FLAGINEXOR: Selinexor (KPT-330) Plus FLAG-Ida for the Treatment of Relapsing/Refractory AML
Study Details
Study Description
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).
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
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:
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Level -1: Selinexor 40 mg/day, once weekly
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Level 1: Selinexor 60 mg/day, once weekly
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Level 2: Selinexor 80 mg/day, once weekly
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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).
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Fludarabine-Idarubicine-Cytarabine- Selinexor 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 |
Drug: Selinexor
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
Drug: fludarabine
fludarabine 30 mg/m2/day intravenously on days 1 to 4
Drug: idarubicin
idarubicin 10 mg/m2/day intravenously on days 1 to 3
Drug: cytarabine
cytarabine 2 g/m2/day intravenously on days 1 to 4
Drug: G-CSF
G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5
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Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written informed consent in accordance with national, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
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Age ≥ 18, and ≤ 65 years old.
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Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
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Diagnosis of AML (defined using WHO criteria) of any type except for acute promyelocytic leukemia (APL; AML M3).
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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.
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No contraindications to receive intensive chemotherapy.
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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).
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Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
Exclusion Criteria:
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Patients with APL/AML M3.
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Patients who are pregnant or lactating.
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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.
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Previous treatment with a SINE compound.
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Major surgery within 2 weeks of first dose of study drug.
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Any life-threatening illness, medical condition or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety.
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Unstable cardiovascular function:
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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.
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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.
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Active hepatitis B or hepatitis C infection.
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Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study).
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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.
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Any of the following laboratory abnormalities unless due to leukemia:
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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.
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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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Hospital Germans Tries i Pujol, Badalona | Badalona | Spain | ||
2 | Hospital San Pedro de Alcántara, | Cáceres | Spain | ||
3 | Hospital Universitario 12 de Octubre, | Madrid | Spain | ||
4 | Hospital la Fe | Valencia | Spain |
Sponsors and Collaborators
- PETHEMA Foundation
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- FLAGINEXOR: IST-ESP-000155