Newly Diagnosed AML With FLT3 Activating Mutations
Conditions
Brief summary
This pilot study is designed to evaluate the safety and tolerability of oral crenolanib besylate given sequentially during standard induction and consolidation chemotherapy in patients with newly diagnosed AML with FLT3 activating mutations.
Interventions
Sponsors
Arog Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Unequivocal diagnosis of AML based on the WHO classification, excluding acute promyelocytic leukemia 2. No prior therapy for AML, except for hydroxyurea, in this setting is allowed. 3. Subjects with AML evolving from MDS may have received prior MDS therapy with demethylating agents 4. Subjects must have tested positive for FLT3-ITD and/or other FLT3 activating mutations 5. Age ≥18 years 6. ECOG PS 0 - 2 7. Adequate liver function, defined as normal total bilirubin, ALT ≤2.0x ULN, and AST ≤2.0x ULN measured within 24 hours prior to crenolanib commencement 8. Adequate renal function, defined as serum creatinine ≤1.5x ULN or GFR \>50 mL/min 9. Negative pregnancy test (serum or urine) for women of childbearing potential (WOCBP) • Women considered not of childbearing potential include any of the following: no menses for at least 2 years or menses within 2 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used) or bilateral oophorectomy or radiation castration and amenorrheic for at least 3 months or with bilateral tubal ligation 10. WOCBP must practice contraception. Acceptable methods of contraception are double barrier methods (condoms with spermicidal jelly or foam and diaphragm with spermicidal jelly or foam), oral, depo provera, or injectable contraceptives, intrauterine devices, tubal ligations, and abstention 11. Male patients (except those with prior surgical contraceptive procedures) with female partners who are of childbearing potential: Recommendation is for male and partner to use effective contraceptive methods, such as latex condoms, during the study 12. Able and willing to provide written informed consent
Exclusion criteria
1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, and sclerosing cholangitis, etc.) 2. Active CNS leukemia 3. Subject with concurrent severe and/or uncontrolled medical conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy 4. NYHA Class III-IV heart failure, myocardial infarction \<6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapy 5. Unable to swallow pills 6. Major surgical procedures within 14 days of administration of crenolanib (does not include line placement as needed for chemotherapy administration). 7. Unwillingness or inability to comply with protocol. 8. Concurrent use of other investigational agents. 9. Subjects who are not eligible for standard chemotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response to Crenolanib With Standard Induction Chemotherapy | 2 years | To determine the response rate to crenolanib. Complete remission (CR) response criteria includes a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, the absence of Auer rods and extramedullary leukemia, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. Complete remission with incomplete blood count recovery (CRi) response includes all CR criteria met, except participant do not achieve either platelet or ANC recovery. Composite Complete CR response includes all subjects who achieve a CR and CRi. Partial Response (PR) response includes all CR criteria met except a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but within 5-25% or bone marrow blasts \<5% with persistent Auer rods. Refractory Disease response includes subjects who do not satisfy the criteria for CR, CRi or PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 3-Year Overall Survival | 3 years | Overall survival (OS) was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive. OS at 3-years is presented. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participants Less Than or Equal to 60 Years of Age Participants ≤60yrs old who had AML with FLT3 activating mutations received 7+3 induction therapy with cytarabine and either daunorubicin or idarubicin followed by 100 mg crenolanib besylate administered orally three times a day. The participants then received up to four cycles of consolidation chemotherapy with high dose cytarabine followed by 100 mg crenolanib besylate three times a day. Participants not undergoing hematopoietic stem cell transplant received crenolanib for an additional 12 cycles and participants undergoing transplant received 12 cycles of crenolanib post-transplant. | 29 |
| Participants Greater Than 60 Years of Age Participants \>60yrs old who had AML with FLT3 activating mutations received 7+3 induction therapy with cytarabine and either daunorubicin or idarubicin followed by 100 mg crenolanib besylate administered orally three times a day. The participants then received up to four cycles of consolidation chemotherapy with high dose cytarabine followed by 100 mg crenolanib besylate three times a day. Participants not undergoing hematopoietic stem cell transplant received crenolanib for an additional 12 cycles and participants undergoing transplant received 12 cycles of crenolanib post-transplant. | 15 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Participants Greater Than 60 Years of Age | Participants Less Than or Equal to 60 Years of Age | Total |
|---|---|---|---|
| Age, Continuous | 68 years | 51 years | 57 years |
| AML with Antecedent Hematological Disorders No | 12 Participants | 28 Participants | 40 Participants |
| AML with Antecedent Hematological Disorders Yes | 3 Participants | 1 Participants | 4 Participants |
| Cytogenetics Abnormal, not complex | 5 Participants | 6 Participants | 11 Participants |
| Cytogenetics Complex | 0 Participants | 2 Participants | 2 Participants |
| Cytogenetics Normal | 9 Participants | 21 Participants | 30 Participants |
| Cytogenetics Not Available | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 27 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| FLT3 Mutations ITD and TKD | 1 Participants | 2 Participants | 3 Participants |
| FLT3 Mutations ITD only | 10 Participants | 23 Participants | 33 Participants |
| FLT3 Mutations TKD only | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 22 Participants | 34 Participants |
| Sex: Female, Male Female | 7 Participants | 15 Participants | 22 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 9 / 29 | 10 / 15 |
| other Total, other adverse events | 29 / 29 | 15 / 15 |
| serious Total, serious adverse events | 18 / 29 | 12 / 15 |
Outcome results
Primary
Clinical Response to Crenolanib With Standard Induction Chemotherapy
To determine the response rate to crenolanib. Complete remission (CR) response criteria includes a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, the absence of Auer rods and extramedullary leukemia, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. Complete remission with incomplete blood count recovery (CRi) response includes all CR criteria met, except participant do not achieve either platelet or ANC recovery. Composite Complete CR response includes all subjects who achieve a CR and CRi. Partial Response (PR) response includes all CR criteria met except a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but within 5-25% or bone marrow blasts \<5% with persistent Auer rods. Refractory Disease response includes subjects who do not satisfy the criteria for CR, CRi or PR.
Time frame: 2 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Composite Complete Remission (CR + CRi) | 26 Participants |
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission (CR) | 22 Participants |
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission with incomplete count recovery (CRi) | 4 Participants |
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Partial Remission (PR) | 0 Participants |
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Refractory Disease | 3 Participants |
| Participants Less Than or Equal to 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Not evaluable | 0 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Not evaluable | 1 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Composite Complete Remission (CR + CRi) | 12 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Partial Remission (PR) | 1 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Refractory Disease | 1 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission (CR) | 12 Participants |
| Participants Greater Than 60 Years of Age | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission with incomplete count recovery (CRi) | 0 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission (CR) | 34 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Complete Remission with incomplete count recovery (CRi) | 4 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Not evaluable | 1 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Partial Remission (PR) | 1 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Composite Complete Remission (CR + CRi) | 38 Participants |
| All Patients | Clinical Response to Crenolanib With Standard Induction Chemotherapy | Refractory Disease | 4 Participants |
Secondary
3-Year Overall Survival
Overall survival (OS) was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive. OS at 3-years is presented.
Time frame: 3 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Participants Less Than or Equal to 60 Years of Age | 3-Year Overall Survival | 71.4 percentage of participants |
| Participants Greater Than 60 Years of Age | 3-Year Overall Survival | 33.3 percentage of participants |
| All Patients | 3-Year Overall Survival | 58 percentage of participants |