Study of Crenolanib in Combination Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations
Conditions
Acute Myeloid Leukemia
Conditions: official terms
Leukemia - Leukemia, Myeloid - Leukemia, Myeloid, Acute
Conditions: Keywords
Acute myeloid leukemia, FLT3 mutations, Crenolanib
Study Type
Interventional
Study Phase
Phase 3
Study Design
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Intervention
Name: chemotherapy (Mitoxantrone, Cytarabine) Type: Drug
Name: Placebo Type: Drug
Name: Crenolanib Type: Drug
Name: Allogeneic stem cell transplantation Type: Other
Overall Status
Not yet recruiting
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 safety run-in phase of the study will be performed in an open- label administering the study drug crenolanib with salvage chemotherapy consisting of mitoxantrone and cytarabine (MC) in 12 patients according to the experimental arm of the study. After completion of this safety run-in phase, 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 safety run-in phase and positive opinion of the Trial Committee.

Crenolanib starts on day 7 of MC and is given continuously thereafter, except for days of chemotherapy; if receiving allogeneic HSCT, crenolanib is held during conditioning and transplant and restarts no sooner than 30 days 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 stem 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

1. Patients with confirmed diagnosis of AML either refractory to induction therapy or relapsed after first line treatment including chemotherapy, autologous and allogeneic HSCT

1. refractory to induction therapy is defined as no CR, CRi, PR (according to standard criteria, 28) after one intensive induction therapy including at least 7 days of cytarabine 100-200mg/m² continuously and 3 days of an anthracycline (e.g. daunorubicin, idarubucin )

2. relapsed after first line therapy is defined as relapsed AML (according to standard criteria, 28) after a first line therapy including at least one intensive induction and consolidation therapy

2. Presence of FLT3-activating mutation at the time of refractory disease or relapse assessed in the central AMLSG reference laboratories; Positivity positivity of FLT3-ITD and FLT3-TKD is defined based on genescan analysis with a mutant to wild-type ratio equal or above 5%

3. Patients considered eligible for intensive chemotherapy

4. ECOG performance status of ≤ 2

5. Age ≥ 18 years with the capacity to give written informed consent

6. 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)

7. Female patients of reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and for 3 months after the last dose of crenolanib

8. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy). Hormonal contraception is an inadequate method of birth control

9. Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy (while on therapy and for 3 month after the last dose of crenolanib)

10. Willing to adhere to protocol specific requirements

11. Following receipt of verbal and written information about the study, the patient must provide signed informed consent before any study related activity is carried out

Exclusion Criteria:

The presence of any of the following will exclude a patient from study enrollment:

1. Known or suspected hypersensitivity to the study drugs and/or any excipients 2. ECOG performance status >2 3. Inadequate cardiac, hepatic and/or renal function at the Screening Visit defined as:

- ejection fraction < 45% confirmed by echocardiography

- creatinine >1.5x upper normal serum level

- total bilirubin, AST or ALT >2.5 upper normal serum level 4. Extramedullary involvement

5. Any clinically significant, advanced or unstable disease or history of that may interfere with primary or secondary variable evaluations or put the patient at special risk, such as:

- Myocardial infarction, unstable angina within 3 months before screening

- Heart failure NYHA III/IV

- Severe obstructive or restrictive ventilation disorder

- Uncontrolled infection 6. Severe neurological or psychiatric disorder interfering with ability of giving an informed consent 7. Currently receiving a therapy not permitted during the study, as defined in Section 10.6.5 8. Active Graft-versus-Host Disease (GvHD) under immunosuppressive therapy different from steroids 9. Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year 10. Known history of positive test for Hepatitis B surface Antigen (HsbAg) or hepatitis C antibody or history of positive test for Human Immunodeficiency Virus (HIV) 11. Hematological disorder independent of leukemia 12. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation 13. No consent for biobanking 14. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study 15. Patients known or suspected of not being able to comply with this trial protocol 16. Breast feeding women or women with a positive pregnancy test at Screening visit 17. Patients of childbearing potential not willing to use adequate contraception during study and 3 months after last dose of crenolanib
Location
University hospital of Ulm
Ulm, Germany
Status: Not yet recruiting
Contact: Richard F Schlenk, MD
Start Date
April 2015
Completion Date
October 2023
Sponsors
University of Ulm
Source
University of Ulm
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page