Sorafenib With Either Temsirolimus or Tipifarnib in Treating Patients With Stage IV Malignant Melanoma That Cannot Be Removed By Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00281957
• Collaborator: (none)
• Enrollment: 109
• Locations: 173
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying how well giving sorafenib together with either temsirolimus or tipifarnib works in treating patients with stage IV melanoma that cannot be removed by surgery. Sorafenib, temsirolimus, and tipifarnib 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 by blocking blood flow to the tumor. It is not yet known whether sorafenib is more effective when given together with temsirolimus or tipifarnib in treating patients with malignant melanoma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IV Melanoma	Drug: sorafenib tosylate; Drug: tipifarnib; Drug: temsirolimus	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Compare the response rate (confirmed and unconfirmed and complete and partial) in patients with unresectable stage IV malignant melanoma treated with sorafenib in combination with either temsirolimus or tipifarnib.

2. Compare the 4-month progression-free survival rate of patients treated with these regimens.

3. Compare the safety and tolerability of these regimens, with an emphasis on long-term side effects and toxic effects, in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to metastatic (M) stage (M1a/b vs M1c). Patients are randomized to 1 of 2 treatment arms.

ARM I (reopened to accrual as of 8/15/2009): Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.

ARM II (closed to accrual as of 8/15/2009): Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of BAY 43-9006 (Sorafenib; NSC-724772) With Either CCI-779 (Temsirolimus; NSC-683864) or R115777 (Tipifarnib; NSC-702818) in Metastatic Melanoma
• Study Start Date: Aug 1, 2007
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Jan 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (sorafenib, temsirolimus) Patients receive oral sorafenib twice daily on days 1-28 and 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; Given IV; Other Names: CCI-779 cell cycle inhibitor 779 Torisel
Experimental: Arm II (sorafenib, tipifarnib) Patients receive oral sorafenib as in arm I and 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. Response Rate (Complete and Partial) [Every 8 weeks until progression]

   Complete response corresponds to complete disappearance of all measurable and non-measurable lesions with no new lesions. Partial response corresponds to greater than or equal to 30fi decrease of sum of longest diameter of all target measurable lesions with no new lesion and non unequivocal progression of non-measurable disease.

2. 4-month Progression-free Survival [4 months after registration]

   Progression was defined as one or more of the following: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed, unequivocal progression of non-measurable disease, appearance of any new lesions, death due to disease without prior documentation of progression and without symptomatic deterioration.

Secondary Outcome Measures

1. One-year Overall Survival [One year after registration]

2. Toxicity [Weekly during first cycle, every two weeks during the second cycle, and once a cycle further cycles (one cycle = 4 weeks).]

   Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria:

• Histologically confirmed malignant melanoma of cutaneous origin

• Patients with unknown primary allowed

• Stage IV disease

• Measurable disease by physical examination, CT scan, MRI or plain x-ray

• Unresectable disease

• Residual or recurrent disease after prior surgery for stage IV disease allowed

• Residual tumor at the site of incomplete resection may be included only as nonmeasurable disease

• Must have serum lactate dehydrogenase (LDH) levels measured

• Must have tissue specimens available

• Negative brain CT scan or MRI within the past 42 days

• Creatinine =< 1.5 times ULN

• Absolute neutrophil count >= 1,000/mm^3

• Platelet count >= 100,000/mm^3

• Hemoglobin >= 9.0 g/dL

• Fasting cholesterol =< 350 mg/dL (lipid-lowering agents allowed)

• Triglycerides =< 300 mg/dL (lipid-lowering agents allowed)

• No symptomatic sensory neuropathy >= grade 2

• No evidence of bleeding diathesis or coagulopathy

• No congestive heart failure

• No myocardial infarction within the past 2 months

• No New York Heart Association class III or IV heart disease

• No condition that impairs the ability to swallow pills (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for IV alimentation, prior surgical procedure affecting absorption, or active peptic ulcer disease)

• No known allergy to imidazoles (e.g. clotrimazole, ketoconazole, miconazole, or econazole)

• No history of allergic reaction to compounds of similar chemical or biologic composition as tipifarnib

• No hypertension with systolic blood pressure (BP) > 140 mm Hg or diastolic BP > 90 mm Hg

• Patients with well-controlled hypertension allowed

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No uncontrolled diabetes

• No uncontrolled diabetes

• No active uncontrolled infection

• No other severe or uncontrolled medical disease

• No psychologic or medical condition that would preclude study treatment or compliance

