Acute Myeloid Leukemia
Conditions
Keywords
acute myeloid leukemia, AML, antibody-drug conjugate
Brief summary
This study will examine the safety and anti-leukemic profile of SGN-CD33A (vadastuximab talirine) in patients with relapsed chemo-resistant AML, who are given vadastuximab talirine in sequence with standard treatments before a planned stem cell transplant, or as maintenance therapy after a stem cell transplant. The main purpose of the study is to find the best dose and determine the anti-leukemic activity of vadastuximab talirine, given either pre- or post-allogeneic stem cell transplant (alloSCT) for adults with relapsed or refractory AML. This will be determined by assessing the safety and tolerability of vadastuximab talirine. In addition, the pharmacokinetic profile and anti-leukemic activity of the study treatment will be assessed.
Interventions
DRUGFludarabine
30 mg/m2/day intravenously, 5 to 2 days before the transplant (total dose of 120 mg/m2)
DRUGMelphalan
Melphalan 140 mg/m2 intravenously, 2 days before the transplant
Pre-allo (before stem cell transplant) given 14 days before the stem cell transplant
Sponsors
Seagen Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Relapsed/refractory acute myeloid leukemia (AML) except for acute promyelocytic leukemia * Eastern Cooperative Oncology Group status of 0 or 1 * Adequate baseline renal and hepatic function * For Pre-allo Part A (before stem cell transplant): Relapsed or refractory AML (greater than 5% blasts) * For Pre-allo Part A (before stem cell transplant): Availability of an HLA matched related or unrelated donor * For Pre-allo Part A (before stem cell transplant): Eligible for an allogeneic hematopoietic stem cell transplant * For Post-allo Part B: Transplant must have been performed with active AML (greater than 5% blasts) using a conventional conditioning regimen and have achieved CR or CRi post-alloSCT (with ANC greater than or equal to 1,000 and platelet greater than or equal to 50,000) * For Post-allo Part B: Treatment must begin at least 42 days, but no more than 100 days post-transplant.
Exclusion criteria
* Inadequate heart function * Inadequate lung function * Previous central nervous system leukemia * Any history of another metastatic malignancy * Anti-leukemia treatment within14 days of study drug (other than hydroxyurea or 6-mercaptopurine), immunosuppressive therapy (except for GVHD treatment/prophylaxis in Part B), or investigational agents * For Pre-allo Part A (before stem cell transplant): Partially matched donors (related or unrelated) and umbilical cord blood cells are excluded as the source of hematopoietic stem cells * For Pre-allo Part A (before stem cell transplant): Prior alloSCT * For Post-allo Part B: Active GVHD Grade 2 or higher * For Post-allo Part B:History of veno-occlusive disease requiring defibrotide * For Post-allo Part B: History of Grade 2 or higher hepatic GVHD * For Post-allo Part B: Concurrent use of corticosteroids equivalent of prednisone at a dose of greater than 0.5 mg/kg
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events | Approximately 1 year | AE: Adverse events; TEAE: Treatment-emergent adverse event. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. An AE is considered serious if it was fatal, life threatening, required hospitalization, was disabling/incapacitating, resulted in a birth defect or congenital anomally, or was otherwise considered to be medically significant. |
| Incidence of Laboratory Abnormalities | Approximately 1 year | Number (count) of participants that experienced a Grade 3 or higher laboratory toxicity (hematology and chemistry). Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. |
| 1-year Survival Rate | 12 months | 1-year survival rate estimated using Kaplan-Meier methods The start date for overall survival is the day of alloSCT. |
| Rate of MRD Negativity | 30 days | Rate of MRD (minimal residual disease) negativity at Day -1 (1 day prior to transplant) and Day 30 post-transplant (Part A only) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | 9 weeks | Defined as the time from the start of the first documented complete response (CR) or complete remission with incomplete blood count recovery (CRi) to the documentation of relapse or death due to any cause. |
| Overall Survival | Approximately 96 weeks | Defined as the time from the day of alloSCT to the date of death due to any cause. |
| Best Response of CR or CRi | 9 weeks | Percentage of patients who achieved a best response of CRi (complete remission with incomplete blood count recovery) or CR (complete remission) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pre-allo (Before Stem Cell Transplant) Pre-allo reduced intensity chemotherapy vadastuximab talirine (melphalan and fludarabine)
Fludarabine: 30 mg/m2/day intravenously, 5 to 2 days before the transplant (total dose of 120 mg/m2)
Melphalan: Melphalan 140 mg/m2 intravenously, 2 days before the transplant
vadastuximab talirine: Pre-allo (before stem cell transplant) given 14 days before the stem cell transplant | 6 |
| Post-allo (After Stem Cell Transplant) Post-allo vadastuximab talirine
vadastuximab talirine: Post-allo (after stem cell transplant) given on Day 1 of each cycle | 8 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 6 | 2 |
Baseline characteristics
| Characteristic | Pre-allo (Before Stem Cell Transplant) | Post-allo (After Stem Cell Transplant) | Total |
|---|---|---|---|
| Age, Continuous | 58.0 years | 58.0 years | 58.0 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 0: Normal activity | 0 Participants | 1 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Grade 1: Symptoms but ambulatory | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 7 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 8 Participants | 13 Participants |
| Region of Enrollment United States | 6 participants | 8 participants | 14 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 6 | 2 / 8 |
| other Total, other adverse events | 6 / 6 | 8 / 8 |
| serious Total, serious adverse events | 5 / 6 | 2 / 8 |
Outcome results
Primary
1-year Survival Rate
1-year survival rate estimated using Kaplan-Meier methods The start date for overall survival is the day of alloSCT.
