Relapsed/Refractory Acute Myeloid Leukemia (AML)
Conditions
Brief summary
The proposed study is designed to combine crenolanib with standard salvage chemotherapy to treat patients with R/R AML irrespective the FLT3 status.
Detailed description
Open label, dose de-escalation, pilot trial of crenolanib with standard salvage chemotherapy. Subjects may receive up to 2 cycles of induction with standard salvage chemotherapy followed by crenolanib. Each arm will enroll approximately 24 patients (72 total); stratification to each arm will be per physician's choice
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. Confirmed diagnosis of AML, including treatment-related secondary AML (except prior MDS) according to World Health Organization (WHO) 2008 classification at treating institution 2. Subjects who are refractory\* or who have relapsed\*\* following first line AML therapy with cytarabine/anthracycline based chemotherapy, with or without a tyrosine kinase inhibitor. \*Refractory to induction therapy is defined as never achieving CR, CRi or CRp (according to International Working Group criteria) after one line of intensive regimen for AML (re-induction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700mg/m² per cycle and 3 days of an anthracycline with or without a TKI. or \*\*First relapse is defined as untreated hematologic relapse (according to International Working Group criteria) after one line of intensive regimen for AML (re-induction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700mg/m² per cycle and 3 days of an anthracycline with or without a TKI that induced a CR/CRi/CRp. Subjects are allowed to receive induction, consolidation, transplant and/or maintenance prior to achieving their first CR/CRi/CRp. 3. Subjects considered eligible for intensive chemotherapy 4. ECOG performance status ≤ 2 5. Age ≥ 18 years 6. Adequate liver function within 72 hours of enrollment, defined as: * Normal total serum bilirubin * ALT and AST ≤ 2.0 x ULN 7. Adequate renal function, defined as serum creatinine ≤ 1.5x ULN 8. Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 72 hours prior to enrollment Woman of childbearing potential is defined as any woman who has not undergone a hysterectomy and who has had menses at any time in the preceding 24 consecutive months 9. 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) while on crenolanib and for 3 months following the last dose of crenolanib. Hormonal contraception alone is not an acceptable method of birth control for the purpose of this trial. 10. Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 3 month after the last dose of crenolanib). 11. Willing to adhere to protocol specific requirements 12. Following receipt of verbal and written information about the study, the subject must provide signed informed consent before any study related activity is carried out. 13. Clinically significant toxic effects of prior therapy (expect hydroxyuria) resolved to Grade ≤ 1 before the start of study.
Exclusion criteria
1. \< 5% blasts in blood or marrow at screening, except if measurable extramedullary AML is confirmed 2. Acute promyelocytic leukemia (APL) 3. Known clinically active CNS leukemia 4. Clinically active or unstable graft-versus-host disease (GvHD) requiring treatment which precludes administration of chemotherapy as defined in this protocol 5. Prior anti-leukemia therapy within 14 days of enrollment for classical cytotoxic agents, and within 5x the half-life for other investigational agents * Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e., control of WBC) are allowed but should be discontinued at least 24 hrs prior to enrollment. * Other agents used strictly with palliative intent might be allowed during this period after discussing with principal investigator 6. Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis) 7. Known HIV infection. 8. Evidence of ongoing, uncontrolled systemic infection or an uncontrolled local infection requiring therapy at the start of study. 9. Currently active second malignancy (other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostatic intraepithelial neoplasia within 1 year). Subjects 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 1 year. 10. Concurrent participation in another therapeutic clinical trial. 11. Pregnant or breastfeeding women 12. Subjects of childbearing potential not willing to use adequate contraception during study and 3 months after last dose of crenolanib 13. Subject with uncontrolled cardiac disease including congestive heart failure class III or IV by the NYHA, unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months 14. Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy 15. Inability to give an informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response to Crenolanib With Standard Salvage Chemotherapy | 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 have either platelet recovery or ANC recovery. CRh response included all CR criteria met, except subject only has partial platelet recovery and ANC recovery. Complete CR (CRc) response includes all subjects who achieve a CR, CRi and CRh. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but \>5%. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: HAM Chemotherapy Participants who had relapsed/refractory AML with FLT3 activating mutations who progressed on one prior chemotherapy received 100 mg crenolanib besylate tablets administered orally three times a day following HAM salvage chemotherapy. | 9 |
