Acute Myeloid Leukemia
Conditions
Brief summary
This is an open label, two-arm, Phase I-II trial, non-randomized. Arm 1: crenolanib with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin) Arm 2: crenolanib with 5-azacitidine
Detailed description
For each arm: The phase I with dose-limiting toxicity (DLT) determination will use 3+3 design. Phase II total of 52 patients (26 per arm) will be treated at established phase I dose. Enrollment to be simultaneous to each arm.
Interventions
Sponsors
Arog Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of refractory/relapsed AML or high-risk MDS * Arm 1: Subjects must have received at least one prior therapy and a maximum of three prior therapies * Arm 2: Subjects must have received at least one prior therapy and a maximum of three prior therapies. No prior treatment with 5-Azacitidine is allowed in this arm. 2. FLT3 mutation positive (ITD, TKD or other) 3. ECOG PS 0-2 4. Adequate liver and renal function 5. Negative pregnancy test 6. Extramedullary leukemia allowed except CNS disease
Exclusion criteria
* Arm 1 and 2 Exclusion: 1. \<5% blasts in marrow or blood at time of screening 2. Active HIV, hepatitis B or C 3. CNS leukemia 4. Clinically significant GVHD or organ dysfunction where chemotherapy specified by protocol cannot be given 5. Patient with AML-M3 (APL) 6. Pre-existing liver diseases (i.e. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate of Crenolanib Besylate Combination Therapy | Baseline up to first documented response, persistent disease, or death (whichever occurs first), 1 year. | To determine the response rate to crenolanib. CR Complete remission (CR) response criteria include a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. CRi response included all CR criteria met, except participant did not experience either platelet recovery or ANC recovery. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS. Death in aplasia response include deaths occurring following chemotherapy while cytopenic with an aplastic or hypoplastic BM prior to death without evidence of persistent leukemia. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 Patients received 60 mg TID (dose level 1) crenolanib combined with standard salvage chemotherapy. Salvage chemotherapy options included IA (Idarubicin (Ida) 12 mg/m2 for 3 days (d) with cytarabine (AraC) 1.5 g/m2 for 4 days (3 d if age \> 60 yrs)), FLAG-Ida (Fludarabine 30 mg/m2, AraC 2g/m2 each for 5 days, and Ida 8 mg/m2 for 3 days) or MEC (Mitoxantrone 8 mg/m2, etoposide 100 mg/m2, AraC 1g/m2 all for 5 days). Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 3 |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 Patients received 80 mg TID (dose level 2) crenolanib combined with standard salvage chemotherapy. Salvage chemotherapy options included IA (Idarubicin (Ida) 12 mg/m2 for 3 days (d) with cytarabine (AraC) 1.5 g/m2 for 4 days (3 d if age \> 60 yrs)), FLAG-Ida (Fludarabine 30 mg/m2, AraC 2g/m2 each for 5 days, and Ida 8 mg/m2 for 3 days) or MEC (Mitoxantrone 8 mg/m2, etoposide 100 mg/m2, AraC 1g/m2 all for 5 days). Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 5 |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 Patients received 100 mg TID (dose level 3) crenolanib combined with standard salvage chemotherapy. Salvage chemotherapy options included IA (Idarubicin (Ida) 12 mg/m2 for 3 days (d) with cytarabine (AraC) 1.5 g/m2 for 4 days (3 d if age \> 60 yrs)), FLAG-Ida (Fludarabine 30 mg/m2, AraC 2g/m2 each for 5 days, and Ida 8 mg/m2 for 3 days) or MEC (Mitoxantrone 8 mg/m2, etoposide 100 mg/m2, AraC 1g/m2 all for 5 days). Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 12 |
| Crenolanib With 5-azacitidine - Dose Level 1 Patients received 60 mg TID crenolanib combined with 5-azacitidine. 5-azacitidine was given at 75 mg/m2/day for 7 days each cycle. Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 5 |
| Crenolanib With 5-azacitidine - Dose Level 2 Patients received 80 mg TID crenolanib combined with 5-azacitidine. 5-azacitidine was given at 75 mg/m2/day for 7 days each cycle. Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 3 |
| Crenolanib With 5-azacitidine - Dose Level 3 Patients received 100 mg TID crenolanib combined with 5-azacitidine. 5-azacitidine was given at 75 mg/m2/day for 7 days each cycle. Patients were allowed to continue receiving crenolanib for up to 365 days after the completion of cytotoxic therapy if they remained in remission. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Crenolanib was given continuously starting at the end of chemotherapy, and discontinued 3 days before the next cycle. | 0 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Crenolanib With 5-azacitidine - Dose Level 1 | Crenolanib With 5-azacitidine - Dose Level 2 | Total | Crenolanib With 5-azacitidine - Dose Level 3 |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 43 years | 51 years | 65 years | 69 years | 60 years | 59.5 years | — |
