Temsirolimus/AZD 6244 for Treatment-naive With BRAF Mutant Unresectable Stage IV

Phase 2

Terminated

Conditions: Mucosal Melanoma
Recurrent Melanoma
Stage IV Melanoma

Interventions: Drug: temsirolimus
Drug: selumetinib
Other: laboratory biomarker analysis

Registration Number: NCT01166126

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: The purpose of this study is to find out how often two investigational drugs that are given together will shrink the patient's tumor and how well they will prolong the time it takes their tumor to grow. The investigators also wish to find out how they affect certain substances in the patient's tumor and in their blood important for tumor growth. The combination of these drugs is experimental, and has not been proven to help treat melanoma

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the clinical response rate (Response Evaluation Criteria in Solid Tumors \[RECIST\]) and one-year overall survival to the study drugs temsirolimus and AZD6244 (selumetinib) hydrogen sulfate in BRAF V600E mutant unresectable stage IV melanoma.

SECONDARY OBJECTIVES:

I. Estimate 6-month progression-free survival in patients receiving temsirolimus and AZD6244 hydrogen sulfate.

II. Determine the pharmacodynamic effects of temsirolimus and AZD6244 on pERK, s6K, PTEN and mediators of apoptosis.

III. Determine the toxicity profile of temsirolimus with AZD6244 hydrogen sulfate.

OUTLINE:

Treatment Phase: This period begins with the first intravenous (through the vein) infusion of TEMSIROLIMUS and the first AZD6244 administration by mouth (visit 2, Week 1) and will continue until Week 8 (Visit 4).

As many as 38 patients will receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 will be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 will be given to participants as an outpatient, unless admission to the hospital was needed for treatment of related side effects or underlying disease. The subsequent cycles of TEMSIROLIMUS and AZD6244 will be given every 8 weeks. The TEMSIROLIMUS will be injected in a vein over 30 minutes.

The continuation phase begins with visits at weeks 12 in patients who receive at least two cycles of treatments.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 4

Inclusion Criteria

Subject must have read, understood, and provided written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained
Subjects with a histologic diagnosis of unresectable stage IV melanoma (may include mucosal melanoma)
Tumor must be BRAF V600E mutation positive from a certified lab
At least 4 weeks since any previous treatment (surgery, radiotherapy, or systemic treatment)
Women should be either: post-menopausal for at least 1 year; surgically incapable of bearing children; or utilizing a reliable form of contraception during the study and for at least 4 months after the final study drug infusion or ingestion; women of childbearing potential must have a negative serum hCG-beta pregnancy test conducted during the screening period
Men who may father a child must agree to the use of male contraception for the duration of their participation in the trial and for at least 4 months after the final temsirolimus and AZD6244 hydrogen sulfate administration
Life expectancy >= 3 months
ECOG performance status of 0 or 1
Patients with brain metastases treated with surgery, radiation, or stereotactic radiosurgery who are without evidence of progression in their brain metastases after MRI imaging performed at least 30 days after treatment, and are not taking systemic steroids will be eligible
WBC >= 3000 cells/mm^3
ANC >= 1500 cells/mm^3
Platelets >= 100,000/mm^3
Hematocrit >= 30%
Hemoglobin >= 9 g/dL
Creatinine =< 2.0 mg/dL
AST/ALT =< 2 x ULN
Bilirubin =< 1.5 x ULN, (except subjects with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dL)
HIV negative
HBsAg negative
Anti-HCV Ab nonreactive; if reactive, subject must have a negative HCV RNA qualitative PCR
Patients with hyperlipidemia must have adequate control with a lipid lowering agent

Exclusion Criteria

Any prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix, or any other cancer from which the subject has been disease-free for at least 5 years
Active infection, requiring therapy, chronic active HBV or HCV; patients with HIV, who have adequate CD4 counts and who do not require HAART therapy, are NOT excluded
Pregnancy or nursing: due to the possibility that temsirolimus and AZD6244 hydrogen sulfate could have a detrimental effect on the developing fetus or infant, exposure in utero or via breast milk will not be allowed
Any underlying medical condition which, in the opinion of the principal investigator, will make the administration of study drug hazardous or obscure the interpretation of adverse events
Prior treatment with temsirolimus or AZD6244 or any prior mTOR or MEK inhibitor
Evidence or history of significant cardiac, pulmonary, hepatic, renal, psychiatric or gastrointestinal disease that would make the administration of temsirolimus or AZD6244 hydrogen sulfate unsafe
Tumor that is BRAF V600E mutation negative

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (temsirolimus and selumetinib)	selumetinib	Treatment Phase: This period begins with the first intravenous (through the vein) infusion of TEMSIROLIMUS and the first AZD6244 administration by mouth (visit 2, Week 1) and will continue until Week 8 (Visit 4). As many as 38 patients will receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 will be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 will be given to participants as an outpatient, unless admission to the hospital was needed for treatment of related side effects or underlying disease. The subsequent cycles of TEMSIROLIMUS and AZD6244 will be given every 8 weeks. The TEMSIROLIMUS will be injected in a vein over 30 minutes. The continuation phase begins with visits at weeks 12 in patients who receive at least two cycles of treatments.
Treatment (temsirolimus and selumetinib)	laboratory biomarker analysis	Treatment Phase: This period begins with the first intravenous (through the vein) infusion of TEMSIROLIMUS and the first AZD6244 administration by mouth (visit 2, Week 1) and will continue until Week 8 (Visit 4). As many as 38 patients will receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 will be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 will be given to participants as an outpatient, unless admission to the hospital was needed for treatment of related side effects or underlying disease. The subsequent cycles of TEMSIROLIMUS and AZD6244 will be given every 8 weeks. The TEMSIROLIMUS will be injected in a vein over 30 minutes. The continuation phase begins with visits at weeks 12 in patients who receive at least two cycles of treatments.
Treatment (temsirolimus and selumetinib)	temsirolimus	Treatment Phase: This period begins with the first intravenous (through the vein) infusion of TEMSIROLIMUS and the first AZD6244 administration by mouth (visit 2, Week 1) and will continue until Week 8 (Visit 4). As many as 38 patients will receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 will be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 will be given to participants as an outpatient, unless admission to the hospital was needed for treatment of related side effects or underlying disease. The subsequent cycles of TEMSIROLIMUS and AZD6244 will be given every 8 weeks. The TEMSIROLIMUS will be injected in a vein over 30 minutes. The continuation phase begins with visits at weeks 12 in patients who receive at least two cycles of treatments.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Complete Response (CR) and Partial Response (PR)	1 year	Anti-tumor response (CR+PR) was defined by Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Number of Participants With Overall Survival (OS) at One Year	1 year post last treatment	The one-year overall survival of the combination of temsirolimus and AZD6244 Hydrogen Sulfate.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Progression Free Survival (PFS) at 6 Months.	6 months from day 1 of treatment	Patients will be evaluated by physical examination and imaging assessments (brain MRI and CT scans of the chest, abdomen and pelvis). Disease progression will be defined by RECIST criteria on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Number of Participants With Related Serious Adverse Events (SAEs)	1 year	Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.