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, adequately treated stage I or II cancer that is in complete remission, or carcinoma in situ of the cervix

• At least 90 days since prior adjuvant therapy, including cytotoxic agents

• At least 28 days since prior radiotherapy

• At least 28 days since prior surgery to remove the tumor

• No prior systemic therapy for stage IV melanoma

• No prior therapy with agents targeting farnesyl transferase, the MAP kinase pathway, or vascular endothelial growth factors (VEGF) or receptors (VEFGR), including drugs such as sorafenib, temsirolimus, or tipifarnib

• Concurrent lipid-lowering agents allowed

• Not requiring full-dose anticoagulation for recent thrombotic event

• No concurrent highly active antiretroviral therapy (HAART) in HIV-positive patients

• No concurrent use of any of the following: dilantin; carbamazepine; Phenobarbital; rifampin; hypericum perforatum (St. John's wort); ketoconazole; itraconazole; ritonavir; cyclosporine; phenytoin; grapefruit juice

• Bilirubin =< 1.5 times upper limit of normal (ULN)

• SGOT or SGPT =< 2.5 times ULN (5 times ULN if hepatic metastases)

• No history of brain metastases

• Zubrod performance status 0-1

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	East Bay Radiation Oncology Center	Castro Valley	California	United States	94546
3	Eden Hospital Medical Center	Castro Valley	California	United States	94546
4	Valley Medical Oncology Consultants-Castro Valley	Castro Valley	California	United States	94546
5	Valley Medical Oncology Consultants-Fremont	Fremont	California	United States	94538
6	University of Southern California/Norris Cancer Center	Los Angeles	California	United States	90033
7	Contra Costa Regional Medical Center	Martinez	California	United States	94553-3156
8	El Camino Hospital	Mountain View	California	United States	94040
9	Highland General Hospital	Oakland	California	United States	94602
10	Alta Bates Summit Medical Center - Summit Campus	Oakland	California	United States	94609
11	Bay Area Breast Surgeons Inc	Oakland	California	United States	94609
12	Bay Area Tumor Institute CCOP	Oakland	California	United States	94609
13	Larry G Strieff MD Medical Corporation	Oakland	California	United States	94609
14	Tom K Lee Inc	Oakland	California	United States	94609
15	Valley Care Health System - Pleasanton	Pleasanton	California	United States	94588
16	Valley Medical Oncology Consultants	Pleasanton	California	United States	94588
17	Sutter Roseville Medical Center	Roseville	California	United States	95661
18	Sutter General Hospital	Sacramento	California	United States	95816
19	Doctors Medical Center- JC Robinson Regional Cancer Center	San Pablo	California	United States	94806
20	The Medical Center of Aurora	Aurora	Colorado	United States	80012
21	Boulder Community Hospital	Boulder	Colorado	United States	80301
22	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
23	Porter Adventist Hospital	Denver	Colorado	United States	80210
24	Exempla Saint Joseph Hospital	Denver	Colorado	United States	80218
25	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
26	Rose Medical Center	Denver	Colorado	United States	80220
27	Colorado Cancer Research Program CCOP	Denver	Colorado	United States	80224-2522
28	Swedish Medical Center	Englewood	Colorado	United States	80113
29	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado	United States	81502
30	North Colorado Medical Center	Greeley	Colorado	United States	80631
31	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
32	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
33	Longmont United Hospital	Longmont	Colorado	United States	80501
34	McKee Medical Center	Loveland	Colorado	United States	80539
35	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
36	North Suburban Medical Center	Thornton	Colorado	United States	80229
37	Exempla Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
38	Cancer Centers of Central Florida PA	Leesburg	Florida	United States	34788
39	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
40	Memorial Health University Medical Center	Savannah	Georgia	United States	31403
41	South Georgia Medical Center	Valdosta	Georgia	United States	31603
42	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
43	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
44	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois	United States	60435
45	Loyola University Medical Center	Maywood	Illinois	United States	60153
46	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois	United States	61265
47	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois	United States	61265
48	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois	United States	61265
49	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois	United States	61265
50	Memorial Medical Center	Springfield	Illinois	United States	62781-0001
51	Carle Cancer Center	Urbana	Illinois	United States	61801
52	Carle Clinic-Urbana Main	Urbana	Illinois	United States	61801
53	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
54	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa	United States	50010
55	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa	United States	52722
56	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
57	Genesis Medical Center - East Campus	Davenport	Iowa	United States	52803
58	Genesis Medical Center - West Campus	Davenport	Iowa	United States	52804
59	Mercy Capitol	Des Moines	Iowa	United States	50307
60	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
61	Iowa Oncology Research Association CCOP	Des Moines	Iowa	United States	50309
62	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
63	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
64	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
65	Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
66	Siouxland Hematology Oncology Associates	Sioux City	Iowa	United States	51101
67	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51104
68	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
69	Hospital District Sixth of Harper County	Anthony	Kansas	United States	67003
70	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
71	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
72	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
73	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
74	Hays Medical Center	Hays	Kansas	United States	67601
75	Promise Regional Medical Center-Hutchinson	Hutchinson	Kansas	United States	65702
76	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
77	Providence Medical Center	Kansas City	Kansas	United States	66112
78	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
