Pentostatin for High Risk and Refractory Chronic Graft Versus Host Disease in Children

Graft vs Host Disease Clinical Trial

Official title:

A Phase II Study of Pentostatin For the Treatment of High Risk or Refractory Chronic GVHD in Children

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00144430
• Other study ID #: GVH 0313
• Status: Completed
• Phase: Phase 2
• First received: August 31, 2005
• Last updated: February 2, 2009
• Start date: January 2004
• Est. completion date: August 2008

Study information

• Verified date: February 2009
• Source: Ann & Robert H Lurie Children's Hospital of Chicago
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a multicenter trial through the Pediatric Blood and Marrow Transplant Consortium.

The Primary hypothesis of this study is that because of its effect as a potent immunosuppressive agent targeting lymphocytes, pentostatin will show a sustained response in pediatric subjects with severe chronic GVHD. Secondary hypotheses include that the infection and toxicity rate of pentostatin in this setting will be acceptable given its lack of severe myelosuppression, and subjects with refractory chronic GVHD will have significant QOL impairment and symptomatology. These may change as subjects are being treated for their chronic GVHD with pentostatin.

Description:

To participate in this study, subjects must have diagnosed chronic Graft versus Host Disease that is refractory to therapy or that is considered high risk (i.e. low platelet count, progressive onset and greater than 50% of body surface area affected). Subjects must have not failed more than 2 immunosuppressive regimens in order to be considered for this trial. Eligible subjects will receive intravenous pentostatin every 2 weeks for 24 weeks. If the subject has had a complete response, the therapy will end at 24 weeks. If the subject has had a partial or mixed response or stable disease, they will continue on study receiving pentostatin for 52 weeks.

Other known NCT identifiers

• NCT00228826

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: August 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Month to 21 Years

Eligibility

Inclusion criteria:

• Allogeneic BMT or SCT recipients. Includes cord blood and peripheral blood.

• Age 0-21 years.

FOR REFRACTORY GROUP:

• Diagnosis of chronic GVHD, confirmed by biopsy of any organ after SCT. Given the variability among centers, biopsy needs to say, at the very least, "consistent with GVHD." If there is a medical contra-indication (such as severe sclerosis with poor wound healing) or the need for an open procedure to obtain a fascial biopsy then a photograph documenting the skin and abnormal ROM studies may be submitted instead. If current GVHD represents the same episode which was previously biopsied, then a new biopsy is not necessary. If the previous biopsy was for an episode that went into remission and this is a new episode of GVHD, then a new biopsy is necessary.

To be eligible for this portion of the study, a patient's chronic GVHD can be extensive or limited, as defined below:

• All subjects with extensive chronic GVHD are eligible. These subjects must meet the following criteria:

• Generalized skin involvement (>50% BSA)

• OR Localized skin involvement and/or liver dysfunction plus at least one of the following:

• Liver histology showing chronic aggressive hepatitis, bridging necrosis, cirrhosis, or ductopenia.

• Eye involvement (Schirmer's test with < 5 mm wetting)

• Involvement of minor salivary glands or oral mucosa on lip biopsy

• Involvement of any other target organs

• OR Involvement of at least 2 target organs.(Target organs are listed below under "Examples of characteristic manifestations)

• Subjects with limited chronic GVHD (defined as those with skin involvement in less than 50% BSA or isolated organ involvement 51 are also eligible. Examples of these subjects would be those with limited sclerodermatous or fascial skin disease or oral disease that is unresponsive to therapy and may be debilitating to the patient. Subjects with isolated refractory liver chronic GVHD may go on study provided they have liver histology as above.

Examples of characteristic manifestations include:

• skin changes - rash, lichenoid changes, sclerodermatous changes, hypopigmentation, hyperpigmentation, loss of appendages (hair follicles, sweat glands), alopecia

• oral changes - erythema, lichenoid changes, ulceration

• hepatic involvement - obstructive jaundice, chronic hepatitis, cirrhosis

• GI involvement - nausea, vomiting, weight loss, esophageal dysmotility, malabsorption, chronic diarrhea, abdominal cramps

• sicca syndrome - dry eyes and mouth (decreased tearing, keratoconjunctivitis, oral mucosal erythema and ulcerations)

• other inflammatory conditions - myositis, arthritis, polyserositis

To be eligible for this portion of the study subjects must have refractory disease defined below:

• Development of new sites of disease while being treated for chronic GVHD* (These criteria can be met at any time post-transplant after treatment for chronic GVHD has begun. This includes subjects who develop new sites of disease while on steroid therapy, tapering steroid therapy, or other therapy. The only necessary elements are TREATMENT of chronic GVHD and NEW area of disease. -OR-

• Progression of an initially affected site of chronic GVHD while being treated for chronic GVHD, the chronic GVHD worsens. This type of patient has worsening of any initially affected area at any time. This includes subjects that are judged to be steroid-dependent, and once a taper of steroids is initiated, they flare in the same organ. -OR-

• Failure to improve despite at least 1 month of standard therapy (These subjects have shown no response (not improved but not worse) to cGVHD therapy. These therapies include, but are not limited to:

• Prednisone at an average of 0.5 mg/kg/day or equivalent steroid.

