Giving Chemotherapy and rATG for a Shortened Amount of Time before a Donor Stem Cell Transplantation for the Treatment of Patients with Blood Cancers

Status: Active

Description

This phase I trial studies the side effects of giving chemotherapy and a drug called rATG for a shorter period of time before a donor stem cell transplant in treating patients with blood cancers. This study will also look at whether the condensed regimen can shorten hospitalization following the transplantation. A chemotherapy regimen with the drugs busulfan, melphalan, and fludarabine may kill cancer cells in the body, making room in the bone marrow for new blood stem cells to grow and reducing the chance of transplanted cell rejection. The chemotherapy drugs work to interrupt the DNA (genetic information) in the cancer cells, stopping the cells from dividing and causing them to die. rATG targets and deactivates white blood cells called T cells that survive the chemotherapy. T cells may see the donor’s cells as foreign, causing a serious condition called graft-versus-host disease (GVHD). rATG helps prevent the donor stem cells from being rejected. Giving chemotherapy and rATG for a shorter period of time before a donor stem cell transplantation may help in reducing the number of side effects and shortening hospitalization following the transplantation.

Eligibility Criteria

Inclusion Criteria

  • Patients with any of the following hematologic malignancies for which allogeneic (allo)-hematopoietic cell transplantation (HCT) is indicated, including: * Acute myeloid leukemia (AML) with intermediate or high-risk features in first complete remission (CR1) * Relapsed AML in >= second complete remission (CR2) * Acute leukemias of ambiguous lineage in >= CR1 * Acute lymphoid leukemia (ALL) in CR1 with clinical, flow cytometric, or molecular features indicating a high risk for relapse, or ALL in >= CR2 * Chronic myelogenous leukemia (CML) meeting one of the following criteria: ** Failed response to or intolerant to BCR-ABL tyrosine kinase inhibitors (TKIs) ** CML with BCR-ABL mutation consistent with poor response to TKIs (e.g., T315I mutation) ** CML in accelerated phase or blast crisis with < 10% blasts after therapy, or in second chronic phase * Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), or MDS/MPN overlap syndromes with least one of the following: ** Revised International Prognostic Scoring System risk score of intermediate or higher at the time of transplant evaluation ** Life-threatening cytopenias ** Karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia, including abnormalities of chromosome 7 or 3, mutations of TP53, or complex or monosomal karyotype ** Therapy related disease or disease evolving from other malignant processes * Chronic myelomonocytic leukemia (CMML-1 or CMML-2) * Severe aplastic anemia * Relapsed Hodgkin lymphoma meeting both of the following criteria: ** Responding to therapy prior to enrollment ** Relapse after autologous HCT or are ineligible for autologous HCT * Relapsed non-Hodgkin lymphoma meeting both of the following criteria: ** Responding to therapy prior to enrollment ** Relapse after prior autologous HCT or are ineligible for autologous HCT * High-risk multiple myeloma following autologous HCT or relapsed multiple myeloma following autologous HCT with chemosensitive disease
  • Serum bilirubin =< 2 mg/dL, unless benign congenital hyperbilirubinemia. Patients with hyperbilirubinemia related to paroxysmal nocturnal hemoglobinuria or other hemolytic disorders are eligible with principal investigator (PI) approval
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase < 3 times the upper limit of normal unless thought to be disease-related
  • Creatinine clearance >= 50 ml/min (calculated by Cockcroft Gault)
  • Left ventricular ejection fraction (LVEF) >= 45% by multigated acquisition scan (MUGA) or resting echocardiogram
  • Pulmonary function (forced expiratory volume in one second [FEV1] and corrected diffusing capacity for carbon monoxide [DLCO]) >= 50% predicted
  • Adequate performance status of Eastern Cooperative Oncology Group (ECOG) =< 2
  • Each patient must be willing to participate as a research subject and must sign an informed consent form
  • DONOR: Must be a 10/10 human leukocyte antigen (HLA) genotypically matched related or unrelated donor at A, B, C, DRB1, and DQB1 loci, as tested by deoxyribonucleic acid (DNA) analysis
  • DONOR: Able to provide informed consent for the donation process per institutional standards
  • DONOR: Meet standard criteria for donor collection as defined by the National Marrow Donor Program Guidelines