79	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
80	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
81	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
82	Olathe Cancer Center	Olathe	Kansas	United States	66061
83	Radiation Oncology Practice Corporation Southwest	Overland Park	Kansas	United States	66210
84	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
85	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
86	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
87	Stormont-Vail Regional Health Center	Topeka	Kansas	United States	66604
88	Saint Francis Hospital and Medical Center - Topeka	Topeka	Kansas	United States	66606
89	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
90	Associates In Womens Health	Wichita	Kansas	United States	67208
91	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
92	Cancer Center of Kansas - Main Office	Wichita	Kansas	United States	67214
93	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
94	Wichita CCOP	Wichita	Kansas	United States	67214
95	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
96	Louisiana State University Sciences Center- Monroe	Monroe	Louisiana	United States	71210
97	Highland Clinic	Shreveport	Louisiana	United States	71105
98	Louisiana State University Health Sciences Center Shreveport	Shreveport	Louisiana	United States	71130
99	Boston Medical Center	Boston	Massachusetts	United States	02118
100	University of Michigan	Ann Arbor	Michigan	United States	48109
101	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
102	Spectrum Health Big Rapids Hospital	Big Rapids	Michigan	United States	49307
103	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
104	Henry Ford Hospital	Detroit	Michigan	United States	48202
105	Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan	United States	49503
106	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
107	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
108	Holland Community Hospital	Holland	Michigan	United States	49423
109	Mercy Health Partners-Hackley Campus	Muskegon	Michigan	United States	49442
110	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
111	Munson Medical Center	Traverse City	Michigan	United States	49684
112	Metro Health Hospital	Wyoming	Michigan	United States	49519
113	Meeker County Memorial Hospital	Litchfield	Minnesota	United States	55355
114	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
115	Southeast Missouri Hospital	Cape Girardeau	Missouri	United States	63701
116	Centerpoint Medical Center LLC	Independence	Missouri	United States	64057
117	Radiation Oncology Practice Corporation South	Kansas City	Missouri	United States	64114
118	Radiation Oncology Practice Corporation - North	Kansas City	Missouri	United States	64154
119	Montana Cancer Consortium CCOP	Billings	Montana	United States	59101
120	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
121	Saint Vincent Healthcare	Billings	Montana	United States	59101
122	Hematology-Oncology Centers of the Northern Rockies PC	Billings	Montana	United States	59102
123	Billings Clinic	Billings	Montana	United States	59107-7000
124	Bozeman Deaconess Cancer Center	Bozeman	Montana	United States	59715
125	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
126	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
127	Berdeaux, Donald MD (UIA Investigator)	Great Falls	Montana	United States	59405
128	Great Falls Clinic	Great Falls	Montana	United States	59405
129	Northern Montana Hospital	Havre	Montana	United States	59501
130	Saint Peter's Community Hospital	Helena	Montana	United States	59601
131	Glacier Oncology PLLC	Kalispell	Montana	United States	59901
132	Kalispell Medical Oncology	Kalispell	Montana	United States	59901
133	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
134	Community Medical Hospital	Missoula	Montana	United States	59801
135	Montana Cancer Specialists	Missoula	Montana	United States	59802
136	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
137	Guardian Oncology and Center for Wellness	Missoula	Montana	United States	59804
138	Good Samaritan Hospital	Kearney	Nebraska	United States	68847
139	Nebraska Cancer Research Center	Lincoln	Nebraska	United States	68510
140	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
141	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
142	Mary Imogene Bassett Hospital	Cooperstown	New York	United States	13326
143	Orange Regional Medical Center	Middletown	New York	United States	10940
144	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
145	Rutherford Hospital	Rutherfordton	North Carolina	United States	28139
146	University of Cincinnati	Cincinnati	Ohio	United States	45267
147	Mansfield General Hospital-MedCentral Health System	Mansfield	Ohio	United States	44903
148	Adventist Medical Center	Portland	Oregon	United States	97216
149	SWOG	Portland	Oregon	United States	97239
150	Delaware County Memorial Hospital	Drexel Hill	Pennsylvania	United States	19026
151	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
152	AnMed Health Hospital	Anderson	South Carolina	United States	29621
153	Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303
154	Upstate Carolina CCOP	Spartanburg	South Carolina	United States	29303
155	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
156	Danville Regional Medical Center	Danville	Virginia	United States	24541
157	Southwest VA Regional Cancer Center	Norton	Virginia	United States	24273
158	PeaceHealth Saint Joseph Medical Center	Bellingham	Washington	United States	98225
159	Harrison HealthPartners Hematology and Oncology-Bremerton	Bremerton	Washington	United States	98310
160	Columbia Basin Hematology and Oncology PLLC	Kennewick	Washington	United States	99336
161	Skagit Valley Hospital	Mount Vernon	Washington	United States	98274
162	Harborview Medical Center	Seattle	Washington	United States	98104
163	Minor and James Medical PLLC	Seattle	Washington	United States	98104
164	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109
165	Group Health Cooperative-Seattle	Seattle	Washington	United States	98112
166	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
167	The Polyclinic	Seattle	Washington	United States	98122
168	University of Washington Medical Center	Seattle	Washington	United States	98195
169	United General Hospital	Sedro-Woolley	Washington	United States	98284
170	Cancer Care Northwest - Spokane South	Spokane	Washington	United States	99202
171	Wenatchee Valley Medical Center	Wenatchee	Washington	United States	98801
172	Dean Hematology and Oncology Clinic	Madison	Wisconsin	United States	53717
173	Welch Cancer Center	Sheridan	Wyoming	United States	82801

