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

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

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00281957
Enrollment
109
Registered
2006-01-25
Start date
2007-08-31
Completion date
2011-01-31
Last updated
2014-05-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Recurrent Melanoma, Stage IV Melanoma

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.

Detailed description

PRIMARY OBJECTIVES: I. 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. II. Compare the 4-month progression-free survival rate of patients treated with these regimens. III. 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.

Interventions

DRUGsorafenib tosylate

Given orally

DRUGtipifarnib

Given orally

DRUGtemsirolimus

Given IV

Sponsors

National Cancer Institute (NCI)
Lead SponsorNIH

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

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

Design outcomes

Primary

MeasureTime frameDescription
Response Rate (Complete and Partial)Every 8 weeks until progressionComplete 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.
4-month Progression-free Survival4 months after registrationProgression 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

MeasureTime frameDescription
One-year Overall SurvivalOne year after registration
ToxicityWeekly 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

Countries

United States

Participant flow

Participants by arm

ArmCount
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.
63
Arm II: Sorafenib + Tipifarnib
Patients receive oral sorafenib as in arm I and oral tipifarnib twice daily on days 1-21
39
Total102

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyAdverse Event72
Overall StudyDeath10
Overall StudyDid not start treatment31
Overall StudyNot eligible12
Overall StudyNot protocol specified81
Overall StudyProgression/relapse4735
Overall StudyRefusal unrelated to adverse events01

Baseline characteristics

CharacteristicArm I: Sorafenib + TemsirolimusArm II: Sorafenib + TipifarnibTotal
Age, Continuous64 years58 years62 years
Region of Enrollment
United States
63 participants39 participants102 participants
Sex: Female, Male
Female
29 Participants17 Participants46 Participants
Sex: Female, Male
Male
34 Participants22 Participants56 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
61 / 6335 / 39
serious
Total, serious adverse events
13 / 636 / 39

Outcome results

Primary

4-month Progression-free Survival

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

ArmMeasureValue (NUMBER)
Sorafenib+Temsirolimus4-month Progression-free Survival29 Percent of population
Sorafenib+Tipifarnib4-month Progression-free Survival18 Percent of population
Primary

Response Rate (Complete and Partial)

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

ArmMeasureValue (NUMBER)
Sorafenib+TemsirolimusResponse Rate (Complete and Partial)5 Percent of participants
Sorafenib+TipifarnibResponse Rate (Complete and Partial)3 Percent of participants
Secondary

One-year Overall Survival

Time frame: One year after registration

ArmMeasureValue (NUMBER)
Sorafenib+TemsirolimusOne-year Overall Survival19 Percent of population
Sorafenib+TipifarnibOne-year Overall Survival31 Percent of population
Secondary

Toxicity

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).

