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|NCT02231775 : Neoadjuvant and Adjuvant Dabrafenib and Trametinib in Patients With Clinical Stage III Melanoma (Combi-Neo)|
|Ages||Min: 18 Years Max: N/A|
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
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
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. 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
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
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