Recurrent MelanomaPhase 2NCT01519427
Selumetinib and Akt Inhibitor MK2206 in Treating Patients With Stage III or Stage IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib
A Phase 2 study testing Akt inhibitor MK2206, selumetinib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIIA Melanoma, run by National Cancer Institute (NCI) at 4 sites in United States.
Trial summary
This phase II trial studies how well selumetinib and Akt inhibitor MK2206 works in treating patients with stage III or stage IV melanoma who failed prior therapy with vemurafenib or dabrafenib. Selumetinib and Akt inhibitor MK2206 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma
- What is being tested?
- Akt inhibitor MK2206, selumetinib and laboratory biomarker analysis
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 2 participants
- Where
- 4 sitesUnited States
- Study dates
- Jan 2012to May 2013
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients must have incurable unresectable stage III or IV histologically confirmed Melanoma with V600-mutant BRAF disease and must have progressed after therapy on selective BRAF inhibitor; all patients must have biopsiable tumor and a biopsy must be performed with the collection of FFPE and if possible FF prior to initiation of treatment on this protocol; archival tumor tissue must also be obtained if at all available; this required biopsy will not be necessary if a previous biopsy of progressing tumor after selective BRAF therapy had already been obtained and is adequate
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan
- Patients must have received prior therapy and progressed following a selective BRAF inhibitor (i.e., vemurafenib, dabrafenib, LGX818, etc.); patients must have completed prior therapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation therapy; all treatment related toxicity must have resolved to grade 2 or less as well; patients may initiate the protocol treatment at 48 hours following the completion of BRAF inhibitor; patients must have had no more than 2 prior chemotherapy regimens; patients cannot receive chemotherapy after the BRAF inhibitor treatment and prior to enrollment on this protocol; up to two prior immunotherapy regimens for advanced disease are allowed and one may be given between BRAF inhibitor therapy and this trial
- Patients must not be refractory to the BRAF inhibitor; patients must demonstrate some degree of tumor regression initially on BRAF inhibitor prior to progression; (tumor regression does not require RECIST objective response); they cannot have progressive disease at the time of first evaluation (4 or 8 weeks) on the BRAF inhibitor
- Baseline Ophthalmologic exam must be done at screening to include slit lamp exam and fundoscopy; an OCT scan should be considered in case of retinal abnormality at exam
- Life expectancy of greater than or equal to 3 months
Show all 33Show fewer
- Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (Karnofsky ≥ 70%)
- Absolute neutrophil count ≥ 1,500 mm³
- Hemoglobin ≥ 9.0 g/dL (patients may be transfused to achieve level)
- Platelet count ≥ 100,000/μL
- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase(SGPT) < 2.5 X upper limit of normal (ULN)
- Total bilirubin < 1.5 mg/dL
- Serum creatinine ≤ 2.0 mg/dL OR creatinine clearance > 50 mL/min, determined by 24-hour urine collection
- Fasting blood glucose < 160 mg/dL OR
- HgbA1C < 8% disease (uncontrolled diabetes)
- 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 and for the duration of study participation
- Patients must have a negative serum pregnancy test prior to being eligible to take part in the study
- Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD6244 hydrogen sulfate and MK-2206
- Baseline echocardiogram or MUGA must be performed at screening and patients must have LVEF > 55%; additionally baseline EKG must be performed and corrected QTc must be < 480 milliseconds
- Baseline electrocardiogram(EKG) must be performed and corrected QTc must be < 480 milliseconds
- Patients must be able to swallow tablets and capsules to participate in the study
- No history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 hydrogen sulfate, MK-2206, or other agents used in the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, psychiatric illness/social situations that would limit compliance with study requirements, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension (BP >= 150/95 despite optimal therapy), baseline ejection fraction < 55% or the lower limit of institutional normal, heart failure NYHA Class II or above, prior or current cardiomyopathy, atrial fibrillation with heart rate > 100 bpm, and uncontrolled angina (Canadian Cardiovascular society grade II-IV despite medical therapy); acute coronary syndrome within 6 months from starting therapy
- Patients must have completed prior therapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation therapy
- All treatment-related toxicity must have resolved to grade 2 or less
- No patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Patients must have had no more than 2 prior chemotherapy regimens
- Patients cannot receive chemotherapy after the BRAF-inhibitor treatment and prior to enrollment on this protocol
- Up to two prior immunotherapy regimens for advanced disease are allowed and one may be given between BRAF-inhibitor therapy and this trial
- Patients may not be receiving any other investigational agents at the same time as study treatment
- Patients receiving medications or substances that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) are ineligible
- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- Patients must not have received chemotherapy in the time between the failure of BRAF inhibitor and the enrollment onto the present trial
Who cannot join
None listed.
Trial locations and contacts
4 sites in 1 country.
United States4 sites
Emory University
Atlanta, Georgia, 30322
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, 37232
Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Virginia Commonwealth University/Massey Cancer Center
Richmond, Virginia, 23298
About this study
Official title: A Phase II Trial of MAP Kinase Inhibition With AZD6244 Hydrogen Sulfate in Combination With MK-2206 (Akt Inhibitor) in Patients With BRAF V600-Mutant Advanced Melanoma Whose Disease Has Progressed on Prior Therapy With a Selective BRAF Inhibitor (i.e., Vemurafenib, Dabrafenib, LGX818)
This phase II trial studies how well selumetinib and Akt inhibitor MK2206 works in treating patients with stage III or stage IV melanoma who failed prior therapy with vemurafenib or dabrafenib. Selumetinib and Akt inhibitor MK2206 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether giving selumetinib and Akt inhibitor MK2206 together is an effective treatment for advanced melanoma.
Read the detailed description
PRIMARY OBJECTIVES:
- To determine the frequency of objective clinical responses by RECIST 1.1 for these melanoma patients who have previously progressed on selective BRAF inhibitors when treated with MEK inhibitor, AZD6244 hydrogen sulfate plus Akt inhibitor, MK-2206.
II. To further characterize toxicities of both regimens in these patients who have progressed after BRAF inhibitor therapy.
SECONDARY OBJECTIVES:
- With required fresh pretreatment biopsies on all patients, we plan to characterize the molecular state (genetic and proteomic) associated with BRAF inhibitor resistance. This may include an analysis of pathway activation, PI3/Akt or MAP kinase pathway; loss of expression of PTEN, secondary mutations in BRAF, other mutations in the MAP kinase pathway (NRAS, KRAS, HRAS, CRAF, MEK), activation of other RTKs (amplification, over expression, phosphorylation).
OUTLINE:
Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 and Akt inhibitor MK2206 PO once weekly.
After completion of study treatment, patients are followed up every 12 weeks.
- Conditions
- Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
- Being tested
- Akt inhibitor MK2206, selumetinib, laboratory biomarker analysis
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Akt inhibitor MK2206Drug
Also called MK2206
Given PO
selumetinibDrug
Also called ARRY-142886, AZD6244
Given PO
laboratory biomarker analysisOther
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| Treatment (selumetinib and Akt inhibitor MK2206) | Experimental | Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly. Receives: Drug: Akt inhibitor MK2206; Drug: selumetinib; Other: laboratory biomarker analysis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response
Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) >=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD.
Measured: On-treatment date to date of progressive disease (assessed up to 30 days after end of treatment)
Secondary outcomes (3)
Changes in Biomarker Expression
Pre-treatment tumor biopsy tissue and blood and day 7-14 tumor biopsy tissue and blood will be examined by immunohistochemistry for expression and phosphorylation of the proteins pERK, pMEK, pAKT, Ki67, pRpS6, CRAF, cyclin D, PDGFr, pPDGFr. IGFr1, and COT/Tp12 for changes from baseline
Measured: Before initiation of treatment and at 7-14 days, up to 2 years
Progression-free Survival (PFS)
Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: >= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions
Measured: On-study to lesser of date of progression or date of death from any cause, up to 2 years
Overall Survival
Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details).
Measured: On-study date to date of death from any cause, up to 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2012 (estimated)
- Study startJan 2012
- Primary completionMay 2013
- Study completionMay 2013
Why it stopped: Study terminated due to slow accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Recurrent MelanomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 2 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Jeffrey Sosman, Principal investigator, H. Lee Moffitt Cancer Center and Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01519427
- Sponsor's protocol ID
- NCI-2012-00238
- Other IDs
- NCI-2012-00238, CDR0000722048, VICCMEL1120, 8867, N01CM00100, 16950
- Status last verified
- Jan 2014
- First submitted
- 25 Jan 2012
- Last updated
- 18 Jun 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 18 Jun 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Trial of MAP Kinase Inhibition With AZD6244 Hydrogen Sulfate in Combination With MK-2206 (Akt Inhibitor) in Patients With BRAF V600-Mutant Advanced Melanoma Whose Disease Has Progressed on Prior Therapy With a Selective BRAF Inhibitor (i.e., Vemurafenib, Dabrafenib, LGX818)
- ClinicalTrials.gov ID
- NCT01519427
- Acronym / sponsor ID
- NCI-2012-00238
- Conditions
- Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study terminated due to slow accrual
- Enrolment
- 2 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- Jan 2012
- Primary completion
- May 2013 (actual)
- Study completion
- May 2013 (actual)
- First posted
- 27 Jan 2012 (estimated)
- Results
- Posted 18 Jun 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial studies how well selumetinib and Akt inhibitor MK2206 works in treating patients with stage III or stage IV melanoma who failed prior therapy with vemurafenib or dabrafenib. Selumetinib and Akt inhibitor MK2206 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet know whether giving selumetinib and Akt inhibitor MK2206 together is an effective treatment for advanced melanoma.
