Ignite Creation Date:
2025-12-24 @ 3:51 PM
Ignite Modification Date:
2025-12-25 @ 10:47 PM
Study NCT ID:
NCT02138292
Status:
COMPLETED
Last Update Posted:
2018-05-15
First Post:
2014-05-12
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma
Sponsor:
University of Texas Southwestern Medical Center
Organization:
Study Overview
Official Title:
A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma
Status:
COMPLETED
Status Verified Date:
2018-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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
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 drugs.
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.
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
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 drugs.
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.
Detailed Description:
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.
* 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.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: