Peginterferon Alfa-2a to Enhance Anti-leukemic Responses After Allogeneic Transplantation in Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Targeting Cross-presentation With Peginterferon Alfa-2a to Enhance Anti-leukemic Responses After Allogeneic Transplantation in High Risk Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: peg-IFN-α
* Procedure: Hematopoietic Cell Transplant (HCT)
* Drug: Tacrolimus
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: peg-IFN-α<br>peg-IFN-α will be administered prior to HCT (Hematopoietic Cell Transplant) and at three subsequent time points post HCT. (Maximum of 4 doses) It will be administered by subcutaneous injection every 14 days beginning with dose level 1. Dose Level -1 - 45mcg Dose Level 1 - 90mcg Dose Level 2 - 180 mcg | Drug: peg-IFN-α<br> <br> * Other names: PEGASYS®;Procedure: Hematopoietic Cell Transplant (HCT)<br> <br> Drug: Tacrolimus<br>* Calcineurin inhibitor administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis. Cyclosporine may be substituted if patients cannot tolerate tacrolimus.<br>Drug: Methotrexate<br>* Administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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). | 6 Months Post HCT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. | 
| Phase 2: Event Free Survival Time | Defined for this study as Leukemia Free Survival, and estimated using Kaplan-Meier methods. | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. | 
| 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. | 6 months | 
| Non-Relapse Mortality | The cumulative incidence of non-relapse mortality is estimated by proportional hazard models methods. | 1 year or until study stops, whichever is later. Median time of follow-up was 25 months. |