ESHAP-Imatinib for Refractory/Relapsed Non-Hodgkin's Lymphoma

Lymphoma, Non-Hodgkin Clinical Trial

Official title:

Open-labeled, Multicenter, Phase I/II Study of Imatinib Combined With ESHAP as Salvage Therapy in Relapsed/Refractory Non-Hodgkin's Lymphoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02431403
• Other study ID #: IMACEL
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: April 21, 2015
• Last updated: May 3, 2015
• Start date: February 2015

Study information

• Verified date: May 2015
• Source: Pusan National University Hospital
• Contact: Hyunhee Jung
• Phone: +82-51-240-7053
• Email: jung77[@]pnuh.co.kr
• Is FDA regulated: No
• Health authority: Korea: Ministry of Food and Drug Safety
• Study type: Interventional

Clinical Trial Summary

Open-labeled, multicenter, phase I/II study of imatinib combined with ESHAP as salvage therapy in relapsed/refractory non-Hodgkin's lymphoma

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 94
• Est. primary completion date: February 2020
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years and older

Eligibility

Inclusion Criteria:

1. Histologically diagnosed non-Hodgkin's lymphoma, refractory or relapsed after 1st line treatment.

2. Paraffin block of the lesions available for immunohistochemical analysis

3. Candidate for ESHAP salvage therapy

4. Evidence of at least one lesion with a diameter of 1.5 cm

5. Age of over 20 years

6. Eastern cooperative oncology group performance status (ECOG) less than or equal to 2.

7. Adequate kidney function with serum creatinine< 2.5 mg/dL, creatinine clearance = 50 mL/min

8. Adequate liver function with aspartate transaminase (AST)/alanine aminotransferase (ALT) lower than or equal to 3 times the normal upper limit; Total bilirubin lower than or equal to 1.5 times the upper limit ;alkaline phosphatase lower than or equal to 5 times the normal upper limit.

9. Adequate bone marrow function with absolute neutrophil count = 1,000/uL; platelets = 75,000/uL; hemoglobin = 9.0 g/dL

10. Patients who gave voluntarily informed consent before performing any test test that is not part of routine care of patients

Exclusion Criteria:

1. Patients with history of exposure to imatinib or other Bcr-Abl tyrosine-kinase inhibitors

2. Known or suspected hypersensitivity to imatinib

3. Potential use or usage alteration of CYP3A4 inducers or inhibitors from prior to 21 days of to the test regimen until the initiation of round 2 ESHAP. Exceptions are itraconazole and fluconazole for treatment or prevention of fungal infection, hydrocortisone and dexamethasone for treatment of nausea/vomiting/fluid retention, and methylprednisolone as a part of the ESHAP regimen.

4. Known involvement of the central nervous system (CNS) by lymphoma.

5. Pregnant or breast-feeding. Females of childbearing potential who do not agree to undergo pregnancy tests or repeated use effective birth control while included in the clinical trial.

6. Serious or uncontrolled medical condition, such as presence of abnormal or clinically significant cardiac disease, such as acute myocardial infarction or unstable angina within 6 months prior to initiation of treatment with ESHAP-imatinib, serious neurological or psychological conditions such as dementia or epilepsy, or uncontrolled active infection.

7. Prior history of malignancy other than to non-Hodgkin's lymphoma (except basal or squamous cell skin and in situ carcinoma of the cervix) unless the patient free of disease beyond 5 years are.

8. HIV positive and in treatment.

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

• Lymphoma
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• ESHAP-Imatinib
After selection of the maximum-tolerated dose of the combination ESHAP with imatinib a phase 2 of the study will be performed in order to evaluate the ORR of ESHAP-imatinib.

