Standard of Care vs. Bortezomib in Graft-Versus Host Disease After Hematopoietic Stem Cell Transplant

NCT01754389 | Completed Phase 2 Results DMC

• 1 other identifier: 12-404
• Study Type: interventional
• Target: 138
• Locations: 1 country
• Sites: 4

Brief Summary

This research study is a Phase II clinical trial. Phase II clinical trials test the effectiveness of an investigational drug to learn whether the drug works in treating a specific cancer. "Investigational" means that the drug is still being studied and that research doctors are trying to find out more about it-such as the safest dose to use, the side effects it may cause, and if the drug is effective for treating different types of cancer. It also means that the FDA has not yet approved bortezomib to treat or prevent graft-versus-host disease. Bortezomib is approved by the FDA to treat other human malignancies. Bortezomib is a drug that has an anti-cancer effect that involves inhibiting cell growth and causing cell death. This drug has been used in other research studies, and information from thos other research studies suggests that bortezomib may help to lower the risk of GVHD after allogeneic stem cell transplantation in patients who have matched unrelated, unmatched related or unrelated donors in this research study. Allogeneic stem cell transplantation is a procedure in which selected blood cells taken from your sibling or unrelated donor are given to you. Lower doses of chemotherapy drugs are given before the donor cells are infused in a process known as reduced-intensity conditioning. Stem cell transplant destroys cancer in two ways: The conditioning regimen destroys cancer cells and teh immune cells from the donor can recognize cancer cells and kill them. A common problem after stem cell transplant is graft-versus-host disease (GVHD). The word "graft" refers to the donor blood cells that you will receive during your transplant. The word "host" refers to the person (in this case, you) receiving the cells. GVHD is a complication of transplantation where the donor graft attacks and damages some of your tissues. GVHD can cause skin rash, intestinal problems such as nausea, vomiting or diarrhea. GVHD may also damage your liver and cause hepatitis or jaundice. GVHD may also increase your risk of infection. After stem cell transplant, all patients receive prophylactic medications against GVHD. In this research study we are studying the safety and effectiveness of preventing GVHD using bortezomib treatment in combination with other drugs versus standard of care prophylaxis (tacrolimus + methotrexate). If you take part in this study, there is a 33% chance you will receive any one of the following GVHD prevention treatments:

• tacrolimus + methotrexate (standard of care GVHD prophylaxis)
• bortezomib + tacrolimus + methotrexate
• bortezomib + sirolimus + tacrolimus Sirolimus, tacrolimus and methotrexate are drugs that suppress the immune system to try to prevent GVHD.

Conditions

Graft Versus Host Disease

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Incidence of Grade II-IV GVHD

  The primary outcome of this study is the cumulative incidence of grade II-IV acute GVHD up to Day 180 after stem cell infusion. Acute GHVD is graded according to the modified Glucksberg criteria (adapted from Thomas et al., NEJM ,1975, pp. 895-90), which is based on criteria by which the provider classifies acute GVHD per its objective organ staging. Acute GVHD is assessed in weekly standard of care visits post stem cell infusion and is captured in the protocol EDC upon evaluation of clinical notes up to Day 100. Data for acute GVHD organ staging and etiologies are collected in an acute GVHD separate case report form and do not include system organ class, expectedness or attribution.

  6 months

Secondary Outcomes (4)

• Percentage of Participants With Non-relapse Mortality

  1 year

• Percentage of Participants With Relapse

  1 year

• Percentage of Participants With Progression-free and Overall Survival

  1 year

• Percentage of Participants With Chronic Graft Versus Host Disease

  1 year

Study Arms (3)

Arm A (Standard of Care)

ACTIVE COMPARATOR

Tacrolimus intravenously and orally, Day -3 through 3-6 months post-transplant Methotrexate intravenously on days 1, 3, 6 and 11 post-transplant

Drug: Tacrolimus; Drug: Methotrexate

Arm B (Experimental)

EXPERIMENTAL

Bortezomib intravenously 1, 4 and 7 days post-transplant Tacrolimus intravenously and orally, Day -3 through 3-6 months post-transplant Methotrexate intravenously 1,3,6 and 11 days post-transplant

Drug: Tacrolimus; Drug: Methotrexate; Drug: Bortezomib

Arm C (Experimental)

EXPERIMENTAL

Bortezomib intravenously 1,4 and 7 days post-transplant Sirolimus, intravenously and orally, Day -3 through 3-6 months post-transplant Tacrolimus, intravenously and orally, Day -3 through 3-6 months post-transplant

Drug: Tacrolimus; Drug: Bortezomib; Drug: Sirolimus

Interventions

Tacrolimus DRUG

Arm A (Standard of Care); Arm B (Experimental); Arm C (Experimental)

Methotrexate DRUG

Arm A (Standard of Care); Arm B (Experimental)

Bortezomib DRUG

Arm B (Experimental); Arm C (Experimental)

Sirolimus DRUG

Arm C (Experimental)

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed advanced/aggressive hematologic malignancy unlikely to be cured by alternative therapies
• HLA matched unrelated donors or 1-locus HLA mismatched related or unrelated donors
• Adequate organ function
• Willing to use appropriate contraception

You may not qualify if:

• Pregnant or breastfeeding
• Recipient of prior allogeneic hematopoietic stem cell transplantation
• Recipient of prior abdominal radiation therapy
• HIV positive on combination anti-retroviral therapy
• Seropositive for hepatitis B or C
• Known allergy to bortezomib, boron or mannitol
• Myocardial infarction within 6 months prior to enrollment or any other cardiac dysfunction
• Uncontrolled infection
• Inability to withhold agents that may interact with hepatic cytochrome P450 enzymes or gluthathione S-transferases
• Seizures or history of seizures
• Grade greater than or equal to 2 peripheral neuropathy within 21 days of enrollment
• Use of other investigational drugs within 21 days of enrollment
• History of another non-hematologic malignancy except if disease free for at least 5 years or cervical cancer in situ, or basal/squamous cell carcinoma of the skin
• Uncontrolled intercurrent illness

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (4)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02215, United States

Location

Dana-Farber Cancer Insitute

Boston, Massachusetts, 02215, United States

Location

Related Publications (1)

• Koreth J, Kim HT, Lange PB, Poryanda SJ, Reynolds CG, Rai SC, Armand P, Cutler CS, Ho VT, Glotzbecker B, Yusuf R, Nikiforow S, Chen YB, Dey B, McMasters M, Ritz J, Blazar BR, Soiffer RJ, Antin JH, Alyea EP 3rd. Bortezomib-based immunosuppression after reduced-intensity conditioning hematopoietic stem cell transplantation: randomized phase II results. Haematologica. 2018 Mar;103(3):522-530. doi: 10.3324/haematol.2017.176859. Epub 2018 Jan 11.

  PMID: 29326124 DERIVED

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

Tacrolimus; Methotrexate; Bortezomib; Sirolimus

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr. John Koreth
• Organization: Dana Farber Cancer Institute

John_Koreth@dfci.harvard.edu

617-632-2949

Study Officials

• John Koreth, DPhil, MBBS

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 13, 2012
• First Posted: December 21, 2012
• Study Start: January 1, 2013
• Primary Completion: May 1, 2016
• Study Completion: November 1, 2016
• Last Updated: July 18, 2017
• Results First Posted: July 18, 2017

Record last verified: 2017-06

Locations

US (4)