Mittwoch, 21. April 2021
Navigation öffnen
Anzeige:
Vectibix
JOURNAL ONKOLOGIE – STUDIE
Q-HAM

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

Rekrutierend

NCT-Nummer:
NCT03989713

Studienbeginn:
Juli 2020

Letztes Update:
06.01.2021

Wirkstoff:
MRD-triggered arm, Prophylactic Arm

Indikation (Clinical Trials):
Leukemia, Promyelocytic, Acute

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
Prof. Dr. Richard F Schlenk

Collaborator:
-

Studienleiter

Richard F. Schlenk, Prof. Dr.
Principal Investigator
University Hospital Heidelberg

Kontakt

Richard F. Schlenk, Prof. Dr.
Kontakt:
Phone: 0049 6221 56
Phone (ext.): 6228
E-Mail: Richard.schlenk@nct-heidelberg.de
» Kontaktdaten anzeigen
Lucian Le Cornet, PhD
Kontakt:
Phone: 49 (0)6221 56
Phone (ext.): 6553
E-Mail: lucian.lecornet@nct-heidelberg.de
» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Studien-Informationen

Detailed Description:

Acute myeloid leukemia (AML) is a clonal malignant disorder which is characterized by the

expansion of leukemic blasts in the bone marrow and the peripheral blood, which goes along

with a suppression of normal hematopoiesis including granulopoiesis, erythropoiesis and

thrombocytopoiesis. The prognosis is largely determined by cytogenetic and molecular risk

factors, age, performance status and antecedent myelodysplastic syndrome (MDS). With the

exception of old and frail patients, most AML patients are eligible for intensive

chemotherapy, which is given in curative intent consisting of induction and consolidation

therapy. However, despite intensive therapy, the long-term outcome of AML patients remains

poor, with less than 30% of patients achieving long lasting remission and even cure. This

poor outcome is largely due to refractoriness to induction chemotherapy as well as relapses

during and after completion of intensive induction and consolidation therapy. Regarding

refractoriness, about 20-30% of AML patients under the age of 60 years and about 50% of older

patients fail to attain complete remission (CR) following cytarabine plus anthracycline based

standard induction therapy. In addition, patients having achieved CR are at a high risk of

relapse, particularly within the first two years after completion of chemotherapy. Allogeneic

hematopoietic cell transplantation (allo-HCT) is currently the only treatment strategy to

offer the prospect of cure in relapsed/refractory (r/r)-AML; but outcome after allo-HCT is

largely determined by the remission state before allo-HCT. With the aim to induce a CR before

allo-HCT, salvage chemotherapy regimens are administered in r/r-AML. Typically, these salvage

regimens are based on high dose cytarabine (HiDAC), which is frequently combined with either

mitoxantrone (HAM regimen) or fludarabine plus idarubicin (idaFLA regimen). However, there is

still no commonly accepted standard salvage regimen and overall CR rates remain low with less

than one third of the patients achieving a CR. Apart from already known clinical unfavorable

prognostic parameters in relapsed AML such as short first CR duration, older age and previous

allo-HCT, FLT3-ITD has consistently been identified as an unfavorable molecular marker in

both relapsed and refractory AML. Recently midostaurin has been approved by the FDA and EMA

for the treatment of newly diagnosed AML with activating FLT3 mutations. But still roughly

one quarter of patients, who received midostaurin, was refractory to induction therapy and

relapse rate at 2 years excited 40%. Thus, new treatment options are urgently needed,

particularly in r/r-AML with FLT3-ITD.

The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is very

specific for FLT3, has a high capacity for sustained FLT3 inhibition and an acceptable

toxicity profile. Furthermore, single agent quizartinib doubled the response rate as compared

to standard of care in a randomized study in r/r-AML. Although survival was also improved in

this study the difference was only marginal.