| Age, Customized 18-60 years | 2 Participants | 5 Participants | 5 Participants | 2 Participants | 2 Participants | 16 Participants | 0 Participants |
| Age, Customized >60 years | 1 Participants | 0 Participants | 7 Participants | 3 Participants | 1 Participants | 12 Participants | 0 Participants |
| Antecedent Hematological Disorder | 0 Participants | 3 Participants | 4 Participants | 3 Participants | 0 Participants | 10 Participants | — |
| Baseline ECOG Performance 0 | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 0 Participants |
| Baseline ECOG Performance 1 | 2 Participants | 2 Participants | 9 Participants | 3 Participants | 2 Participants | 18 Participants | 0 Participants |
| Baseline ECOG Performance 2 | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 6 Participants | 0 Participants |
| FLT3 Mutations ITD and TKD | 1 Participants | 3 Participants | 4 Participants | 1 Participants | 0 Participants | 9 Participants | 0 Participants |
| FLT3 Mutations ITD only | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 10 Participants | 0 Participants |
| FLT3 Mutations TKD only | 1 Participants | 1 Participants | 5 Participants | 2 Participants | 0 Participants | 9 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 5 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 3 Participants | 4 Participants | 8 Participants | 3 Participants | 3 Participants | 21 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 6 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 4 Participants | 7 Participants | 4 Participants | 2 Participants | 19 Participants | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 6 Participants | 4 Participants | 2 Participants | 13 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 6 Participants | 1 Participants | 1 Participants | 15 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 5 / 5 | 8 / 12 | 5 / 5 | 3 / 3 | 0 / 0 |
| other Total, other adverse events | 3 / 3 | 5 / 5 | 12 / 12 | 5 / 5 | 3 / 3 | 0 / 0 |
| serious Total, serious adverse events | 3 / 3 | 5 / 5 | 12 / 12 | 5 / 5 | 3 / 3 | 0 / 0 |
Outcome results
Primary
Response Rate of Crenolanib Besylate Combination Therapy
To determine the response rate to crenolanib. CR Complete remission (CR) response criteria include a post-baseline bone marrow (BM) biopsy or aspiration % blasts \<5%, absolute neutrophil count (ANC) \>1×10\^9/L and platelet count \>100×10\^9/L. CRi response included all CR criteria met, except participant did not experience either platelet recovery or ANC recovery. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS. Death in aplasia response include deaths occurring following chemotherapy while cytopenic with an aplastic or hypoplastic BM prior to death without evidence of persistent leukemia.
Time frame: Baseline up to first documented response, persistent disease, or death (whichever occurs first), 1 year.
Population: Number of participants analyzed in the arm Crenolanib With 5-azacitidine - Dose Level 3 (100mg Crenolanib) is zero as the study concluded prior to enrolling any participants on this arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 2 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 2 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 0 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 0 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 0 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 3 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 3 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 7 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 1 Participants |
| Crenolanib With Standard Salvage Chemotherapy - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 4 Participants |
| Crenolanib With 5-azacitidine - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 1 Participants |
| Crenolanib With 5-azacitidine - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 1 Participants |
| Crenolanib With 5-azacitidine - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 1 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 4 Participants |
| Crenolanib With 5-azacitidine - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 2 Participants |
| Crenolanib With 5-azacitidine - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 1 Participants |
| Crenolanib With 5-azacitidine - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 2 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 1 Participants |
| Crenolanib With 5-azacitidine - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | CR/CRi | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | Death in Aplasia | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | ORR (CR/CRi+MLFS) | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | Persistent Disease (PD) | 0 Participants |
| Crenolanib With 5-azacitidine - Dose Level 3 | Response Rate of Crenolanib Besylate Combination Therapy | MLFS | 0 Participants |