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

Conditions:Skin Cancer
Therapuetic Areas:Oncology
Age Range:19 - Any
Start Date:July 2014
End Date:February 23, 2017

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The study is a prospective, single-arm, one-site therapeutic trial of the combination of
trametinib plus digoxin for advanced melanoma. endpoints are toxicities assessed by nCi CTCae
v4.1 within the first 8 weeks, responses measured by ReCiST v1.1 criteria every 8 weeks with
scans and exams, tumor sensitivity to the drug combination quantified by tumor regressions in
nSG mice, and correlations of response with tumor sensitivity, BRaF status, MaPK inhibitor
exposure history, and tumor sodium pump expression.

Treatment Dosage and administration

Study Drugs:

1. Trametinib (2mg) will be administered orally on a daily basis.

2. Digoxin (0.25mg) will be administered orally on a daily basis.

on a 8-week cycle, duration of treatment can last from 8 to 104 weeks.


1. Toxicities will be assessed via nCi's CTCae v4.1 toxicity criteria. DLTs will be defined
based on the rate of drug-related (definitely or probably) grade 3-5 adverse events
experienced within the first 8 weeks of study treatment. The MTD will be exceeded if
more than 20% of patients on the study experience DLTs.

2. Responses will be measured by ReCiST v1.1 every 8 weeks. Response duration will be
defined as time from first documented response until disease progression. PFS is time
from treatment until disease progression.

3. Patient tumor sensitivity to the drug combination will be quantified by the amount of
subcutaneous established tumor growth inhibition in nSG mice by 5d/week oral gavage with

4. Tumor nRaS status will be determined by tumor Dna extraction, PCR amplification of exons
and Sanger sequencing of nRaS.

5. History of prior MaPK inhibitor therapies will document MeK inhibitor exposures.

6. Sodium pump subunit expression will be analyzed by pretreatment tumor
immunohistochemistry and a qualitative 0 to 3+ grading system.

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.
We found this trial at
2201 Inwood Rd
Dallas, Texas 75235
(214) 645-8300
Phone: 214-648-4180
U.T. Southwestern Medical Center The story of UT Southwestern Medical Center is one of commitment...
Dallas, TX
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