Selinexor (KPT-330) Plus FLAG-Ida for the Treatment of Relapsing/Refractory AML (FLAGINEXOR)

An Investigator Sponsored Phase I Trial of Selinexor (KPT-330) Plus FLAG-Ida for the Treatment of Relapsing/Refractory AML

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 Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Selinexor; Drug: fludarabine; Drug: idarubicin; Drug: cytarabine; Drug: G-CSF

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).

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Spain
  • Badalona, Spain
    • Hospital Germans Tries i Pujol, Badalona
  • Cáceres, Spain
    • Hospital San Pedro de Alcántara,
  • Madrid, Spain
    • Hospital Universitario 12 de Octubre,
  • Valencia, Spain
    • Hospital la Fé

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) of selinexor in combination with FLAG-Ida regimen	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.	At the end of Cycle 1 (each cycle is 56 days)
Find recommended phase 2 dose	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.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of toxicity: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0.	1 year
CR and CRi	antileukemic effects, including its ability to produce complete remissions, of Selinexor in combination with chemotherapy	3 months

Collaborators and Investigators

• Sponsor: PETHEMA Foundation

Publications and helpful links

General Publications

• Martinez Sanchez MP, Megias-Vericat JE, Rodriguez-Veiga R, Vives S, Bergua JM, Torrent A, Suarez-Varela S, Boluda B, Martinez-Lopez J, Cano-Ferri I, Acuna-Cruz E, Torres-Minana L, Martin-Herreros B, Serrano A, Sempere A, Barragan E, Sargas C, Sanz M, Martinez-Cuadron D, Montesinos P; PETHEMA group. A phase I trial of selinexor plus FLAG-Ida for the treatment of refractory/relapsed adult acute myeloid leukemia patients. Ann Hematol. 2021 Jun;100(6):1497-1508. doi: 10.1007/s00277-021-04542-8. Epub 2021 Apr 29.

Study record dates

Study Major Dates

• Study Start (Actual): July 17, 2018
• Primary Completion (Actual): July 15, 2019
• Study Completion (Actual): October 15, 2019

Study Registration Dates

• First Submitted: July 17, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 7, 2018

Study Record Updates

• Last Update Posted (Actual): May 20, 2020
• Last Update Submitted That Met QC Criteria: May 19, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; Relapsed; Refractory; Selinexor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Fludarabine; Cytarabine; Idarubicin
• Other Study ID Numbers: FLAGINEXOR: IST-ESP-000155

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No