Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02231775
Recruitment Status : Recruiting
First Posted : September 4, 2014
Last Update Posted : July 31, 2018
Novartis Pharmaceuticals
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to compare receiving the combination of dabrafenib and trametinib before surgery to having surgery alone in patients with melanoma. The safety of the study drug combination will also be studied.

This is an investigational study. Dabrafenib and trametinib are both FDA approved and commercially available for the treatment of melanoma that is unable to be removed or has spread in patients with V600E/K mutations. The use of the drugs in this study is investigational.

Up to 78 participants will be enrolled in this study. All will take part at MD Anderson.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Dabrafenib Drug: Trametinib Procedure: Surgery Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 78 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)
Actual Study Start Date : October 2014
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Dabrafenib + Trametinib + Surgery

Starting Dose of Dabrafenib: 150 mg by mouth twice a day. Starting Dose of Trametinib: 2 mg by mouth once daily.

At Week 8 after starting Dabrafenib and Trametinib, participant has MRI and/or CT scans of brain to check status of disease. Participant also has CT scans of the chest, abdomen, and pelvis. If scans show disease has not spread or grown, surgery is scheduled. Participant continues taking study drugs until day of surgery. Study drugs continued after surgical recovery for up to an additional 44 weeks.

Drug: Dabrafenib
Starting Dose: 150 mg by mouth twice a day.
Other Names:
  • Tafinlar
  • GSK2118436

Drug: Trametinib
Starting Dose: 2 mg by mouth once daily.
Other Name: GSK1120212

Procedure: Surgery
Participant has MRI and/or CT scans of brain to check status of disease after taking study drugs for 8 weeks. Participant also has CT scans of the chest, abdomen, and pelvis. If scans show disease has not spread or grown, surgical resection of gross disease is scheduled.

Primary Outcome Measures :
  1. Relapse-Free Survival (RFS) Between Participants Who Develop a Pathologic Complete Response (pCR) or do Not Achieve a pCR Following Dabrafenib and Trametinib Neoadjuvant Combination Therapy in Participants with Locally Advanced BRAF V600 Mutated Melanoma [ Time Frame: 2 years ]

    RFS compared between patients with a pCR and patients without a pCR using a two-sided log-rank test. RFS calculated starting from the time of surgery.

    Disease response recorded as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) according to RECIST 1.1 criteria.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
  2. Patients must have histologically or cytologically confirmed Stage IIIB/C melanoma by 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.
  3. Patients must be medically fit enough to undergo surgery as determined by the surgical oncology team.
  4. BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory.
  5. Patients must have measurable disease, defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
  6. Age >/= 18 years.
  7. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
  8. Patients must have organ and marrow function as defined below: 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 ^1; Albumin >/= 2.5 g/dL; Creatinine </=1.5 X ULN 2 OR Calculated creatinine clearance >/= 50 mL/min OR 24-hour urine creatinine clearance >/= 50 mL/min.
  9. 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).
  10. A female subject is eligible to participate if she is of: a) 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 in Inclusion # 12 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. Continued in Inclusion # 11.
  11. Continued from Inclusion # 10. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method. b) Child-bearing potential and agrees to use one of the contraception methods listed in Inclusion # 12 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.
  12. 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:

  1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug within 28 days.
  2. Current use of a prohibited medication or requires any of these medications during treatment with study drug.
  3. Prior BRAF or MEK directed therapy
  4. 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
  5. Any major surgery within the last 3 weeks.
  6. 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).
  7. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
  8. Brain metastases or bone metastases; patients with brain metastases must have received treatment for them (resection or SRS) and these metastatic foci must be stable for 8 weeks prior to starting study drug.
  9. QTc interval >/= 480 msec (>/= 500 msec for subjects with Bundle Branch Block).
  10. Uncontrolled arrhythmias.
  11. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  12. Pregnant or lactating female.
  13. Unwillingness or inability to follow the procedures required in the protocol.
  14. Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
  15. Subjects with known glucose 6 phosphate dehydrogenase (G6PD) deficiency

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02231775

Contact: Jennifer Wargo, MD 713-745-1553

United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: MD Anderson Health Information Specialist    877-632-6789      
Sponsors and Collaborators
M.D. Anderson Cancer Center
Novartis Pharmaceuticals
Study Chair: Jennifer Wargo, MD M.D. Anderson Cancer Center

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: M.D. Anderson Cancer Center Identifier: NCT02231775     History of Changes
Other Study ID Numbers: 2014-0409
NCI-2014-01969 ( Registry Identifier: NCI CTRP )
First Posted: September 4, 2014    Key Record Dates
Last Update Posted: July 31, 2018
Last Verified: July 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Combination therapy
Adjuvant therapy

Additional relevant MeSH terms:
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action