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Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation

Primary Purpose

Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Dabrafenib
Laboratory Biomarker Analysis
Therapeutic Conventional Surgery
Trametinib
Sponsored by
M.D. Anderson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stage IIIB Cutaneous Melanoma AJCC v7

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable

    • Multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team
  • Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team
  • BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory
  • Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Hemoglobin >= 9.5 g/dL
  • Platelets >= 100 x 10^9/L
  • Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN)
  • Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Albumin >= 2.5 g/dL
  • Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
  • Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b) condom (during non-vaginal intercourse with any partner - male or female) OR c) condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female)
  • A female subject is eligible to participate if she is of:

    • Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] > 40 MlU/mL and estradiol < 40 pg/mL [< 140 pmol/L] is confirmatory); females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed below if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment; for most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT; following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
    • Child-bearing potential and agrees to use one of the contraception methods listed below for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point; female subjects must agree to use contraception until 4 weeks after the last dose of study medication, and must have a negative serum or urine pregnancy test within 14 days prior to the start of dosing
  • Female subjects contraception methods: a) abstinence; b) intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1% failure rate as stated in the product label; c) male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject; d) double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)

Exclusion Criteria:

  • Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug within 28 days
  • Current use of a prohibited medication or requires any of these medications during treatment with study drug
  • Prior BRAF or mitogen-activated protein kinase kinase (MEK) directed therapy
  • Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years
  • Any major surgery within the last 3 weeks
  • History of central serous retinopathy (CSR) or retinal vein occlusion (RVO), or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)
  • Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs
  • Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug
  • Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block)
  • Uncontrolled arrhythmias
  • Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Pregnant or lactating female
  • Unwillingness or inability to follow the procedures required in the protocol
  • Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity
  • Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (dabrafenib, trametinib, surgery)

Arm Description

Patients receive dabrafenib PO BID and trametinib PO QD for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and trametinib PO QD for 44 additional weeks in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Relapse-free survival (RFS)
RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.

Secondary Outcome Measures

Overall survival (OS)
The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.
Complete pathologic response
Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.
Incidence of adverse events
Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
Markers predictive of response collected by serial blood draws and biopsies
Indicators of treatment response and resistance will be obtained by analysis of serial blood and tumor biopsy samples. Specific assays include analysis of circulating tumor deoxyribonucleic acid (DNA), flow cytometry, immunohistochemistry and genomic sequencing. Patterns of these factors will be correlated with pathologic response.

Full Information

First Posted
September 2, 2014
Last Updated
September 1, 2023
Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02231775
Brief Title
Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation
Official Title
Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 22, 2014 (Actual)
Primary Completion Date
April 1, 2024 (Anticipated)
Study Completion Date
April 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
M.D. Anderson Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a single arm phase II trial focused on how dabrafenib and trametinib before and after surgery works in treating patients with stage IIIB-C melanoma that has a specific mutation in the BRAF gene. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving dabrafenib and trametinib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving dabrafenib and trametinib after surgery may kill any remaining tumor cells.
Detailed Description
PRIMARY OBJECTIVE: I. To compare relapse-free survival (RFS) between patients who develop a pathologic complete response (pCR) or do not achieve a pCR following dabrafenib and trametinib neoadjuvant combination therapy in patients with locally advanced BRAF V600 mutated melanoma. SECONDARY OBJECTIVES: I. To compare overall survival of patients with pathologic complete response (pCR) and patients without pCR who are receiving dabrafenib and trametinib neoadjuvant therapy followed by adjuvant combination therapy. II. To identify biomarkers predictive of response through collection of serial blood draws and biopsies in patients receiving neoadjuvant dabrafenib and trametinib combination therapy. III. To evaluate the safety of dabrafenib and trametinib in combination in this patient population. EXPLORATORY OBJECTIVE: I. To evaluate and perform further advanced imaging analysis on magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET) scanned (if available) images collected on patients enrolled onto this study. OUTLINE: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD) for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and trametinib PO QD for 44 additional weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stage IIIB Cutaneous Melanoma AJCC v7, Stage IIIC Cutaneous Melanoma AJCC v7