Time frame: 12 months
Population: All treated patients set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | 1-year Survival Rate | 0 percentage of participants |
| Post-allo (After Stem Cell Transplant) | 1-year Survival Rate | 75 percentage of participants |
Primary
Incidence of Adverse Events
AE: Adverse events; TEAE: Treatment-emergent adverse event. Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event. An AE is considered serious if it was fatal, life threatening, required hospitalization, was disabling/incapacitating, resulted in a birth defect or congenital anomally, or was otherwise considered to be medically significant.
Time frame: Approximately 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Incidence of Adverse Events | AEs Related to Vadatuximab Talirine | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Adverse Events | Grade 3 or Higher TEAEs | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Adverse Events | AEs Leading to Treatment Discontinuation | 0 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Adverse Events | Serious AEs | 5 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Adverse Events | TEAEs | 6 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Adverse Events | Serious AEs | 2 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Adverse Events | TEAEs | 8 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Adverse Events | AEs Related to Vadatuximab Talirine | 7 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Adverse Events | AEs Leading to Treatment Discontinuation | 1 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Adverse Events | Grade 3 or Higher TEAEs | 6 Participants |
Primary
Incidence of Laboratory Abnormalities
Number (count) of participants that experienced a Grade 3 or higher laboratory toxicity (hematology and chemistry). Grades are defined using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), v4.03. Grade 1 = mild, no intervention needed; Grade 2 = moderate, minimal intervention needed; Grade 3 = severe or medically significant, hospitalization is required; Grade 4 = life-threatening, urgent intervention needed; Grade 5 = death related to adverse event.
Time frame: Approximately 1 year
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | White blood cell count (x10^3/ul) | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Amylase (iu/l) | 3 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Alanine aminotransferase (iu/l) | 1 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Aspartate aminotransferase (iu/l) | 1 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Total bilirubin (mg/dl) | 3 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Uric acid (mg/dl) | 1 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Lipase (iu/l) | 0 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Sodium (meq/l) | 0 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Any hematology test | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Hemoglobin (g/dl) | 3 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Lymphocytes (x10^3/ul) | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Neutrophils (x10^3/ul) | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Platlets (x10^3/ul) | 6 Participants |
| Pre-allo (Before Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Any chemistry test | 4 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | White blood cell count (x10^3/ul) | 5 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Any chemistry test | 3 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Neutrophils (x10^3/ul) | 4 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Amylase (iu/l) | 0 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Any hematology test | 5 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Alanine aminotransferase (iu/l) | 1 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Sodium (meq/l) | 1 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Aspartate aminotransferase (iu/l) | 0 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Hemoglobin (g/dl) | 0 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Total bilirubin (mg/dl) | 0 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Platlets (x10^3/ul) | 4 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Uric acid (mg/dl) | 0 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Lymphocytes (x10^3/ul) | 1 Participants |
| Post-allo (After Stem Cell Transplant) | Incidence of Laboratory Abnormalities | Lipase (iu/l) | 1 Participants |
Primary
Rate of MRD Negativity
Rate of MRD (minimal residual disease) negativity at Day -1 (1 day prior to transplant) and Day 30 post-transplant (Part A only)
Time frame: 30 days
Population: All treated patients set, pre-allo cohort
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Rate of MRD Negativity | Day -1 Rate of MRD Negativity | NA Percentage of participants |
| Pre-allo (Before Stem Cell Transplant) | Rate of MRD Negativity | Day 30 Rate of MRD Negativity | 75 Percentage of participants |
Secondary
Best Response of CR or CRi
Percentage of patients who achieved a best response of CRi (complete remission with incomplete blood count recovery) or CR (complete remission)
Time frame: 9 weeks
Population: Part A (pre-alloSCT) only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Best Response of CR or CRi | 4 Participants |
Secondary
Duration of Response
Defined as the time from the start of the first documented complete response (CR) or complete remission with incomplete blood count recovery (CRi) to the documentation of relapse or death due to any cause.
Time frame: 9 weeks
Population: Part A (pre-alloSCT) only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Duration of Response | 6.57 weeks |
Secondary
Overall Survival
Defined as the time from the day of alloSCT to the date of death due to any cause.
Time frame: Approximately 96 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pre-allo (Before Stem Cell Transplant) | Overall Survival | 11.07 weeks |
| Post-allo (After Stem Cell Transplant) | Overall Survival | NA weeks |