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Trametinib

Protein Kinase Inhibitors

Enzyme Inhibitors

Trametinib orally once daily (PO QD) and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Akt Inhibitor GSK2141795

Laboratory Biomarker Analysis

Nitin Jain

This phase II trial studies how well trametinib and protein kinase B (Akt) inhibitor GSK2141795 work in treating patients with acute myeloid leukemia. Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the proportion of patients achieving complete remission (CR) or CR with incomplete recovery of platelets (CRp) as best response within 4 cycles of therapy of trametinib in combination with GSK2141795 (Akt inhibitor GSK2141795) in acute myeloid leukemia (AML) patients with rat sarcoma (RAS) mutations.

SECONDARY OBJECTIVES:

I. To determine the disease-free survival of patients achieving CR/CRp. II. To determine the duration of response of patients achieving CR/CRp. III. To determine the toxicity profile of trametinib in combination with GSK2141795 in this patient population.

IV. To determine the biologic effects of trametinib in combination with GSK2141795 on leukemia cells.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) and Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Acute Myeloid Leukemia

A Phase 2 Study of MEK 1/2 Inhibitor Trametinib in Combination With AKT Inhibitor GSK2141795 in Acute Myeloid Leukemia (AML) With RAS Mutations

Change in total and phospho-proteins assessed by densitometric quantitative data by western blot analysis, or mean fluorescent intensities by flow cytometry and will be assessed for each patient for all time points and graphically plotted for each dose level.

The 95% confidence interval will be assessed.

Proportion of participants achieving complete remission (CR) or CR with incomplete recovery of platelets (CRp) as best response within 4 cycles of therapy. Complete Response (CR): Disappearance all clinical \&/or radiologic evidence of disease. Neutrophil count ≥ 1.0x10\^9/L; Platelet count ≥ 100x109/L; Normal bone marrow differential (≤ 5% blasts); No extra-medullary leukemia. Complete Remission without Platelet Recovery (CRp): Peripheral blood \& bone marrow results as for CR, but platelet counts of \< 100x10\^9/L. Partial Remission (PR): Blood count recovery as for CR, but decrease of at least 50% in % marrow blasts to \>5% to 25% in bone marrow aspirate. Morphologic leukemia-free state: Normal marrow differential (\<5% blasts); neutrophil \& platelet counts not considered.95% confidence interval will be estimated for the combination regimen.

National Cancer Institute (NCI) published standardized definitions for adverse events (AEs), known as Common Terminology Criteria for Adverse Events (CTCAE), to describe the severity of organ toxicity for those receiving cancer therapy. Toxicity data is summarized by number of incidents experienced while participants were on study using most frequently reported AEs regardless of grade or relatedness as assessed by CTCAE version 4.0. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved. Death (Grade 5) is used for some of the criteria to denote a fatality. For full adverse event reporting see Adverse Event Section. Data collection over first four cycles (16 weeks) of therapy, with evaluation after full cycle of therapy (28 days), continuing AE collection until 28 days following last study drug dose.

Estimated using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

Estimated disease-free survival period using the Kaplan-Meier method. Log-rank test will be performed to test the difference in time-to-event distributions between patient groups. Cox proportional hazards model will be used to include multiple covariates in the time-to-event analysis.

Time to Progression (TTP) is defined as the length of time from the start of treatment to disease progression as measured in days for participants with complete response.

National Cancer Institute (NCI)

One participant in first cohort withdrew prior to treatment therefore excluded from all study analysis.

Trametinib 2.0 mg PO QD + GSK2141795 25 mg PO QD on days 1-28.

Trametinib 2.0 mg + GSK2141795 25 mg

Trametinib 1.5 mg PO QD + GSK2141795 50 mg PO QD on days 1-28.

Trametinib 1.5 mg + GSK2141795 50 mg

Total

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

One participant withdrew prior to treatment so is included in baseline demographics but not in study analysis.

Nitin Jain, MD, Assistant Professor, Leukemia

Trametinib 2.0 mg PO QD \& GSK2141795 25 mg PO QD on days 1-28.

One participant in first cohort withdrew prior to treatment therefore excluded from study analysis.

Complete Response Rate (CRR, Defined as CR+CRp) Assessed by AML 2003 Response Criteria

Anemia

Diarrhea

Fatigue

Fever

Nausea

Rash maculo-papular

Mucositis oral

Vomiting

Trametinib 2.0 + GSK2141795 25 mg

One participant of the 17 registered in first cohort (Trametinib 2.0) withdrew without treatment and is excluded from adverse event reporting.

Most Frequently Reported Adverse Events (AE)

No participants achieved CR/CRp therefore analysis not available.

Overall Survival of Participants Achieving CR/CRp

Progression Free Survival of Participants Achieving CR/CRp

Outcome data were not collected and the Outcome will never be analyzed.

Time to Progression for Participants Achieving CR/CRp

Maximum Percentage Change in Total and Phospho-proteins

Percentage Change in Cellular Proteins

Trametinib 2.0 mg orally once daily (PO QD) and Akt inhibitor GSK2141795 25 mg PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

Trametinib 1.5 mg PO QD + GSK2141795 50 mg PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Acute Myeloid Leukemia	NCT01907815	Recurrent Adult... Untreated Adult...	Akt Inhibitor G... Laboratory Biom... Trametinib	18 Years -	National Cancer Institute (NCI)
Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Acute Myeloid Leukemia	NCT01907815	Recurrent Adult... Untreated Adult...	Akt Inhibitor G... Laboratory Biom... Trametinib	18 Years -	National Cancer Institute (NCI)

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