Multi-Ctr PII Cmb.Modality Tx Ruxolitinib, Decitabine, and DLI for Post HSCT in AML/MDS

A Multi-Center Phase 2 Study of Combined Modality Treatment With Ruxolitinib, Decitabine, and Donor Lymphocyte Infusion for Post-Transplant Relapse of AML or MDS

This is a multi-center, single-arm, open-label, phase II trial for the frontline treatment of relapsed AML or MDS following allo-HCT. Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Myeloid and Monocytic Leukemia
• Intervention / Treatment: Drug: Decitabine; Drug: Ruxolitinib; Drug: Donor Lymphocyte Infusion (DLI)

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University Medical School
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Patient Inclusion Criteria:

• Age ≥12 years
• Have undergone first allo-HCT from a 6/6 matched sibling donor, 8/8 matched unrelated donor, or an HLA haploidentical donor.
• History of AML or MDS for which allo-HCT was performed. Overlap MPN/MDS is included.
• Untreated relapse of the underlying malignancy as defined by >5% of malignant blasts (by morphology and/or flow cytometry) in the bone marrow, or myeloid sarcoma.
• Additional cells sufficient for the first DLI available from the same donor, or the donor must be willing to donate. Both G-CSF mobilized and unmobilized products are allowed and the choice is at the discretion of the treating physician.
• Partial (or better) engraftment from the bone marrow showing relapse, defined as >50% donor chimerism on non-split RFLP. Patients with chimerism of 25-50% may be enrolled with approval of the site PI and Sponsor/Investigator
• Karnofsky performance status ≥ 50%

• Adequate organ function within 14 days of study registration defined as:

  • Total bilirubin < 1.5 x upper limit of institutional normal, unless a diagnosis of Gilbert's disease
  • AST/ALT < 2.5 x upper limit of institutional normal
  • Creatinine clearance ≥40 mL/minute as calculated by the Cockcroft-Gault formula. Cockcroft-Gault CrCl = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr).
• Peripheral white blood cell count <50 x 10^9/L. The use of hydroxyurea for cytoreduction is allowed and may continue until cycle 2 day 1

• Subjects and spouse/partner who are of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least 1 of which must be a barrier method) starting at Screening and continuing through the entire study (for at least 3 months after the last dose of ruxolitinib if study treatment is stopped early or subject withdraws consent). Highly effective contraception is defined as:

  • Established use of oral, injected or implanted hormonal methods of contraception.
  • Placement of an intrauterine device or intrauterine system.
  • Double barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (double barrier method will count as 2 forms of contraception).
• Male subjects must not donate sperm during the Screening and Treatment Periods, and for at least 3 months after the last dose of ruxolitinib.
• Subjects are willing and able to give written informed consent and to comply with all study visits and procedures. Parents or legal guardians will consent for minors and minors will be asked to assent.

Patient Exclusion Criteria:

• Active uncontrolled infection at the time of consent. An active uncontrolled infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without signs or symptoms of infection will not be interpreted as an active uncontrolled infection. Subjects with a controlled infection receiving definitive therapy for 72 hours prior to enrollment are eligible.
• History of infection with human immunodeficiency virus (HIV), unresolved hepatitis B, or hepatitis C.
• Untreated CNS leukemia
• Untreated or active GVHD (acute or chronic)
• History of grade III-IV acute GVHD at any point in time
• Any form of iatrogenic immunosuppression except <0.5 mg/kg/day of prednisone or equivalent at the time of consent.
• Unresolved veno-occlusive disease of the liver, defined as persistent bilirubin abnormalities not attributable to GVHD and ongoing organ dysfunction (renal, ascites).
• Subjects who are pregnant, breast feeding or sexually active and unwilling to use effective birth control for the duration of the study, as agents in this study are in pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, and category D: there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans.
• Radiation therapy within 14 days prior to consent.
• Any prior therapy for relapse after allo-HCT.
• Prior DLI. CD34-selected boost is allowed
• Exposure to any other investigational agent, device or procedure within 14 days prior to consent
• Patients or donors with any medical or psychological condition that, in the opinion of the Investigator, might interfere with the subject's participation in the trial, pose any additional risk for the patient/donor, or confounds the assessments of the subject.
• Subjects with known allergies, hypersensitivity or intolerance to ruxolitinib or similar compounds.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Decitabine + Ruxolitinib + DLI; Eligible subjects will receive up to 4 cycles of combined modality treatment. The number of cycles depends on response, toxicity, and the remaining cell dose.

Drug: Decitabine; 10 days of decitabine 20 mg/m2 IV daily; or, alternatively, per institution, physician, or patient preference on a 5-2-5 schedule with no weekend infusion. If a CR is achieved after 2 cycles using the 10-day schedule, subsequent cycles will change to a 5-day schedule.; Drug: Ruxolitinib; Starting with day 1 of cycle 1 and continuing for up to 6 months after the end of the last cycle, patients will receive ruxolitinib 5 mg twice daily orally. Dose may be increased to 10 mg twice daily in cycles 2 through 4 if platelets improve to >100 x 10^9/L.; Drug: Donor Lymphocyte Infusion (DLI); DLI from the original donor will be infused within 10 days after the last dose of decitabine in each cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS)	Rate of Overall Survival (OS)	6 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Rate of Progression Free Survival (PFS)	6 Months
Progression Free Survival (PFS)	Rate of Progression Free Survival (PFS)	1 Year
Relapse	Cumulative Incidence of Relapse	6 Months
Relapse	Cumulative Incidence of Relapse	1 Year
Complete Remission (CR)	Rate of Complete Remission (CR)	6 Months
Complete Remission (CR)	Rate of Complete Remission (CR)	1 Year
Non-Relapse Mortality (NRM)	Cumulative Incidence of Non-Relapse Mortality (NRM)	6 Months
Non-Relapse Mortality (NRM)	Cumulative Incidence of Non-Relapse Mortality (NRM)	1 Year
Best Response	Best response until next line of treatment, death, or last follow up, whichever occurs sooner	1 Year
Efficacy of Combined Modality Treatment (Ruxolitinib, Decitabine, and DLI) for Relapsed AML or MDS Post Allo-HCT: Rate of Overall Survival (OS)	Rate of Overall Survival (OS)	1 Year
Percentage of Participants With Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV)	Percentage of Participants with Grade II-IV Acute Graft-versus-host Disease (aGVHD II-IV)	3 Months

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: Incyte Corporation
• Investigators: Principal Investigator: Mark A Schroeder, M.D., Washington University School of Medicine; Principal Investigator: Armin Rashidi, MD, PhD, Division of Hematology, Oncology and Transplantation, University of Minnesota; Principal Investigator: Eric Huselton, M.D., University of Rochester; Principal Investigator: John F Dipersio, M.D., Ph.D., Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 17, 2020
• Primary Completion (Actual): September 6, 2022
• Study Completion (Actual): September 6, 2022

Study Registration Dates

• First Submitted: August 12, 2019
• First Submitted That Met QC Criteria: August 13, 2019
• First Posted (Actual): August 14, 2019

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 3, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: AML; MDS
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: 2018LS066; MT2018-07 (Other Identifier: University of Minnesota Masonic Cancer Center)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No