Quizartinib and High-dose Ara-C Plus Mitoxantrone in Relapsed/Refractory AML With FLT3-ITD

NCT03989713 | Terminated Phase 2 DMC

• 1 other identifier: HeLeNe-18-03-#545
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 1

Brief Summary

In this multicenter, upfront randomized phase II trial, all patients receive quizartinib in combination with HAM (high-dose cytarabine, mitoxantrone) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach. During consolidation therapy (chemotherapy as well as allo-HCT) patients receive either prophylactic quizartinib therapy or MRD-triggered preemptive continuation therapy with quizartinib according to up-front randomization.

Conditions

AML According to WHO 2016 Classification (Except Acute Promyelocytic Leukemia) AND (Refractory to Induction Therapy OR Relapsed After First Line Treatment)

Outcome Measures

Primary Outcomes (1)

• CRR

  Composite remission rate defined as the proportion of patients experiencing a CR (Complete remission)/CRi (Complete remission with incomplete hematological recovery rate) after salvage therapy.

  Collected during the first MRD-analysis / after approximately 100 study days

Secondary Outcomes (6)

• EFS

  Collected at a minimum at baseline, day 22 of Salvage therapy, last day of second cycle of consolidation therapy, 3-monthly during maintenance therapy, at EOT, 3-monthly during FU, and yearly after 2 years during FU, at EOS

• RFS

  Collected at a minimum at baseline, day 22 of Salvage therapy, last day of second cycle of consolidation therapy, 3-monthly during maintenance therapy, at EOT, 3-monthly during FU, and yearly after 2 years during FU, at EOS

• OS

  Collected at a minimum at baseline, day 22 of Salvage therapy, last day of second cycle of consolidation therapy, 3-monthly during maintenance therapy, at EOT, 3-monthly during FU, and yearly after 2 years during FU, at EOS

• CIR

  Collected at a minimum at baseline, day 22 of Salvage therapy, last day of second cycle of consolidation therapy, 3-monthly during maintenance therapy, at EOT, 3-monthly during FU, and yearly after 2 years during FU, at EOS

• CID

  Collected at a minimum at baseline, day 22 of Salvage therapy, last day of second cycle of consolidation therapy, 3-monthly during maintenance therapy, at EOT, 3-monthly during FU, and yearly after 2 years during FU, at EOS

Study Arms (2)

MRD-triggered arm

EXPERIMENTAL

1. Salvage therapy: All patients are randomized upfront and receive one cycle Q-HAM salvage therapy. All patients achieving CR or CRi are allocated according to randomization to either MRD-triggered or prophylactic arm. (Duration: one cycle á 21 days followed by up to 3 weeks recovery period if needed, 22-42 days in total) 2. Consolidation therapy: Patients receive one cycle of HAM and are further allocated based on the MRD-results assessed by flow cytometry with a cut of level of 0.1%: if the MRD is negative they remain in the MRD-triggered arm, whereas MRD positive patients cross over to the prophylactic arm. (Up to 2 cycles. Duration: two cycles á 28 days each followed by up to two weeks recovery period if needed, 56-84 days in total.) 3. Observation: No treatment will be given in the MRD-triggered arm. (Duration: 48 weeks in total.) 4. Safety follow-up and observational follow-up

Drug: MRD-triggered arm

Prophylactic Arm

EXPERIMENTAL

1. Salvage therapy: All patients are randomized upfront and receive one cycle Q-HAM salvage therapy. All patients achieving CR or CRi are allocated according to randomization to either MRD-triggered or prophylactic arm. (Duration: one cycle á 21 days followed by up to 3 weeks recovery period if needed, 22-42 days in total) 2. Consolidation therapy: Patients may receive up to two cycle of Q-HAM. (Up to 2 cycles. Duration: two cycles á 28 days each followed by up to two weeks recovery period if needed, 56-84 days in total.) 3. Maintenance therapy: Quizartinib will be given as single-agent therapy. The dose of quizartinib is aimed to be increased during maintenance therapy. (Up to 12 cycles. Duration: four times three cycles á 28 days, 48 weeks in total.) 4. Safety follow-up and observational follow-up

Drug: Prophylactic Arm

Interventions

MRD-triggered arm DRUG

1. Salvage therapy: Quizartinib: 40mg, p.o., Days: 4 - 21 Cytarabine: 18-60yrs: 3g/m² bid / \>-60yrs: 1g/m² bid, i.v. 3h i.v. 3h, Days: 1,2,3; Mitoxantrone: 10mg, i.v. 30min: Days: 2,3; 2. Consolidation therapy: Cytarabine: 18-60yrs: 3g/m² bid, i.v. 3h / \>-60yrs: 1g/m² bid, i.v. 3h, Days: 1,2,3; Mitoxantrone: 10mg, i.v. 30min, Days: 2,3 3. Observation therapy: No treatment

MRD-triggered arm

Prophylactic Arm DRUG

1. Salvage therapy: Quizartinib: 40mg, p.o., Days: 4 - 21 Cytarabine: 18-60yrs: 3g/m² bid / \>-60yrs: 1g/m² bid, i.v. 3h i.v. 3h, Days: 1,2,3; Mitoxantrone: 10mg, i.v. 30min: Days: 2,3; 2. Consolidation therapy: Quizartinib: 40mg, p.o., Days: 4 - 21 Cytarabine: 18-60yrs: 3g/m² bid, i.v. 3h / \>-60yrs: 1g/m² bid, i.v. 3h, Days: 1,2,3; Mitoxantrone: 10mg, i.v. 30min, Days: 2,3; 3. Maintenance therapy: Quizartinib: Cycle 1, Days 1-15: 40mg, p.o. and Day 16-28: 60mg, p.o.

