Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations

Summary

The main trial is a double-blinded, placebo-controlled, randomized, phase III, multi-center trial in adult patients with relapsed or refractory AML harboring an activating FLT3 mutation as defined in the inclusion /exclusion criteria.

An initial open label dose-finding run-in phase I of the study will be performed administering the study drug crenolanib with salvage chemotherapy consisting of mitoxantrone and cytarabine (MC) in 18 patients according to the experimental arm of the study. After completion of this dose-finding run-in phase I, toxicity and response data will be provided to the external Data and Safety Monitoring Board (DSMB) and the Trial Committee by the Coordinating Investigator. The Trial Committee will decide on the basis of these data and the recommendation of the DSMB on dose modification and the further conduct of the study with regard to the double-blinded, placebo-controlled, randomized phase of the study.

The double-blinded, placebo-controlled randomized portion will start after the completion of the dose-finding run-in phase I and positive opinion of the Trial Committee.

Crenolanib starts on day 7 of MC and is given continuously until 48 hours prior to the next chemotherapy; if receiving allogeneic HCT, crenolanib is held 48 hours prior to conditioning and restarts no sooner than 30 days and not later than day 100 after transplant.

Sample size randomized phase: 276 patients

Primary objective: To evaluate the impact of crenolanib given in combination with salvage chemotherapy and consolidation including allogeneic hematopoietic cell transplantation and ongoing single agent maintenance therapy with crenolanib on event-free (EFS) and overall survival (OS) in adult patients with relapsed or refractory AML harboring FLT3 activating mutations.

Conditions

• Acute Myeloid Leukemia

Interventions

DRUG

chemotherapy (Mitoxantrone, Cytarabine)

Induction therapy: * Mitoxantrone 10 mg/m² IV, push (8 mg/m² for patients \> 60 years of age and/or previous allogeneic HCT) d 1-3 * Cytarabine 1000 mg/m² IV (500 mg/m² for patients \> 60 years of age and/or previous allogeneic HCT), over 3 hours, d 1-6 Consolidation therapy: Younger adult patients (18 to 60 yrs): Cytarabine 1500 mg/m² by i.v infusion over 3 hours BID on days 1-3 (total dose 9000 mg/m²). Older patients (\> 60 yrs) and or previous allogeneic HCT: Cytarabine 1000 mg/m² by i.v. infusion over 3 hours BID on days 1-3 (total dose 6000 mg/m²).

DRUG

Placebo

Induction therapy: Placebo to be given as p.o. TID starting d 7+, given continuously thereafter until 48 hours prior to the next chemotherapy. Consolidation therapy: Placebo will start on day 4, thereafter with continuous dosing until 48h before start of subsequent consolidation chemotherapy. Maintenance therapy with placebo is intended in all patients after allogeneic HCT or intermediate-dose cytarabine consolidation therapy. Maintenance therapy will be given for 364 days (equivalent to 13 cycles à 28 days) after recovery from allogeneic HCT or IDAC. Maintenance with placebo will be given at the same dose tolerated during induction therapy.

DRUG

Crenolanib

Induction therapy: Crenolanib to be given as p.o. TID starting d 7+, given continuously until 48 hours prior to the next chemotherapy. Consolidation therapy: Crenolanib will start on day 4, thereafter with continuous dosing until 48h before start of subsequent consolidation chemotherapy. Maintenance therapy with Crenolanib is intended in all patients after allogeneic HCT or intermediate-dose cytarabine consolidation therapy. Maintenance therapy will be given for 364 days (equivalent to 13 cycles à 28 days) after recovery from allogeneic HCT or IDAC. Maintenance with Crenolanib will be given at the same dose tolerated during induction therapy.

OTHER

Allogeneic stem cell transplantation

In patients achieving a CR or CRi after salvage-reinduction chemotherapy allogeneic HCT from a matched related or unrelated donor is the preferred form of consolidation. Preferred source of allogeneic HSC are mobilized peripheral blood stem cells. Other forms of allogeneic transplantation (haploidentical donor; cord blood) are allowed. Allogeneic HCT should be conducted at the earliest time point after the start of the last chemotherapy but no later than after 56 days. A delay of transplant beyond this time window need to be discussed with the Coordinating Investigator. Patients can receive allogeneic HCT directly after salvage re-induction chemotherapy with MC, but also later on following consolidation with IDAC.

Sponsors & Collaborators

• University of Ulm

  lead OTHER

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2016-11-17

Primary Completion

2020-03-09

Completion

2020-03-09

Countries

• Germany

Study Locations