Phase I/II Trial of MEK Inhibitor MEK162 in Patients with Relapsed and or Refractory Acute Myeloid Leukemia and Patients with Poor Prognosis Acute Myeloid Leukemia Not Suitable for or Unwilling to Receive Standard Therapy.
The goal of Phase 1 of this clinical research study is to find the highest tolerable dose of MEK162 that can be given to patients with advanced leukemia.
Disease Group: Leukemia
Treatment Agent: MEK162
Treatment Location: Only at MD Anderson
Primary Objective(s) for Phase I and II Phase 1 -- To determine the MTD/RP2D (recommended phase 2 dose) of MEK 162 in subjects with advanced Leukemias. Phase II -- To assess the anti-leukemic activity of MEK 162 (overall response including CR and CRi) in older subjects with newly diagnosed KRAS/NRAS mutant poor prognosis AML, who are not candidates for intensive chemotherapy. Secondary Objective(s) for Phase I and II Phase I -- To determine the safety of MEK 162 in patients with relapsed and/or refractory Leukemias. -- To assess the PK of MEK 162 in patients with Leukemias. -- To assess anti-leukemic activity (CR and CRi) of MEK 162 in patients with leukemia. Phase II -- To determine the safety and tolerability of MEK 162 in older subjects with newly diagnosed KRAS/NRAS mutant poor prognosis AML. Exploratory Objective(s) for Phase I and II (if necessary) Phase I and II - To explore potential molecular variations in leukemia blasts (e.g. FLT3, K-RAS, N-RAS and other known mutations (IDH1, IDH2, DNMT3A and others) or gene copy number in candidate genes) that may be predictive of differences in response to MEK 162. The dose finding phase I portion allows for any patient with advanced AML/MDS/ALL/CMML who meets the eligiblity criteria as there is a possibility of activity in partients with those disorders with aberrant signaling along the RAF/RAS/MAPK signaling pathway although the main intention of the phase I is to determine whether the drug is reasonably safe. In the phase II portion of the study Array was only interested in determining the activity in patients with known aberrant pathway (i.e. mutated RAS) as this can also be potentially used as a marker for patient selection. Clearly, if we see significant responses in other patients in the phase I and particularly if it is determined that this activity is related to aberrant RAF/RAS/MAPK signaling, future trials will be conducted in a broader poulation and more dependent of demonstrating aberrant pathway signaling.
IRB Review and Approval Date: 08/27/2014
Recruitment Status: Open
Projected Accrual: N/A
1) PHASE I -- a. Primary or secondary AML according to WHO
classification, with relapsed or refractory disease or newly diagnosed
older subjects (greater than or equal to 65 years of age), not
candidates for intensive chemotherapy; b. Subjects with MDS, IPSS Int-2
or high risk (RAEB-2 only, i.e. greater than or equal to 10% blast) who
are resistant or intolerant to standard treatment and are not candidates
for transplantation; c. Subjects with ALL, relapsed, refractory or
intolerant to standard treatment and for whom no effective treatment
options are available.
2) Age greater or equal to 18 years.
3) Patients should be willing and able to give informed consent.
4) Eastern Cooperative Group (ECOG) PS less than or equal to 2.
5) PHASE II -- Patients aged 60 and older with newly diagnosed primary or secondary AML according to WHO classification, without any prior therapy for AML with the exception of (a) emergency Leukapheresis and (b) emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before start of the trial treatment. Note: Prior therapy for preexisting hematological condition e.g. MDS or MPD, including but not limited to hypomethylating agents is allowed until at least 2 weeks have elapsed from completion of that agent before the first dose of MEK 162. Patients with relapsed AML, and relapsed MDS and CMML, after prior hypomethylating therapy are also eligible to participate
6) Patients with untreated AML must meet at least one of the following conditions: a. Age greater than or equal to 75 years; b. Age greater or equal to 60 and less than 75 years with at least one of the following poor prognostic factors: i. Secondary AML, as determined by known and documented exposure to chemotherapy or radiation therapy; ii. antecedent history of MDS or myeloproliferative disorder according to WHO criteria for at least 3 months prior to trial entry; iii. unfavorable cytogenetic abnormalities including chromosome 5 and 7 as well as complex; iv. ECOG Performance status 2.
7) Patients are willing and able to give informed consent. (Phase II only)
8) Only patients with mutated RAS (KRAS and NRAS) mutations are eligible to participate. (Phase II only)
9) Adequate cardiac function defined as: --left ventricular ejection fraction (LVEF) greater than or equal to 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram; -- QTcF interval less than or equal to 480 ms. (Phase II only)
1) PHASE I and II -- Administration of any antineoplastic therapy within
at least 4 weeks (cytotoxic chemotherapy) or 2 weeks (biological and
targeted therapy; hypomethylating agents are considered to be biological
therapy) of that therapy of the first MEK 162/MEK 162 dose; except the
use of hydroxyurea which can be administered up to 5 g/day up to 24
hours before the initiation of the study drug.
2) Patients should not have received an investigational agent for at least 2 weeks prior to the first study drug dose.
3) Clinical evidence of active CNS leukemia requiring active therapy; prior CNS leukemia well-controlled by ongoing therapy is allowed.
4) Active and uncontrolled infection including but not limited to known infection with HIV, active hepatitis B, or hepatitis C.
5) Major surgery within two weeks prior to trial entry.
6) Liver function tests above the following limits at the screening: total bilirubin > 1.5 x ULN unless related to Gilbert's syndrome or hemolysis, AST and/or ALT > 2.5 X ULN, or for subjects with liver involvement AST and/or ALT > 5 x ULN.
7) Serum creatinine > 1.5 x ULN and/or Creatinine Clearance (CrCl) < 30 mL/min at screening (calculation according to Cockroft & Gault formula).
8) Pregnant or nursing (lactating) women;
9) Female patients of childbearing ptential and male patients with partners of childbearing potential who are not willing ot use highly effective methods of contraception throughout the study and for 1 month after study drug discontinuation. Highly effective contraception methods include: **Total abstinence; or **Male or female sterilization; **Combination of any two of the following (a+b or a+c or b+c); a. Use of oral, injected, or implanted hormonal methods of contraception; b. Placement of an intrauterine device (IUD) or intrauterine system (IUS); c. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
10) Female patients with reproductive potential who do not have a negative blood or urine prgenancy test at screening;
11) History of significant difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product.
12) Has significant cardiac conduction abnormalities and/ or pacemaker or any of the following criteria: -- History of acute coronary syndromes (including myocardial infarction, unstable angina, CABG, coronary angioplasty, or stenting) <6 months prior to screening, --Symptomatic chronic heart failure; evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening --Uncontrolled arterial hypertension, defined as BP > 140/100 mmHg (average of 3 consecutive readings)
13) History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO).
14) Any ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO by the ophthalmologist (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
15) Subjects with active other tumors, except early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN).
16) Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
17) Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment. NB: Muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment.
18) Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
Information and next steps
Phase I/Phase II
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