Know Cancer

or
forgot password

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)


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma

Thank you

Trial Information

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)


PRIMARY OBJECTIVES:

I. 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:

I. 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.


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

Type of Study:

Interventional

Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response (CR or PR)

Outcome Time Frame:

After the first 12 patients have been treated

Safety Issue:

No

Principal Investigator

Jeffrey Sosman

Investigator Role:

Principal Investigator

Investigator Affiliation:

H. Lee Moffitt Cancer Center and Research Institute

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-00238

NCT ID:

NCT01519427

Start Date:

January 2012

Completion Date:

Related Keywords:

  • Recurrent Melanoma
  • Stage IIIA Melanoma
  • Stage IIIB Melanoma
  • Stage IIIC Melanoma
  • Stage IV Melanoma
  • Melanoma

Name

Location

Cancer Institute of New JerseyNew Brunswick, New Jersey  08901
Vanderbilt UniversityNashville, Tennessee  37232-6305
Emory UniversityAtlanta, Georgia  30322
Virginia Commonwealth University/Massey Cancer CenterRichmond, Virginia  23298