Phase Ib Trial of Gilteritinib in Combination With Mitoxantrone, Cladribine, Cytarabine and Filgrastim (GM-CLAG) for Relapsed/Refractory FLT3-mutated Acute Myeloid Leukemia
Overview
- Phase
- Phase 1
- Intervention
- Gilteritinib 40 MG Oral Tablet
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- Ayman H Qasrawi
- Locations
- 1
- Primary Endpoint
- Dose-limiting toxicities (DLT) of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG)
- Status
- Withdrawn
- Last Updated
- 3 years ago
Overview
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).
Detailed Description
The treatment of FLT3- mutated relapsed or refractory (R/R) is challenging. Gilteritinib, as a single agent, is the first FLT3 inhibitor to be FDA approved in the R/R setting. This phase I clinical trial will evaluate DLT/MTD and the recommended phase II study dose of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (CLAG-M) in patients with FLT3- mutated R/R AML. This study will also evaluate the pharmacodynamics and pharmacokinetics of gilteritinib when combined with CLAG-M at specific time points. Although this combination has not been established to have superior clinical benefit in comparison to single-agent gilteritinib, the objective of this trial is to provide a possible therapeutic benefit in addition to safety and tolerability.
Investigators
Ayman H Qasrawi
Assistant Professor
University of Kentucky
Eligibility Criteria
Inclusion Criteria
- •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).
Exclusion Criteria
- •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.
Arms & Interventions
Gilteritinib (Dose Level -1: 40 mg/day)
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
Intervention: Gilteritinib 40 MG Oral Tablet
Gilteritinib (Dose Level -1: 40 mg/day)
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
Intervention: Cladribine
Gilteritinib (Dose Level -1: 40 mg/day)
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
Intervention: Cytarabine
Gilteritinib (Dose Level -1: 40 mg/day)
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
Intervention: Filgrastim
Gilteritinib (Dose Level -1: 40 mg/day)
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
Intervention: Mitoxantrone
Gilteritinib (Dose Level 1: 80 mg/day)
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
Intervention: Gilteritinib 40 MG Oral Tablet
Gilteritinib (Dose Level 1: 80 mg/day)
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
Intervention: Cladribine
Gilteritinib (Dose Level 1: 80 mg/day)
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
Intervention: Cytarabine
Gilteritinib (Dose Level 1: 80 mg/day)
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
Intervention: Filgrastim
Gilteritinib (Dose Level 1: 80 mg/day)
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
Intervention: Mitoxantrone
Gilteritinib (Dose Level 2: 120 mg/day)
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
Intervention: Gilteritinib 40 MG Oral Tablet
Gilteritinib (Dose Level 2: 120 mg/day)
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
Intervention: Cladribine
Gilteritinib (Dose Level 2: 120 mg/day)
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
Intervention: Cytarabine
Gilteritinib (Dose Level 2: 120 mg/day)
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
Intervention: Filgrastim
Gilteritinib (Dose Level 2: 120 mg/day)
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
Intervention: Mitoxantrone
Outcomes
Primary Outcomes
Dose-limiting toxicities (DLT) of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG)
Time Frame: 42 days
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
Maximally Tolerated Dose (MTD) of gilteritinib when combined with mitoxantrone, cladribine, cytarabine and filgrastim (GM-CLAG)
Time Frame: 42 days
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.
Secondary Outcomes
- Minimal residual disease status (MRD) after completing induction chemotherapy with the GM-CLAG combination.(Two Induction Cycles (each up to 42 days))
- Percentage of patients proceeding to transplantation(Up to 2 years)
- Leukemia-free survival (LFS)(Up to 2 years)
- 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)
- Overall survival (OS)(Up to 2 years)
- 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)
- Best response to Induction Therapy(Two Induction Cycles (each up to 42 days))