• Another immunosuppressive regimen (e.g.. FK506/MMF or photopheresis).

FOR HIGH-RISK GROUP:

• The vast majority of these subjects will be identified at initial diagnosis of chronic GVHD and will be subjects progressing from acute to chronic. These subjects are likely to be on steroids for acute GVHD and have skin changes that are rapidly shifting from simple erythema to a lichenoid/pebbly appearance consistent with chronic GVHD. For inclusion into this arm, the following are required:

• Extensive skin involvement (>50%BSA) with either lichenoid or sclerodermatous changes.

• Either one or both of the following high-risk features:

• Thrombocytopenia (PLT<100,000)

• Progressive onset ( i.e. Changes suggestive of progression from acute to chronic). This includes, but is not limited to, skin becoming increasingly scaly, pebbly, raised, and lymphedematous. It is not unusual to see this transition even before day 100, especially in non-myeloablative SCT and DLI. If there are any questions regarding these changes and whether they qualify, call the PI, Dr. David Jacobsohn, 773-880-3694.

• A biopsy after SCT showing acute or chronic GVHD. A biopsy showing acute GVHD is acceptable if the clinical picture is progressing to chronic GVHD.

• Patient is on prednisone =2 mg/kg/day (or equivalent dose if on another steroid) and has received more than 7 days of therapy.

Exclusion Criteria:

• More than two previous regimens to treat chronic GVHD. A regimen for the purpose of this study is defined as an adequate trial of an immunosuppressive or immunosuppressive combination (patient was given drug or drugs for 3 months unless there was clear progression during regimen).

• Calculated Cr. Clearance<30 ml/min/1.73m2

• Active infection not responding to oral or IV antibiotics.

• Subjects and families unwilling to firmly commit to return for follow-up doses and appointments.

• Use of any investigational agent in the past 30 days (this does not include the use of licensed agents for indications not listed in the package insert).

• Pregnancy or nursing mother; Females of child-bearing potential and sexually active males should use effective contraception while on study.

• Active veno-occlusive disease of the liver.

• Bronchiolitis obliterans (defined for the purpose of this study by respiratory symptoms such as shortness of breath or cough and FEV1<50%).

• Karnofsky performance score less than 40 (or Lansky performance less than 40 in subjects under 16 years of age).

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Graft vs Host Disease

Intervention

Drug:
• Pentostatin
The drug, Pentostatin, is given every 2 weeks. This drug will be given by intravenous (IV) infusion.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta	Atlanta	Georgia
United States	John's Hopkins	Baltimore	Maryland
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Rainbow Babies and Children's	Cleveland	Ohio
United States	Columbus Children's Hospital	Columbus	Ohio
United States	Victor Aquino, MD	Dallas	Texas
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	DeVos Children's Hospital	Grand Rapids	Michigan
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	Nemour's Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Loma Linda University Medical Center	Loma Linda	California
United States	University of Miami	Miami	Florida
United States	LSUHSC	New Orleans	Louisiana
United States	Columbia Presbyterian Medical Center	New York	New York
United States	Pediatric Medical Center for Northern California	Oakland	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Utah	Salt Lake City	Utah
United States	Southwest Texas Methodist Hospital	San Antonio	Texas
United States	St. Louis University	St. Louis	Missouri
United States	All Children's Health System	St. Petersburg	Florida
United States	New York Medical College	Valhalla	New York

Sponsors (2)

Lead Sponsor	Collaborator
Ann & Robert H Lurie Children's Hospital of Chicago	Astex Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To estimate the response rate (CR and PR) of pentostatin when used to treat refractory-chronic GVHD in children.		To end of study	No
Secondary	To gather initial efficacy and safety data in high-risk untreated chronic GVHD in children.		To end of study	Yes
Secondary	To evaluate toxicities of pentostatin when used to treat chronic GVHD in children.		To end of study	Yes
Secondary	To evaluate quality of life (QOL) and symptoms at diagnosis and after therapy with pentostatin in pediatric patients with refractory chronic GVHD.		To end of study	No