Detailed description
PRIMARY OBJECTIVES:
- To determine the frequency of objective clinical responses by RECIST 1.1 for these melanoma patients who have previously progressed on selective BRAF inhibitors when treated with MEK inhibitor, AZD6244 hydrogen sulfate plus Akt inhibitor, MK-2206.
II. To further characterize toxicities of both regimens in these patients who have progressed after BRAF inhibitor therapy.
SECONDARY OBJECTIVES:
- With required fresh pretreatment biopsies on all patients, we plan to characterize the molecular state (genetic and proteomic) associated with BRAF inhibitor resistance. This may include an analysis of pathway activation, PI3/Akt or MAP kinase pathway; loss of expression of PTEN, secondary mutations in BRAF, other mutations in the MAP kinase pathway (NRAS, KRAS, HRAS, CRAF, MEK), activation of other RTKs (amplification, over expression, phosphorylation).
OUTLINE:
Patients receive selumetinib orally (PO) twice daily (BID) on days 1-21 and Akt inhibitor MK2206 PO once weekly.
After completion of study treatment, patients are followed up every 12 weeks.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (selumetinib and Akt inhibitor MK2206) | Experimental | Drug: Akt inhibitor MK2206, Drug: selumetinib, Other: laboratory biomarker analysisPatients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (33 listed)
- Patients must have incurable unresectable stage III or IV histologically confirmed Melanoma with V600-mutant BRAF disease and must have progressed after therapy on selective BRAF inhibitor; all patients must have biopsiable tumor and a biopsy must be performed with the collection of FFPE and if possible FF prior to initiation of treatment on this protocol; archival tumor tissue must also be obtained if at all available; this required biopsy will not be necessary if a previous biopsy of progressing tumor after selective BRAF therapy had already been obtained and is adequate
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan
- Patients must have received prior therapy and progressed following a selective BRAF inhibitor (i.e., vemurafenib, dabrafenib, LGX818, etc.); patients must have completed prior therapy a minimum of 4 weeks previously (6 weeks for BCNU and/or mitomycin C), 4 weeks for prior biologic therapy, and 2 weeks for localized radiation therapy; all treatment related toxicity must have resolved to grade 2 or less as well; patients may initiate the protocol treatment at 48 hours following the completion of BRAF inhibitor; patients must have had no more than 2 prior chemotherapy regimens; patients cannot receive chemotherapy after the BRAF inhibitor treatment and prior to enrollment on this protocol; up to two prior immunotherapy regimens for advanced disease are allowed and one may be given between BRAF inhibitor therapy and this trial
- Patients must not be refractory to the BRAF inhibitor; patients must demonstrate some degree of tumor regression initially on BRAF inhibitor prior to progression; (tumor regression does not require RECIST objective response); they cannot have progressive disease at the time of first evaluation (4 or 8 weeks) on the BRAF inhibitor
- Baseline Ophthalmologic exam must be done at screening to include slit lamp exam and fundoscopy; an OCT scan should be considered in case of retinal abnormality at exam
Key exclusion criteria (0 listed)
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 |
|---|---|---|
| Akt inhibitor MK2206Also: MK2206Given PO | Drug | Treatment (selumetinib and Akt inhibitor MK2206) |
| selumetinibAlso: ARRY-142886, AZD6244Given PO | Drug | Treatment (selumetinib and Akt inhibitor MK2206) |
| laboratory biomarker analysisCorrelative studies | Other | Treatment (selumetinib and Akt inhibitor MK2206) |
Primary outcome
Objective Response
Time frame: On-treatment date to date of progressive disease (assessed up to 30 days after end of treatment)
Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) >=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), >=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR>PR>SD>PD.
3 secondary outcomes
Changes in Biomarker Expression
Time frame: Before initiation of treatment and at 7-14 days, up to 2 years
Progression-free Survival (PFS)
Time frame: On-study to lesser of date of progression or date of death from any cause, up to 2 years
Overall Survival
Time frame: On-study date to date of death from any cause, up to 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jun 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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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.
Jeffrey Sosman principal investigator
H. Lee Moffitt Cancer Center and Research Institute
4 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Akt inhibitor MK2206, selumetinib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIIA Melanoma, run by National Cancer Institute (NCI) at 4 sites 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 33 inclusion and 0 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: stopped early, as of the sponsor's last update on 18 Jun 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 4 sites 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jun 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Objective Response (time frame: On-treatment date to date of progressive disease (assessed up to 30 days after end of 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 18 Jun 2014.