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
66 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (dabrafenib, trametinib, surgery)
Arm Type
Experimental
Arm Description
Patients receive dabrafenib PO BID and trametinib PO QD for 8 weeks. After completion of 8 weeks of dabrafenib and trametinib, patients undergo surgery. Approximately 1 week after surgery, patients receive dabrafenib PO BID and trametinib PO QD for 44 additional weeks in the absence of disease progression or unacceptable toxicity.
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Other Intervention Name(s)
BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Procedure
Intervention Name(s)
Therapeutic Conventional Surgery
Intervention Description
Undergo surgery
Intervention Type
Drug
Intervention Name(s)
Trametinib
Other Intervention Name(s)
GSK1120212, JTP-74057, MEK Inhibitor GSK1120212
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Relapse-free survival (RFS)
Description
RFS will be compared between patients with a pathologic complete response (pCR) and patients without a pCR using a two-sided log-rank test.
Time Frame
Up to 1 year
Secondary Outcome Measure Information:
Title
Overall survival (OS)
Description
The association between RFS and OS and covariates of interest will be assessed using Cox proportional hazards regression analysis.
Time Frame
Up to 1 year
Title
Complete pathologic response
Description
Logistic regression will be used to assess the association between the probability of complete pathologic response and clinical and disease covariates of interest.
Time Frame
Up to 1 year
Title
Incidence of adverse events
Description
Safety parameters will be tabulated by using Fisher's exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables.
Time Frame
Up to 1 year
Title
Markers predictive of response collected by serial blood draws and biopsies
Description
Indicators of treatment response and resistance will be obtained by analysis of serial blood and tumor biopsy samples. Specific assays include analysis of circulating tumor deoxyribonucleic acid (DNA), flow cytometry, immunohistochemistry and genomic sequencing. Patterns of these factors will be correlated with pathologic response.
Time Frame
Up to 1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Patients must have histologically or cytologically confirmed stage IIIB/C melanoma by American Joint Committee on Cancer (AJCC) version 7; the definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at Multidisciplinary Tumor Conference attended by melanoma medical and surgical oncology staff; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable Multicenter sites: confirmation of diagnosis via histology or cytology will be made by the local site pathologist; likewise, resectability determination will be made by the site's multidisciplinary team Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Absolute neutrophil count (ANC) >= 1.5 x 10^9/L Hemoglobin >= 9.5 g/dL Platelets >= 100 x 10^9/L Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) =< 1.5 x upper limit of normal (ULN) Total bilirubin =< 1.5 x ULN (isolated bilirubin > 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN Albumin >= 2.5 g/dL Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min Male subjects must agree to use one of the contraception methods listed below; this criterion must be followed from the time of the first dose of study medication until 4 weeks after the last dose of study medication; however, it is advised that contraception be used for a total of 16 weeks following the last dose (based on the lifecycle of sperm); methods: a) abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle of the subject; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; b) condom (during non-vaginal intercourse with any partner - male or female) OR c) condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual intercourse with a female) A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] > 40 MlU/mL and estradiol < 40 pg/mL [< 140 pmol/L] is confirmatory); females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods listed below if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment; for most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT; following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method Child-bearing potential and agrees to use one of the contraception methods listed below for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point; female subjects must agree to use contraception until 4 weeks after the last dose of study medication, and must have a negative serum or urine pregnancy test within 14 days prior to the start of dosing Female subjects contraception methods: a) abstinence; b) intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1% failure rate as stated in the product label; c) male partner sterilization prior to the female subject's entry into the study, and this male is the sole partner for that subject; d) double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository) Exclusion Criteria: Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug within 28 days Current use of a prohibited medication or requires any of these medications during treatment with study drug Prior BRAF or mitogen-activated protein kinase kinase (MEK) directed therapy Prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, thyroid cancer (except anaplastic) or any cancer from which the patient has been disease-free for 2 years Any major surgery within the last 3 weeks History of central serous retinopathy (CSR) or retinal vein occlusion (RVO), or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes) Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or stereotactic radiosurgery [SRS]) and these metastatic foci must be stable for 8 weeks prior to starting study drug Corrected QT (QTc) interval >= 480 msec (>= 500 msec for subjects with bundle branch block) Uncontrolled arrhythmias Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system Pregnant or lactating female Unwillingness or inability to follow the procedures required in the protocol Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rodabe N Amaria
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29361468
Citation
Amaria RN, Prieto PA, Tetzlaff MT, Reuben A, Andrews MC, Ross MI, Glitza IC, Cormier J, Hwu WJ, Tawbi HA, Patel SP, Lee JE, Gershenwald JE, Spencer CN, Gopalakrishnan V, Bassett R, Simpson L, Mouton R, Hudgens CW, Zhao L, Zhu H, Cooper ZA, Wani K, Lazar A, Hwu P, Diab A, Wong MK, McQuade JL, Royal R, Lucci A, Burton EM, Reddy S, Sharma P, Allison J, Futreal PA, Woodman SE, Davies MA, Wargo JA. Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial. Lancet Oncol. 2018 Feb;19(2):181-193. doi: 10.1016/S1470-2045(18)30015-9. Epub 2018 Jan 18.
Results Reference
derived
Links:
URL
http://www.mdanderson.org
Description
MD Anderson Cancer Center Website

Learn more about this trial

Dabrafenib and Trametinib Before and After Surgery in Treating Patients With Stage IIIB-C Melanoma With BRAF V600 Mutation

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