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Kim Margolin, Southwest Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00281957
• Other Study ID Numbers: NCI-2009-00774; NCI-2009-00774; S0438; CDR0000454925; S0438; S0438; U10CA032102
• First Posted: Jan 25, 2006
• Last Update Posted: May 20, 2014
• Last Verified: Apr 1, 2013

• Additional relevant MeSH terms: Melanoma; Sirolimus; Sorafenib; Tipifarnib

Study Results

Participant Flow

Arm/Group Title	Sorafenib + Temsirolimus	Sorafenib + Tipifarnib
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21
Period Title: Overall Study
STARTED	67	42
Eligible	66	40
Eligible and Received Treatment	63	39
COMPLETED	0	0
NOT COMPLETED	67	42

Baseline Characteristics

Arm/Group Title	Arm I: Sorafenib + Temsirolimus	Arm II: Sorafenib + Tipifarnib	Total
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21	Total of all reporting groups
Overall Participants	63	39	102
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	58	62
Sex: Female, Male (Count of Participants)
Female	29 46%	17 43.6%	46 45.1%
Male	34 54%	22 56.4%	56 54.9%
Region of Enrollment (participants) [Number]
United States	63 100%	39 100%	102 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate (Complete and Partial)
Description	Complete response corresponds to complete disappearance of all measurable and non-measurable lesions with no new lesions. Partial response corresponds to greater than or equal to 30fi decrease of sum of longest diameter of all target measurable lesions with no new lesion and non unequivocal progression of non-measurable disease.
Time Frame	Every 8 weeks until progression

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib+Temsirolimus	Sorafenib+Tipifarnib
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21
Measure Participants	63	39
Number (95% Confidence Interval) [Percent of participants]	5 7.9%	3 7.7%

2. Primary Outcome

Title	4-month Progression-free Survival
Description	Progression was defined as one or more of the following: 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed, unequivocal progression of non-measurable disease, appearance of any new lesions, death due to disease without prior documentation of progression and without symptomatic deterioration.
Time Frame	4 months after registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib+Temsirolimus	Sorafenib+Tipifarnib
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21
Measure Participants	63	39
Number (95% Confidence Interval) [Percent of population]	29	18

3. Secondary Outcome

Title	One-year Overall Survival
Time Frame	One year after registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib+Temsirolimus	Sorafenib+Tipifarnib
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22.	Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21
Measure Participants	63	39
Number (95% Confidence Interval) [Percent of population]	19	31

4. Secondary Outcome

Title	Toxicity
Description	Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event
Time Frame	Weekly during first cycle, every two weeks during the second cycle, and once a cycle further cycles (one cycle = 4 weeks).

