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Report for Clinical Trial NCT01166126

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase II Trial of mTOR Inhibitor Temsirolimus Combined With MEK Inhibitor AZD 6244 in Patients With BRAF Mutant Stage IV Melanoma

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

NCT01166126 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma
MeSH: Melanoma
HPO: Cutaneous melanoma Melanoma

3 Interventions

Name: temsirolimus

Description: Given IV

Type: Drug

Treatment (temsirolimus and selumetinib)

Name: selumetinib

Description: Given orally

Type: Drug

Treatment (temsirolimus and selumetinib)

Name: laboratory biomarker analysis

Description: Correlative studies

Type: Other

Treatment (temsirolimus and selumetinib)


Primary Outcomes

Description: 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.

Measure: Number of Participants With Complete Response (CR) and Partial Response (PR)

Time: 1 year

Description: The one-year overall survival of the combination of temsirolimus and AZD6244 Hydrogen Sulfate.

Measure: Number of Participants With Overall Survival (OS) at One Year

Time: 1 year post last treatment

Secondary Outcomes

Description: 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).

Measure: Number of Participants With Progression Free Survival (PFS) at 6 Months.

Time: 6 months from day 1 of treatment

Description: Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.

Measure: Number of Participants With Related Serious Adverse Events (SAEs)

Time: 1 year

Purpose: Treatment

Single Group Assignment


There is one SNP

SNPs


1 V600E

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. 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 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 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma 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. --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. 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 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 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma 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. --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. 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 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 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma 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. --- V600E --- --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. 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 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 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma 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. --- V600E --- --- V600E --- --- V600E --- --- V600E ---

Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0.. 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 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 Mucosal Melanoma Recurrent Melanoma Stage IV Melanoma Melanoma 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. --- V600E --- --- V600E --- --- V600E --- --- V600E --- --- V600E ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R