A Phase 1B Clinical Trial of Trametinib plus Digoxin in Patients with Unresectable or Metastatic BRAF wild-type Melanoma

Summary

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.


endpoints
* 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.

* 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.

* 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 drugs.

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

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

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

Participant Eligibility

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. Failure, ineligible or intolerant or approved therapies.

4. ECOG Performance status 0-1.

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 < 2.0 mg/dL
- cardiac ejection fraction > 50%
- QTc < 480msec
- Hemoglobin >9g/dL
- PT/INR and PTT <1.5 x institutional upper limit of normal
- Creatinine clearance >30 mL/min
- Albumin >2.5g/dL
- Potassium 3.4 x 4.5 mmol/L
- Magnesium 1.6 x 2.6 mg/dL

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 4 months 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.