Outcome Measure Data

Analysis Population Description

Eligible patients who had received any hydroxyurea

Arm/Group Title	Sorafenib+Temsirolimus	Sorafenib+Tipifarnib
Arm/Group Description	Sorafenib and Temsirolimus	Sorafenib and Tipifarnib
Measure Participants	63	39
ALT, SGPT (serum glutamic pyruvic transaminase)	0 0%	1 2.6%
AST, SGOT (serum glut oxaloacetic transaminase)	0 0%	1 2.6%
Amylase	0 0%	1 2.6%
Anorexia	1 1.6%	0 0%
Calcium, serum-low (hypocalcemia)	1 1.6%	0 0%
Confusion	2 3.2%	0 0%
Constitutional Symptoms-Other (Specify)	1 1.6%	0 0%
Cough	1 1.6%	0 0%
Creatinine	1 1.6%	0 0%
Dehydration	3 4.8%	0 0%
Dermatology/Skin-Other (Specify)	0 0%	1 2.6%
Diarrhea	4 6.3%	1 2.6%
Dyspnea (shortness of breath)	1 1.6%	1 2.6%
Fatigue (asthenia, lethargy, malaise)	8 12.7%	2 5.1%
Gastrointestinal-Other (Specify)	1 1.6%	0 0%
Glucose, serum-high (hyperglycemia)	1 1.6%	0 0%
Heartburn/dyspepsia	0 0%	1 2.6%
Hemoglobin	2 3.2%	0 0%
Hemorrhage, GI - Stomach	1 1.6%	0 0%
Hypertension	1 1.6%	2 5.1%
Hypotension	1 1.6%	0 0%
Ileus, GI	1 1.6%	0 0%
Infec with norm ANC or Gr 1/2 neut- Nose	1 1.6%	0 0%
Infec with norm ANC or Gr 1/2 neut-Skin	1 1.6%	0 0%
Left ventricular systolic dysfunction	1 1.6%	0 0%
Lipase	0 0%	1 2.6%
Lymphopenia	1 1.6%	0 0%
Mood alteration - depression	0 0%	1 2.6%
Mucositis/stomatitis (clinical exam) - Oral cavity	2 3.2%	0 0%
Muscle weakness, gen or spec area-Extraocular	1 1.6%	0 0%
Muscle weakness, gen or spec area-Whole body	2 3.2%	1 2.6%
Nausea	3 4.8%	0 0%
Neurology-Other (Specify)	1 1.6%	0 0%
Neuropathy: motor	0 0%	1 2.6%
Obstruction, GI - Small bowel NOS	1 1.6%	0 0%
Pain - Abdomen NOS	1 1.6%	2 5.1%
Pain - Back	1 1.6%	2 5.1%
Pain - Chest wall	1 1.6%	0 0%
Pain - Chest/thorax NOS	1 1.6%	1 2.6%
Pain - Extremity-limb	1 1.6%	1 2.6%
Pain - Head/headache	1 1.6%	0 0%
Pain - Joint	1 1.6%	1 2.6%
Pain - Muscle	1 1.6%	0 0%
Pain - Neuralgia/peripheral nerve	0 0%	1 2.6%
Pain - Oral cavity	1 1.6%	0 0%
Pain - Pelvis	0 0%	1 2.6%
Pain - Rectum	1 1.6%	0 0%
Pain - Skin	1 1.6%	0 0%
Pain - Stomach	1 1.6%	0 0%
Pancreatitis	1 1.6%	1 2.6%
Phosphate, serum-low (hypophosphatemia)	8 12.7%	1 2.6%
Platelets	1 1.6%	0 0%
Pneumonitis/pulmonary infiltrates	2 3.2%	0 0%
Potassium, serum-low (hypokalemia)	4 6.3%	0 0%
Proteinuria	1 1.6%	0 0%
Pruritus/itching	2 3.2%	1 2.6%
Pulmonary/Upper Respiratory-Other (Specify)	1 1.6%	0 0%
Rash/desquamation	4 6.3%	2 5.1%
Rash: acne/acneiform	3 4.8%	5 12.8%
Rash: erythema multiforme	1 1.6%	0 0%
Rash: hand-foot skin reaction	2 3.2%	4 10.3%
Renal failure	2 3.2%	0 0%
Sodium, serum-low (hyponatremia)	1 1.6%	0 0%
Thrombosis/thrombus/embolism	0 0%	1 2.6%
Vomiting	3 4.8%	0 0%

