Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Daiichi Sankyo Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

4 Dec 2018 → ongoing

Decision date (initial)

2024-04-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2023-510009-16-00

EudraCT number

2016-002919-18

ClinicalTrials.gov

NCT03793478

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Pharmacodynamic, Pharmacokinetic

Phase 1 only:
- To determine the recommended Phase 2 dose (RP2D) of quizartinib, in combination with chemotherapy, for subjects in the older (≥1 year to ≤ 21 years) and younger (≥1 month to <12 months) age groups.
- To determine the composite complete remission (CRc) rate (ie, complete remission [CR] + CR with incomplete recovery [CRi]) after completion of up to 2 Re-Induction Cycles.
- To determine the safety and cumulative toxicity of quizartinib administered in combination with re-induction chemotherapy for up to 2 cycles, with optional consolidation therapy, and as a single-agent continuation therapy over ≤12 cycles.
- To determine estimates of individual pharmacokinetic (PK) parameters of quizartinib and AC886 (metabolite of quizartinib).

Secondary objectives 10

1. To determine: CR and CRi rate after completion of up to 2 Re-Induction Cycles and Durations of CRi, CRc, and CR.
2. To assess time to relapse, rate of relapse after 1, 2 and 3 years, and cumulative incidence of relapse at the EoT.
3. To determine the rates of CR, CRi, and CRc after completion of Re-Induction Cycle 1.
4. To assess OS and EFS at 1, 2, and 3 years.
5. To assess number of subjects proceeding to high-dose conditioning therapy/ HSCT.
6. To assess activity of quizartinib on FLT3-ITD autophosphorylation activity by an ex-vivo PIA during Re-Induction, Continuation, and at time of relapse.
7. To assess FLT-ITD/FLT3-wild-type (WT) allelic ratio at Screening, during Re- Induction, and at time of relapse.
8. To evaluate somatic mutations present in blasts at Screening and at time of refractory disease or relapse.
9. To assess rate of CRc (CR, CRi) without FLT3-ITD minimal residual disease (MRD) using next-generation sequencing.
10. To assess acceptability including palatability of quizartinib formulations.

Conditions and MedDRA coding

Acute Myeloid Leukemia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001821-PIP01-15

Plan to share IPD

Yes

IPD plan description

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Has diagnosis of AML according to the World Health Organization (WHO) 2008 classification with ≥5% blasts in bone marrow, with or without extramedullary disease
2. 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
3. Has presence of the FLT3-ITD activating mutation in bone marrow or peripheral blood as defined in the protocol
4. Is between 1 month and 21 years of age at the time the Informed Consent/Assent form is signed
5. Has protocol-defined adequate performance status score
6. Has fully recovered from the acute clinically significant toxicity effects of previous anti-cancer therapy prior to Re-Induction Cycle 1, Day 1, defined as toxicities (other than alopecia) not yet resolved by the National Cancer Institute - Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) to Grade ≤ 1 or baseline.
7. Has protocol-defined adequate renal, hepatic and cardiac functions
8. 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
9. If female of child-bearing potential, tests negative for pregnancy and agrees not to breast feed
10. 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.
11. 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
12. Female subjects must not donate or retrieve for their own use ova from the time of Screening and throughout the treatment period, and for at least 7 months following the last dose
13. Male subjects must not freeze or donate sperm starting at Screening and throughout the treatment period, and at least 4 months following the last dose.

Exclusion criteria 10

1. 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
2. Has uncontrolled or pre-defined significant cardiovascular disease as detailed in the protocol
3. 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
4. Has known active clinically relevant liver disease (e.g., active hepatitis B or active hepatitis C)
5. Has known history of human immunodeficiency virus (HIV)
6. Has history of hypersensitivity to any of the study medications or their excipients
7. Is receiving or is anticipated to receive concomitant chemotherapy, radiation, or immunotherapy other than as specified in the protocol
8. 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
9. Is currently participating in another investigative interventional procedure (observational or long-term interventional follow-up is allowed)
10. Is otherwise considered inappropriate for the study by the Investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Efficacy (ie, the primary outcome measure): CRc rate after completion of up to 2 Re-Induction Cycles.(based on investigator’s assessment).
2. Safety: The safety profile of quizartinib administered in combination with reinduction chemotherapy for up to 2 cycles, with optional consolidation chemotherapy, and as a single-agent continuation therapy over ≤12 cycles. And phase 1 only: Number of DLTs in dose cohorts in Re-Induction Cycle 1
3. Estimates of AUC, apparent clearance (CL/F), and apparent volume of distribution (Vz/F) for quizartinib and AC886 by the use of PopPK modeling or other applicable methods

Secondary endpoints 18

1. Efficacy (ie, the secondary outcome measures): CR rate, which is defined as the percent of subjects achieving a CR after completion of up to 2 Re-Induction cycles
2. CRi rate, which is defined as the percent of subjects achieving CRi after completion of up to 2 Re-Induction Cycles.
3. Duration of CR defined as the time from the first documented CR until documented relapse
4. Duration of CRi, defined as the time from the first documented CRi until documented relapse
5. Duration of CRc, defined as the time from the first documented CR or CRi until documented relapse
6. CR rate after completion of Re-Induction Cycle 1 which is defined as the percent of subjects achieving CR after completion of Re-Induction Cycle 1
7. CRi rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving a CRi after completion of Re-Induction Cycle 1
8. CRc rate after completion of Re-Induction Cycle 1, which is defined as the percent of subjects achieving CR+ CRi after completion of Re- Induction Cycle 1
9. Time to relapse, defined as the time from the first documented response (CR, CRi) until documented relapse
10. Rate of relapse after 1, 2 and 3 years
11. Cumulative incidence of relapse at the end of the study, defined as the percentage of subjects who achieved CRc at the end of Re-Induction and relapse at these defined time points
12. OS, defined as the time from the start of Re-Induction therapy until death from any cause
13. EFS defined as the time from the start of Re-Induction therapy until the earliest date of the following: - Refractory disease (or treatmetn failure) at the end of Re-Induction. - Relapse after CR or CRi. - Death from any cause at any time during the study.
14. Pharmacodynamic: Inhibition of FLT3-ITD autophosphorylation activity in an ex-vivo PIA during Re-Induction, Continuation, and at the time of relapse
15. FLT3-ITD to FLT3-WT allelic ratio at Screening, during Re- Induction, and at the time of relapse
16. Mutations present in blasts (eg, in the kinase and juxtamembrane domains of FLT3 and other mutations known to be associated with AML) at Screening and at the time of refractory disease or relapse
17. Biomarker: Rate of CRc (CR, CRi) without MRD using next generation sequencing
18. Others: Acceptability including palatability of quizartinib formulations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Daiichi Sankyo Inc.

Sponsor organisation

Daiichi Sankyo Inc.

Address

211 Mount Airy Road

City

Basking Ridge

Postcode

07920-2311

Country

United States

Scientific contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Public contact point

Organisation

Daiichi Sankyo Inc.

Contact name

Clinical Trial Office

Third parties 8

Locations

7 EU/EEA countries · 12 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 72 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications