Study of Imatinib and Peginterferon α-2b in Gastrointestinal Stromal Tumor (GIST) Patients - Full Text View

Sponsor:	University of Utah
Collaborator:	Schering-Plough
Information provided by:	University of Utah
ClinicalTrials.gov Identifier:	NCT00585221

Purpose

Imatinib (IM) has dramatically improved survival of gastrointestinal stromal tumors (GIST). However, most patients become resistant to IM in less than two years. This clinical trial combines targeted therapy (IM) with immunotherapy (peginterferon α-2b). Hypothesis: Apoptosis/necrosis of imatinib-sensitive GIST releases GIST-specific antigens in vivo while Peginterferon α-2b fulfills the role of cytokine signal (danger signal), this combination can induce effective innate and adaptive anti-GIST immunity, which can eradicate imatinib-resistant clones and GIST stem cells via recognition of common antigens shared with imatinib-sensitive GIST, leading to improved response rate and remission duration.

Condition	Intervention	Phase
Gastrointestinal Stromal Tumors, Cancer, Solid Tumors	Drug: Peginterferon-alpha 2b (PegIFNa2b); imatinib	Phase II

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 II Study Combining Targeted Therapy With Immunotherapy Using Imatinib Plus Peginterferon α-2b in Gastrointestinal Stromal Tumor (GIST) Patients

Resource links provided by NLM:

Genetics Home Reference related topics: gastrointestinal stromal tumor

MedlinePlus related topics: Cancer

Drug Information available for: Imatinib Peginterferon Alfa-2b Imatinib mesylate

U.S. FDA Resources

Further study details as provided by University of Utah:

Primary Outcome Measures:

Response rate is measured by PET-CT scan (a decrease in SUV by 25%), Response Evaluation Criteria in Solid Tumors (RECIST), and Choi criteria (10% decrease in tumor size or a 15% decrease in tumor density on contrast-enhanced CT scan). [ Time Frame: May 2007-July 2009 ] [ Designated as safety issue: No ]
8 pts were enrolled. Response rate is 100% by PET-CT (7/7, Pt #2 GIST is not FDG avid), 100% by Choi (8/8), and 100% (6/6, Pt #1 and #2 are Not Assessable) by RECIST.
Time to progression (TTP). [ Time Frame: two years ] [ Designated as safety issue: No ]
Eight patients were enrolled and tolerated combination treatment well, continuing remission (6 patients), and TTP (one patient) are superior to historical controls of IM monotherapy.

Secondary Outcome Measures:

Flowcytometry analysis of peripheral blood monocytes (PBMC) [ Time Frame: May 2007-July 2009 ] [ Designated as safety issue: No ]
PBMC showed significant induction of IFN-γ-secreting CD8, CD4, and NK cells indicative of induction of innate and adaptive cellular immunity.

Enrollment:	8
Study Start Date:	July 2007
Study Completion Date:	July 2009
Primary Completion Date:	July 2009 (Final data collection date for primary outcome measure)

Intervention Details:

Treatment include PegIFNa2b high dose (3 mcg/kg/wk) X 4 doses and low dose (1.5 mcg/kg/wk) X 18 doses, followed by surgical evaluation to render pt disease free if possible. Continue imatinib until progression.

Other Names:

Trade name: Peg-Intron
Trade name: gleevec

Detailed Description:

Imatinib (IM), a selective tyrosine kinase inhibitor, has dramatically improved survival of gastrointestinal stromal tumors (GIST). However, median time to tumor progression (TTP) is <2 years due to IM resistance. We sought to enhance and harness endogenous anti-tumor immunity to overcome IM-resistance and tumor stem cell self-renewal by a new strategy combining targeted therapy (IM) with immunotherapy (peginterferon α-2b [PegIFNa2b]). Please refer to above section for hypothesis. Eight patients were enrolled and tolerated combination treatment well, the response rate, continuing remission (6 patients), and TTP (one patient) are superior to historical controls of IM monotherapy. One patient developed IM resistance, when PegIFNa2b was re-initiated, a 2nd remission was induced─recall of the endogenous anti-tumor immunity overcoming IM resistance, an unprecedented finding. Combination treatment induced significant IFN-γ-secreting CD8+ (24-48% total CD8+ cells), IFN-γ-secreting CD4+ (11-12% total CD4+ cells), and IFN-γ-secreting natural killer (NK) (6-7% total NK cells) on all five patients studied signifies robust activation of innate and adaptive cellular immunity. A treated GIST showed necrosis and heavy infiltration of IFN-γ+CD8+ & IFN-γ+CD4+ T cells, and IFN-γ+CD56+ NK cells overcoming tumor-induced anergy leading to pathological complete remission. Both clinical and laboratory data indicate effective anti-GIST immunity and support our hypothesis. This trial is closed in preparation for a larger future trial.

