Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood
- Conditions
- Acute Myeloid Leukemia
- Interventions
- Drug: Intrathecal (IT) triple chemotherapy prophylaxis
- Registration Number
- NCT03793478
- Lead Sponsor
- Daiichi Sankyo
- Brief Summary
Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.
Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.
- Detailed Description
The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.
The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.
A. Dose Escalation/De-escalation Phase:
Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.
B. Dose-Expansion Phase:
Participants will receive the RP2D of quizartinib for their respective age group.
During both dose escalation and dose expansion phases, participants will receive:
Re-Induction Therapy
* Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles
* In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as a single agent
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:
After re-induction therapy, participants will be evaluated for eligibility to undergo allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants may receive a single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without quizartinib) if an allogeneic HSCT is not available immediately. The options for consolidation therapy are as follows:
* High intensity chemotherapy with quizartinib, or
* Low intensity chemotherapy alone, or
* Low intensity therapy with quizartinib as a single agent
Continuation Therapy:
Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of quizartinib continuation therapy at the same dose received during re-induction in the dose expansion phase.
Long-term Follow-up:
The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation Therapy or permanent discontinuation of quizartinib at any time. After completion of the 30-day safety follow-up visit, subsequent visits will occur at the following frequencies to assess survival and anti-leukemic treatments:
* every 3 months for the first 2 years, and then
* once a year thereafter until the last participant enrolled has been followed for three years from the date of enrollment
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 65
Participants must meet all of the following criteria to be eligible for enrollment into the study:
- Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease
- In first relapse or refractory to first-line high-dose chemotherapy with no more than 1 attempt (1 to 2 cycles of induction chemotherapy) at remission induction - prior HSCT is permitted
- Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol
- Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed
- Has protocol-defined adequate performance status score
- Has fully recovered from the acute clinically significant toxicity effects of all prior chemotherapy, immunotherapy, or radiotherapy, per protocol guidelines
- Has protocol-defined adequate renal, hepatic and cardiac functions
- If of reproductive potential, is permanently sterile or agrees to use highly effective birth control upon enrollment, during the period of therapy, and for 6 months following the last dose of quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later
- If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
- Male participants must be surgically sterile or willing to use highly effective birth control during the treatment period, and for 6 months following the last dose of quizartinib, etoposide, fludarabine, methotrexate, or cytarabine, whichever is later.
- Participant/legal representative is capable of understanding the investigational nature of the study, potential risks, and benefits, and the patient (and/or legal representative) signs a written assent/informed consent
Participants who meet any of the following criteria will be disqualified from entering the study:
- Has been diagnosed with isolated central nervous system relapse, acute promyelocytic leukemia (APL), juvenile myelomonocytic leukemia, French-American-British classification M3 or WHO classification of APL with translocation, or with myeloid proliferations related to Down syndrome
- Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol
- Has systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient must be off vasopressors and have negative blood cultures for at least 48 hours prior to the start of systematic protocol therapy.
- Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
- Has known history of human immunodeficiency virus (HIV)
- Has history of hypersensitivity to any of the study medications or their excipients
- Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol
- Has any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise subject safety or compliance, interfere with consent/assent, study participation, follow up, or interpretation of study results
- Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)
- Is otherwise considered inappropriate for the study by the Investigator
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description All Participants Intrathecal (IT) triple chemotherapy prophylaxis All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib. All Participants Fludarabine All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib. All Participants Cytarabine All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib. All Participants Etoposide All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib. All Participants Quizartinib All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.
