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.
Recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Quizartinib | Quizartinib dihydrochloride, Vanflyta | All Participants |
| Intrathecal (IT) triple chemotherapy prophylaxis | All Participants | |
| Fludarabine | All Participants | |
| Cytarabine | All Participants | |
| Etoposide | All Participants |
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
| Name | Type | Description | Interventions |
|---|---|---|---|
| All Participants | Experimental | 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. |
|
Inclusion Criteria:
- Has diagnosis of AML according to the World Health Organization (WHO) 2008
classification with >5% blasts in bone marrow, with or without extramedullary disease
- Is 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 study drug or cytarabine, whichever is later
- If female of child-bearing potential, tests negative for pregnancy and agrees not to
breast feed
- 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
- Meets protocol-specified guidelines before inclusion in the continuation therapy phase
Exclusion Criteria:
- Has been diagnosed with isolated central nervous system relapse, certain kinds of
leukemia, 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
| Maximum Eligible Age: | 21 Years |
| Minimum Eligible Age: | 1 Month |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Complete remission (CR) rate among participants with acute myeloid leukemia (AML) |
| Time Frame: | on Day 56 (± 3 Days) for the last subject, within 4 years |
| Safety Issue: | |
| Description: | CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles |
| Measure: | Complete remission with incomplete recovery (CRi) rate among participants with acute myeloid leukemia (AML) |
| Time Frame: | on Day 56 (± 3 Days) for the last subject, within 4 years |
| Safety Issue: | |
| Description: | CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles |
| Measure: | Duration of complete remission (CR) among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | Duration of CR is defined as the time from the first documented CR until documented relapse |
| Measure: | Duration of complete remission with incomplete recovery (CRi) among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | Duration of CRi is defined as the time from the first documented CRi until documented relapse |
| Measure: | Duration of composite complete remission (CRc) among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse |
| Measure: | Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) |
| Time Frame: | on Day 56 (± 3 Days) for the last subject, within 4 years |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) |
| Time Frame: | on Day 56 (± 3 Days) for the last subject, within 4 years |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) |
| Time Frame: | on Day 56 (± 3 Days) for the last subject, within 4 years |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Time to relapse among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse |
| Measure: | Rate of relapse among participants with acute myeloid leukemia (AML) after 1, 2 and 3 years |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Cumulative incidence of relapse among participants with acute myeloid leukemia (AML) at the end of study |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Overall survival among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | Overall survival is defined as the time from the start of re-induction therapy until death from any cause |
| Measure: | Event-free survival among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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 study |
| Measure: | Number of participants proceeding to high-dose conditioning therapy/allogeneic hematopoietic stem cell transplantation (HSCT) (including transplant-related mortality) among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: |
| Measure: | Rate of composite complete remission (CRc; complete remission [CR] or complete remission with incomplete recovery [CRi]) without minimal residual disease (MRD) using next generation sequencing among participants with acute myeloid leukemia (AML) |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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 relapse |
| Measure: | Acceptability of including the palatability of quizartinib formulations among participants with acute myeloid leukemia (AML): 5-point hedonic scale |
| Time Frame: | within 8 years, 8 months |
| Safety Issue: | |
| Description: | 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. |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Daiichi Sankyo, Inc. |
April 5, 2021
