Selumetinib and Akt Inhibitor MK2206 in Treating Patients With Stage III or Stage IV Melanoma Who Failed Prior Therapy With Vemurafenib or Dabrafenib

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT01519427
• Collaborator: (none)
• Enrollment: 2
• Locations: 4
• Arm: 1
• Duration (Months): 16
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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. It is not yet know whether giving selumetinib and Akt inhibitor MK2206 together is an effective treatment for advanced melanoma.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Melanoma; Stage IIIA Melanoma; Stage IIIB Melanoma; Stage IIIC Melanoma; Stage IV Melanoma	Drug: Akt inhibitor MK2206; Drug: selumetinib; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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.

2. To further characterize toxicities of both regimens in these patients who have progressed after BRAF inhibitor therapy.

SECONDARY OBJECTIVES:

1. 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

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (selumetinib and Akt inhibitor MK2206) Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.	Drug: Akt inhibitor MK2206; Given PO; Other Names: MK2206 ; Drug: selumetinib; Given PO; Other Names: ARRY-142886 AZD6244 ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Response [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.

Secondary Outcome Measures

1. Changes in Biomarker Expression [Before initiation of treatment and at 7-14 days, up to 2 years]

   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

2. Progression-free Survival (PFS) [On-study to lesser of date of progression or date of death from any cause, up to 2 years]

   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

3. Overall Survival [On-study date to date of death from any cause, up to 2 years]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 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

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University	Atlanta	Georgia	United States	30322
2	Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
3	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
4	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jeffrey Sosman, H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01519427
• Other Study ID Numbers: NCI-2012-00238; NCI-2012-00238; CDR0000722048; VICCMEL1120; 8867; N01CM00100; 16950; NCT01510444
• First Posted: Jan 27, 2012
• Last Update Posted: Jun 18, 2014
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Melanoma

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from January 2012 through February 2013.
Pre-assignment Detail	Four potential subjects consented. Two were ineligible.

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Period Title: Overall Study
STARTED	2
COMPLETED	0
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Overall Participants	2
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44 (14)
Sex: Female, Male (Count of Participants)
Female	1 50%
Male	1 50%
Region of Enrollment (participants) [Number]
United States	2 100%

Outcome Measures

1. Primary Outcome

Title	Objective Response
Description	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.
Time Frame	On-treatment date to date of progressive disease (assessed up to 30 days after end of treatment)

Outcome Measure Data

Analysis Population Description

All patients with best overall response data; patients are excluded if best overall response data is missing or if the patient is non-evaluable for best overall response.

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Measure Participants	2
Complete response	0 0%
Partial response	0 0%
Progressive disease	1 50%
Stable disease	1 50%

2. Secondary Outcome

Title	Changes in Biomarker Expression
Description	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
Time Frame	Before initiation of treatment and at 7-14 days, up to 2 years

Outcome Measure Data

Analysis Population Description

This clinical trial was terminated early. The investigators did not perform any biomarker expression analyses.

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Measure Participants	0

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	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
Time Frame	On-study to lesser of date of progression or date of death from any cause, up to 2 years

Outcome Measure Data

Analysis Population Description

All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where either death or progression is an event, with censoring for non-progressed, non-expired patients at greater of off-study date or last known date alive.

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Measure Participants	2
Median (Full Range) [days]	105

4. Secondary Outcome

Title	Overall Survival
Description	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).
Time Frame	On-study date to date of death from any cause, up to 2 years

Outcome Measure Data

Analysis Population Description

All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where death is an event, with censoring for non-expired patients at greater of off-study date or last known alive date.

Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
Measure Participants	2
Median (Full Range) [days]	153

Adverse Events

Time Frame	day 0 through day 168 (week 24)
Arm/Group Title	Treatment (Selumetinib and Akt Inhibitor MK2206)
Arm/Group Description	Patients receive selumetinib PO BID on days 1-21 and Akt inhibitor MK2206 PO once weekly.
All Cause Mortality
	Treatment (Selumetinib and Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Selumetinib and Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	1/2 (50%)
Blood and lymphatic system disorders
anemia	1/2 (50%)	1
Musculoskeletal and connective tissue disorders
pelvic pain	1/2 (50%)	1
Renal and urinary disorders
Urinary tract obstruction	1/2 (50%)	1
acute renal failure	1/2 (50%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Selumetinib and Akt Inhibitor MK2206)
	Affected / at Risk (%)	# Events
Total	2/2 (100%)
Blood and lymphatic system disorders
lymphocyte count decreased	1/2 (50%)	2
anemia	1/2 (50%)	5
Cardiac disorders
electrocardiogram QT corrected interval prolonged	1/2 (50%)	1
Atrial fibrillation	1/2 (50%)	1
Eye disorders
blurred vision	1/2 (50%)	1
pain eye	1/2 (50%)	2
Gastrointestinal disorders
vomiting	1/2 (50%)	1
Diarrhea	1/2 (50%)	1
General disorders
pain	2/2 (100%)	2
chills	1/2 (50%)	1
fatigue	1/2 (50%)	2
Infections and infestations
bladder infection	1/2 (50%)	1
urinary tract infection	1/2 (50%)	1
Investigations
alanine aminotransferase increased	2/2 (100%)	6
aspartate aminotransferase increased	1/2 (50%)	2
creatinine increased	1/2 (50%)	1
Metabolism and nutrition disorders
anorexia	1/2 (50%)	1
hyperglycemia	2/2 (100%)	5
hypoalbuminemia	1/2 (50%)	3
hypokalemia	1/2 (50%)	2
hyponatremia	1/2 (50%)	1
Musculoskeletal and connective tissue disorders
pain in extremity	1/2 (50%)	1
pain extremity	1/2 (50%)	1
Arthralgia	1/2 (50%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
tumor pain	1/2 (50%)	1
Nervous system disorders
Nervous system disorders - Other	1/2 (50%)	1
Psychiatric disorders
Depression	1/2 (50%)	1
Renal and urinary disorders
hematuria	1/2 (50%)	1
Skin and subcutaneous tissue disorders
rash maculo-papular	1/2 (50%)	1
Vascular disorders
lymphedema	1/2 (50%)	1

Limitations/Caveats

Because this study terminated early due to slow accrual, data were available for only the two eligible patients that enrolled before study closure.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.