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

NCT03661515 | Completed Phase 1

• 1 other identifier: FLAGINEXOR: IST-ESP-000155
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 4

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).

Conditions

Acute Myeloid Leukemia

Keywords

Acute Myeloid Leukemia; Relapsed; Refractory; Selinexor

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Assessment of toxicity: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

  1 year

• CR and CRi

  3 months

Study Arms (1)

Fludarabine-Idarubicine-Cytarabine- Selinexor

EXPERIMENTAL

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; Drug: fludarabine; Drug: idarubicin; Drug: cytarabine; Drug: G-CSF

Interventions

Selinexor DRUG

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

Fludarabine-Idarubicine-Cytarabine- Selinexor

fludarabine DRUG

fludarabine 30 mg/m2/day intravenously on days 1 to 4

Fludarabine-Idarubicine-Cytarabine- Selinexor

idarubicin DRUG

idarubicin 10 mg/m2/day intravenously on days 1 to 3

Fludarabine-Idarubicine-Cytarabine- Selinexor

cytarabine DRUG

cytarabine 2 g/m2/day intravenously on days 1 to 4

Fludarabine-Idarubicine-Cytarabine- Selinexor

G-CSF DRUG

G-CSF 300 mcg/m2/day subcutaneously from days -1 to 5

Fludarabine-Idarubicine-Cytarabine- Selinexor

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• PETHEMA Foundation: lead

Study Sites (4)

Hospital Germans Tries i Pujol, Badalona

Badalona, Spain

Location

Hospital San Pedro de Alcántara,

Cáceres, Spain

Location

Hospital Universitario 12 de Octubre,

Madrid, Spain

Location

Hospital la Fe

Valencia, Spain

Location

Related Publications (1)

• 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.

  PMID: 33914097 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

selinexor; fludarabine; Idarubicin; Cytarabine; Granulocyte Colony-Stimulating Factor

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 17, 2018
• First Posted: September 7, 2018
• Study Start: July 17, 2018
• Primary Completion: July 15, 2019
• Study Completion: October 15, 2019
• Last Updated: May 20, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

ES (4)