Exclusion Criteria

  • Patients with active extramedullary disease
  • Patients with active central nervous system malignancy
  • Active and/or uncontrolled infection at the time of allo-HCT
  • Patients who have undergone previous allo-HCT
  • Patients who have undergone previous autologous HCT within the last 6 months, with the exclusion of high-risk multiple myeloma patients
  • Patient seropositivity for human immunodeficiency virus (HIV) I/II and/or human T-cell leukemia virus (HTLV) I/II
  • Females who are pregnant or breastfeeding
  • Patients unwilling to use contraception during the study period
  • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol

Locations & Contacts

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Michael Scordo
Phone: 212-639-6052

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. To estimate the number of patients who have grade 4 Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 toxicities in the first 30 days for patients undergoing ex-vivo CD34-selected allogeneic (allo)-hematopoietic cell transplantation (HCT) with condensed busulfan/melphalan hydrochloride/fludarabine phosphate (bu/mel/flu).

SECONDARY OBJECTIVES:

I. Estimate the total length of hospital stay.

II. Determine the feasibility of administering test-dose busulfan and measuring busulfan pharmacokinetics prior to admission to calculate the daily dose of busulfan needed for the conditioning regimen.

III. Determine the time to neutrophil engraftment defined as the first of 3 consecutive days of absolute neutrophil count (ANC) >= 500 K/mcL.

IV. Determine the time to platelet engraftment defined as the first of 7 consecutive days with a platelet count exceeding 20,000/mcL without transfusion support.

V. Evaluate the incidence of grade >= 3 non-hematologic adverse events by CTCAE version 5.0 by day +100, and at +180, and +1 year post allo-HCT in patients undergoing condensed bu/mel/flu.

VI. Determine the incidence and severity of acute and chronic graft versus host disease (GVHD) at day +100 and +1 year post allo-HCT.

VII. Determine the cumulative incidence of non-relapse mortality (NRM) at day +100 and +1 year post allo-HCT.

VIII. Estimate the probabilities of overall (OS) and disease-free survival (DFS) at +180 days and +1 year post allo-HCT.

IX. Determine immune recovery by evaluating lymphocyte subsets at days +30, +100, +180, and at +1 year.

OUTLINE:

CONDITIONING REGIMEN: Patients are assigned to 1 of 2 arms.

ARM I: Patients with hematologic malignancies other than multiple myeloma receive busulfan IV over 2 hours daily on days -6 to -4, fludarabine phosphate IV over 30 minutes on days -6 to -2, rabbit anti-thymocyte globulin IV over 12 hours on days -3 to -2, and melphalan hydrochloride IV over 30 minutes on days -3 and -2 in the absence of disease progression or unacceptable toxicity.

ARM II: Patients with multiple myeloma receive busulfan IV over 2 hours every 6 hours for 10 doses on days -6 to -4, melphalan hydrochloride IV over 30 minutes on days -6 and -5, fludarabine phosphate IV over 30 minutes on days -6 to -2, and rabbit anti-thymocyte globulin IV over 12 hours on days -3 and -2 in the absence of disease progression or unacceptable toxicity.

STEM CELL TRANSPLANTATION: All patients undergo a filgrastim (G-CSF) mobilized peripheral blood stem cell transplantation (PBSC) on day 0.

After completion of study treatment, patients are followed up on days 7, 14, 21, 30, 60, 100, 180, 270, and 365.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Michael Scordo

Trial IDs

Primary ID 19-245
Secondary IDs NCI-2019-06668
Clinicaltrials.gov ID NCT04098393