A Phase I Study of Abatacept in the Treatment of Patients With Steroid Refractory Chronic Graft Versus Host Disease (cGVHD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Dana-Farber Cancer Institute
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Jacalyn Rosenblatt, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:
NCT01954979
First received: September 27, 2013
Last updated: July 10, 2014
Last verified: July 2014
  Purpose

The participant is invited to take part in this study because they have chronic Graft versus Host Disease (cGVHD) that is not responding to standard treatment with steroids. This research study is a way of gaining new knowledge about the treatment of patients with cGVHD. This research study is evaluating a drug called abatacept.

Abatacept is a drug that alters and suppresses the immune system. Abatacept is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe active rheumatoid arthritis in adults and of severe juvenile idiopathic arthritis (JIA) in patients who have failed prior therapy with disease-modifying anti-rheumatic drugs (DMARDs). These are autoimmune conditions, ie caused by an overactive immune system that attacks normal tissues and organs. It is currently being tested in a variety of other autoimmune conditions. In this case it is considered experimental.

cGVHD is caused by the donor cells attacking various organs of the recipient. The investigators try to minimize this immune attack by using corticosteroids such as prednisone. In severe cases prednisone is not sufficient and other immunosuppressive medications are used in addition in order to more efficiently control cGVHD and to limit the dose and consequently the multiple side-effects of corticosteroids. This study is being done to determine if the use of abatacept is safe in patients with cGVHD and if it can facilitate a better control of cGVHD.

During this study the participants will be evaluated for side effects from the treatment with abatacept, and for response of the cGVHD to the treatment. There will be two groups of participants in the study. The first group will be treated at a relatively low dose of abatacept. If this is found to be safe then the second group will be treated at a higher dose. Three to four tablespoons of blood will be drawn at every 2 week visit in order to determine your blood counts, kidney and liver function. Some of the blood will be used in a research lab in order to study measures of your immune system and how they might be affected by the treatment.


Condition Intervention Phase
Chronic Graft Versus Host Disease
Drug: Abatacept
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Abatacept in the Treatment of Patients With Steroid Refractory Chronic Graft Versus Host Disease (cGVHD)

Resource links provided by NLM:


Further study details as provided by Dana-Farber Cancer Institute:

Primary Outcome Measures:
  • Determination of the Maximum Tolerated Dose (among two dose levels) and toxicity profile of a 141 day/6 dose course of abatacept in patients with steroid refractory cGVHD. [ Time Frame: 2 Years ] [ Designated as safety issue: Yes ]
    Determination of the Maximum Tolerated Dose (among two dose levels) and toxicity profile of a 141 day/6 dose course of abatacept in patients with steroid refractory cGVHD.


Secondary Outcome Measures:
  • Determination of the efficacy (in terms of cGVHD symptoms, score and steroid dose) of a 141 day/6 dose course of abatacept in patients with steroid refractory cGVHD [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    Determination of the efficacy (in terms of cGVHD symptoms, score and steroid dose) of a 141 day/6 dose course of abatacept in patients with steroid refractory cGVHD

  • Examination of the immunologic effects associated with the administration of abatacept in patients with steroid refractory cGVHD. [ Time Frame: 2 Years ] [ Designated as safety issue: No ]
    Examination of the immunologic effects associated with the administration of abatacept in patients with steroid refractory cGVHD.


Estimated Enrollment: 22
Study Start Date: October 2013
Estimated Study Completion Date: September 2018
Estimated Primary Completion Date: January 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Abatacept
Abatacept will be administered for a total of 6 doses. Doses 1-3 will be administered at two week intervals (+/-2 days). One month following Dose 3, abatacept will be administered, and given at four-week intervals (+/-2 days) for three doses (Doses 4-6.) Patients will be followed for toxicity for 28 days following last dose of Abatacept. Patients will then be seen monthly for six months.
Drug: Abatacept
The study will follow a standard 3+3 design with two escalating doses of abatacept to determine the maximum tolerated dose (MTD): 3 mg/kg (dose level 1) and 10 mg/kg (dose level 2). Dose-limiting toxicities (DLTs) are defined as any Grade 3 or 4 toxicities judged to be probably or definitely related to abatacept.