Locations

Country	Name	City	State
Korea, Republic of	Dong-A University Hospital	Busan
Korea, Republic of	Inje University Busan Paik Hospital	Busan
Korea, Republic of	Kosin University Gospel Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Ulsan University Hospital	Ulsan

Sponsors (1)

Lead Sponsor	Collaborator
Pusan National University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (29)

Aloyz R, Grzywacz K, Xu ZY, Loignon M, Alaoui-Jamali MA, Panasci L. Imatinib sensitizes CLL lymphocytes to chlorambucil. Leukemia. 2004 Mar;18(3):409-14. — View Citation

Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008 May 15;22(10):1276-312. doi: 10.1101/gad.1653708. Review. — View Citation

Aozasa K, Zaki MA. Epidemiology and pathogenesis of nasal NK/T-cell lymphoma: a mini-review. ScientificWorldJournal. 2011 Feb 14;11:422-8. doi: 10.1100/tsw.2011.41. Review. — View Citation

Arefi M, García JL, Briz MM, de Arriba F, Rodríguez JN, Martín-Núñez G, Martínez J, López J, Suárez JG, Moreno MJ, Merino MA, Gutiérrez NC, Hernández-Rivas JM. Response to imatinib mesylate in patients with hypereosinophilic syndrome. Int J Hematol. 2012 Sep;96(3):320-6. doi: 10.1007/s12185-012-1141-7. Epub 2012 Jul 18. — View Citation

Brauns TC, Schultewolter T, Dissemond J, Maschke J, Goos M. C-KIT expression in primary cutaneous T-cell lymphomas. J Cutan Pathol. 2004 Oct;31(9):577-82. — View Citation

Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002 Jul;1(7):493-502. Review. — View Citation

Chen YP, Chang KC, Su WC, Chen TY. The expression and prognostic significance of platelet-derived growth factor receptor alpha in mature T- and natural killer-cell lymphomas. Ann Hematol. 2008 Dec;87(12):985-90. doi: 10.1007/s00277-008-0539-z. Epub 2008 Jul 17. — View Citation

Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. Epub 2007 Jan 22. — View Citation

Choe YS, Kim JG, Sohn SK, Kim DH, Baek JH, Lee KB, Do YR, Kwon KY, Song HS, Lee MH, Park TI. c-kit Expression and mutations in peripheral T cell lymphomas, except for extra-nodal NK/T cell lymphomas. Leuk Lymphoma. 2006 Feb;47(2):267-70. — View Citation

Edling CE, Hallberg B. c-Kit--a hematopoietic cell essential receptor tyrosine kinase. Int J Biochem Cell Biol. 2007;39(11):1995-8. Epub 2007 Jan 20. Review. — View Citation

Escribano L, Ocqueteau M, Almeida J, Orfao A, San Miguel JF. Expression of the c-kit (CD117) molecule in normal and malignant hematopoiesis. Leuk Lymphoma. 1998 Aug;30(5-6):459-66. Review. — View Citation

Giantin M, Aresu L, Aricò A, Gelain ME, Riondato F, Comazzi S, Dacasto M. Evaluation of tyrosine-kinase receptor c-kit mutations, mRNA and protein expression in canine lymphoma: might c-kit represent a therapeutic target? Vet Immunol Immunopathol. 2013 Aug 15;154(3-4):153-9. doi: 10.1016/j.vetimm.2013.05.014. Epub 2013 May 30. — View Citation

Gutierrez M, Chabner BA, Pearson D, Steinberg SM, Jaffe ES, Cheson BD, Fojo A, Wilson WH. Role of a doxorubicin-containing regimen in relapsed and resistant lymphomas: an 8-year follow-up study of EPOCH. J Clin Oncol. 2000 Nov 1;18(21):3633-42. — View Citation

Hebb J, Assouline S, Rousseau C, Desjardins P, Caplan S, Egorin MJ, Amrein L, Aloyz R, Panasci L. A phase I study of imatinib mesylate in combination with chlorambucil in previously treated chronic lymphocytic leukemia patients. Cancer Chemother Pharmacol. 2011 Sep;68(3):643-51. doi: 10.1007/s00280-010-1530-7. Epub 2010 Dec 1. — View Citation

Hollmann CA, Tzankov A, Martínez-Marignac VL, Baker K, Grygorczyk C, Grygorczyk R, Foulkes W, Nadeau J, Dirnhofer S, Aloyz R. Therapeutic implications of Src independent calcium mobilization in diffuse large B-cell lymphoma. Leuk Res. 2010 May;34(5):585-93. doi: 10.1016/j.leukres.2009.08.030. Epub 2009 Sep 16. — View Citation

Hongyo T, Li T, Syaifudin M, Baskar R, Ikeda H, Kanakura Y, Aozasa K, Nomura T. Specific c-kit mutations in sinonasal natural killer/T-cell lymphoma in China and Japan. Cancer Res. 2000 May 1;60(9):2345-7. — View Citation

