GM-CLAG in Relapsed/Refractory FLT3-mutated AML

NCT05330377 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: MCC-21-LEUK-18-PMC
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate the dose-limiting toxicities (DLT) and define the maximum tolerated dose (MTD) and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG) in participants with FLT3- mutated relapsed or refractory (R/R) acute myeloid leukemia (AML).

Conditions

Acute Myeloid Leukemia

Keywords

FLT3; CLAG-M; AML; Relapsed; Refractory; Gilteritinib

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicities (DLT) of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG)

  DLT is defined as: * Any treatment-related death * Grade 4 neutropenia or thrombocytopenia lasting \> 42 days from start of cycle in the absence of active AML * Any Grade 4 or greater ANC lasting past cycle day 42 * Any Grade 4 or greater platelets lasting past cycle day 42 * Grade ≥ 4 organ toxicity (i.e., adverse reactions involving neurologic, pulmonary, cardiac, gastrointestinal, genitourinary, renal, hepatic, or cutaneous systems.) * Confirmed Hy's law cases

  42 days

• Maximally Tolerated Dose (MTD) of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG)

  The MTD will be defined as the highest dose of Gilteritinib estimated to have less than 20% hematologic or non-hematologic DLT rates. Enrollment of next patient will be allowed only after prior cohort has completed Cycle 1 and recovered or failure of response has been documented by Day 42.

  42 days

Secondary Outcomes (9)

• Complete remission (CR) rate after completing induction chemotherapy with the GM-CLAG combination.

  42 days

• Complete remission with incomplete hematologic recovery (CRi) after completing induction chemotherapy with the GM-CLAG combination.

  42 days

• Complete remission with partial hematologic recovery (CRh) after completing induction chemotherapy with the GM-CLAG combination.

  42 days

• Composite complete remission (CRc) after completing induction chemotherapy with the GM-CLAG combination.

  42 days

• Minimal residual disease status (MRD) after completing induction chemotherapy with the GM-CLAG combination.

  Two Induction Cycles (each up to 42 days)

Study Arms (3)

Gilteritinib (Dose Level -1: 40 mg/day)

EXPERIMENTAL

Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 40 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following: * Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first. * Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine. * Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted. * Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Drug: Gilteritinib 40 MG Oral Tablet; Drug: Cladribine; Drug: Cytarabine; Drug: Filgrastim; Drug: Mitoxantrone

Gilteritinib (Dose Level 1: 80 mg/day)

EXPERIMENTAL

Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 80 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following: * Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first. * Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine. * Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted. * Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Drug: Gilteritinib 40 MG Oral Tablet; Drug: Cladribine; Drug: Cytarabine; Drug: Filgrastim; Drug: Mitoxantrone

Gilteritinib (Dose Level 2: 120 mg/day)

EXPERIMENTAL

Dose escalation for gilteritinib will be conducted according to a BOIN design. Gilteritinib 120 mg/day will be given orally starting day 6 until day 19. CLAG-M chemotherapy will be administered at a fixed dose and schedule as following: * Cladribine (CL) 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5, given first. * Cytarabine (A) 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine. * Filgrastim (GCSF) 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted. * Mitoxantrone (M) 10 mg/m2 I.V. once per day on days 1 to 3

Drug: Gilteritinib 40 MG Oral Tablet; Drug: Cladribine; Drug: Cytarabine; Drug: Filgrastim; Drug: Mitoxantrone

Interventions

Gilteritinib 40 MG Oral Tablet DRUG

Gilteritinib is an oral FLT3 inhibitor, and is active against both FLT3-ITD and FLT3-TKD mutations. Gilteritinib will be given orally according to the assigned phase I dose cohort starting day 6 until day 19. Participants will be given the daily dose with water as at the same time each morning. Gilteritinib should be taken at least 2 hours after or 1 hour before consuming food.

Also known as: Xospata

Gilteritinib (Dose Level -1: 40 mg/day); Gilteritinib (Dose Level 1: 80 mg/day); Gilteritinib (Dose Level 2: 120 mg/day)

Cladribine DRUG

Cladribine is given intravenously at a dose of 5 mg/m2 I.V. over 2 hours once per day on days 1 to 5.

Also known as: Leustatin

Gilteritinib (Dose Level -1: 40 mg/day); Gilteritinib (Dose Level 1: 80 mg/day); Gilteritinib (Dose Level 2: 120 mg/day)

Cytarabine DRUG

Cytarabine is given intravenously at a dose of 2,000 mg/m2 I.V. over 4 hours once per day on days 1 to 5, given second, 2 hours after cladribine.

Also known as: cytosine arabinoside (Ara-C)

Gilteritinib (Dose Level -1: 40 mg/day); Gilteritinib (Dose Level 1: 80 mg/day); Gilteritinib (Dose Level 2: 120 mg/day)

Filgrastim DRUG

Filgrastim (GCSF) or biosimilar, will be given at a dose of 300 mcg S.C. once per day on days 0 to 5, started 24 hours prior to chemotherapy. If WBC is \> 20 × 109/L on day 0, the filgrastim dose on day 0 will be omitted.

Also known as: GCSF, Filgrastim sndz

Gilteritinib (Dose Level -1: 40 mg/day); Gilteritinib (Dose Level 1: 80 mg/day); Gilteritinib (Dose Level 2: 120 mg/day)

Mitoxantrone DRUG

Mitoxantrone is given intravenously at a dose of 10 mg/m2 I.V. over 2 hours once per day on days 1 to 3.

