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

• Sponsor: University of Michigan Rogel Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT02328755
• Collaborator: (none)
• Enrollment: 37
• Location: 1
• Arm: 1
• Duration (Months): 50.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: peg-IFN-α; Procedure: Hematopoietic Cell Transplant (HCT); Drug: Tacrolimus; Drug: Methotrexate	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Targeting Cross-presentation With Peginterferon Alfa-2a to Enhance Anti-leukemic Responses After Allogeneic Transplantation in High Risk Acute Myeloid Leukemia
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Mar 25, 2019
• Actual Study Completion Date: Mar 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: peg-IFN-α 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; Other Names: PEGASYS® ; Procedure: Hematopoietic Cell Transplant (HCT); Drug: Tacrolimus; Calcineurin inhibitor administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis. Cyclosporine may be substituted if patients cannot tolerate tacrolimus.; Drug: Methotrexate; Administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis.

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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

2. 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.

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan Rogel Cancer Center

Investigators

• Principal Investigator: John M Magenau, M.D., University of Michigan Rogel Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 17, 2018

More Information

Publications

None provided.

• Responsible Party: University of Michigan Rogel Cancer Center
• ClinicalTrials.gov Identifier: NCT02328755
• Other Study ID Numbers: UMCC 2014.107; HUM00093471
• First Posted: Dec 31, 2014
• Last Update Posted: Oct 6, 2021
• Last Verified: Oct 1, 2021

• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Methotrexate; Tacrolimus

Study Results

Participant Flow

Pre-assignment Detail	One person did not start study treatment; no participants were assigned or de-escalated to Dose Level -1 (45mcg).

Arm/Group Title	Dose Level 1, 90 mcg Peg-IFN-α	Dose Level 2, 180 mcg Peg-IFN-α
Arm/Group Description	90 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.	180 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.
Period Title: Overall Study
STARTED	3	33
COMPLETED	0	31
NOT COMPLETED	3	2

Baseline Characteristics

Arm/Group Title	Dose Level 1 - 90 mcg Peg-IFN-α	Dose Level 2 - 180 mcg Peg-IFN-α	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	3	33	36
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56	60	60
Sex: Female, Male (Count of Participants)
Female	1 33.3%	13 39.4%	14 38.9%
Male	2 66.7%	20 60.6%	22 61.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 100%	33 100%	36 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 3%	1 2.8%
White	3 100%	32 97%	35 97.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	33 100%	36 100%
Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI)CT-Cl (units on a scale) [Median (Full Range) ]
Median (Full Range) [units on a scale]	5	3	3
Disease Status at HCT (Count of Participants)
Not in remission	3 100%	32 97%	35 97.2%
Remission	0 0%	1 3%	1 2.8%
Cytogenic risk (Count of Participants)
Poor	2 66.7%	16 48.5%	18 50%
Intermediate	1 33.3%	16 48.5%	17 47.2%
Unknown	0 0%	1 3%	1 2.8%
Disease Risk Score (Count of Participants)
Greater or equal to 3	2 66.7%	19 57.6%	21 58.3%
2	1 33.3%	11 33.3%	12 33.3%
1	0 0%	3 9.1%	3 8.3%
Time to HCT from AML Diagnosis (days) [Median (Full Range) ]
Median (Full Range) [days]	98	192	142
Donor Type (Count of Participants)
Unrelated	2 66.7%	18 54.5%	20 55.6%
Related	1 33.3%	15 45.5%	16 44.4%
Human Leukocyte Antigen match (Count of Participants)
Yes	3 100%	31 93.9%	34 94.4%
No	0 0%	2 6.1%	2 5.6%
Donor Source (Count of Participants)
Peripheral Blood Stem Cells	2 66.7%	29 87.9%	31 86.1%
Bone Marrow	1 33.3%	4 12.1%	5 13.9%

Outcome Measures

1. Primary Outcome

Title	Phase 1: Maximum Tolerated Dose (MTD) of Peg-IFN-α
Description	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.

Outcome Measure Data

Analysis Population Description

All participants (n=36)

Arm/Group Title	Peg-IFN-α
Arm/Group Description	peg-IFN-α was administered prior to HCT (Hematopoietic Cell Transplant) and at three subsequent time points post HCT. (Maximum of 4 doses) It was 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 peg-IFN-α It was begun at 90 mcg, would have been reduced back to 45 mcg if necessary, and after 3 participants it was increased to 180 mcg.
Measure Participants	36
Number [mcg]	180

2. Primary Outcome

Title	Phase 2: Number of Patients That Relapse
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Dose Level 1 - 90 mg Peg-IFN-α	Dose Level 2 - 180 mg Peg-IFN-α
Arm/Group Description	90 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.	180 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.
Measure Participants	3	33
Phase II MTD (180mcg) participants with fully matched donor HCT	39 1300%
All participants	67 2233.3%	39 118.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dose Level 2 - 180 mg Peg-IFN-α
	Comments	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).
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	cumulative incidence
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.24 to 0.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Phase 2: Overall Survival Time
Description	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.

