Patient case: 38-year-old male with melanoma; genetic feature: BRAF (K601E)

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

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.

Detailed description: Study Drug Administration:
  If participant is found to be eligible to take part in this study, participant will receive dabrafenib and trametinib for 8 weeks and then participant will have surgery. Participant will not have surgery if the disease has grown or spread during the 8 weeks participant has received the study drugs. After participant has recovered from surgery and are eating and drinking normally, participant will continue taking the study drugs for up to an additional 44 weeks.
  Participant will take capsules of dabrafenib twice a day and tablets of trametinib one time every day. The dabrafenib and trametinib should be taken at the same time in the morning, and the second dose of dabrafenib should be taken about 12 hours later. Participant should take the capsules and tablets with a cup (about 8 ounces) of water every time, either 1 hour before or 2 hours after eating a meal. Participant will stop taking the study drugs 1 day before surgery, and resume taking the study drugs within 1 week after surgery.
  Study Visits:
  Participants will have tissue collected during surgery for routine tests.
  Cycle 1 will be 8 weeks (before surgery) and Cycle 2 will be 44 weeks (after surgery). During Cycle 1, participant will have study visits at Weeks 1, 3, 5, and 8. During Cycle 2, participant will have study visits once a month.
  At every visit, blood (about 2 tablespoons) will be drawn for routine tests and participant will have a physical exam.
  Blood (about 2 tablespoons) will be drawn at Weeks 1, 3, 5, 8, 12, 24, 36, and 48 for tests that measure whether a certain gene is expressed or not and to check participant's immune system function. Blood (about 2 tablespoons) will be drawn before participant has surgery and at Weeks 12, 24, 36, and 48. If participant is taken off the study early, participant will have this blood drawn at that time as well.
  During Cycle 1, the following tests and procedures will also be performed:
  If participant's doctor thinks it can be safely performed, at Week 3 after starting dabrafenib/trametinib, participant will have a tumor biopsy to check how the study drugs are affecting participant's immune system cells and the way participant's genes are being expressed in response to the study drugs. If the location of the melanoma is not easily biopsied in the clinic, a doctor in interventional radiology may perform the biopsy outside the clinic at Week 3 instead. The type of biopsy participant has will depend on the location and size of the tumor.
  At Week 8 after starting dabrafenib/trametinib, participant will have MRI and/or CT scans of participant's brain to check the status of the disease. Participant will also have CT scans of the chest, abdomen, and pelvis. If the scans show the disease has not spread or grown, participant will be scheduled for surgery. Participant will continue taking the study drugs until the day of participant's surgery.
  During Cycle 2, the following tests and procedure will be performed in addition to the monthly blood draws and physical exams:
  At Weeks 12, 24, 36, and 48, participant will have an EKG and an ECHO to check participant's heart function.
  At Weeks 20, 32, and 44, participant will have MRI and/or CT scans of participant's brain, as well as CT scans of the chest, abdomen, and pelvis, to check the status of the disease.
  Length of Treatment:
  You may receive the study drugs for up to 1 year. Participant will be taken off study if the disease gets worse, if the study doctor thinks it is in participant's best interest, or if participant is unable to follow study directions. Participant will be taken off study if intolerable side effects occur.
  Participation on the study will be over after participant's last study visit.
  Follow-Up Visits:
  If participant stops taking the study drugs before participant has completed the 52-week schedule, participant has follow-up visits at least every 3 months after surgery for 1 year. The following tests and procedures will be performed:
  -  Participant will have a physical exam.
  -  Blood (about 2 tablespoons) will be drawn for routine tests.
  -  Participant will have CT scans and/or MRI to check the status of the disease.
  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.

Eligibility: 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. 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.
  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.
  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; patients who have received prior interferon are eligible.
  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
  16. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels.

Relevance to patient case: not relevant