MelanomaPhase 1NCT02138292
A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma
A Phase 1 study testing Trametinib (2mg)/Digoxin (.25mg) in people with Melanoma, run by University of Texas Southwestern Medical Center at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Trametinib (2mg)/Digoxin (.25mg)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2014to 23 Feb 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 17Show fewer
- 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.
Who cannot join
- 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.
- Active infection with hepatitis B or C or HIV.
- 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.
- 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.
- 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.
- History of predisposition to retinal vein occlusion or central serous retinopathy.
- Inability to assess BRAF or NRAS mutation status. Hypersensitivity to digoxin.
- Wolff-Parkinson White syndrome or AV block or sinus node dysfunction.
Trial locations and contacts
1 site in 1 country.
About this study
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
Read more
Study Drugs:
- Trametinib (2mg) will be administered orally on a daily basis.
- 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.
Read the 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.
- Conditions
- Melanoma
- Being tested
- Trametinib (2mg)/Digoxin (.25mg)
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Trametinib (2mg)/Digoxin (.25mg)Drug
- Trametinib (2mg) will be administered orally on a daily basis.
- 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.
| Study group | Role | What they receive |
|---|---|---|
| Trametinib (2mg)/Digoxin (0.25mg) | Experimental | 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. Receives: Drug: Trametinib (2mg)/Digoxin (.25mg) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose Limiting Doxicities (DLTs)
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.
Measured: within the first 8 weeks of study treatment
Secondary outcomes (1)
Response Rate
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.
Measured: up to 104 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 May 2014 (estimated)
- Study startJul 2014
- Primary completion23 Feb 2017
- Study completion23 Feb 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for MelanomaStudies of the same condition, open and under way.
- More trials run by University of Texas Southwestern Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 27 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Arthur Frankel, MD, Principal investigator, Professor Internal Medicine-Hematology Oncology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02138292
- Sponsor's protocol ID
- STU 012014-007
- Status last verified
- May 2018
- First submitted
- 12 May 2014
- Last updated
- 15 May 2018
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 15 May 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1B Clinical Trial of Trametinib Plus Digoxin in Patients With Unresectable or Metastatic BRAF Wild-type Melanoma
- ClinicalTrials.gov ID
- NCT02138292
- Acronym / sponsor ID
- STU 012014-007
- Conditions
- Melanoma
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- University of Texas Southwestern Medical CenterUniversity, hospital or other
- Study start
- Jul 2014
- Primary completion
- 23 Feb 2017 (actual)
- Study completion
- 23 Feb 2017 (actual)
- First posted
- 14 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Trametinib (2mg) will be administered orally on a daily basis.
- 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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Trametinib (2mg)/Digoxin (0.25mg) | Experimental | Drug: Trametinib (2mg)/Digoxin (.25mg)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. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- 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.
- leukocytes ≥ 2,000/mcL
Key exclusion criteria (8 listed)
- 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.
- Active infection with hepatitis B or C or HIV.
- 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.
- 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.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Trametinib (2mg)/Digoxin (.25mg)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. | Drug | Trametinib (2mg)/Digoxin (0.25mg) |
Primary outcome
Dose Limiting Doxicities (DLTs)
Time frame: within the first 8 weeks of study treatment
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.
1 secondary outcome
Response Rate
Time frame: up to 104 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 May 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arthur Frankel, MD principal investigator
Professor Internal Medicine-Hematology Oncology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Trametinib (2mg)/Digoxin (.25mg) in people with Melanoma, run by University of Texas Southwestern Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 May 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dose Limiting Doxicities (DLTs) (time frame: within the first 8 weeks of study treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 May 2018.