Prophylactic Arm

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with acute myeloid leukemia according to the 2016 WHO classification (except acute promyelocytic leukemia) who are either A) refractory to induction therapy or B) relapsed after first line treatment including chemotherapy, autologous and/or allo-HCT (details below).
• ECOG performance status ≤ 2. See appendix 18.1
• Adequate renal function defined as creatinine clearance \>50 mL/min (calculated using the standard method for the institution)
• Discontinuation of prior AML treatment for at least A) 10 days for cytotoxic agents and B) 28 days for investigational drug treatment before the start of study treatment (except hydroxyurea or other treatment to control hyperleukocytosis)
• Age ≥ 18 years, no upper age limit
• Pregnancy and childbearing potential:
• A) Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration ("Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months).
• B) Female patients of reproductive age must agree to avoid getting pregnant while on therapy.
• C) WOCBP must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy) during study and 6 months after end of study/treatment. Hormonal contraception is an inadequate method of birth control.
• D) Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child during study and 6 months after end of study/treatment
• Signed written informed consent
• Ability of patient to understand character and consequences of the clinical trial
• Refractory to induction therapy is defined as no CR, or CRi, or PR (according to standard criteria) \[1\] after 1 or 2 intensive induction cycles of at least 7 days of cytarabine 100-200mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 700mg/m² per cycle and 2 days of an anthracycline (e.g. daunorubicin, idarubicin).
• Relapsed after first line therapy is defined as relapsed AML (according to standard criteria) \[1\] after a first line therapy including at least one intensive induction and consolidation therapy including (but not limited to) allo-HCT.

You may not qualify if:

• Acute promyelocytic leukemia (AML FAB M3 with t(15;17)(q22;q12) / PML-RARA)
• Patients with known CNS leukemia
• Isolated extramedullary manifestation of AML
• Patients with a "currently active" second malignancy other than non-melanoma skin cancer. Patients are not considered to have a "currently active" malignancy if they have completed therapy for more than one year and are considered by their physician to be at less than 30% risk of relapse within one year
• Hyperleukocytosis (leukocytes \> 30,000/µl) at the time of study entry. 1)
• Uncontrolled or significant cardiovascular disease, including any of the following:
• History of heart failure NYHA class 3 or 4
• Left ventricular ejection fraction (LVEF) ≤ 40% by echocardiogram (ECHO)
• History of uncontrolled angina pectoris or myocardial infarction within 12 months prior to screening
• History of second (Mobitz II) or third degree heart block or any cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• Inadequate liver function: ALT and AST ≥ 2.5 x ULN), total bilirubin ≥ 1.5 x ULN; Alkaline phosphatase ≥ 2.5 x ULN. Known liver cirrhosis or history of veno-occlusive disease (VOD) or history of Sinusoidal Obstruction Syndrome (SOS)
• Known positivity for HIV, active HBV, HCV or hepatitis A infection (active hepatitis B defined by HBs Ag positivity, active hepatitis C defined by positive virus load)
• Uncontrolled active infection
• Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
• within 100 days after allo-HCTat the time of screening

Sponsors & Collaborators

• Prof. Dr. Richard F Schlenk: lead

Study Sites (1)

University Hospital Heidelberg Med5

Heidelberg, Baden-Wurttemberg, 69124, Germany

Location

Related Publications (1)

• Jaramillo S, Le Cornet L, Kratzmann M, Krisam J, Gorner M, Hanel M, Rollig C, Wass M, Scholl S, Ringhoffer M, Reichart A, Steffen B, Kayser S, Mikesch JH, Schaefer-Eckart K, Schubert J, Geer T, Martin S, Kieser M, Sauer T, Kriegsmann K, Hundemer M, Serve H, Bornhauser M, Muller-Tidow C, Schlenk RF. Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD. Trials. 2023 Sep 15;24(1):591. doi: 10.1186/s13063-023-07421-x.

  PMID: 37715270 DERIVED

Study Officials

• Richard F. Schlenk, Prof. Dr.

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of NCT trials center and Clinical Trials Office Hematology/Oncology

Study Record Dates

• First Submitted: April 12, 2019
• First Posted: June 18, 2019
• Study Start: July 17, 2020
• Primary Completion: September 11, 2022
• Study Completion: September 11, 2022
• Last Updated: September 15, 2022

Record last verified: 2022-09

Locations

DE (1)