Compassionate Use Program to Access Trametinib and Dabrafenib for Patients With BRAF Mutation-positive Metastatic Melanoma

Inclusion Criteria:

Patients eligible for inclusion in this Treatment Plan have to meet all of the following criteria:

1. Has or is willing to give consent to the Treating Physician in accordance with thelocal regulatory requirements, with age at the time of consent ≥18 years.

2. Has confirmed BRAF V600 or other BRAF activating mutation-positive metastaticmelanoma. Histologically Stage IIIC (unresectable) or Stage IV (metastatic)cutaneous melanoma with confirmed BRAF V600E/K positive mutation.

3. All clinical trials that the patient might qualify for have been ruled out.

4. Is receiving care at a clinical site with a Treating Physician who has experiencewith administering investigational agents for the end-stage melanoma population, orthe patient is willing and/or able to travel to a site and receive treatment underthe guidance of physician with this experience. NOTE: The latter option wouldrequire the patient being evaluated in advance by the Treating Physician at theexperienced site and his/her agreement to assume responsibility for the care of thepatient.

5. Is able to retain oral medication and swallow tablets/capsules (appropriateexceptions allowed for patients who are unable to swallow tablets/capsules - this issubject to availability of alternative (liquid) oral formulations).

6. Does not require treatment with any (other) anti-cancer medication (exceptions mightbe allowed and are subject to individual evaluation).

7. For patients with active brain metastases: the patient does not require or isineligible for immediate local treatment.

8. Is not eligible for participation in any of the IMP's ongoing clinical trials or hasrecently completed a clinical trial that has been terminated and, after consideringother options (e.g., trial extensions, amendments, etc.), the clinical team hasdetermined that treatment is necessary and there are no other feasible alternativesfor the patient.

9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 3 (orequivalent) and is in stable clinical condition. NOTE: patient in rapidlydeteriorating clinical condition prior to start of therapy should not be consideredfor this program.

10. Does not require treatment with prohibited concomitant medications

11. Women of childbearing potential must have a negative serum beta-human chorionicgonadotropin (HCG) pregnancy test performed within 14 days prior to startingdabrafenib and trametinib treatment. Subjects with a positive pregnancy test resultmust be excluded from the program. Subjects with a negative pregnancy test resultmust agree to use an effective contraception method as described below throughoutthe treatment period and for a total of 4 months following the last dose oftreatment.

Contraceptive Methods for Females of Childbearing Potential:

• An intrauterine device with a documented failure rate of less than 1% per year

• Vasectomized partner who is sterile prior to the female patient's entry into theCompassionate Use program, and this male is the sole sexual partner for that female.

• Complete abstinence from sexual intercourse for 14 days prior to first dose oftreatment, through the dosing period, and for at least 4 months after the last doseof treatment. Abstinence is only acceptable when in line with the preferred andusual lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,symptothermal, post-ovulation methods, etc.) and withdrawal are not acceptablemethods of contraception.

• Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vaultcaps) with vaginal spermicidal agent (foam/gel/cream/suppository).

Note: Hormonal-based methods (e.g., oral contraceptives) are not permitted as contraception due to potential drug-drug interactions with dabrafenib.

Females Not of Childbearing Potential Non-childbearing potential (i.e., physiologically incapable of becoming pregnant) is defined as any female who has had a documented hysterectomy, bilateral oophorectomy (ovariectomy), bilateral tubal ligation or tubal occlusion, or is post-menopausal.

A practical definition accepts menopause after 1 year without menses with an appropriate clinical profile; e.g., age appropriate, >45 years in the absence of hormone replacement therapy (HRT). In questionable cases, the patient must have a follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L).

Female patients determined not to be post-menopausal must use adequate contraception, as defined immediately above for females of childbearing potential.

Female subjects who are lactating must discontinue nursing prior to the first dose of program treatment and must refrain from nursing throughout the treatment period and for 4 months following the last dose of program treatment.

If a subject becomes pregnant during the treatment period of the program, the treatments should be stopped immediately.

Written patient informed consent must be obtained by the Treating Physician prior to start of treatment in accordance with the applicable local regulatory requirements.

Exclusion Criteria:

Patients eligible for this Treatment Plan must not meet any of the following criteria:

1. Uveal or mucosal melanoma.

2. Female who is pregnant or nursing (patient must discontinue nursing in order toenroll in the program). NOTE: Safety and efficacy in pregnant or nursing women has not been investigated.Inclusion of pregnant or nursing woman may be considered in individually upon reviewby the Novartis Country Pharma Organization Medical Advisor/Director.

3. Patients who have any lab abnormalities or AE/SAEs greater than Grade 3 (CTCAE v5.0)

4. Concurrent treatment with other systemic anti-cancer therapies is not allowed, withthe exception of whole brain radiation and brain radiosurgery. Patients who arecurrently being treated with another systemic anti-cancer therapy (e.g.,chemotherapy, immune, biologic, or targeted therapy) must discontinue use prior toinitiation of treatment with trametinib and dabrafenib. NOTE: Radiation skin injuryhas been reported with concurrent use of dabrafenib and radiation. All AEs/SAEsrelated to WBRT (whole brain radiation) or brain radiosurgery are required toresolve to Grade 1 or less (CTCAE v5.0) prior to start of the Managed Access Programtreatment.

5. Patients who have received prior therapy with a BRAF inhibitor other thandabrafenib. NOTE: Consideration may be given to those patients who have either (1) receivedprior BRAF therapy and there is disease progression in the CNS only or (2)discontinued prior BRAF therapy due to an adverse event that is not likely to recurin response to treatment with Dabrafenib

6. Presence of any malignancy with confirmed activating RAS mutation. NOTE: ProspectiveRAS testing is not required. However, if the results of previous RAS testing areknown, they must be used in assessing eligibility.

7. Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugschemically related to trametinib or dabrafenib, or excipients or to dimethylsulfoxide (DMSO).

8. Any medical conditions or physical examination or clinical laboratory findings whichwould put the patient at high risk for an adverse outcome.

9. Current evidence / risk of retinal vein occlusion (RVO) or central serousretinopathy.

10. Current evidence of cardiovascular risk including any of the following:

• LVEF<LLN

• A QT interval corrected for heart rate using the Bazett's formula greater orequal to 480 msec;

• Clinically significant uncontrolled arrhythmias

• Acute coronary syndromes (including myocardial infarction and unstable angina).

• Congestive heart failure ≥ Class II as defined by New York Heart Association

11. Not able to understand and to comply with treatment instructions and requirements.