Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies
Conditions
Keywords
FLT3, Crenolanib, Acute, Myeloid, AML
Brief summary
This pilot Phase II study is designed to evaluate the efficacy and tolerability of crenolanib in two cohorts of AML patients with FLT3 activation mutations (patients whose leukemia has recurred after prior chemotherapy not including a FLT3 TKI and patients whose leukemia has progressed after prior therapy with a FLT3 TKI).
Detailed description
This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed acute myeloid leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy without a FLT3 TKI, and those whose AML has progressed after prior therapy with FLT3 TKIs. Subjects will take Crenolanib besylate at 100 mg TID until disease progression, death, or unacceptable toxicities. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.
Interventions
Crenolanib besylate, 100 mg TID, taken orally at least 30 minutes pre- or post- meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule. Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.
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
* Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria with presence of either FLT3 ITD and/or other FLT3 activating mutations * Patients with secondary AML should have failed no more than two (2) prior regimens * Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN * Patients with primary AML should have received no more than two (2) prior cytotoxic containing salvage regimens. Reinduction with the same regimen or stem cell transplant will not be considered a separate salvage regimen. Change of drugs will be considered a salvage regimen. Unlimited FLT3 TKI therapy (even in combination with cytotoxics/hypomethylating agents) is allowed for patients enrolled in cohort B * Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within 30 day screening period * Males and females age ≥18 years * ECOG PS 0-2 * Adequate liver function, defined as bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, and AST ≤3.0x ULN * Adequate renal function, defined as serum creatinine ≤1.5x ULN * Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more than grade 1 (except alopecia) * Subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first dose of crenolanib as follows: for 14 days for classical cytotoxic agents and for five times the t1/2 (half-life) for FLT3 inhibitors and antineoplastic agents that are neither cytotoxic nor FLT3 inhibitors (e.g. hypomethylating agent or MEK inhibitor) * Negative pregnancy test for WOCBP * Able and willing to provide written informed consent.
Exclusion criteria
* Absence of a FLT3 activating mutation * \<5% blasts in blood or marrow at screening * Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea * Patient 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 * HIV infection or active hepatitis B (defined as hepatitis B surface antigen positive) or C (defined as hepatitis C antibody positive) * Known clinically active central nervous system (CNS) leukemia * Patients less than 30 days post HSCT * Subjects who have clinically significant graft versus host disease requiring treatment and /or have \>grade 2 persistent non hematological toxicity related to transplant * Prior crenolanib treatment for a non-leukemic indication * Major surgical procedures within 14 days of Day 1 administration of crenolanib. * Unwillingness or inability to comply with protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate of Patients Receiving Crenolanib Therapy | From the date of first dose to the end of protocol treatment. | 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. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline to a post-baseline result between 5% to 25% in the bone marrow aspirate or biopsy. Blast reduction (BR) response included a decrease of ≥50% in % blasts. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Overall Survival | From the date of first dose up to end of treatment, up to 24 months. | To determine the overall survival of AML patients with activating FLT3 mutations treated with crenolanib |
| Study Drug Exposure | Defined as the duration from first day to the last dose, up to 24 months, interruptions in study drug administration were not counted. | To determine the study drug exposure of relapse/refractory AML patients receiving 100 mg crenolanib besylate tablets three times daily. |
Countries
United States
Participant flow
Recruitment details
A total of 56 participants who met all inclusion criteria and none of the exclusion criteria were included in the study and were enrolled at 1 center in the United States.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A - No Prior FLT3 TKI Exposure Participants who had relapsed/refractory AML with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding any FLT3 TKI received 100 mg crenolanib besylate tablets administered orally three times a day. | 13 |
| Cohort B - Prior Therapy With FLT3 TKI Participants who had relapsed/refractory AML with FLT3 activating mutations whose leukemia progressed and have history of prior therapy with one or more FLT3 TKIs received 100 mg crenolanib besylate tablets administered orally three times a day. | 30 |
| Cohort C - Antecedent Hematological Disorder Participants who had relapsed/refractory AML with FLT3 activating mutations whose leukemia progressed and have history of antecedent hematological disorder received 100 mg crenolanib besylate tablets administered orally three times a day. | 13 |
| Total | 56 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Cohort C - Antecedent Hematological Disorder | Cohort B - Prior Therapy With FLT3 TKI | Cohort A - No Prior FLT3 TKI Exposure |
