Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, Relapsed, Refractory, Selinexor
Brief 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).
Detailed description
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).
Interventions
DRUGSelinexor
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
DRUGfludarabine
fludarabine 30 mg/m2/day intravenously on days 1 to 4
DRUGidarubicin
idarubicin 10 mg/m2/day intravenously on days 1 to 3
DRUGcytarabine
cytarabine 2 g/m2/day intravenously on days 1 to 4
DRUGG-CSF
G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5
Sponsors
PETHEMA Foundation
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) of selinexor in combination with FLAG-Ida regimen | At the end of Cycle 1 (each cycle is 56 days) | A standard 3 + 3 dose escalation schedule will be used for all escalations. Initially, three patients will be entered in each cohort at the scheduled starting dose level for that cohort. If a drug-related DLT (see Section 5.1.5.3) is not seen at the scheduled dose, the dose will be escalated for the subsequent group of 3 patients. If 1 of 3 patients experiences a drug-related DLT, then 3 additional patients will receive that dose. If ≤ 2 of 6 patients experiences a drug-related DLT, the next scheduled dose level will be available. If, at a given dose level, \> 2 patients experience a drug-related DLT, the MTD will have been exceeded, additional enrollment within that cohort will cease, and dose escalation will stop. If a dose level proves intolerable (≥ 3 patients experience a DLT), enrollment will proceed at one dose-level lower. |
| Find recommended phase 2 dose | 3 months | A standard 3 + 3 dose escalation schedule will be used for all escalations. Initially, three patients will be entered in each cohort at the scheduled starting dose level for that cohort. If a drug-related DLT (see Section 5.1.5.3) is not seen at the scheduled dose, the dose will be escalated for the subsequent group of 3 patients. If 1 of 3 patients experiences a drug-related DLT, then 3 additional patients will receive that dose. If ≤ 2 of 6 patients experiences a drug-related DLT, the next scheduled dose level will be available. If, at a given dose level, \> 2 patients experience a drug-related DLT, the MTD will have been exceeded, additional enrollment within that cohort will cease, and dose escalation will stop. If a dose level proves intolerable (≥ 3 patients experience a DLT), enrollment will proceed at one dose-level lower. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of toxicity: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 1 year | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0. |
| CR and CRi | 3 months | antileukemic effects, including its ability to produce complete remissions, of Selinexor in combination with chemotherapy |
Countries
Spain
Outcome results
None listed