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

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT03793478
• Collaborator: Innovative Therapies For Children with Cancer Consortium (Other), Children's Oncology Group (Other)
• Enrollment: 65
• Locations: 37
• Arm: 1
• Anticipated Duration (Months): 104.5
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Quizartinib; Drug: Intrathecal (IT) triple chemotherapy prophylaxis; Drug: Fludarabine; Drug: Cytarabine; Drug: Etoposide	Phase 1/Phase 2

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

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: A single group will progress through a multiple phase study design as described in the detailed description.A single group will progress through a multiple phase study design as described in the detailed description.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination With Re-Induction Chemotherapy, and as a Single-Agent Continuation Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) With FLT3-ITD Mutations
• Actual Study Start Date: Aug 15, 2018
• Anticipated Primary Completion Date: May 1, 2027
• Anticipated Study Completion Date: May 1, 2027

Arms and Interventions

Arm

Intervention/Treatment

Experimental: All Participants 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.

Drug: Quizartinib; Administered orally once daily starting on Day 6 and continuing through Day 28; Other Names: Quizartinib dihydrochloride Vanflyta ; Drug: Intrathecal (IT) triple chemotherapy prophylaxis; IT cytarabine, methotrexate, and either prednisolone or hydrocortisone; doses are based on the participant's age and standard practice at each site; Drug: Fludarabine; 30 mg/m^2/day IV infusion given over 30 minutes on Days 1 through 5 (administered based on body weight); Drug: Cytarabine; 2000 mg/m^2/day IV infusion given over 3 hours on Days 1 through 5 (begin 4 hours after the start of fludarabine) (administered in accordance with standard of care) or 500 mg/m^2/day as a continuous 96-hour IV infusion on Days 1 through (administered based on body weight as optional high intensity consolidation therapy).; Drug: Etoposide; 100 mg/m^2/dose once daily as an IV infusion over 3 hours on Days 1 through 5 (administered based on body weight as optional high intensity consolidation therapy)

Outcome Measures

Primary Outcome Measures

1. Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) [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

Secondary Outcome Measures

1. Complete remission (CR) rate among participants with acute myeloid leukemia (AML) [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

2. Complete remission with incomplete recovery (CRi) rate among participants with acute myeloid leukemia (AML) [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

3. Duration of complete remission (CR) among participants with acute myeloid leukemia (AML) [within 8 years, 8 months]

   Duration of CR is defined as the time from the first documented CR until documented relapse

4. Duration of complete remission with incomplete recovery (CRi) among participants with acute myeloid leukemia (AML) [within 8 years, 8 months]

   Duration of CRi is defined as the time from the first documented CRi until documented relapse

5. Duration of composite complete remission (CRc) among participants with acute myeloid leukemia (AML) [within 8 years, 8 months]

   Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse

6. Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) [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

7. Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) [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

8. Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with acute myeloid leukemia (AML) [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

9. Time to relapse among participants with acute myeloid leukemia (AML) [within 8 years, 8 months]

   Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse

10. Rate of relapse among participants with acute myeloid leukemia (AML) after 1, 2 and 3 years [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

11. Cumulative incidence of relapse among participants with acute myeloid leukemia (AML) at the end of study [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

12. Overall survival among participants with acute myeloid leukemia (AML) [within 8 years, 8 months]

    Overall survival is defined as the time from the start of re-induction therapy until death from any cause

13. Event-free survival among participants with acute myeloid leukemia (AML) [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 study

14. 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) [within 8 years, 8 months]

15. 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) [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 relapse

16. Acceptability of including the palatability of quizartinib formulations among participants with acute myeloid leukemia (AML): 5-point hedonic scale [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Month to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Cancer Center	Loma Linda	California	United States	92354
2	University of California, San Francisco	San Francisco	California	United States	94158
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	A.I. duPont Hospital for Children	Wilmington	Delaware	United States	19803
5	Children's National Medical Center	Washington	District of Columbia	United States	20010
6	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
7	Riley Hospital for Children - Indiana University	Indianapolis	Indiana	United States	46202
8	Johns Hopkins	Baltimore	Maryland	United States	21287
9	University of Minnesota/Masonic Cancer Center	Minneapolis	Minnesota	United States	55455
10	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
11	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
12	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
13	New York Medical College	Valhalla	New York	United States	10595
14	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
15	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
16	UPMC Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15224
17	The University of Texas Southwestern Medical Center Children's Health	Dallas	Texas	United States	75390
18	Seattle Children's Hospital	Seattle	Washington	United States	98105
19	Universitair Ziekenhuis Gent	Gent		Belgium
20	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G1X8
21	Montreal Children's Hospital	Montréal	Quebec	Canada	H4A3J1
22	British Columbia Children's Hospital	Vancouver		Canada	V6H 3V4
23	Rigshospitalet	Copenhagen		Denmark	2100
24	Centre Léon Bérard	Lyon		France	69008
25	Hôpital Armand-Trousseau	Paris		France	75012
26	Hôpital des Enfants	Toulouse		France	31300
27	Rambam Medical Center	Haifa		Israel	31096
28	Schneider Children's Medical Center of Israel	Petah Tikva		Israel	49202
29	Tel Aviv Sourasky Medical Center	Tel Aviv-Yafo		Israel	64239
30	Fondazione MBBM - Clinica Pediatrica	Monza		Italy	20900
31	IRCCS Ospedale Pediatrico Bambino Gesù	Rome		Italy	00165
32	Ospedale Infantile Regina Margherita	Torino		Italy	10126
33	Prinses Maxima Centrum voor Kinderoncologie	Utrecht		Netherlands	3584 EA
34	Hospital Infantil Universitario Nino Jesus	Madrid		Spain	28009
35	Hospital Universitario La Paz	Madrid		Spain	28046
36	Sahlgrenska Universitetssjukhuset - Drottning Silvias Barn- och Ungdomssjukhus	Göteborg		Sweden	41685
37	NHS Greater Glasgow and Clyde - The Queen Elizabeth University Hospital	Glasgow		United Kingdom	G51 4TF

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Innovative Therapies For Children with Cancer Consortium
• Children's Oncology Group

Investigators

• Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT03793478
• Other Study ID Numbers: AC220-A-U202; 2016-002919-18
• First Posted: Jan 4, 2019
• Last Update Posted: Aug 3, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Daiichi Sankyo, Inc.: Acute myeloid leukemia recurrent; Relapsed or refractory; FMS-like tyrosine kinase 3 positive; Cancer of the blood; AML; FLT3-ITD mutation
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Cytarabine; Fludarabine; Etoposide

Study Results

No Results Posted as of Aug 3, 2022