Huang Y, de Reyniès A, de Leval L, Ghazi B, Martin-Garcia N, Travert M, Bosq J, Brière J, Petit B, Thomas E, Coppo P, Marafioti T, Emile JF, Delfau-Larue MH, Schmitt C, Gaulard P. Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type. Blood. 2010 Feb 11;115(6):1226-37. doi: 10.1182/blood-2009-05-221275. Epub 2009 Nov 30. — View Citation

Ikeda H, Kanakura Y, Tamaki T, Kuriu A, Kitayama H, Ishikawa J, Kanayama Y, Yonezawa T, Tarui S, Griffin JD. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. Blood. 1991 Dec 1;78(11):2962-8. — View Citation

Melnyk A, Rodriguez A, Pugh WC, Cabannillas F. Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin's lymphoma. Blood. 1997 Jun 15;89(12):4514-20. — View Citation

Passam FH, Alexandrakis MG, Kafousi M, Fotinou M, Darivianaki K, Tsirakis G, Roussou PA, Stathopoulos EN, Siafakas NM. Histological expression of angiogenic factors: VEGF, PDGFRalpha, and HIF-1alpha in Hodgkin lymphoma. Pathol Res Pract. 2009;205(1):11-20. doi: 10.1016/j.prp.2008.07.007. Epub 2008 Oct 23. — View Citation

Piccaluga PP, Agostinelli C, Califano A, Rossi M, Basso K, Zupo S, Went P, Klein U, Zinzani PL, Baccarani M, Dalla Favera R, Pileri SA. Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. J Clin Invest. 2007 Mar;117(3):823-34. Epub 2007 Feb 15. — View Citation

Pinto A, Gloghini A, Gattei V, Aldinucci D, Zagonel V, Carbone A. Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas. Blood. 1994 Feb 1;83(3):785-92. — View Citation

Renné C, Willenbrock K, Küppers R, Hansmann ML, Bräuninger A. Autocrine- and paracrine-activated receptor tyrosine kinases in classic Hodgkin lymphoma. Blood. 2005 May 15;105(10):4051-9. Epub 2005 Jan 27. — View Citation

Rodriguez MA, Cabanillas FC, Hagemeister FB, McLaughlin P, Romaguera JE, Swan F, Velasquez W. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphomas. Ann Oncol. 1995 Jul;6(6):609-11. — View Citation

Ruan J, Luo M, Wang C, Fan L, Yang SN, Cardenas M, Geng H, Leonard JP, Melnick A, Cerchietti L, Hajjar KA. Imatinib disrupts lymphoma angiogenesis by targeting vascular pericytes. Blood. 2013 Jun 27;121(26):5192-202. doi: 10.1182/blood-2013-03-490763. Epub 2013 Apr 30. — View Citation

Shimizu H, Popova M, Fleury F, Kobayashi M, Hayashi N, Sakane I, Kurumizaka H, Venkitaraman AR, Takahashi M, Yamamoto K. c-ABL tyrosine kinase stabilizes RAD51 chromatin association. Biochem Biophys Res Commun. 2009 May 1;382(2):286-91. doi: 10.1016/j.bbrc.2009.03.020. Epub 2009 Mar 11. — View Citation

Velasquez WS, Cabanillas F, Salvador P, McLaughlin P, Fridrik M, Tucker S, Jagannath S, Hagemeister FB, Redman JR, Swan F, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988 Jan;71(1):117-22. — View Citation

Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, Romaguera J, Rubenstein E, Cabanillas F. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994 Jun;12(6):1169-76. — View Citation

Zhu Y, Qian SX. Clinical efficacy and safety of imatinib in the management of Ph(+) chronic myeloid or acute lymphoblastic leukemia in Chinese patients. Onco Targets Ther. 2014 Mar 6;7:395-404. doi: 10.2147/OTT.S38846. eCollection 2014. Review. — View Citation

* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Adverse Events	Adverse events are recorded and analyzed from the time of enrollment to last day of ESHAP-imatinib treatment	Up to 33 weeks	Yes
Secondary	Phase I/II Overall Response Rate (ORR)		Week 4, Week 10, Week 16	No
Secondary	Phase II Event-Free Survival		Up to 3 years	No
Secondary	Phase II Overall Survival		Up to 3 years	No