Temsirolimus/AZD 6244 for Treatment-naive With BRAF Mutant Unresectable Stage IV
Study Details
Study Description
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
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
-
Estimate 6-month progression-free survival in patients receiving temsirolimus and AZD6244 hydrogen sulfate.
-
Determine the pharmacodynamic effects of temsirolimus and AZD6244 on pERK, s6K, PTEN and mediators of apoptosis.
-
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Treatment (temsirolimus and 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. |
Drug: temsirolimus
Given IV
Other Names:
Drug: selumetinib
Given orally
Other Names:
Other: laboratory biomarker analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- 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
- 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.
Eligibility Criteria
Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | H. Lee Moffitt Cancer Center and Research Institute | Tampa | Florida | United States | 33612 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Ragini Kudchadkar, H. Lee Moffitt Cancer Center and Research Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NCI-2012-02846
- NCI-2012-02846
- MCC-16066
- 8436
- P30CA076292
Study Results
Participant Flow
Recruitment Details | Up to 35 subjects with a histologic diagnosis of unresectable Stage IV melanoma were to be enrolled into this study over 24 months. |
---|---|
Pre-assignment Detail | 11 of 15 patients consented were not eligible to receive the study drug after screening. |
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Period Title: Overall Study | |
STARTED | 4 |
COMPLETED | 4 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Overall Participants | 4 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
3
75%
|
>=65 years |
1
25%
|
Age (years) [Mean (Full Range) ] | |
Mean (Full Range) [years] |
52.5
|
Sex: Female, Male (Count of Participants) | |
Female |
1
25%
|
Male |
3
75%
|
Region of Enrollment (participants) [Number] | |
United States |
4
100%
|
Outcome Measures
Title | Number of Participants With Complete Response (CR) and Partial Response (PR) |
---|---|
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. |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | Treatment Phase: This period began 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Measure Participants | 4 |
Complete Response |
0
0%
|
Partial Response |
0
0%
|
Title | Number of Participants With Overall Survival (OS) at One Year |
---|---|
Description | The one-year overall survival of the combination of temsirolimus and AZD6244 Hydrogen Sulfate. |
Time Frame | 1 year post last treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | Treatment Phase: This period began 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Measure Participants | 4 |
Number [participants] |
0
0%
|
Title | Number of Participants With Progression Free Survival (PFS) at 6 Months. |
---|---|
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). |
Time Frame | 6 months from day 1 of treatment |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | Treatment Phase: This period began 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Measure Participants | 4 |
Number [participants] |
1
25%
|
Title | Number of Participants With Related Serious Adverse Events (SAEs) |
---|---|
Description | Toxicities assessed using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v4.0. |
Time Frame | 1 year |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) |
---|---|
Arm/Group Description | Treatment Phase: This period began 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. |
Measure Participants | 4 |
Number [participants] |
0
0%
|
Adverse Events
Time Frame | 1 year | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Treatment (Temsirolimus and Selumetinib) | |
