Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

This is an interventional treatment trial for Recurrent Acute Myeloid Leukemia Read More

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative
• Age: >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2

• Patients with histologically confirmed acute myeloid leukemia (AML), according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease who are ineligible for therapies known to be effective for treatment of their acute myeloid leukemia (AML)

  • Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow involvement
  • Patients with acute promyelocytic leukemia (APL) will not be eligible
  • Patients with IDH2 mutations, who were previously treated with enasidenib are allowed
• Have a confirmed susceptible IDH2 mutation (R140 or R172) with a concomitant RAS-pathway mutation, involving NRAS, KRAS, PTPN11, CBL or NF1 genes
• Fully recovered from the acute toxic effects (except alopecia) to =< Grade 1 to prior anti-cancer therapy
• Ability to swallow pills
• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed within 14 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) =< 2.0 x ULN (performed within 14 days prior to day 1 of protocol therapy)
• Alanine aminotransferase (ALT) =< 2.0 x ULN (performed within 14 days prior to day 1 of protocol therapy)
• Creatinine clearance of >= 50 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 14 days prior to day 1 of protocol therapy)
• International normalized ratio (INR) OR prothrombin (PT) =< 1.5 x ULN
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy)

• Left ventricular ejection fraction (LVEF) >= 50%

  • Note: Echocardiogram scan to be performed within 7 days prior to day 1 of protocol therapy

• Tricuspid valve regurgitation jet (TRJ) velocity < 2.5 m/sec

  • Note: To be performed within 7days prior to day 1 of protocol therapy

• Corrected QT (QTc) =< 480 ms

  • Note: To be performed within 28 days prior to day 1 of protocol therapy
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential* to use an effective method of birth control (non-hormonal) or abstain from heterosexual activity from 4 weeks prior to first dose of study treatment through at least 2 months after the last dose of protocol therapy. Coadministration of enasidenib may increase or decrease the concentrations of combined hormonal contraceptives

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).
• Also, male subjects should refrain from sperm donation from the start of treatment throughout the study treatment period and for 6 months following the last dose of treatment

Exclusion Criteria:

• Current or planned use of other investigational agents, antineoplastic, chemotherapy, radiation therapy, biological therapy, immunotherapy or major surgery within 4 weeks or 5 half-lives, whichever is shorter, prior to Day 1 of protocol therapy (exception: hydroxyurea is allowed in cycles 1 and 2 for control of rapidly progressing leukemia or for treatment of enasidenib-related leukocytosis)
• Systemic steroid therapy > 10 mg/day (=< 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 28 days, except as required for treatment of differentiation syndrome
• Strong and moderate CYP3A4 inducers/inhibitors (moderate CYP3A4 inhibitors only allowed on principal Investigator approval) within 14 days prior to Day 1 of protocol therapy
• Foods/supplements that are strong and moderate inhibitors or inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 7 days prior to initiation of and during study treatment
• Received a live-virus vaccination within 28 days of planned treatment start
• Concurrent use of granulocyte-macrophage colony stimulating factor (GMCSF) or granulocyte colony stimulating factor (G-CSF), erythropoietin, eltrombopag, or other hematopoietic growth factors 14 days prior to start of study
• Class III/IV cardiovascular disability according to the New York Heart Association Classification
• Participants with clinically significant arrhythmia or arrhythmias not stable on medical management within two weeks of enrollment. Subjects with controlled, asymptomatic atrial fibrillation can enroll
• History of acute cardiovascular ischemic event, i.e., myocardial infarction or unstable angina within 6 months of enrollment

• Participant has ophthalmologic conditions, including any of the following:

  • Current or past history of central serous retinopathy
  • Current or past history of retinal vein occlusion
  • Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
• Gastrointestinal disorder such as malabsorption syndrome or any other disorder that may interfere with oral drug absorption
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
• Active central nervous system (CNS) disease
• Clinically significant uncontrolled illness
• Active infection requiring antibiotics
• Other active malignancy
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).