Acute Myeloid Leukemia
Conditions
Brief summary
This protocol is an open label, single arm, non-randomized, phase I / II clinical trial investigating the use of pegylated interferon alpha-2a (peg-IFN-α, Pegasys®, Genentech) for prevention of relapse in acute myeloid leukemia (AML) not in remission at the time of allogeneic hematopoietic stem cell transplantation (HCT).
Detailed description
This protocol is an open label, single arm, non-randomized, phase I / II clinical trial investigating the use of pegylated interferon alpha-2a (peg-IFN-α, Pegasys®, Genentech) for prevention of relapse in acute myeloid leukemia (AML) not in remission at the time of allogeneic hematopoietic stem cell transplantation (HCT). The inability to attain remission status following induction therapy for AML remains a significant problem and is associated with poor outcomes. While HCT remains a curative option, its activity in the setting of relapsed or refractory AML is significantly diminished due to high relapse.
Interventions
DRUGpeg-IFN-α
PROCEDUREHematopoietic Cell Transplant (HCT)
DRUGTacrolimus
Calcineurin inhibitor administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis. Cyclosporine may be substituted if patients cannot tolerate tacrolimus.
DRUGMethotrexate
Administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis.
Sponsors
University of Michigan Rogel Cancer Center
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
* Patient must have AML not in remission or at very high risk for HCT (Hematopoietic Cell Transplantation) relapse. * For newly diagnosed AML, patients must have achieved two consecutive induction attempts without achieving complete remission * For patients initially in complete remission whose AML relapses \> 6 months after preceding remission, one re-induction must be attempted to be eligible * For AML patients with early relapse, in whom the preceding remission is shorter than 6 months duration, no re-induction regimen is necessary to be eligible * Patients with antecedent MDS (Myelodysplastic Syndrome) who progress to AML may have therapies rendered during both phases counted towards these requirements. * Patients with poor cytogenetic or molecular risk associated with very high risk for relapse after HCT may proceed without provisions for prior treatment. However, they must have received at least one induction attempt. * Patients must be ≥ 18 years of age and considered a candidate for HCT * Karnofsky ≥ 70% (Karnofsky performance status is measure of a cancer patients general well being and activities of daily life. Scores range from 100 to 0 where 100 is perfect health and 0 is death * Patients must meet acceptable organ function criteria: Total Bilirubin ≤2.5 mg%; AST (Aspartate transaminase) and ALT (Alanine transaminase) \<5.0 X institutional upper limit of normal; GFR (Glomerular filtration rate) \>40 mL/min/1.73 m2 for patients with creatinine levels above institutional normal; Lung function tests (DLCO, FEV1, FVC) \> 50%; Ejection fraction \> 50% * All patients must sign an informed consent * Women and men of child-bearing potential must agree to use adequate contraception
Exclusion criteria
* Prior chemotherapy treatment for AML within 21 days from the initiation of HCT conditioning * Patients may NOT have evidence or symptoms of CNS disease at the time of enrollment * HIV or HTLV1 / HTLV2 (Human T-lymphotrophic virus) (seropositivity and/or PCR positivity) * Patients less than 18 years of age * Pregnant and nursing mothers are excluded from this study * Patients with untreated or uncontrolled neuropsychiatric illness * Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the patient * Uncontrolled infections
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) of Peg-IFN-α | Up to day 56 post-transplant or up to 14 days after final treatment with peg-IFN-α, whichever comes later. Data was collected up to 63 days. | The dose level assigned to the most participants is selected as the MTD. Participants from the arms for dose level 1 (90mcg, 3 participants) and dose level 2 (180mcg, 33 participants) were analyzed together to determine the MTD. Dosage levels are determined by dose-limiting toxicities (DLTs). Only DLTs encountered during the treatment period, prior to day 56 post HCT (or 14 days after final treatment, whichever comes later), are counted. DLTs after the treatment period are counted only if they reflect an ongoing toxicity that initiated in the treatment period. |
| Phase 2: Number of Patients That Relapse | 6 Months Post HCT | The cumulative incidence of relapse, estimated using proportional hazard model for the competing risk of non-relapse mortality (NRM). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Overall Survival Time | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. | Estimated using Kaplan-Meier methods, overall survival (OS) will be calculated from the day of transplantation (day 0) until death; shown at 6 month and 2 year estimates |
| Phase 2: Event Free Survival Time | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. | Defined for this study as Leukemia Free Survival, and estimated using Kaplan-Meier methods. |
| Acute GVHD | 6 months | Grade 2-4 Acute GVHD estimated using proportional hazards ratio. Graded according to CTCAE v. 4.0; higher grades represent more severe events. |
| Non-Relapse Mortality | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. | The cumulative incidence of non-relapse mortality is estimated by proportional hazard models methods. |
Countries
United States
Participant flow
Pre-assignment details
One person did not start study treatment; no participants were assigned or de-escalated to Dose Level -1 (45mcg).
