selinexor (kpt-330) plus flag-ida for the treatment of relapsing/refractory aml

Conditions: Acute Myeloid Leukemia

Summary: this protocol corresponds to a multicenter, open-label, non-randomized, phase i study designed to determine the safety of the combination of selinexor with chemotherapy in young patients with relapsed or refractory aml. the clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a phase i design in which es-calating doses of selinexor will be given to 3 groups, each with 3-6 patients until achieving the maximum tolerated dose (mtd).

study design: this protocol corresponds to a multicenter, open-label, non-randomized, phase i study designed to determine the safety of the combination of selinexor with chemotherapy in young patients with relapsed or refractory aml. the clinical trial is divided into pre-treatment, treatment (induction and consolidation cycles) and follow-up periods and consists of a phase i design in which es-calating doses of selinexor will be given to 3 groups, each with 3-6 patients until achieving the maximum tolerated dose (mtd). each cycle (second induction, consolidation or maintenance) of treatment will compromise 3 weeks of selinexor treatment, and at least one week off treatment. the new cycle will not start if there is an ongoing grade 3 or higher non-hematologic toxicity or persistent grade 3 neutropenia in patients achieving cr. study design allows a maximum of 18 patients. induction cycle (up to 2 cycles): treatment will consist of fludarabine 30 mg/m2/day intravenously on days 1 to 4, idarubicin 10 mg/m2/day intravenously on days 1 to 3, cytarabine 2 g/m2/day intravenously on days 1 to 4, g-csf 300 mcg/m2/day subcutaneously from days -1 to 5. this schedule will be combined with oral selinexor (kpt-330) for three weeks at days and dose according to escalation level: * level -1: selinexor 40 mg/day, once weekly * level 1: selinexor 60 mg/day, once weekly * level 2: selinexor 80 mg/day, once weekly * level 3: selinexor 100 mg/day, once weekly if a partial response is obtained after the first cycle of treatment, an identical induction therapy will be administered. if a patient achieves a complete remission after 1 or 2 cycles of flag-ida plus selinexor, allogeneic stem cell transplantation (allo-sct) will be attempted. if allo-sct is not possible, this patient will receive consolidation treatment as described below. consolidation cycle (up to 2 cycles): treatment will consist of cytarabine 1 g/m2/day intravenously (3 hours) on days 1 to 6. this schedule will be combined with oral selinexor (the same dosage that was administered to the patient in the induction cycle). at most, patients will receive up to 4 cycles of combined chemotherapy. maintenance cycle: for patients in cr, and when an allo-sct is not feasible, a maintenance treatment with selinexor could be started for up to 6 cycles. selinexor will be given at the same level as during induction therapy in cycles of four weeks (3 weeks on selinexor and 1 week off).

Eligibility criteria:
inclusion criteria: * written informed consent in accordance with national, local, and institutional guidelines. the patient must provide informed consent prior to the first screening procedure. * age ≥ 18, and ≤ 65 years old. * eastern cooperative oncology group (ecog) performance status of ≤ 2. * diagnosis of aml (defined using who criteria) of any type except for acute promyelocytic leukemia (apl; aml m3). * relapsing or refractory aml, defined as either: recurrence of disease after first cr (duration of cr ≤ 24 months), or failure to achieve cr or cri after 1 or 2 identical induction cycles containing an anthracycline plus cytarabine based schedule. * no contraindications to receive intensive chemotherapy. * female patients of child-bearing potential must have a negative serum pregnancy test at screening and agree to use two reliable methods of contraception for three months after their last dose of medication. male patients must use a reliable method of contraception (if sexually active with a female of child-bearing potential). * willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures. exclusion criteria: * patients with apl/aml m3. * patients who are pregnant or lactating. * radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤ 2 weeks prior to cycle 1 day 1 or radio-immunotherapy 4 weeks prior to cycle 1 day 1. hydroxyurea is permitted until 1 day prior to cycle 1 day 1. * previous treatment with a sine compound. * major surgery within 2 weeks of first dose of study drug. * any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety. * unstable cardiovascular function: * symptomatic ischemia, or uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree av block or asymptomatic lafb/rbbb will not be excluded), or congestive heart failure (chf) of nyha class ≥ 3, or myocardial infarction (mi) within 3 months. * uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral. * active hepatitis b or hepatitis c infection. * known human immunodeficiency virus (hiv) infection (hiv testing is not required as part of this study). * patients unable to swallow tablets, patients with malabsorption syndrome, or any other gastrointestinal (gi) disease or gi dysfunction that could interfere with absorption of study treatment. * any of the following laboratory abnormalities unless due to leukemia: * hepatic dysfunction: bilirubin \> 2.0 times the upper limit of normal (uln) (except patients with gilbert's syndrome: total bilirubin of \> 3 x uln) and alanine aminotransferase (alt) and aspartic aminotransferase (ast) \> 2.5 times uln or in case of liver metastases: in patients with known liver involvement of their cancer, ast and alt \> 5 x uln. * severe renal dysfunction: estimated creatinine clearance of \< 30 ml/min, measured in 24 hour urine or calculated using the formula of cockroft and gault: (140-age) x mass (kg)/\[72 x creatinine (mg/dl)\]; multiply by 0.85 if female

Keywords: acute myeloid leukemia relapsed refractory selinexor