- Primary Outcome Measures
Name Time Method Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2) Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) (Phase 1 and 2) within 8 years, 8 months CRc rate is defined as percentage of participants with best response of complete remission (CR) or CR with incomplete hematological recovery (CRi) after completion of up to 2 re-induction cycles
Pharmacokinetic parameter area under the concentration curve for quizartinib and AC886 (Phase 1 and 2) Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2) Re-induction Phase 1 and 2,Cycle 1: Days 6, 20:Predose, 1 hour (Phase 1 only), 2, 4, and 6 hours; Days 7 and 21:24 hours; Phase 1 and 2 Cycle 2: Days 6 and 20:predose, 3 hours; Continuation Cycle 1 Days 1 and 15:predose, 2-4 hours (each cycle, 28 days) Number of dose-limiting toxicities (Phase 1) Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days)
- Secondary Outcome Measures
Name Time Method Complete remission (CR) rate among participants with AML (Phase 1 and 2) on Day 56 (± 3 Days) for the last subject, within 4 years CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles
Complete remission with incomplete recovery (CRi) rate among participants with AML (Phase 1 and 2) on Day 56 (± 3 Days) for the last subject, within 4 years CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles
Duration of CR among participants with AML (Phase 1 and 2) within 8 years, 8 months Duration of CR is defined as the time from the first documented CR until documented relapse
Cumulative incidence of relapse among participants with AML at the end of study (Phase 1 and 2) within 8 years, 8 months Cumulative incidence of relapse at the end of the study is defined as the percentage of participants who achieved CRc at the end of re-induction and relapsed by the end of the study
Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) on Day 56 (± 3 Days) for the last subject, within 4 years CR rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CR after completion of re-induction Cycle 1
Time to relapse among participants with AML (Phase 1 and 2) within 8 years, 8 months Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse
Duration of CRi among participants with AML (Phase 1 and 2) within 8 years, 8 months Duration of CRi is defined as the time from the first documented CRi until documented relapse
Duration of composite complete remission (CRc) among participants with AML (Phase 1 and 2) within 8 years, 8 months Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse
Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) on Day 56 (± 3 Days) for the last subject, within 4 years CRi rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CRi after completion of re-induction Cycle 1
Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2) on Day 56 (± 3 Days) for the last subject, within 4 years CRc rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving CRc after completion of re-induction Cycle 1
Rate of relapse among participants with AML after 1, 2 and 3 years (Phase 1 and 2) within 8 years, 8 months Rate of relapse is defined as the percentage of participants who achieved CRc at the end of re-induction and had relapsed at 3 categorical time points Categories: 1 year, 2 years, 3 years
Overall survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) within 8 years, 8 months Overall survival is defined as the time from the start of re-induction therapy until death from any cause
Event-free survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2) within 8 years, 8 months Event-free survival is defined as the time from the start of re-induction therapy until the earliest date of the following:
* Refractory disease at the end of re-induction
* Relapse after CR or CRi
* Death from any cause at any time during the studyNumber of participants proceeding to high-dose conditioning therapy/allogeneic hematopoietic stem cell transplantation (HSCT) (including transplant-related mortality) among participants with AML (Phase 1 and 2) within 8 years, 8 months Rate of CRc (CR or CRi) without minimal residual disease (MRD) using next generation sequencing among participants with AML (Phase 1 and 2) within 8 years, 8 months MRD is defined as the presence of leukemic cells in the bone marrow detected above a predefined cut-off level by a validated assay in participants who achieved a CR or CRi
Categories: at screening, at re-induction cycle 1, at re-induction cycle 2, at time of relapseAcceptability of including the palatability of quizartinib formulations among participants with AML (Phase 1 and 2) within 8 years, 8 months Acceptability is assessed by palatability using a 5-point hedonic scale (from "Super bad" to "Super good") for participants who are developmentally able to answer. If unable, the caregiver provides information in a free text field stating whether the participant spit it out, may not have liked the flavor, etc.
Trial Locations
- Locations (27)
Loma Linda University Cancer Center
🇺🇸Loma Linda, California, United States
University of California, San Francisco
🇺🇸San Francisco, California, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
A.I. duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
The University of Texas Southwestern Medical Center Children's Health
🇺🇸Dallas, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
British Columbia Children's Hospital
🇨🇦Vancouver, Canada
Rigshospitalet
🇩🇰Copenhagen, Denmark
Centre Léon Bérard
🇫🇷Lyon, France
Hôpital Armand-Trousseau
🇫🇷Paris, France
Hôpital des Enfants
🇫🇷Toulouse, France
Rambam Medical Center
🇮🇱Haifa, Israel
Tel Aviv Sourasky Medical Center
🇮🇱Tel Aviv-Yafo, Israel
Fondazione IRCCS San Gerardo dei Tintori
🇮🇹Monza, Italy
IRCCS Ospedale Pediatrico Bambino Gesù
🇮🇹Rome, Italy
Ospedale Infantile Regina Margherita
🇮🇹Torino, Italy
Prinses Maxima Centrum voor Kinderoncologie
🇳🇱Utrecht, Netherlands
Hospital Infantil Universitario Nino Jesus
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Sahlgrenska Universitetssjukhuset - Drottning Silvias Barn- och Ungdomssjukhus
🇸🇪Göteborg, Sweden