Outcome Measure Data

Analysis Population Description

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/Group Title	Dose Level 1 - 90 mcg Peg-IFN-α	Dose Level 2 - 180 mcg Peg-IFN-α
Arm/Group Description	90 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.	180 mcg peg-IFN-α administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days.
Measure Participants	3	33
6 months (Phase II MTD [180 mcg] participants with fully matched donor HCT)	55 1833.3%
6 months - all participants	33 1100%	55 166.7%
2 years (Phase II MTD [180 mcg] participants with fully matched donor HCT)	33 1100%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dose Level 2 - 180 mg Peg-IFN-α
	Comments	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).
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	55
	Confidence Interval	(2-Sided) 95%; 40 to 75
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Survival proportion estimates at 6 months and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Dose Level 2 - 180 mg Peg-IFN-α
	Comments	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).
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Kaplan-Meier
	Estimated Value	33
	Confidence Interval	(2-Sided) 95%; 19 to 58
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Survival proportion estimates at 6 months and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method.

4. Secondary Outcome

Title	Phase 2: Event Free Survival Time
Description	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.

Outcome Measure Data

Analysis Population Description

Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-α (n=31)

Arm/Group Title	Peg-IFN-α
Arm/Group Description	peg-IFN-α was administered prior to HCT (Hematopoietic Cell Transplant) and at three subsequent time points post HCT. (Maximum of 4 doses) It was administered by subcutaneous injection every 14 days beginning with dose level 1. Dose Level 1 - 90 mcg Dose Level 2 - 180 mcg peg-IFN-α
Measure Participants	31
6 months	48 1600%
2 years	28 933.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peg-IFN-α
	Comments
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Survival proportion estimates at 6 months and 2 years were calculated using Kaplan-Meier methods, and the 2-sided, 95% confidence intervals calculated by the Greenwood method.

5. Secondary Outcome

Title	Acute GVHD
Description	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

Outcome Measure Data

Analysis Population Description

Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-a (n=31)

Arm/Group Title	180mcg Peg-IFN-α, HLA-matched
Arm/Group Description	180 mcg peg-IFN-a administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days
Measure Participants	31
Number (95% Confidence Interval) [percentage of participants]	39 1300%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peg-IFN-α
	Comments
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		GVHD proportion estimates and corresponding 95% confidence intervals were calculated using methods of Fine and Gray.

6. Secondary Outcome

Title	Non-Relapse Mortality
Description	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.

Outcome Measure Data

Analysis Population Description

Recipients of HLA-matched HCT who received phase II MTD (180mcg) peg-IFN-α (n=31)

Arm/Group Title	189mcg Peg-IFN-α, HLA-matched
Arm/Group Description	180 mcg peg-IFN-a administered prior to hematopoietic cell transplantation (HCT) and at three subsequent time points post HCT (maximum of 4 doses) every 14 days
Measure Participants	31
6 months	13 433.3%
2 years	25 833.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Peg-IFN-α
	Comments
	Type of Statistical Test	Other
	Comments	Single group
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		Non-relapse mortality estimates and corresponding 95% confidence intervals were calculated using methods of Fine and Gray.

Adverse Events

Time Frame	The assessment and reporting period for all adverse events will occur from the first day the treatment with peg-IFN-α is administered until day +56 post transplant or until 14 days after the last dose of peg-IFN-α is administered, whichever comes last. Adverse event data were collected up to 63 days. All-Cause Mortality assessed up to 4 years; median of 25 months.
Adverse Event Reporting Description	Only grade >=3 events were recorded; infectious disease and hematologic events were not included.
Arm/Group Title	Phase I/Dose Level 1 - 90 mcg		Phase 2/Dose Level 2 - 180 mcg Peg-IFN-α
Arm/Group Description	peg-IFN-α 90 mcg administered prior to hematopoietic cell transplant (HCT) and at three subsequent time points post HCT (maximum of 4 doses), every 14 days. Tacrolimus: Calcineurin inhibitor administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis. Cyclosporine could be substituted if patients cannot tolerate tacrolimus. Methotrexate: Administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis.		peg-IFN-α 180 mcg administered prior to hematopoietic cell transplant (HCT) and at three subsequent time points post HCT (maximum of 4 doses), every 14 days. Tacrolimus: Calcineurin inhibitor administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis. Cyclosporine could be substituted if patients cannot tolerate tacrolimus. Methotrexate: Administered along with HCT for Graft Versus Host Disease (GVHD) prophylaxis.
All Cause Mortality
	Phase I/Dose Level 1 - 90 mcg		Phase 2/Dose Level 2 - 180 mcg Peg-IFN-α
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		22/33 (66.7%)
Serious Adverse Events
	Phase I/Dose Level 1 - 90 mcg		Phase 2/Dose Level 2 - 180 mcg Peg-IFN-α
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)		8/33 (24.2%)
Cardiac disorders
Hypertension	1/3 (33.3%)		0/33 (0%)
Hypotension	0/3 (0%)		1/33 (3%)
Hepatobiliary disorders
Liver Function Test elevation	0/3 (0%)		1/33 (3%)
Immune system disorders
Graft Failure	0/3 (0%)		1/33 (3%)
Musculoskeletal and connective tissue disorders
Arthritis	1/3 (33.3%)		0/33 (0%)
Renal and urinary disorders
Acute Kidney Injury	0/3 (0%)		1/33 (3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary	0/3 (0%)		2/33 (6.1%)
Skin and subcutaneous tissue disorders
Rash	2/3 (66.7%)		2/33 (6.1%)
Other (Not Including Serious) Adverse Events
	Phase I/Dose Level 1 - 90 mcg		Phase 2/Dose Level 2 - 180 mcg Peg-IFN-α
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/33 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.