| Arm B: FLAG-Ida Chemotherapy Participants who had relapsed/refractory AML with FLT3 activating mutations who progressed on one prior chemotherapy received 100 mg crenolanib besylate tablets administered orally three times a day following FLAG-Ida salvage chemotherapy. | 6 |
| Arm C: MEC Chemotherapy Participants who had relapsed/refractory AML with FLT3 activating mutations who progressed on one prior chemotherapy received 100 mg crenolanib besylate tablets administered orally three times a day following MEC salvage chemotherapy. | 1 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 3 | 2 | 0 |
Baseline characteristics
| Characteristic | Arm A: HAM Chemotherapy | Arm B: FLAG-Ida Chemotherapy | Arm C: MEC Chemotherapy | Total |
|---|---|---|---|---|
| Age, Continuous | 65 years | 66 years | 31 years | 65 years |
| Age, Customized 18 to 60 years | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Age, Customized ≥ 60 years | 7 Participants | 4 Participants | 0 Participants | 11 Participants |
| Antecedent Hematological Disorder | 2 Participants | 4 Participants | 0 Participants | 6 Participants |
| ECOG 0 | 2 Participants | 0 Participants | 1 Participants | 3 Participants |
| ECOG 1 | 5 Participants | 5 Participants | 0 Participants | 10 Participants |
| ECOG 2 | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| FLT3 Mutations FLT3 wildtype | 5 Participants | 6 Participants | 0 Participants | 11 Participants |
| FLT3 Mutations ITD and TKD | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| FLT3 Mutations ITD only | 3 Participants | 0 Participants | 1 Participants | 4 Participants |
| FLT3 Mutations TKD only | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 8 Participants | 4 Participants | 0 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 7 Participants | 6 Participants | 1 Participants | 14 Participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 1 Participants | 11 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 | 0 / 16 | 0 / 9 | 0 / 6 | 0 / 1 |
| other Total, other adverse events | 16 / 16 | 9 / 9 | 6 / 6 | 1 / 1 |
| serious Total, serious adverse events | 6 / 16 | 4 / 9 | 2 / 6 | 0 / 1 |
Outcome results
Primary
Clinical Response to Crenolanib With Standard Salvage Chemotherapy
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 have either platelet recovery or ANC recovery. CRh response included all CR criteria met, except subject only has partial platelet recovery and ANC recovery. Complete CR (CRc) response includes all subjects who achieve a CR, CRi and CRh. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but \>5%. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy.
Time frame: 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| All Subjects | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Composite complete remission (CR+CRh+CRi) | 7 Participants |
| All Subjects | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Clinical benefit (CRc+PR+MLFS) | 7 Participants |
| All Subjects | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | MLFS | 3 Participants |
| Arm A: HAM Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Composite complete remission (CR+CRh+CRi) | 3 Participants |
| Arm A: HAM Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Clinical benefit (CRc+PR+MLFS) | 3 Participants |
| Arm A: HAM Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | MLFS | 2 Participants |
| Arm B: FLAG-Ida Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | MLFS | 0 Participants |
| Arm B: FLAG-Ida Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Composite complete remission (CR+CRh+CRi) | 4 Participants |
| Arm B: FLAG-Ida Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Clinical benefit (CRc+PR+MLFS) | 4 Participants |
| Arm C: MEC Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Composite complete remission (CR+CRh+CRi) | 0 Participants |
| Arm C: MEC Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | Clinical benefit (CRc+PR+MLFS) | 0 Participants |
| Arm C: MEC Chemotherapy | Clinical Response to Crenolanib With Standard Salvage Chemotherapy | MLFS | 1 Participants |