Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Temozolomide and Sorafenib in Treating Patients With Metastatic or Unresectable Melanoma

Summary: RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving temozolomide together with sorafenib may kill more tumor cells.
  PURPOSE: This randomized phase II trial is studying two different schedules of temozolomide when given together with sorafenib to compare how well they work in treating patients with metastatic or unresectable melanoma.

Detailed description: OBJECTIVES:
  Primary
  -  To measure the progression-free survival of patients with metastatic or unresectable melanoma with no brain metastasis or no prior treatment with temozolomide (TMZ) treated with sorafenib tosylate in combination with two different schedules (extended daily dosing vs standard dosing) of TMZ.
  -  To measure the progression-free survival of patients with or without brain metastasis and prior treatment with TMZ treated with sorafenib in combination with extended daily dosing of TMZ.
  -  To measure the progression-free survival of patients with brain metastasis and no prior treatment with TMZ treated with sorafenib in combination with standard dosing TMZ.
  -  To estimate the median time to progression in all patients.
  -  To quantify the number and percent of patients who have stable disease after 6 months of treatment (failure to progress).
  -  To choose the optimal combination dosing regimen for further study.
  Secondary
  -  To estimate and define the objective response rate in these patients.
  -  To characterize the duration of objective responses in these patients.
  -  To estimate the incidence of new symptomatic brain metastasis in these patients.
  -  To measure overall survival of these patients.
  OUTLINE: This is a multicenter study. Patients are stratified according to prior brain metastases (yes vs no) and prior treatment with temozolomide (TMZ) (yes vs no). Patients with no prior brain metastases who did not receive prior treatment with TMZ are randomized to 1 of 2 treatment arms. These patients are further stratified according to prior treatment with sorafenib tosylate (yes vs no). Patients with or without prior brain metastases who received prior treatment with TMZ are assigned to arm I. Patients with prior brain metastases who did not receive prior treatment with TMZ are assigned to arm II.
  -  Arm I: Patients receive oral sorafenib tosylate twice daily on days -7 to 56 of course 1 and on days 1-56 of all subsequent courses. Patients also receive oral TMZ once daily on days 1-42.
  -  Arm II: Patients receive sorafenib tosylate as in arm I and oral TMZ once daily on days 1-5 and 29-33.
  In both arms, courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Eligibility: DISEASE CHARACTERISTICS:
  -  Histologically or cytologically confirmed melanoma
  -  Metastatic or unresectable disease
  -  Measurable disease by RECIST criteria
  -  Cutaneous lesions measuring at least 1 cm will be considered measurable disease
  -  Brain metastases allowed provided patient completed radiotherapy, if radiotherapy was clinically indicated at the time of diagnosis, AND discontinued steroids prior to study enrollment
  PATIENT CHARACTERISTICS:
  -  ECOG performance status 0-1
  -  WBC ≥ 3,000/mm³
  -  Absolute granulocyte count ≥ 1,500/mm³
  -  Platelet count ≥ 100,000/mm³
  -  Serum creatinine ≤ 2.0 times upper limit of normal (ULN)
  -  Total bilirubin ≤ 1.5 times ULN (< 3.0 times ULN if Gilbert's disease is present)
  -  AST or ALT ≤ 2.5 times ULN (≤ 5.0 times ULN if liver metastases are present)
  -  INR ≤ 1.5 (if on anticoagulation, baseline INR must be < 1.5 before starting anticoagulation)
  -  PTT normal
  -  No other concurrent malignancies, except basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast
  -  No concurrent serious illness including, but not limited to, any of the following:
  -  Ongoing or active infection requiring parenteral antibiotics
  -  Clinically significant cardiovascular disease (e.g., uncontrolled hypertension, myocardial infarction, unstable angina)
  -  New York Heart Association class II-IV congestive heart failure
  -  Serious cardiac arrhythmia requiring medication
  -  Peripheral vascular disease ≥ grade II within the past year
  -  Psychiatric illness/social situation that would limit compliance with study requirements
  -  Not pregnant or nursing
  -  Negative pregnancy test
  -  Fertile patients must use effective contraception
  -  No HIV positivity
  PRIOR CONCURRENT THERAPY:
  -  See Disease Characteristics
  -  Recovered from all prior therapy
  -  Prior radiotherapy allowed
  -  If radiotherapy has been administered to a lesion, there must be radiographic evidence of progression of that lesion for that lesion to constitute measurable disease or to be included in the measured target lesions
  -  Prior temozolomide or sorafenib tosylate allowed
  -  At least 4 weeks since prior chemotherapy
  -  At least 4 weeks since prior active immunotherapy (aldesleukin, interferon, sargramostim [GM-CSF], or CTLA-4)
  -  At least 4 weeks since prior and no other concurrent investigational anticancer therapy (except vaccines)
  -  No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital), rifampin, or Hypericum perforatum (St. John's wort)

Relevance to patient case: not relevant