|---|---|---|---|---|
| Age, Customized >60 years | 30 Participants | 8 Participants | 15 Participants | 7 Participants |
| Age, Customized Between 18 and 44 years | 11 Participants | 2 Participants | 7 Participants | 2 Participants |
| Age, Customized Between 45 and 60 years | 15 Participants | 3 Participants | 8 Participants | 4 Participants |
| Baseline ECOG Performance 0 - Normal activity | 6 Participants | 1 Participants | 3 Participants | 2 Participants |
| Baseline ECOG Performance 1 - Symptoms but ambulatory | 39 Participants | 9 Participants | 21 Participants | 9 Participants |
| Baseline ECOG Performance 2 - In bed < 50% of time | 11 Participants | 3 Participants | 6 Participants | 2 Participants |
| Baseline FLT3 mutation FLT3-ITD and FLT3-TKD | 19 Participants | 6 Participants | 13 Participants | 0 Participants |
| Baseline FLT3 mutation FLT3-ITD only | 26 Participants | 3 Participants | 15 Participants | 8 Participants |
| Baseline FLT3 mutation FLT3-TKD only | 11 Participants | 4 Participants | 2 Participants | 5 Participants |
| Number of Prior Therapies | 3 prior therapies | 2 prior therapies | 3 prior therapies | 2 prior therapies |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 5 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 50 Participants | 13 Participants | 25 Participants | 12 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 7 Participants | 1 Participants | 5 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 5 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 40 Participants | 11 Participants | 18 Participants | 11 Participants |
| Sex: Female, Male Female | 30 Participants | 7 Participants | 15 Participants | 8 Participants |
| Sex: Female, Male Male | 26 Participants | 6 Participants | 15 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 53 / 56 | 12 / 13 | 29 / 30 | 12 / 13 |
| other Total, other adverse events | 56 / 56 | 13 / 13 | 30 / 30 | 13 / 13 |
| serious Total, serious adverse events | 52 / 56 | 10 / 13 | 30 / 30 | 12 / 13 |
Outcome results
Primary
Response Rate of Patients Receiving Crenolanib 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. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline to a post-baseline result between 5% to 25% in the bone marrow aspirate or biopsy. Blast reduction (BR) response included a decrease of ≥50% in % blasts. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS.
Time frame: From the date of first dose to the end of protocol treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | PR | 9 Participants |
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | CR/CRi | 8 Participants |
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | ORR (CR+PR) | 17 Participants |
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | BR | 21 Participants |
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | Clinical Benefit (CR+PR+BR) | 38 Participants |
| All Patients | Response Rate of Patients Receiving Crenolanib Therapy | Resistant disease (RD) | 18 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | Clinical Benefit (CR+PR+BR) | 10 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | PR | 2 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | ORR (CR+PR) | 5 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | CR/CRi | 3 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | BR | 5 Participants |
| Cohort A - No Prior FLT3 TKI Exposure | Response Rate of Patients Receiving Crenolanib Therapy | Resistant disease (RD) | 3 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | CR/CRi | 4 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | Resistant disease (RD) | 10 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | PR | 5 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | Clinical Benefit (CR+PR+BR) | 20 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | ORR (CR+PR) | 9 Participants |
| Cohort B - Prior Therapy With FLT3 TKI | Response Rate of Patients Receiving Crenolanib Therapy | BR | 11 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | ORR (CR+PR) | 3 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | CR/CRi | 1 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | PR | 2 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | Clinical Benefit (CR+PR+BR) | 8 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | BR | 5 Participants |
| Cohort C - Antecedent Hematological Disorder | Response Rate of Patients Receiving Crenolanib Therapy | Resistant disease (RD) | 5 Participants |
Secondary
Duration of Overall Survival
To determine the overall survival of AML patients with activating FLT3 mutations treated with crenolanib
Time frame: From the date of first dose up to end of treatment, up to 24 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Duration of Overall Survival | 237 days |
| Cohort A - No Prior FLT3 TKI Exposure | Duration of Overall Survival | 100 days |
| Cohort B - Prior Therapy With FLT3 TKI | Duration of Overall Survival | 85 days |
Secondary
Study Drug Exposure
To determine the study drug exposure of relapse/refractory AML patients receiving 100 mg crenolanib besylate tablets three times daily.
Time frame: Defined as the duration from first day to the last dose, up to 24 months, interruptions in study drug administration were not counted.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Patients | Study Drug Exposure | 57 days |
| Cohort A - No Prior FLT3 TKI Exposure | Study Drug Exposure | 43.5 days |
| Cohort B - Prior Therapy With FLT3 TKI | Study Drug Exposure | 50 days |