Pentostatin in Treating Patients With Refractory Chronic Graft-Versus-Host Disease

A Phase II Trial Of Intravenous Pentostatin For The Treatment Of Patients With Refractory Chronic Graft-Versus-Host Disease

RATIONALE: Pentostatin may be effective in treating chronic graft-versus-host disease by stopping the immune system from rejecting donor stem cells or donor white blood cells.

PURPOSE: This phase II trial is studying how well pentostatin works in treating patients with chronic graft-versus-host disease that is refractory (not responsive) to treatment with steroids.

Study Overview

• Status: Completed
• Conditions: Graft Versus Host Disease
• Intervention / Treatment: Drug: pentostatin

Detailed Description

OBJECTIVES:

Primary

• Determine the response rate in patients with refractory chronic graft-versus-host disease treated with pentostatin.

Secondary

• Determine the time to next immunosuppressive agent (i.e., the time to progression from best response) in patients treated with this drug.
• Determine the toxicity of this drug in these patients.
• Determine the infection rate in patients treated with this drug.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the changes in lymphocyte populations in patients treated with this drug.
• Determine the survival of patients treated with this drug.

OUTLINE: This is a multicenter study.

Patients receive pentostatin IV over 20-30 minutes on day 1. Treatment repeats every 14 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients who achieve a complete response after 6 courses receive 4 additional courses. Patients who achieve a partial response, minor response, or stable disease after 6 courses may receive up to 6 additional courses.

Patients are followed every 4 weeks for 1 year, every 3 months for 2 years, and then annually for 5 years.

PROJECTED ACCRUAL: Approximately 37 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612-7243
      • University of Illinois Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Greenebaum Cancer Center at University of Maryland Medical Center
    • Elkton, Maryland, United States, 21921
      • Union Hospital Cancer Program at Union Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
  • New York
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19104-4283
      • Abramson Cancer Center of the University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224-1791
      • Western Pennsylvania Cancer Institute at Western Pennsylvania Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298-0037
      • Virginia Commonwealth University Massey Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

1. Histologic documentation of chronic GvHD following allogeneic HCT or donor lymphocyte infusion.
2. Patients may have progressive, quiescent, or de novo onset chronic GvHD.

3. Patients with extensive stage chronic GvHD requiring systemic immunosuppressive therapy are eligible. Patients with limited stage disease are excluded. Extensive stage is defined according to Seattle criteria (9) as either:

   • Generalized skin involvement or

   • Limited skin involvement or hepatic involvement with any one of the following:

     • Liver histology showing chronic progressive hepatitis, bridging necrosis or cirrhosis
     • Eye involvement (Schirmer's test with < 5 mm wetting)
     • Involvement of minor salivary glands or oral mucosa
     • Involvement of any other organ

4. Patients must have failed treatment with, or experience progression after, prior corticosteroids for extensive stage chronic GvHD, as defined below.

   4.1 Patients will be considered to have failed corticosteroids if they have any one of the following criteria:

   • Progressive disease or less than a minor response in any organ system despite 2 weeks on corticosteroid treatment at least 1 mg/kg methylprednisolone or equivalent.
   • Failure to achieve at least a minor response after at least 4 weeks of treatment with a dose of ≥ 0.5 mg/kg methylprednisolone or equivalent.
   • Achievement of less than a partial response at 8 weeks of corticosteroid treatment despite use of a dose ≥ 0.5 mg/kg methylprednisolone or equivalent.
   • Requirement of ≥ 0.5 mg/kg methylprednisolone or equivalent to maintain a partial response or better at 12 weeks of corticosteroid treatment.
   • Requirement of > 10 mg/kg methylprednisolone or equivalent to maintain a partial response or better at 18 weeks of corticosteroid treatment.

   4.2 Patients with progression of extensive stage chronic GvHD after a prior history of treatment with at least 18 weeks of corticosteroids, now requiring the reintroduction of corticosteroids (> 10 mg/day methylprednisolone or equivalent) or an additional agent (including photopheresis, PUVA) for treatment.

5. Patients with established chronic GvHD not improving or progressing on other immunosuppressive agents are also eligible if steroid refractoriness has been established previously.
6. Age ≥ 18 years
7. Performance Status 0-3
8. Patients on mechanical ventilation are excluded.
9. No active infection. Patients with active infection requiring antibiotic therapy are not eligible until infection is controlled.
10. No HIV infection. Patients with HIV infection are excluded because of safety concerns in this patient population.
11. Non-pregnant and non-nursing. Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial (although it is unlikely that successful pregnancy will occur in patients with chronic GvHD). Appropriate methods of birth control include oral contraceptives, implantable hormonal contraceptives (Norplant®), or double barrier method (diaphragm plus condom).

12. Required Initial Laboratory Values:

    • Calc. Creatinine Clearance ≥ 30 mL/min/1.73 m^2
    • ANC > 1000/μL
    • Platelets > 50,000/μL without transfusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pentostatin; treatment of pts with refractory graft vs host disease	Drug: pentostatin; 4 mg/sq m IV infusion over 20-30 min q 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response Rate	Percentage of participants who had a complete or partial response defined by the Hopkins scoring system. A complete response is defined as the disappearance of signs and symptoms of chronic GVHD in all involved systems that is sustained for at lest 4 weeks. A partial response is an improvement by 2 or more points in at least one system score, which is sustained for at least 4 weeks, with no signs of worsening in others.	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grade 3 or Higher Non-hematologic Adverse Events	Number of participants experiencing a grade 3, 4 or 5 clinically significant non-hematologic adverse events, at least possibly related to treatment.	Duration of treatment (up to 5 years)
Overall Survival At 1 Year	Percentage of patients who were alive at 1 year.	1 year
Overall Survival At 2 Years	Percentage of patients who were alive at 2 years.	2 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics Association Between Exposure and Response At 3 Months	The individual PK parameters will be derived by using a noncompartmental analysis of the plasma-concentration-time data	3 months

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Sherif S. Farag, MD, PhD, Ohio State University

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2003
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: December 10, 2003
• First Submitted That Met QC Criteria: December 10, 2003
• First Posted (Estimate): December 11, 2003

Study Record Updates

• Last Update Posted (Actual): November 3, 2021
• Last Update Submitted That Met QC Criteria: October 5, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Graft vs Host Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Adenosine Deaminase Inhibitors; Pentostatin
• Other Study ID Numbers: CALGB-100101; U10CA031946 (U.S. NIH Grant/Contract); CDR0000341678 (Registry Identifier: NCI Physician Data Query)