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Ruxolitinib, Decitabine, and Donor Lymphocyte Infusion in Treating Patients with Relapsed Acute Myeloid Leukemia or Myelodysplastic Syndrome after Stem Cell Transplant

Trial Status: Active

This phase II trial studies how well ruxolitinib, decitabine, and donor white blood cells (donor lymphocyte infusion [DLI]) work in treating patients with acute myeloid leukemia or myelodysplastic syndrome that has come back after a stem cell transplant. Patients who have relapsed after a stem cell transplant commonly receive an infusion of immune cells from the original donor called a DLI. A DLI uses high dose chemotherapy prior to the infusion which increases the risk of graft versus host disease, a condition in which the transplanted cells attack the recipient’s body. While the cancer responds temporarily to high dose chemotherapy alone, it hasn’t been shown to bring about long-term remission. Instead of high dose chemotherapy, this study pairs DLI with decitabine, another chemotherapy drug, and adds ruxolitinib. Ruxolitinib is a type of drug called a "JAK" inhibitor and may help prevent graft-versus host disease. Giving ruxolitinib with decitabine and a DLI may decrease the risk of graft-versus host disease and increase the chances of remission.

Inclusion Criteria

  • 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 myeloproliferative neoplasm (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 granulocyte colony-stimulating factor (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 restriction fragment length polymorphism (RFLP).
  • Karnofsky performance status >= 50%.
  • Total bilirubin < 1.5 x upper limit of institutional normal, unless a diagnosis of Gilbert’s disease (within 14 days of study registration).
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of institutional normal (within 14 days of study registration).
  • Creatinine clearance >= 40 mL/minute within 3 days prior to consent, as calculated by the Cockcroft-Gault formula. (within 14 days of study registration)
  • Peripheral white blood cell count < 50 x 10^9/L within 3 days prior to consent. 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, or be given a minor information sheet, per institutional Institutional Review Board (IRB) requirements.
  • DONORS: Body weight of at least 40 kilograms.
  • DONORS: In general good health as determined by the medical provider.
  • DONORS: Hemoglobin within 10% of upper and lower limit of normal range of test (gender based for hemoglobin)
  • DONORS: White blood cell (WBC) within 10% of upper and lower limit of normal range of test
  • DONORS: Platelet within 10% of upper and lower limit of normal range of test
  • DONORS: ALT < 2 x upper limit of normal.
  • DONORS: Serum creatinine < 1.8 mg/dl.
  • DONORS: Performance of a donor infectious disease screen panel including cytomegalovirus (CMV) antibody, hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, human immunodeficiency virus (HIV) 1/2 antibody, human T-lymphotropic virus (HTLV)A 1/2 antibody, Treponema, and Trypanosoma cruzi (T. cruzi) plus hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV), HIV by nucleic acid testing (NAT); or per current standard institutional donor screen – must be negative for HIV and active hepatitis B.
  • DONORS: Not pregnant - females of childbearing potential must have a negative pregnancy test within 7 days of mobilization start (if applicable) or within 7 days of cell collection (if not using mobilization).
  • DONORS: Voluntary written consent prior to the performance of any research related procedure.

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 central nervous system (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.

Minnesota

Minneapolis
University of Minnesota / Masonic Cancer Center
Status: ACTIVE
Contact: Armin Rashidi
Phone: 612-625-9604

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: ACTIVE
Contact: Mark Andrew Schroeder
Washington University School of Medicine
Status: APPROVED
Contact: Mark Thomas Schroeder
Phone: 314-454-8323

New York

Rochester
University of Rochester
Status: ACTIVE
Contact: Eric J Huselton

PRIMARY OBJECTIVE:

I. To determine the efficacy of combined modality treatment (ruxolitinib phosphate [ruxolitinib], decitabine, and DLI) for relapsed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) post allogeneic hematopoietic stem cell transplantation (allo-HCT) as measured by overall survival (OS) at 6 months.

SECONDARY OBJECTIVES:

I. To evaluate OS.

II. To determine cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD II-IV).

III. To evaluate progression-free survival (PFS).

IV. To determine incidence of relapse.

V. To determine complete remission (CR).

VI. To determine incidence of non-relapse mortality (NRM).

VII. To measure best response.

CORRELATIVE OBJECTIVES:

I. To evaluate incidence and severity of adverse events (AEs) and serious AEs (SAEs) until 3 months after day 1 of the last received cycle.

II. Correlative studies: T cell and natural killer (NK) cell subset analysis by flow cytometry, correlation between TP53 mutation and response, clonal dynamics during and after the course of therapy.

OUTLINE: This is a dose-escalation study of donor lymphocyte infusion.

Patients receive ruxolitinib orally (PO) twice daily (BID) from day 1 until 6 months after the end of the final cycle, and decitabine intravenously (IV) daily on days 1-10 in cycles 1 and 2, (alternative: day 1-5 and day 8-12 with no weekend infusion). Patients who achieve complete remission after cycle 2 then receive decitabine on days 1-5 in cycles 3 and 4. Within 10 days after the last dose of decitabine in each cycle, patients undergo donor lymphocyte infusion. Treatments repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. However, patients may rest in between cycles and begin the next cycle any time between days 29 and 56.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for 12 months.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Minnesota / Masonic Cancer Center

Principal Investigator
Armin Rashidi

  • Primary ID 2018LS066
  • Secondary IDs NCI-2019-02876, MT2018-07
  • Clinicaltrials.gov ID NCT04055844