Adverse Events

Time Frame	While the patient is on treatment until resolution of acute toxicities with maximum grade reported
Adverse Event Reporting Description	Regular investigator assessments are reported after each cycle of protocol treatment
Arm/Group Title	Arm I		Arm II
Arm/Group Description	Sorafenib and Temsirolimu		Sorafenib and Tipifarnib
All Cause Mortality
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/63 (20.6%)		6/39 (15.4%)
Blood and lymphatic system disorders
Hemoglobin	1/63 (1.6%)		0/39 (0%)
Cardiac disorders
Left ventricular systolic dysfunction	1/63 (1.6%)		0/39 (0%)
Gastrointestinal disorders
Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation)	1/63 (1.6%)		0/39 (0%)
Nausea	1/63 (1.6%)		0/39 (0%)
Pain - Abdomen NOS	1/63 (1.6%)		0/39 (0%)
Pancreatitis	1/63 (1.6%)		1/39 (2.6%)
Vomiting	2/63 (3.2%)		0/39 (0%)
General disorders
Fatigue (asthenia, lethargy, malaise)	1/63 (1.6%)		0/39 (0%)
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils - Nose	1/63 (1.6%)		0/39 (0%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Skin (cellulitis)	1/63 (1.6%)		0/39 (0%)
Investigations
Amylase	0/63 (0%)		1/39 (2.6%)
Lipase	0/63 (0%)		1/39 (2.6%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	1/63 (1.6%)		0/39 (0%)
Calcium, serum-low (hypocalcemia)	1/63 (1.6%)		0/39 (0%)
Dehydration	2/63 (3.2%)		0/39 (0%)
Glucose, serum-high (hyperglycemia)	1/63 (1.6%)		0/39 (0%)
Phosphate, serum-low (hypophosphatemia)	2/63 (3.2%)		0/39 (0%)
Potassium, serum-low (hypokalemia)	2/63 (3.2%)		0/39 (0%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized	2/63 (3.2%)		1/39 (2.6%)
Pain - Back	0/63 (0%)		1/39 (2.6%)
Pain - Joint	1/63 (1.6%)		0/39 (0%)
Nervous system disorders
Neurology-Other (Specify)	1/63 (1.6%)		0/39 (0%)
Neuropathy: motor	0/63 (0%)		1/39 (2.6%)
Pain - Head/headache	1/63 (1.6%)		0/39 (0%)
Psychiatric disorders
Confusion	1/63 (1.6%)		0/39 (0%)
Renal and urinary disorders
Renal failure	1/63 (1.6%)		0/39 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis/pulmonary infiltrates	2/63 (3.2%)		0/39 (0%)
Pulmonary/Upper Respiratory-Other (Specify)	1/63 (1.6%)		0/39 (0%)
Skin and subcutaneous tissue disorders
Pruritus/itching	1/63 (1.6%)		0/39 (0%)
Rash/desquamation	1/63 (1.6%)		0/39 (0%)
Vascular disorders
Flushing	1/63 (1.6%)		0/39 (0%)
Hypertension	1/63 (1.6%)		1/39 (2.6%)
Thrombosis/thrombus/embolism	0/63 (0%)		1/39 (2.6%)
Other (Not Including Serious) Adverse Events
	Arm I		Arm II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	61/63 (96.8%)		35/39 (89.7%)
Blood and lymphatic system disorders
Hemoglobin	28/63 (44.4%)		3/39 (7.7%)
Gastrointestinal disorders
Constipation	7/63 (11.1%)		8/39 (20.5%)
Diarrhea	18/63 (28.6%)		17/39 (43.6%)
Mucositis/stomatitis (clinical exam) - Oral cavity	13/63 (20.6%)		4/39 (10.3%)
Nausea	21/63 (33.3%)		7/39 (17.9%)
