Study of Individual Adult and Pediatric Patient Dose-escalated Interleukin-2 Therapy for Refractory Chronic GVHD

NCT02318082 | Completed Phase 1 DMC

• 1 other identifier: 14-452
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is a way of gaining new knowledge about the treatment for cGVHD that has not responded to steroids. This research study is evaluating a drug called Interleukin-2 (IL-2) as a possible treatment for cGVHD. In this Phase I study, the investigators are looking to see if 8- week individual patient dose- escalated IL-2 therapy for cGVHD is safe and its effects on your immune cells.

Conditions

Chronic Versus Graft Host Disease

Keywords

Chronic versus Graft Host Disease

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose (MTD) of 8-week Individual patient dose-escalated Interleukin-2

  Participants will be evaluated over the course of the 8-week treatment for Dose-Limiting Toxicities (DLTs) from the individual dose-escalated IL-2

  8 weeks

Secondary Outcomes (3)

• Overall cGVHD Clinical Response Rate

  Baseline, 8 Weeks

• Overall Survival Rate

  1 year

• Malignant Relapse Rate

  1 Year

Study Arms (1)

Interleukin-2 (IL-2)

EXPERIMENTAL

Interleukin-2: Each participant will receive daily subcutaneous IL-2 for self-administration per cycle. Each participant will start at Dose Level A. In the abscence of DLTs or severe non-DLT adverse events, participants will have daily SC IL-2 dose-escalated at Week 2 (to dose level B) and at Week 4 (to Dose Level C), and continue on their maximum tolerated dose (MTD) IL-2 for 4 weeks total.

Drug: Interleukin-2

Interventions

Interleukin-2 DRUG

Also known as: Proleukin, Aldesleukin, IL-2

Interleukin-2 (IL-2)

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient of 7-8/8 HLA-matched (HLA-A, -B, -C, -DRB1) allogeneic hematopoietic stem cell transplantation
• Participants must have steroid-refractory cGVHD despite use of 2 or more agents. Steroid-refractory cGVHD is defined as having persistent signs and symptoms of cGVHD (Appendix C, D) despite the use of prednisone at ≥ 0.25 mg/kg/day (or 0.5 mg/kg every other day) for at least 4 weeks (or equivalent dosing of alternate glucocorticoids) without complete resolution of signs and symptoms. Participants with either extensive or limited chronic GVHD requiring systemic therapy are eligible.
• Stable dose of glucocorticoids for 4 weeks prior to enrollment.
• No addition or subtraction of other immunosuppressive medications (e.g., calcineurin-inhibitors, sirolimus, mycophenolate-mofetil) for 4 weeks prior to enrollment. The dose of immunosuppressive medicines may be adjusted based on the therapeutic range of that drug.
• Participants must have adequate organ function as defined below:
• Hepatic: Adequate hepatic function (total bilirubin ≤ 2.0 mg/dl-exception permitted in participants with Gilbert's Syndrome; AST (SGOT)/ALT (SGPT) ≤ 2x institutional ULN), unless hepatic dysfunction is a manifestation of presumed cGVHD. For participants with abnormal LFTs as the sole manifestation of cGVHD, documented GVHD on liver biopsy will be required prior to enrollment. Abnormal LFTs in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD, and a liver biopsy will not be mandated in this situation.
• Pulmonary: FEV1 ≥ 50% or DLCO(Hb) ≥ 40% of predicted, unless pulmonary dysfunction is deemed to be due to chronic GVHD.
• Renal: Serum creatinine ≤ institutional ULN or creatinine clearance ≥ 60 mL/min/1.73 m2 for participants with creatinine levels above institutional normal.
• Pediatric patients must have creatinine clearance ≥ 60 mL/min/1.73 m2 regardless of serum creatinine level.
• Adequate bone marrow function indicated by absolute neutrophil count (ANC) ≥1000/mcL and platelets ≥ 50,000/mcL without growth factors or transfusions
• Cardiac: No myocardial infarction within 6 months prior to enrollment or NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant.
• Karnofsky/Lansky performance status ≥ 60% (Appendix A)
• Age ≥ 2 years. In our institutional experience and according to published reports, the incidence of cGVHD in children aged less than 2 years is rare. 41 Daily SC injections of low-dose IL-2 have been used in pediatric post-HSCT patients as young as 2 years. 39 Prolonged daily SC injections of other drugs such as low molecular weight heparin and insulin are commonly administered and well tolerated in the young pediatric population with the use of the Insuflon® indwelling SC catheter. The use of the Insuflon® indwelling SC catheter for IL-2 administration is not required for all pediatric patients and their use will depend on the preference of the patient and provider
• The effects of IL-2 on the developing human fetus are unknown. For this reason and because chemotherapeutic agents are known to be teratogenic, participants of child-bearing and child-fathering potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Males treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of IL-2 administration.
• Ability to understand and/or the willingness of participant or their parent/legally authorized representative to sign a written informed consent document.

You may not qualify if:

• Participants with ongoing prednisone (equivalent) dose requirement \> 1 mg/kg/day (or equivalent).
• Participants with concurrent use of calcineurin-inhibitor plus sirolimus (either agent alone is acceptable).
• Participants with new immunosuppressive medication, extra-corporeal photopheresis or rituximab therapy initiated in the 4 weeks prior.
• Participant with post-transplant exposure to donor lymphocyte infusion (DLI), or T-cell or IL-2 targeted medication (e.g. ATG, alemtuzumab, basiliximab, denileukin diftitox) within 100 days prior.
• Other investigational drugs within 4 weeks prior to enrollment, unless cleared by the Principal Investigator. Previous fixed-dose IL-2 therapy that was discontinued prior to 4 weeks is permitted.
• Participants with active malignant relapse or recrudescence of their prior hematologic disorder.
• Participants with inability to comply with IL-2 treatment regimen.
• Organ transplant (allograft) recipient.
• HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the agents used after allogeneic HSCT. In addition, these individuals are at increased risk of lethal infections. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
• History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to IL-2.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Individuals with active uncontrolled hepatitis B or C are ineligible as they are at high risk of lethal treatment-related hepatotoxicity after HSCT.
• Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother, breastfeeding should be discontinued.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (1)

Dana-Farber Cancer Insitute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Whangbo JS, Kim HT, Mirkovic N, Leonard L, Poryanda S, Silverstein S, Kim S, Reynolds CG, Rai SC, Verrill K, Lee MA, Margossian S, Duncan C, Lehmann L, Huang J, Nikiforow S, Alyea EP 3rd, Armand P, Cutler CS, Ho VT, Blazar BR, Antin JH, Soiffer RJ, Ritz J, Koreth J. Dose-escalated interleukin-2 therapy for refractory chronic graft-versus-host disease in adults and children. Blood Adv. 2019 Sep 10;3(17):2550-2561. doi: 10.1182/bloodadvances.2019000631.

  PMID: 31471324 DERIVED

MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• John Koreth, DPhil, MBBS

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 12, 2014
• First Posted: December 17, 2014
• Study Start: February 1, 2015
• Primary Completion: October 1, 2017
• Study Completion: April 22, 2020
• Last Updated: June 23, 2020

Record last verified: 2020-06

Locations

US (1)