Relapsed or Refractory Acute Myeloid Leukemia With FLT3 Activating Mutations
Conditions
Keywords
FLT3, Crenolanib, Acute, myeloid, leukemia, relapsed, refractory
Brief summary
This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed or refractory AML with FLT3 activating mutations. Prior treatment with other FLT3 TKIs is allowed. Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.
Interventions
DRUGCrenolanib Besylate (CP-868,596-26)
Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.
Sponsors
Arog Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Relapsed/refractory primary AML or AML secondary to antecedent hematologic disorder with an expected survival of 3 months or greater * Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within \< 60 days of the screening period. * Age ≥18 years * ECOG PS 0 - 2 * Adequate liver function, defined as total or direct bilirubin ≤1.5x ULN, ALT ≤3.0x ULN,AST ≤3.0x ULN. Exceptions for ALT and AST restrictions will be made in the setting of documented liver involvement with leukemia * 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 women of childbearing potential * Able and willing to provide written informed consent * Subjects who received crenolanib prior to and are within 30-90 days of an allogeneic stem cell transplant (HSCT) and have either no active GVHD where therapy has been initiated or GVHD where therapy has not been escalated within 14 days prior to start of study drug
Exclusion criteria
* Absence of FLT3 activating mutation * \<5% blasts in blood or marrow at screening * Concurrent chemotherapy, systemic immunosuppressants, 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 manifested as hepatitis surface antigen positive (HepBsAg) or hepatitis C manifested as hepatitis C antibody positive * For post HSCT, subjects who are within 29 days of an allogeneic transplant, and/or are on an unstable dose of immunosuppressive drugs for management or prophylaxis of GVHD or have escalated therapy for GVHD within 14 days of starting study drug and/or have \>/=Grade 2 persistent non hematological toxicity related to the transplant or did not receive crenolanib prior to HSCT * Evidence of lack of engraftment if post allogeneic transplant * Unable to swallow pills * Major surgical procedures within 14 days of Cycle 1 Day 1 administration of crenolanib * Unwillingness or inability to comply with protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From the date of first dose to the end of protocol treatment, 1 year. | To determine the response rate to crenolanib.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 but \>5%. Hematologic improvement (HI) response included erythroid response where Hgb increased ≥ 1.5 g/dL, platelet response where platelets increased ≥ 30 x 10\^9/L for patient starting with \>20 x 10\^9/L platelets or increase from \<20 x 10\^9/L to \>20 x 10\^9/L and by at least 100% and neutrophil response where at least 100% increase and an increase \>0.5 x 10\^9/L. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or HI. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TKI Pre-treated Participants who had relapsed/refractory AML with FLT3 activating mutations whose leukemia progressed and have a history of prior therapy with one or more FLT3 TKIs received either 200mg/m2 /day crenolanib divided in three doses daily or 100mg TID depending on the version of the protocol at the time of their enrolment. (preferably every eight hours), taken orally at least 30 minutes pre or post meal. Crenolanib was taken orally at the abovementioned doses at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who were able to proceed to allogeneic stem cell transplant were able to resume crenolanib therapy post-transplant in an attempt to maintain remission. | 9 |
| TKI Naive Participants who had relapsed/refractory AML with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding any FLT3 TKI received either 200mg/m2 /day crenolanib divided in three doses daily or 100mg TID depending on the version of the protocol at the time of their enrolment. (preferably every eight hours), taken orally at least 30 minutes pre or post meal. Crenolanib was taken orally at the abovementioned doses at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who were able to proceed to allogeneic stem cell transplant were able to resume crenolanib therapy post-transplant in an attempt to maintain remission. | 4 |
| Total | 13 |
Baseline characteristics
| Characteristic | TKI Pre-treated | TKI Naive | Total |
|---|---|---|---|
| Age, Customized 18 to 44 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Customized 45 to 60 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Customized Greater than 60 years | 2 Participants | 2 Participants | 4 Participants |
| Baseline ECOG Performance ECOG 0 | 0 Participants | 1 Participants | 1 Participants |
| Baseline ECOG Performance ECOG 1 | 6 Participants | 3 Participants | 9 Participants |
| Baseline ECOG Performance ECOG 2 | 3 Participants | 0 Participants | 3 Participants |
| FLT3 status FLT3-D835 | 0 Participants | 0 Participants | 0 Participants |
| FLT3 status FLT3-ITD | 1 Participants | 2 Participants | 3 Participants |
| FLT3 status FLT3-ITD and D835 | 8 Participants | 2 Participants | 10 Participants |
| Number of prior therapies | 3 number of lines of therapy | 1.5 number of lines of therapy | 2 number of lines of therapy |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 13 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 12 / 13 |
Outcome results
Primary
Overall Response Rate
To determine the response rate to crenolanib.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 but \>5%. Hematologic improvement (HI) response included erythroid response where Hgb increased ≥ 1.5 g/dL, platelet response where platelets increased ≥ 30 x 10\^9/L for patient starting with \>20 x 10\^9/L platelets or increase from \<20 x 10\^9/L to \>20 x 10\^9/L and by at least 100% and neutrophil response where at least 100% increase and an increase \>0.5 x 10\^9/L. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or HI.
Time frame: From the date of first dose to the end of protocol treatment, 1 year.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Patients | Overall Response Rate | CR/CRi | 5 Participants |
| All Patients | Overall Response Rate | PR | 1 Participants |
| All Patients | Overall Response Rate | HI | 3 Participants |
| All Patients | Overall Response Rate | ORR (CR+PR) | 6 Participants |
| All Patients | Overall Response Rate | Clinical Benefit (CR+PR+HI) | 9 Participants |
| All Patients | Overall Response Rate | RD | 4 Participants |
| TKI Pre-treated | Overall Response Rate | RD | 4 Participants |
| TKI Pre-treated | Overall Response Rate | CR/CRi | 2 Participants |
| TKI Pre-treated | Overall Response Rate | ORR (CR+PR) | 3 Participants |
| TKI Pre-treated | Overall Response Rate | Clinical Benefit (CR+PR+HI) | 5 Participants |
| TKI Pre-treated | Overall Response Rate | PR | 1 Participants |
| TKI Pre-treated | Overall Response Rate | HI | 2 Participants |
| TKI Naive | Overall Response Rate | PR | 0 Participants |
| TKI Naive | Overall Response Rate | HI | 1 Participants |
| TKI Naive | Overall Response Rate | RD | 0 Participants |
| TKI Naive | Overall Response Rate | ORR (CR+PR) | 3 Participants |
| TKI Naive | Overall Response Rate | CR/CRi | 3 Participants |
| TKI Naive | Overall Response Rate | Clinical Benefit (CR+PR+HI) | 4 Participants |