Also known as: Novantrone

Gilteritinib (Dose Level -1: 40 mg/day); Gilteritinib (Dose Level 1: 80 mg/day); Gilteritinib (Dose Level 2: 120 mg/day)

Eligibility Criteria

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

You may qualify if:

• Confirmed, morphologically documented AML in first or subsequent relapse or primary induction failure. The diagnosis should be documented within 28 days prior to enrollment.
• Relapsed AML is defined as the reappearance of leukemic blasts in the bone marrow, peripheral blood, or any extramedullary site after the attainment of a CR/CRi, detected by morphology, flow cytometry, or immunohistochemistry.
• Primary induction failure is defined as failure to achieve a CR or CRi after two courses of induction chemotherapy given per physician's choice or institution's guidelines.
• Patients with previous allogeneic hematopoietic stem cell transplantation are allowed to participate, as are prior autologous HCT.
• Evidence of FLT3-ITD or FLT3-TKD mutations as detected by polymerase chain reaction and/or next-generation sequencing by peripheral blood and/or bone marrow samples obtained at the time of relapse. FLT3 positivity should be documented before enrollment.
• Allowable prior therapies include: First-line AML therapy including cytarabine, anthracyclines, gemtuzumab ozogamicin, prior hypoemethylating agents with or without venetoclax and/or FLT3 inhibitors.
• Prior clinical trial participation is allowed with a washout period of experimental drug of at least 4 weeks.
• Prior treatment with the FLT3 inhibitor gilteritinib is allowed (must be 12 months or greater from time of eligibility screening).
• Age ≥18 years.
• ECOG performance status of 0 or 1; Karnofsky 70% or higher (APPENDIX A).
• Probability of treatment-related mortality (TRM) \<13.1% as calculated by performance status, age, platelet count, albumin, secondary vs primary AML, WBC count, creatinine, and percentage of peripheral blood blasts.50
• a. This score corresponds to corresponding to a ≤13.1% probability of 4-week mortality. Although this score was validated for newly diagnosed AML, it was previously used in the relapsed/refractory setting.30,51,52 (see APPENDIX B). An online calculator is available at: https://cstaging.fhcrc-research.org/TRM/).
• Adequate organ function as defined below:
• Creatinine clearance (CrCl) \>60 mL/min as measured by Cockcroft-Gault formula (APPENDIX C).
• Ejection fraction (EF) ≥ 50% as documented by an echocardiogram or multiple gated cardiac blood pool imaging (MUGA) if the echocardiogram's result is judged to be unreliable by the performing cardiologist.

You may not qualify if:

• History of prior treatment with gilteritinib within the last 12 months.
• Purine analogue (cladribine and fludarabine) treatment as part of their last line of therapy.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to gilteritinib or other agents used in this study (CLAG-M).
• Diagnosis of acute promyelocytic leukemia, BCR/ABL1-positive AML or chronic myelogenous leukemia in blast crisis.
• Inability to swallow oral medications or gastrointestinal disease limiting absorption of oral agents.
• Patients with a history of allo-SCT should not have active or acute chronic GVHD requiring systemic immunosuppression; topical GVHD treatment is allowed.
• Participant has an uncontrolled infection. If a bacterial or viral infection is present, the participant must be receiving definitive therapy and has no signs of progressing infection for 72 hours prior to registration. If a fungal infection is present, the participant must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to registration.
• Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection.
• Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• Active hepatitis B virus (HBV) infection as evidenced by positive hepatitis B surface antigen and/or Nucleic Acid Amplification Testing (NAAT). Patients with prior history of cleared HBV infection (negative hepatitis B surface antigen, positive hepatitis B surface antibody, and positive hepatitis B core IgG antibody) could be allowed to participate after consultation with a hepatologist, in which case Hep B viral load will be monitored by qPCR per institutional guidelines. In this case, concomitant suppressive antiviral therapy against HBV might be warranted.
• Uncontrolled HIV infection. Patients who have controlled infection on antiretroviral therapy are allowed, defined as HIV RNA below level of detection for the institution's standard assay.
• History of heart failure, myocarditis, or cardiomyopathy which requires heart failure directed therapy.
• Participant has long QT Syndrome at screening.
• Participant has a Fridericia-corrected QT interval (QTcF) \> 450 msec (average of triplicate determinations). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the Principal Investigator (PI).
• Untreated CNS leukemia. Evaluation of cerebrospinal fluid (CSF) or brain MRI during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening. Patients who previously had CNS leukemia that resolved with therapy should undergo CSF sampling +/- brain MRI within 2 weeks prior to enrollment to exclude CNS relapse.

Sponsors & Collaborators

• Ayman H Qasrawi: lead
• Astellas Pharma Inc: collaborator

Study Sites (1)

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

gilteritinib; Tablets; Cladribine; Cytarabine; Filgrastim; Granulocyte Colony-Stimulating Factor; Mitoxantrone

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)

Dosage Forms; Pharmaceutical Preparations; 2-Chloroadenosine; Adenosine; Purine Nucleosides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Deoxyadenosines; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds

Study Officials

• Ayman Qasrawi, MD

  University of Kentucky

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: April 8, 2022
• First Posted: April 15, 2022
• Study Start: March 1, 2023
• Primary Completion (Estimated): May 30, 2027
• Study Completion (Estimated): May 30, 2032
• Last Updated: April 25, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)