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 - 90 mcg Peg-IFN-α Dose Level 1 - 90 mcg peg-IFN-α administered prior to hematopoietic cell transplant (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days beginning with dose level 1. | 3 |
| Dose Level 2 - 180 mcg Peg-IFN-α Dose Level 2 - 180 mcg peg-IFN-α administered prior to hematopoietic cell transplant (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days beginning with dose level 1. | 33 |
| Total | 36 |
Baseline characteristics
| Characteristic | Dose Level 2 - 180 mcg Peg-IFN-α | Total | Dose Level 1 - 90 mcg Peg-IFN-α |
|---|---|---|---|
| Age, Continuous | 60 years | 60 years | 56 years |
| Cytogenic risk Intermediate | 16 Participants | 17 Participants | 1 Participants |
| Cytogenic risk Poor | 16 Participants | 18 Participants | 2 Participants |
| Cytogenic risk Unknown | 1 Participants | 1 Participants | 0 Participants |
| Disease Risk Score 1 | 3 Participants | 3 Participants | 0 Participants |
| Disease Risk Score 2 | 11 Participants | 12 Participants | 1 Participants |
| Disease Risk Score Greater or equal to 3 | 19 Participants | 21 Participants | 2 Participants |
| Disease Status at HCT Not in remission | 32 Participants | 35 Participants | 3 Participants |
| Disease Status at HCT Remission | 1 Participants | 1 Participants | 0 Participants |
| Donor Source Bone Marrow | 4 Participants | 5 Participants | 1 Participants |
| Donor Source Peripheral Blood Stem Cells | 29 Participants | 31 Participants | 2 Participants |
| Donor Type Related | 15 Participants | 16 Participants | 1 Participants |
| Donor Type Unrelated | 18 Participants | 20 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 36 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI)CT-Cl | 3 units on a scale | 3 units on a scale | 5 units on a scale |
| Human Leukocyte Antigen match No | 2 Participants | 2 Participants | 0 Participants |
| Human Leukocyte Antigen match Yes | 31 Participants | 34 Participants | 3 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 | 1 Participants | 0 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 | 32 Participants | 35 Participants | 3 Participants |
| Region of Enrollment United States | 33 participants | 36 participants | 3 participants |
| Sex: Female, Male Female | 13 Participants | 14 Participants | 1 Participants |
| Sex: Female, Male Male | 20 Participants | 22 Participants | 2 Participants |
| Time to HCT from AML Diagnosis | 192 days | 142 days | 98 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 22 / 33 |
| other Total, other adverse events | 0 / 3 | 0 / 33 |
| serious Total, serious adverse events | 2 / 3 | 8 / 33 |
Outcome results
Primary
Phase 1: Maximum Tolerated Dose (MTD) of Peg-IFN-α
The dose level assigned to the most participants is selected as the MTD. Participants from the arms for dose level 1 (90mcg, 3 participants) and dose level 2 (180mcg, 33 participants) were analyzed together to determine the MTD. Dosage levels are determined by dose-limiting toxicities (DLTs). Only DLTs encountered during the treatment period, prior to day 56 post HCT (or 14 days after final treatment, whichever comes later), are counted. DLTs after the treatment period are counted only if they reflect an ongoing toxicity that initiated in the treatment period.