Eligibility

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

Criteria

Patients must be >18 years old.
Patients must have histologic evidence of GIST.
If genotyping was not done, a paraffin block or 7 unstained slides or biopsy unstained slides is required for genotyping within one week of enrollment.
Stage I, II, and III patients are eligible if the primary tumor is 6 cm or larger. All stage IV metastatic or recurrent GIST patients who are imatinib-naïve are eligible. For stage IV patients who had initial good response to imatinib and stopped imatinib for 10 months or longer. GIST patients who received imatinib as "adjuvant" treatment in the past, later developed a recurrence are eligible only if the DFS is > 6 months after completion of adjuvant imatinib.
Patients must have a Zubrod Performance Status of 0-1 or Karnofsky PS >70%.
Patients must have a life expectancy of more than twelve months.
Patients must have negative serology tests for HIV. Hepatitis B, Hepatitis C, and ANA titer have to be within 2 times of upper limit of normal within 28 days of enrollment. Patients must have no clinical rheumatoid arthritis (RA). RA criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints.

Criteria 1 through 4 must have been present for at least 6 weeks. RA is defined by the presence of 4 or more criteria. Patients must have normal thyroid function tests (1.5 times of upper and lower normal limit) including TSH, and T4 within 4 weeks of enrollment.
Patients must have adequate liver function as evidenced by the following: total bilirubin, and AST < 2 times of institutional upper limit of normal assessed within 2 weeks of enrollment. If patient has extensive liver metastasis which is the main cause of abnormal liver function, this requirement does not apply. PI can use his or her clinical judgment.
Patients must have serum creatinine <2 mg/dl within 2 weeks of enrollment.
Patients must have WBC > 3x109 /L, absolute neutrophil count (ANC) > 1.5 x 109 /L platelet count > 125 x 109 /L, hemoglobin > 11 within 2 weeks of enrollment.
Patients must have PT, PTT and INR < institutional upper limit of normal within 4 weeks of enrollment.
Patients must have no history of malignancy other than atypical melanocytic hyperplasia, basal or squamous skin cancer or any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, Clark I melanoma in situ or have been continuously disease free for 5 years prior to enrollment.
Patients may not have received chemotherapy within 30 days prior to enrollment.
Patients must have a negative serum pregnancy test if female of childbearing potential.
Patients must agree to use an accepted and effective method of contraception while on PEG-intron and for a period of 18 months after completing or discontinuing PEG-intron.
Patients may not have autoimmune disorder, or immunodeficiency.
Patients may not have undergone splenectomy or gastrectomy for any reason. Total gastrectomy usually results in poor tolerance to the recommended dose of Imatinib.
Patients cannot require antihistamines, non-steroidal anti-inflammatory drugs, or corticosteroids.
Patients may not have active ischemic heart disease or cerebrovascular disease, congestive heart failure (NYHA class III or IV), or angina requiring ongoing medications. EKG may not show acute ischemic changes or acute heart rhythm changes.
Patients cannot show a history of CNS demyelination, inflammatory disease or hereditary or acquired peripheral neuropathy greater than Grade 2.
Patients cannot have an ongoing psychiatric disorder, surgical condition, or medical condition requiring a treatment regimen that may interfere with the completion of this trial or the evaluation of safety and efficacy of the study compound. For any questions, please contact the study PI.
Patients cannot be taking coumadin, lovenox or heparin for metallic heart valve or hypercoagulability.
Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines.
In the opinion of the Principal Investigator the patient is eligible and a good candidate for this study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00585221

Locations

United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

University of Utah

Schering-Plough

Investigators

Principal Investigator:

Lei Chen, MD

University of Utah

More Information

No publications provided

Responsible Party:	University of Utah, Univerisity of Utah
ClinicalTrials.gov Identifier:	NCT00585221 History of Changes
Other Study ID Numbers:	IRB_00022172
Study First Received:	December 21, 2007
Last Updated:	July 29, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by University of Utah:

Gastrointestinal stromal tumors
Imatinib
Peginterferon α-2b
Immunotherapy
Targeted therapy

Additional relevant MeSH terms:

Gastrointestinal Stromal Tumors
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Imatinib
Peginterferon alfa-2b
Interferon-alpha

Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on February 12, 2012