A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma

Primary Objectives:

- To describe the toxicities and estimate the frequency of dose limiting toxicities (DLTs)
of digoxin in combination with trametinib in advanced melanoma patients and estimate the
frequency of DLTs.

- To measure the response rate, response duration and progression free survival (PFS) of
digoxin plus trametinib in advanced melanoma.

Secondary Objectives:

- To correlate NSG xenograft sensivity to the drug combination with clinical response in
the same patient.

- To compare response rates in MAPK inhibitor naive versus refractory patients and NRAS
mutant versus wild-type patients and for sodium pump 3 subunit high tumor expression
versus low tumor expression patients.

Rationale: Having established cell culture and xenograft systems for studying patient
melanoma samples, the researchers were able to grow tumors in vitro and in vivo from single
cells and found a correlation of tumor metastatic behavior in immunocompromised mice and in
patients. Recently they have extended the experiments to examine melanoma sensitivity to
novel compounds. In screens of FDA approved drugs, they found several cardenolides including
digoxin that reproducibly exhibited greater toxicity to primary human melanomas as compared
to a range of normal human cells. They then examined the anti-tumor efficacy against primary
human melanomas growing in vivo as xenografts. While trametinib, vemurafenib, and digoxin and
digitoxin individually slowed the growth of human melanomas xenografts, they did not cause
tumor regression. However, the combination of digoxin or digitoxin and trametinib caused
substantial tumor regression using melanomas obtained from multiple patients, some with BRAF
mutations and some without. The effects were dramatically better than trametinib, digoxin,
digitoxin or vemurafenib alone. No difference in efficacy for the combination was seen in
BRAF mutant and BRAF wild-type samples.

Inclusion Criteria:

- 1. Histologic diagnosis of unresectable or metastatic melanoma. For unknown primary
disease, diagnosis of metastatic disease by cytology FNA is not acceptable. BRAF
wild-type confirmed, and NRAS mutation assessed.

2. Age > 18 years.

3. Any number of prior systemic therapeutic regimens for unresectable stage III or
stage IV melanoma. This includes chemotherapy, immunotherapy, pathway inhibitors,
biochemotherapy, or investigational treatments. Patients may also have received
therapies in the adjuvant setting.

4. ECOG Performance status 0-2.

5. Adequate organ and marrow function as defined below:

- leukocytes ≥ 2,000/mcL

- absolute neutrophil count ≥ 1,000/mcL

- platelets ≥ 75,000/mcl

- total bilirubin < 3 x institutional upper limit of normal

- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal

- creatinine < 1.5 mg/dL

- cardiac ejection fraction > 50%

- QTc < 480msec

6. Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry, for
the duration of study participation, and for 90 days following completion of therapy.
Should a woman become pregnant or suspect she is pregnant while participating in this
study, she should inform her treating physician immediately. A female of child-bearing
potential is any woman (regardless of sexual orientation, having undergone a tubal
ligation, or remaining celibate by choice) who meets the following criteria: Has not
undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally
postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in
the preceding 12 consecutive months).

7. All sites of disease must be evaluated within 4 weeks prior to beginning therapy.
Patients must have measurable disease as defined by RECIST v1.1.

8. Ability to understand and the willingness to sign a written informed consent.

9. Patients must be willing to undergo tumor biopsy pretreatment and at relapse.

Exclusion Criteria:

1. Subjects who have had chemotherapy or radiotherapy or any systemic therapy for
melanoma within 2 weeks prior to entering the study or those who have not recovered
from adverse events due to agents administered more than 2 weeks earlier. No
concomitant therapy is allowed including IL2, interferon, ipilimumab, anti-PD-1 or
anti-PD-L1 antibody, cytotoxic chemotherapy, immunosuppressive agents, or other
investigational therapies.

2. Active infection with hepatitis B or C or HIV.

3. Subjects with active CNS disease are excluded. Patient with brain metastases
previously treated with surgery or radiation therapy and with confirmed SD for >4
weeks are allowed.

4. Patients are excluded if they have a history of any other malignancy from which the
patient has been disease-free for less than 2 years, with the exception of adequately
treated and cured basal or squamous cell skin cancer, superficial bladder cancer or
carcinoma in situ of the cervix.

5. Uncontrolled inter-current illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements. Cardiac symptoms or events within 24 weeks.

6. History of predisposition to retinal vein occlusion or central serous retinopathy.

7. Inability to assess BRAF or NRAS mutation status. Hypersensitivity to digoxin.

8. Wolff-Parkinson White syndrome or AV block or sinus node dysfunction.