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  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants must meet the following criteria on screening examination to be eligible to participate in the study:

  • Participants must be recipients of an allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning regimens.
  • Participants must be at least 100 days after the transplantation or a donor lymphocyte infusion.
  • Participants must have cGVHD (as defined by the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease)
  • Participants may have either extensive or limited cGVHD requiring systemic treatment
  • Participants must have steroid refractory cGVHD, defined as having persistent signs and symptoms of chronic GVHD despite the use of prednisone at ≥ 0. 5 mg/kg/day (or equivalent) for at least 4 weeks in the preceding 12 months. Patients may remain on steroids while enrolled in the study.
  • No addition or subtraction of other immunosuppressive medications for at least 4 weeks prior to starting treatment.
  • On stable immunosuppressive regimen for 2 weeks prior to enrollment. Adjustment of immunosuppressive medications to maintain a therapeutic level is permitted.
  • Age ≥ 18 years at the time of signing the informed consent form.

Reproductive Status: Definition of Women of Child-Bearing Potential (WOCBP). WOCBP comprises women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-menopausal (see definition below).

Post-menopause is defined as:

  • Women who have had amenorrhea for ≥ 12 consecutive months (without another cause) and who have a documented serum follicle-stimulating hormone (FSH) level > 35 mIU/mL.
  • Women who have irregular menstrual periods and a documented serum FSH level > 35 mIU/mL.
  • Women who are taking hormone replacement therapy (HRT).

The following women are WOCBP:

  • Women using the following methods to prevent pregnancy: Oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as intrauterine devices or barrier methods (diaphragm, condoms, spermicides).
  • Women who are practicing abstinence.
  • Women who have a partner who is sterile (eg, due to vasectomy). WOCBP must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 10 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
  • WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 48 hours before the first dose of study drug.
  • Women must not be breast-feeding.
  • Sexually active fertile men must use effective birth control if their partners are WOCBP.
  • Life expectancy of greater than > 3 months.
  • ECOG performance status ≤ 2 (see Appendix A).
  • Laboratory test results within these ranges:
  • Absolute neutrophil count ≥ 1500/mm³
  • Serum creatinine ≤ 2.0 mg/dL
  • Renal function assessed by calculated creatinine clearance ≥ 60ml/min by Cockcroft-Gault formula (see Appendix B: Cockcroft-Gault estimation of CrCl).
  • Total bilirubin ≤ 1.5 x ULN (unless hepatic dysfunction is caused by cGVHD)AST (SGOT) and ALT (SGPT) ≤ 3 x ULN (unless hepatic dysfunction is caused by cGVHD).
  • Patients much have a negative PPD skin test and a negative Quantiferon assay.
  • Must possess the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
  • Any serious medical condition (including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), laboratory abnormality, or psychiatric illness/ social situation that would prevent the subject from signing the informed consent form or limit compliance with study requirements.
  • Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
  • Use of any other experimental drug or therapy within 28 days of starting treatment with abatacept.
  • Use of biologic antibody therapy for cGVHD with rituximab, alemtuzumab, or ATG within 6 months of starting treatment with abatacept.
  • Use of TNF alpha inhibitors within four weeks prior to study entry.
  • Ongoing prednisone requirement >1 mg/kg/day (or equivalent)
  • New immunosuppressive medication or ECP within 28 days of starting treatment with abatacept.
  • Donor lymphocyte infusion within 100 days prior to enrollment.
  • Active malignant disease relapse or other active malignancy with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
  • Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Known seropositive for or positive viral load for HIV or positive viral loads for infectious hepatitis, type B (HBV) or C (HCV).
  • Uncontrolled intercurrent active infection. Controlled infection on long term suppressive or maintenance therapy is permissible.
  • Use of live vaccines within four weeks of starting abatacept.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01954979

Contacts
Contact: Jacalyn Rosenblatt, MD (617) 667-9920 ext 2 jrosenb1@bidmc.harvard.edu
Contact: Emma Breault (617) 667-5984 ebreault@bidmc.harvard.edu

Locations
United States, Massachusetts
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Jacalyn Rosenblatt, MD    617-632-4218    jrosenb1@bidmc.harvard.edu   
Principal Investigator: Jacalyn Rosenblatt, MD         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Robert Soiffer    617-632-4711      
Principal Investigator: Robert Soiffer, MD         
Sponsors and Collaborators
Beth Israel Deaconess Medical Center
Bristol-Myers Squibb
Investigators
Principal Investigator: Jacalyn Rosenblatt, MD Beth Israel Deaconess Medical Center
  More Information

No publications provided

Responsible Party: Jacalyn Rosenblatt, MD, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT01954979     History of Changes
Other Study ID Numbers: 13-358
Study First Received: September 27, 2013
Last Updated: July 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:
Graft versus Host Disease
ABATACEPT

Additional relevant MeSH terms:
Graft vs Host Disease
Immune System Diseases
Abatacept
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 15, 2014