Pain - Abdomen NOS	5/63 (7.9%)		5/39 (12.8%)
Vomiting	9/63 (14.3%)		2/39 (5.1%)
General disorders
Edema: limb	5/63 (7.9%)		0/39 (0%)
Fatigue (asthenia, lethargy, malaise)	42/63 (66.7%)		22/39 (56.4%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC lt1.0 x 10e9/L)	7/63 (11.1%)		2/39 (5.1%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	14/63 (22.2%)		2/39 (5.1%)
AST, SGOT (serum glutamic oxaloacetic transaminase)	15/63 (23.8%)		2/39 (5.1%)
Alkaline phosphatase	9/63 (14.3%)		0/39 (0%)
Bilirubin (hyperbilirubinemia)	0/63 (0%)		2/39 (5.1%)
Cholesterol, serum-high (hypercholesterolemia)	25/63 (39.7%)		7/39 (17.9%)
Creatinine	9/63 (14.3%)		2/39 (5.1%)
Leukocytes (total WBC)	15/63 (23.8%)		0/39 (0%)
Lymphopenia	5/63 (7.9%)		0/39 (0%)
Metabolic/Laboratory-Other (Specify)	8/63 (12.7%)		0/39 (0%)
Neutrophils/granulocytes (ANC/AGC)	6/63 (9.5%)		0/39 (0%)
Platelets	20/63 (31.7%)		3/39 (7.7%)
Weight loss	13/63 (20.6%)		5/39 (12.8%)
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	9/63 (14.3%)		4/39 (10.3%)
Anorexia	20/63 (31.7%)		9/39 (23.1%)
Calcium, serum-low (hypocalcemia)	5/63 (7.9%)		0/39 (0%)
Dehydration	4/63 (6.3%)		0/39 (0%)
Glucose, serum-high (hyperglycemia)	14/63 (22.2%)		4/39 (10.3%)
Phosphate, serum-low (hypophosphatemia)	18/63 (28.6%)		4/39 (10.3%)
Potassium, serum-low (hypokalemia)	6/63 (9.5%)		3/39 (7.7%)
Sodium, serum-low (hyponatremia)	6/63 (9.5%)		3/39 (7.7%)
Triglyceride, serum-high (hypertriglyceridemia)	23/63 (36.5%)		8/39 (20.5%)
Musculoskeletal and connective tissue disorders
Pain - Back	4/63 (6.3%)		2/39 (5.1%)
Pain - Joint	0/63 (0%)		3/39 (7.7%)
Pain - Muscle	0/63 (0%)		4/39 (10.3%)
Nervous system disorders
Dizziness	0/63 (0%)		2/39 (5.1%)
Neuropathy: sensory	5/63 (7.9%)		6/39 (15.4%)
Pain - Head/headache	7/63 (11.1%)		3/39 (7.7%)
Taste alteration (dysgeusia)	11/63 (17.5%)		0/39 (0%)
Psychiatric disorders
Insomnia	4/63 (6.3%)		2/39 (5.1%)
Mood alteration - depression	4/63 (6.3%)		2/39 (5.1%)
Respiratory, thoracic and mediastinal disorders
Cough	4/63 (6.3%)		0/39 (0%)
Dyspnea (shortness of breath)	8/63 (12.7%)		4/39 (10.3%)
Hemorrhage, pulmonary/upper respiratory - Nose	4/63 (6.3%)		0/39 (0%)
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	0/63 (0%)		2/39 (5.1%)
Skin and subcutaneous tissue disorders
Dermatology/Skin-Other (Specify)	0/63 (0%)		3/39 (7.7%)
Dry skin	0/63 (0%)		6/39 (15.4%)
Hair loss/Alopecia (scalp or body)	4/63 (6.3%)		6/39 (15.4%)
Pruritus/itching	8/63 (12.7%)		9/39 (23.1%)
Rash/desquamation	18/63 (28.6%)		11/39 (28.2%)
Rash: acne/acneiform	21/63 (33.3%)		13/39 (33.3%)
Rash: hand-foot skin reaction	5/63 (7.9%)		7/39 (17.9%)
Vascular disorders
Flushing	0/63 (0%)		3/39 (7.7%)
Hypertension	10/63 (15.9%)		7/39 (17.9%)

Limitations/Caveats

[Not Specified]

More Information

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.