Population: Eligible patients who had received any hydroxyurea

ArmMeasureGroupValue (NUMBER)
Sorafenib+TemsirolimusToxicityDiarrhea4 Participants
Sorafenib+TemsirolimusToxicityRash/desquamation4 Participants
Sorafenib+TemsirolimusToxicityVomiting3 Participants
Sorafenib+TemsirolimusToxicityPain - Neuralgia/peripheral nerve0 Participants
Sorafenib+TemsirolimusToxicityPain - Oral cavity1 Participants
Sorafenib+TemsirolimusToxicityPain - Pelvis0 Participants
Sorafenib+TemsirolimusToxicityALT, SGPT (serum glutamic pyruvic transaminase)0 Participants
Sorafenib+TemsirolimusToxicityAST, SGOT (serum glut oxaloacetic transaminase)0 Participants
Sorafenib+TemsirolimusToxicityAmylase0 Participants
Sorafenib+TemsirolimusToxicityAnorexia1 Participants
Sorafenib+TemsirolimusToxicityCalcium, serum-low (hypocalcemia)1 Participants
Sorafenib+TemsirolimusToxicityConfusion2 Participants
Sorafenib+TemsirolimusToxicityConstitutional Symptoms-Other (Specify)1 Participants
Sorafenib+TemsirolimusToxicityCough1 Participants
Sorafenib+TemsirolimusToxicityCreatinine1 Participants
Sorafenib+TemsirolimusToxicityDehydration3 Participants
Sorafenib+TemsirolimusToxicityDermatology/Skin-Other (Specify)0 Participants
Sorafenib+TemsirolimusToxicityPain - Rectum1 Participants
Sorafenib+TemsirolimusToxicityDyspnea (shortness of breath)1 Participants
Sorafenib+TemsirolimusToxicityFatigue (asthenia, lethargy, malaise)8 Participants
Sorafenib+TemsirolimusToxicityGastrointestinal-Other (Specify)1 Participants
Sorafenib+TemsirolimusToxicityGlucose, serum-high (hyperglycemia)1 Participants
Sorafenib+TemsirolimusToxicityHeartburn/dyspepsia0 Participants
Sorafenib+TemsirolimusToxicityHemoglobin2 Participants
Sorafenib+TemsirolimusToxicityHemorrhage, GI - Stomach1 Participants
Sorafenib+TemsirolimusToxicityHypertension1 Participants
Sorafenib+TemsirolimusToxicityHypotension1 Participants
Sorafenib+TemsirolimusToxicityIleus, GI1 Participants
Sorafenib+TemsirolimusToxicityInfec with norm ANC or Gr 1/2 neut- Nose1 Participants
Sorafenib+TemsirolimusToxicityInfec with norm ANC or Gr 1/2 neut-Skin1 Participants
Sorafenib+TemsirolimusToxicityLeft ventricular systolic dysfunction1 Participants
Sorafenib+TemsirolimusToxicityLipase0 Participants
Sorafenib+TemsirolimusToxicityLymphopenia1 Participants
Sorafenib+TemsirolimusToxicityMood alteration - depression0 Participants
Sorafenib+TemsirolimusToxicityMucositis/stomatitis (clinical exam) - Oral cavity2 Participants
Sorafenib+TemsirolimusToxicityMuscle weakness, gen or spec area-Extraocular1 Participants
Sorafenib+TemsirolimusToxicityMuscle weakness, gen or spec area-Whole body2 Participants
Sorafenib+TemsirolimusToxicityNausea3 Participants
Sorafenib+TemsirolimusToxicityNeurology-Other (Specify)1 Participants
Sorafenib+TemsirolimusToxicityNeuropathy: motor0 Participants
Sorafenib+TemsirolimusToxicityObstruction, GI - Small bowel NOS1 Participants
Sorafenib+TemsirolimusToxicityPain - Abdomen NOS1 Participants
Sorafenib+TemsirolimusToxicityPain - Back1 Participants
Sorafenib+TemsirolimusToxicityPain - Chest wall1 Participants
Sorafenib+TemsirolimusToxicityPain - Chest/thorax NOS1 Participants
Sorafenib+TemsirolimusToxicityPain - Extremity-limb1 Participants
Sorafenib+TemsirolimusToxicityPain - Head/headache1 Participants
Sorafenib+TemsirolimusToxicityPain - Joint1 Participants
Sorafenib+TemsirolimusToxicityPain - Muscle1 Participants
Sorafenib+TemsirolimusToxicityPain - Skin1 Participants
Sorafenib+TemsirolimusToxicityPain - Stomach1 Participants
Sorafenib+TemsirolimusToxicityPancreatitis1 Participants
Sorafenib+TemsirolimusToxicityPhosphate, serum-low (hypophosphatemia)8 Participants
Sorafenib+TemsirolimusToxicityPlatelets1 Participants
Sorafenib+TemsirolimusToxicityPneumonitis/pulmonary infiltrates2 Participants
Sorafenib+TemsirolimusToxicityPotassium, serum-low (hypokalemia)4 Participants
Sorafenib+TemsirolimusToxicityProteinuria1 Participants
Sorafenib+TemsirolimusToxicityPruritus/itching2 Participants
Sorafenib+TemsirolimusToxicityPulmonary/Upper Respiratory-Other (Specify)1 Participants
Sorafenib+TemsirolimusToxicityRash: acne/acneiform3 Participants
Sorafenib+TemsirolimusToxicityRash: erythema multiforme1 Participants
Sorafenib+TemsirolimusToxicityRash: hand-foot skin reaction2 Participants
Sorafenib+TemsirolimusToxicityRenal failure2 Participants
Sorafenib+TemsirolimusToxicitySodium, serum-low (hyponatremia)1 Participants
