Brentuximab Vedotin Prevention of (GVHD) After Unrelated Allogeneic Stem Cell Transplantation

A Pilot Study of Brentuximab Vedotin in the Prevention of Graft-Versus-Host Disease (GVHD) After Unrelated Allogeneic Stem Cell Transplantation

This pilot clinical trial studies the safety and maximum tolerated dose of brentuximab vedotin when given with tacrolimus and methotrexate after unrelated allogeneic donor stem cell transplant in patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndromes. The addition of brentuximab vedotin to tacrolimus and methotrexate may result in a significant reduction of graft versus host disease in these patients.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia, Acute Myeloid; Leukemia, Lymphoblastic,Acute
• Intervention / Treatment: Drug: brentuximab vedotin

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient must be scheduled to undergo stem cell transplantation for one of the following diagnoses:

  • acute myeloid leukemia (AML) in CR1 (first complete remission, CR or CRi) or CR2 (second complete remission, CR or CRi),
  • acute lymphoblastic leukemia (ALL) in CR1 or CR2 (CR or CRi)
  • myelodysplastic syndrome (MDS) without progression to AML.
  • Chronic myelogenous leukemia (CML)
  • Non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD)
  • Chronic lymphocytic leukemia (CLL)
  • Multiple myeloma (MM)
• Patients must be the recipient of unrelated donor peripheral blood stem cell products. Mismatches at both antigen and allele level will be eligible. Match must be 6 or 7 out of 8 loci (HLA A, B, C, and DRB1).
• Patient must receive any one of the following conditioning regimens: total body radiation (single or fractionated dose)/cyclophosphamide, busulfan/ cyclophosphamide, or fludarabine/busulfan/lymphocyte immune globulin (ATGAM/thymo).
• Patient must be ≥ 18 years and ≤ 70 years of age.
• Patient must have an ECOG performance status ≤ 2 or Karnofsky performance scale ≥ 60%
• Patient must have CD34+ stem cells ≥ 2x106/kg (actual body weight of the recipient) available for transplantation.

• Patient must have appropriate organ function as defined below (this criterion should be met on screening and on the day of the first dose of brentuximab vedotin (as assessed prior to dosing)):

  • Total bilirubin ≤ 2.0 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Serum creatinine ≤ 2.0 x IULN
  • Estimated Creatinine Clearance > 30 ml/min
  • Cardiac ejection fraction > 40%
  • DLCO/VA > 40%
• Women of childbearing potential and men 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 woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Patient must be able to understand and willing to sign an IRB approved written informed consent document.

Exclusion Criteria:

• Patient must not have had prior exposure to brentuximab vedotin.
• Patient must not have a history of other malignancy that has not been in remission for at least 3 years, with the exception of basal non-melanoma skin cancer which were treated with local resection only or intraepithelial lesions or carcinoma in situ of the cervix or prostate that has been curatively treated.
• Patient must not be receiving any other investigational agents.
• Patient must not have active CNS involvement.
• Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to brentuximab vedotin or other agents used in the study.
• Patients must not have had previous radiation therapy to the mediastinum or lungs.
• Patient must not have an uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, active pulmonary diseases, or psychiatric illness/social situations that would limit compliance with study requirements (this criterion should be met on screening and on the day of but prior to first dose of brentuximab vedotin).
• Patient must not be pregnant and/or breastfeeding.
• Patient must not be known to be HIV-positive on combination antiretroviral therapies.
• Patient must not have had a previous allogeneic or syngeneic transplant. Prior autologous transplant is allowed.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 0 (starting dose); brentuximab vedotin 0.3mg/kg, given IV on Days 7, 28, 49 & 70	Drug: brentuximab vedotin; Other Names: Adcetris
Experimental: Dose Level 1; brentuximab vedotin 0.6mg/kg, given IV on Days 7, 28, 49 & 70	Drug: brentuximab vedotin; Other Names: Adcetris
Experimental: Dose Level 2; brentuximab vedotin 1.2mg/kg, given IV on Days 7, 28, 49 & 70	Drug: brentuximab vedotin; Other Names: Adcetris
Experimental: Dose Level 3; brentuximab vedotin 1.8mg/kg, given IV on Days 7, 28, 49 & 70	Drug: brentuximab vedotin; Other Names: Adcetris
No Intervention: Control Dose Level; The first 3 patients will not receive brentuximab vedotin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MTD of brentuximab vedotin when administered with a GVHD prophylaxis regimen	Defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity; Hematologic DLT is defined as ANC < 500/mm3 for three consecutive days beyond Day +21 that was determined by the investigator to be likely related to brentuximab vedotin. Non-hematologic DLT is defined as any grade 3 or higher non-hematologic toxicity that was determined by the investigator to be possibly, probably, or definitely related to brentuximab vedotin, with the following specific exceptions: Grade 3 or 4 nausea, vomiting, diarrhea, mucositis, or fatigue thought to be associated with conditioning regimens; Grade 3 rash will only be considered a DLT for patients who have received two weeks of supportive care treatment with no improvement.	37 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability of brentuximab vedotin when administered with a GVHD prophylaxis regimen	Toxicities described and graded using CTCAE version 4.0; described by patient, type, and grade for each dose level; summarized by counts and percentage of patients in the corresponding categories	100 days
Rate of acute GVHD	Proportion of all subjects who experience symptoms consistent with grade 2-4 acute GVHD; using the standard grading system adapted from the Glucksberg clinical stage and grade of acute GVHD	100 days
Rate of chronic GVHD	Proportion of all subjects who experience symptoms consistent with chronic GVHD; assessment will begin after Day 100 using the NIH consensus criteria for diagnosis and staging of chronic GVHD	2 years
Progression-free survival	Duration from the time of transplant to time of first progression, death, relapse after complete response, or the date the patient was last known to be in remission; estimated with Kaplan-Meier methods.	2 years
Overall survival.	Duration from the time of transplant to death or last follow-up; estimated with Kaplan-Meier methods.	2 years
1-year non-relapse mortality rate	Defined as the percentage of patients dying from etiologies other than disease relapse; estimated with Kaplan-Meier methods.	1 year
2-year non-relapse mortality rate	Defined as the percentage of patients dying from etiologies other than disease relapse; estimated with Kaplan-Meier methods.	2 years
1-year disease relapse rate	Defined as the percentage of patients who have disease relapse; estimated with Kaplan-Meier methods.	1 year
2-year disease relapse rate	Defined as the percentage of patients who have disease relapse; estimated with Kaplan-Meier methods.	2 years

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Seagen Inc.

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 25, 2013
• Primary Completion (Actual): November 11, 2015
• Study Completion (Actual): November 21, 2016

Study Registration Dates

• First Submitted: September 18, 2012
• First Submitted That Met QC Criteria: October 1, 2012
• First Posted (Estimate): October 4, 2012

Study Record Updates

• Last Update Posted (Actual): April 16, 2019
• Last Update Submitted That Met QC Criteria: April 12, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Leukemia, Myeloid; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Brentuximab Vedotin
• Other Study ID Numbers: 201211047

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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