In this protocol we evaluate the efficacy of quizartinib in combination with HAM (high-dose

cytarabine, mitoxantrone) as compared to historical controls based on the matched threshold

crossing approach followed by randomized prophylactic versus MRD-triggered continuation

therapy with quizartinib including consolidation (chemotherapy as well as allo-HCT) and

maintenance.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- 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).

- Positive for FLT3-ITD (defined as a ratio of mutant to wild-type alleles of at least

0.05; measured within 2 weeks before inclusion)

- 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.

Exclusion Criteria:

- 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

- clinically relevant Graft-versus-Host-Disease (GvHD) requiring initiation of treatment

or treatment escalation within 21 days prior to screening

- Any one of the following ongoing or in the previous 6 months: myocardial infarction,

congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained

ventricular tachyarrhythmia), right or left bundle branch block and bifascicular

block, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular

accident, transient ischemic attack or symptomatic pulmonary embolism; as well as

bradycardia defined as <50 bpms

- QTc interval >470 msec using the Fredericia correction (QTcF).

- Patients known to be refractory to platelet or packed red cell transfusions as per

institutional guidelines, or who are known to refuse or who are likely to refuse blood

product support.

- Severe neurologic or psychiatric disorder interfering with ability of giving informed

consent

- Known or suspected active alcohol or drug abuse

- No consent for biobanking and for registration, storage and processing of the

individual disease-characteristics and course as well as information of the family

physician about study participation.

- Pregnancy and lactation

- History of hypersensitivity to the investigational medicinal product or to any drug

with similar chemical structure or to any excipient present in the pharmaceutical form

of the investigational medicinal product

- Prior treatment with quizartinib

1. These patients should be treated with hydroxyurea and / or receive

leukocytapheresis treatment according to routine practice and are only allowed to

enter into the study when leukocyte counts of 30,000/µl or below are reached. If

hydroxyurea is not sufficient to control hyperleukocytosis, i.v. application of

100mg cytarabine continuously over 24 hours may be discussed with the Principle

Investigator or the Medical Coordinator.

Studien-Rationale

Primary outcome:

1. CRR (Time Frame - Collected during the first MRD-analysis / after approximately 100 study days):
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.



Secondary outcome:

1. EFS (Time Frame - 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):
Event-free survival

2. RFS (Time Frame - 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):
Relapse-free survival

3. OS (Time Frame - 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):
Overall survival

4. CIR (Time Frame - 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):
Cumulative incidence of relapse

5. CID (Time Frame - 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):
Cumulative incidence of deaths

6. QoL (Time Frame - Collected 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):
Quality of life

Studien-Arme

  • Experimental: MRD-triggered arm
    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) 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.) Observation: No treatment will be given in the MRD-triggered arm. (Duration: 48 weeks in total.) Safety follow-up and observational follow-up
  • Experimental: Prophylactic Arm
    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) 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.) 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.) Safety follow-up and observational follow-up

Geprüfte Regime

  • MRD-triggered arm:
    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; 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 Observation therapy: No treatment
  • Prophylactic Arm:
    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; 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; Maintenance therapy: Quizartinib: Cycle 1, Days 1-15: 40mg, p.o. and Day 16-28: 60mg, p.o.

Quelle: ClinicalTrials.gov


Das könnte Sie auch interessieren
70 Prozent der Deutschen fürchten Tumor, Engagement für Gesundheit wächst
70+Prozent+der+Deutschen+f%C3%BCrchten+Tumor%2C+Engagement+f%C3%BCr+Gesundheit+w%C3%A4chst
© pressmaster / Fotolia.com

Sieben von zehn Menschen in Deutschland fürchten sich am meisten vor Krebs. Bei Erwachsenen zwischen 30 und 44 Jahren und Frauen ist die Angst besonders groß. Das zeigt eine aktuelle und repräsentative Studie der DAK-Gesundheit. Ein weiteres zentrales Ergebnis: Das Engagement für die eigene Gesundheit wächst. Immer mehr Menschen gehen zu Vorsorgeuntersuchungen und halten sich mit Sport und gesunder Ernährung fit.