Time frame: Up to day 56 post-transplant or up to 14 days after final treatment with peg-IFN-α, whichever comes later. Data was collected up to 63 days.
Population: All participants (n=36)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peg-IFN-α | Phase 1: Maximum Tolerated Dose (MTD) of Peg-IFN-α | 180 mcg |
Primary
Phase 2: Number of Patients That Relapse
The cumulative incidence of relapse, estimated using proportional hazard model for the competing risk of non-relapse mortality (NRM).
Time frame: 6 Months Post HCT
Population: The first row shows analysis for recipients of HLA-matched HCT who received the phase II MTD (180mcg) peg-IFN-α (n=31); the second row shows all participants (n=36)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peg-IFN-α | Phase 2: Number of Patients That Relapse | All participants | 67 percentage of participants |
| Dose Level 2 - 180 mg Peg-IFN-α | Phase 2: Number of Patients That Relapse | Phase II MTD (180mcg) participants with fully matched donor HCT | 39 percentage of participants |
| Dose Level 2 - 180 mg Peg-IFN-α | Phase 2: Number of Patients That Relapse | All participants | 39 percentage of participants |
Comparison: The analysis applies only to the first row, for recipients of HLA-matched HCT who received the phase II MTD (180mcg) peg-IFN-a (n=31).95% CI: [0.24, 0.58]
Secondary
Acute GVHD
Grade 2-4 Acute GVHD estimated using proportional hazards ratio. Graded according to CTCAE v. 4.0; higher grades represent more severe events.
Time frame: 6 months
Population: Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-a (n=31)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Peg-IFN-α | Acute GVHD | 39 percentage of participants |
Secondary
Non-Relapse Mortality
The cumulative incidence of non-relapse mortality is estimated by proportional hazard models methods.
Time frame: 1 year or until study stops, whichever is later. Median time of follow-up was 25 months.
Population: Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-α (n=31)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peg-IFN-α | Non-Relapse Mortality | 6 months | 13 percentage of participants |
| Peg-IFN-α | Non-Relapse Mortality | 2 years | 25 percentage of participants |
Secondary
Phase 2: Event Free Survival Time
Defined for this study as Leukemia Free Survival, and estimated using Kaplan-Meier methods.
Time frame: 1 year or until study stops, whichever is later. Median time of follow-up was 25 months.
Population: Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-α (n=31)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peg-IFN-α | Phase 2: Event Free Survival Time | 6 months | 48 percentage of participants |
| Peg-IFN-α | Phase 2: Event Free Survival Time | 2 years | 28 percentage of participants |
Secondary
Phase 2: Overall Survival Time
Estimated using Kaplan-Meier methods, overall survival (OS) will be calculated from the day of transplantation (day 0) until death; shown at 6 month and 2 year estimates
Time frame: 1 year or until study stops, whichever is later. Median time of follow-up was 25 months.
Population: Some rows show analysis for recipients of HLA-matched HCT who received the phase II MTD (180mcg) peg-IFN-α(n=31); for 6 month data, the additional row shows all participants (n=36)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Peg-IFN-α | Phase 2: Overall Survival Time | 6 months - all participants | 33 percentage of participants |
| Dose Level 2 - 180 mg Peg-IFN-α | Phase 2: Overall Survival Time | 6 months (Phase II MTD [180 mcg] participants with fully matched donor HCT) | 55 percentage of participants |
| Dose Level 2 - 180 mg Peg-IFN-α | Phase 2: Overall Survival Time | 6 months - all participants | 55 percentage of participants |
| Dose Level 2 - 180 mg Peg-IFN-α | Phase 2: Overall Survival Time | 2 years (Phase II MTD [180 mcg] participants with fully matched donor HCT) | 33 percentage of participants |
Comparison: The analysis applies only to the first row, data at 6 months, for recipients of HLA-matched HCT who received the phase II MTD (180mcg) peg-IFN-a (n=31).95% CI: [40, 75]
Comparison: The analysis applies only to the 3rd row, data at 24 months, for recipients of HLA-matched HCT who received the phase II MTD (180mcg) peg-IFN-a (n=31).95% CI: [19, 58]