Sorafenib+TemsirolimusToxicityThrombosis/thrombus/embolism0 Participants
Sorafenib+TipifarnibToxicityMood alteration - depression1 Participants
Sorafenib+TipifarnibToxicityVomiting0 Participants
Sorafenib+TipifarnibToxicityRash/desquamation2 Participants
Sorafenib+TipifarnibToxicityMucositis/stomatitis (clinical exam) - Oral cavity0 Participants
Sorafenib+TipifarnibToxicityPain - Stomach0 Participants
Sorafenib+TipifarnibToxicityPain - Neuralgia/peripheral nerve1 Participants
Sorafenib+TipifarnibToxicityMuscle weakness, gen or spec area-Extraocular0 Participants
Sorafenib+TipifarnibToxicityPain - Oral cavity0 Participants
Sorafenib+TipifarnibToxicityPulmonary/Upper Respiratory-Other (Specify)0 Participants
Sorafenib+TipifarnibToxicityPain - Pelvis1 Participants
Sorafenib+TipifarnibToxicityMuscle weakness, gen or spec area-Whole body1 Participants
Sorafenib+TipifarnibToxicityALT, SGPT (serum glutamic pyruvic transaminase)1 Participants
Sorafenib+TipifarnibToxicityPancreatitis1 Participants
Sorafenib+TipifarnibToxicityAST, SGOT (serum glut oxaloacetic transaminase)1 Participants
Sorafenib+TipifarnibToxicityNausea0 Participants
Sorafenib+TipifarnibToxicityAmylase1 Participants
Sorafenib+TipifarnibToxicityRenal failure0 Participants
Sorafenib+TipifarnibToxicityAnorexia0 Participants
Sorafenib+TipifarnibToxicityNeurology-Other (Specify)0 Participants
Sorafenib+TipifarnibToxicityCalcium, serum-low (hypocalcemia)0 Participants
Sorafenib+TipifarnibToxicityPhosphate, serum-low (hypophosphatemia)1 Participants
Sorafenib+TipifarnibToxicityConfusion0 Participants
Sorafenib+TipifarnibToxicityNeuropathy: motor1 Participants
Sorafenib+TipifarnibToxicityConstitutional Symptoms-Other (Specify)0 Participants
Sorafenib+TipifarnibToxicityRash: acne/acneiform5 Participants
Sorafenib+TipifarnibToxicityCough0 Participants
Sorafenib+TipifarnibToxicityObstruction, GI - Small bowel NOS0 Participants
Sorafenib+TipifarnibToxicityCreatinine0 Participants
Sorafenib+TipifarnibToxicityPlatelets0 Participants
Sorafenib+TipifarnibToxicityDehydration0 Participants
Sorafenib+TipifarnibToxicityPain - Abdomen NOS2 Participants
Sorafenib+TipifarnibToxicityDermatology/Skin-Other (Specify)1 Participants
Sorafenib+TipifarnibToxicityThrombosis/thrombus/embolism1 Participants
Sorafenib+TipifarnibToxicityDiarrhea1 Participants
Sorafenib+TipifarnibToxicityPain - Back2 Participants
Sorafenib+TipifarnibToxicityDyspnea (shortness of breath)1 Participants
Sorafenib+TipifarnibToxicityPneumonitis/pulmonary infiltrates0 Participants
Sorafenib+TipifarnibToxicityFatigue (asthenia, lethargy, malaise)2 Participants
Sorafenib+TipifarnibToxicityPain - Chest wall0 Participants
Sorafenib+TipifarnibToxicityGastrointestinal-Other (Specify)0 Participants
Sorafenib+TipifarnibToxicityRash: erythema multiforme0 Participants
Sorafenib+TipifarnibToxicityGlucose, serum-high (hyperglycemia)0 Participants
Sorafenib+TipifarnibToxicityPain - Chest/thorax NOS1 Participants
Sorafenib+TipifarnibToxicityHeartburn/dyspepsia1 Participants
Sorafenib+TipifarnibToxicityPotassium, serum-low (hypokalemia)0 Participants
Sorafenib+TipifarnibToxicityHemoglobin0 Participants
Sorafenib+TipifarnibToxicityPain - Extremity-limb1 Participants
Sorafenib+TipifarnibToxicityHemorrhage, GI - Stomach0 Participants
Sorafenib+TipifarnibToxicitySodium, serum-low (hyponatremia)0 Participants
Sorafenib+TipifarnibToxicityHypertension2 Participants
Sorafenib+TipifarnibToxicityPain - Head/headache0 Participants
Sorafenib+TipifarnibToxicityHypotension0 Participants
Sorafenib+TipifarnibToxicityProteinuria0 Participants
Sorafenib+TipifarnibToxicityIleus, GI0 Participants
Sorafenib+TipifarnibToxicityPain - Joint1 Participants
Sorafenib+TipifarnibToxicityInfec with norm ANC or Gr 1/2 neut- Nose0 Participants
Sorafenib+TipifarnibToxicityRash: hand-foot skin reaction4 Participants
Sorafenib+TipifarnibToxicityInfec with norm ANC or Gr 1/2 neut-Skin0 Participants
Sorafenib+TipifarnibToxicityPain - Muscle0 Participants
Sorafenib+TipifarnibToxicityLeft ventricular systolic dysfunction0 Participants
Sorafenib+TipifarnibToxicityPain - Rectum0 Participants
Sorafenib+TipifarnibToxicityLipase1 Participants
Sorafenib+TipifarnibToxicityPruritus/itching1 Participants
Sorafenib+TipifarnibToxicityLymphopenia0 Participants
Sorafenib+TipifarnibToxicityPain - Skin0 Participants

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026