Arm/Group Description | 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). Investigators planned for as many as 38 patients to receive the same dosage of TEMSIROLIMUS injected in the veins once a week for 8 weeks, and the AZD6244 would be given as capsules by mouth twice a day for 8 weeks. That is one cycle. The TEMSIROLIMUS and AZD6244 would 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 would be given every 8 weeks. The TEMSIROLIMUS would be injected in a vein over 30 minutes. The continuation phase would begin with visits at weeks 12 in patients who received at least two cycles of treatments. | |
All Cause Mortality |
||
Treatment (Temsirolimus and Selumetinib) | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Treatment (Temsirolimus and Selumetinib) | ||
Affected / at Risk (%) | # Events | |
Total | 2/4 (50%) | |
Ear and labyrinth disorders | ||
Vertigo | 1/4 (25%) | 1 |
Gastrointestinal disorders | ||
Diarrhea | 1/4 (25%) | 1 |
Nausea | 1/4 (25%) | 1 |
General disorders | ||
Fever | 1/4 (25%) | 1 |
Metabolism and nutrition disorders | ||
Dehydration | 1/4 (25%) | 1 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||
Neoplasms benigh, malignant and unspecified (incl cysts and polyps) - other | 1/4 (25%) | 1 |
Other (Not Including Serious) Adverse Events |
||
Treatment (Temsirolimus and Selumetinib) | ||
Affected / at Risk (%) | # Events | |
Total | 4/4 (100%) | |
Blood and lymphatic system disorders | ||
Anemia | 1/4 (25%) | 2 |
Blood and lymphatic system disorders - other | 1/4 (25%) | 1 |
Ear and labyrinth disorders | ||
Tinnitus | 1/4 (25%) | 1 |
Vertigo | 1/4 (25%) | 1 |
Gastrointestinal disorders | ||
Constipation | 4/4 (100%) | 4 |
Mucositis oral | 4/4 (100%) | 20 |
Nausea | 3/4 (75%) | 8 |
Diarrhea | 2/4 (50%) | 6 |
Abdominal pain | 1/4 (25%) | 1 |
Ascites | 1/4 (25%) | 1 |
Gastrointestinal disorders - other | 1/4 (25%) | 1 |
Vomiting | 1/4 (25%) | 2 |
General disorders | ||
Fatigue | 4/4 (100%) | 8 |
Fever | 3/4 (75%) | 5 |
Edima - limbs | 2/4 (50%) | 3 |
Pain | 2/4 (50%) | 4 |
Chills | 1/4 (25%) | 1 |
Edema - face | 1/4 (25%) | 1 |
General disorders and administration site conditions - other | 1/4 (25%) | 1 |
Hepatobiliary disorders | ||
Hepatic pain | 1/4 (25%) | 1 |
Hepatobiliary disorders - other | 1/4 (25%) | 1 |
Infections and infestations | ||
Tooth infection | 1/4 (25%) | 1 |
Investigations | ||
Lipase increased | 2/4 (50%) | 2 |
Alkaline phosphatase increased | 1/4 (25%) | 2 |
Aspartate aminotransferase increased | 1/4 (25%) | 1 |
Cholesterol high | 1/4 (25%) | 1 |
Neutrophil count decreased | 1/4 (25%) | 14 |
Serum amylase increased | 1/4 (25%) | 1 |
Metabolism and nutrition disorders | ||
Hypertriglyceridemia | 2/4 (50%) | 5 |
Anorexia | 1/4 (25%) | 2 |
Hyperglycemia | 1/4 (25%) | 1 |
Hyponatremia | 1/4 (25%) | 1 |
Musculoskeletal and connective tissue disorders | ||
Arthralgia | 1/4 (25%) | 2 |
Pain in extremity | 1/4 (25%) | 1 |
Nervous system disorders | ||
Dizziness | 2/4 (50%) | 2 |
Dysgeusia | 1/4 (25%) | 1 |
Headache | 1/4 (25%) | 2 |
Paresthesia | 1/4 (25%) | 1 |
Seizure | 1/4 (25%) | 1 |
Psychiatric disorders | ||
Anxiety | 2/4 (50%) | 2 |
Insomnia | 2/4 (50%) | 2 |
Respiratory, thoracic and mediastinal disorders | ||
Cough | 3/4 (75%) | 3 |
Dyspnea | 2/4 (50%) | 5 |
Hiccups | 1/4 (25%) | 1 |
Nasal congestion | 1/4 (25%) | 1 |
Skin and subcutaneous tissue disorders | ||
Pain of skin | 3/4 (75%) | 3 |
Rash maculo-papular | 3/4 (75%) | 9 |
Pruritus | 2/4 (50%) | 4 |
Rash acneiform | 2/4 (50%) | 9 |
Alopecia | 1/4 (25%) | 3 |
Skin hyperpigmentation | 1/4 (25%) | 1 |
Vascular disorders | ||
Hypertension | 1/4 (25%) | 2 |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Ragini Kudchadkar, M.D. |
---|---|
Organization | H. Lee Moffitt Cancer Center and Research Institute |
Phone | 813-745-8581 |
ragini.kudchadkar@moffitt.org |
- NCI-2012-02846
- NCI-2012-02846
- MCC-16066
- 8436
- P30CA076292