Clinical trial NCT03793478: Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: Acute myeloid leukemia recurrent
Relapsed or refractory
FMS-like tyrosine kinase 3 positive
Cancer of the blood
AML
FLT3-ITD mutation
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Innovative Therapies For Children with Cancer Consortium
name: Children's Oncology Group
First posted: 2019-01-04
Enrollment: 65
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: A single group will progress through a multiple phase study design as described in the detailed description.
Primary purpose: TREATMENT

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

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

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

Primary outcomes:
measure: Number of dose-limiting toxicities (Phase 1)
timeFrame: Re-induction Cycle 1 Day 1 up to Day 28 (each cycle is 28 days)
measure: Composite complete remission (CRc) rate among participants with acute myeloid leukemia (AML) (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Pharmacokinetic parameter area under the concentration curve for quizartinib and AC886 (Phase 1 and 2)
timeFrame: 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)
measure: Pharmacokinetic parameter apparent clearance (CL/F) for quizartinib and AC886 (Phase 1 and 2)
timeFrame: 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)
measure: Pharmacokinetic parameter apparent volume of distribution (Vz/F) for quizartinib and AC886 (Phase 1 and 2)
timeFrame: 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)
Secondary outcomes:
measure: Complete remission (CR) rate among participants with AML (Phase 1 and 2)
timeFrame: on Day 56 (± 3 Days) for the last subject, within 4 years
measure: Complete remission with incomplete recovery (CRi) rate among participants with AML (Phase 1 and 2)
timeFrame: on Day 56 (± 3 Days) for the last subject, within 4 years
measure: Duration of CR among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Duration of CRi among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Duration of composite complete remission (CRc) among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Complete remission (CR) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)
timeFrame: on Day 56 (± 3 Days) for the last subject, within 4 years
measure: Complete remission with incomplete recovery (CRi) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)
timeFrame: on Day 56 (± 3 Days) for the last subject, within 4 years
measure: Composite complete remission (CRc) rate after completion of re-induction Cycle 1 among participants with AML (Phase 1 and 2)
timeFrame: on Day 56 (± 3 Days) for the last subject, within 4 years
measure: Time to relapse among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Rate of relapse among participants with AML after 1, 2 and 3 years (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Cumulative incidence of relapse among participants with AML at the end of study (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Overall survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Event-free survival among participants with AML at 1, 2, and 3 years (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Number 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)
timeFrame: within 8 years, 8 months
measure: Rate of CRc (CR or CRi) without minimal residual disease (MRD) using next generation sequencing among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
measure: Acceptability of including the palatability of quizartinib formulations among participants with AML (Phase 1 and 2)
timeFrame: within 8 years, 8 months
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Wilmington
country: United States
facility: A.I. duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center Children's Health
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Gent
country: Belgium
facility: Universitair Ziekenhuis Gent
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
city: Copenhagen
country: Denmark
facility: Rigshospitalet
city: Lyon
country: France
facility: Centre Léon Bérard
city: Paris
country: France
facility: Hôpital Armand-Trousseau
city: Toulouse
country: France
facility: Hôpital des Enfants
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Tel Aviv-Yafo
country: Israel
facility: Tel Aviv Sourasky Medical Center
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
city: Rome
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesù
city: Torino
country: Italy
facility: Ospedale Infantile Regina Margherita
city: Utrecht
country: Netherlands
facility: Prinses Maxima Centrum voor Kinderoncologie
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Nino Jesus
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset - Drottning Silvias Barn- och Ungdomssjukhus
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: