Combination of Gemcitabine and Imatinib Mesylate in Pemetrexed-pretreated Patients With Pleural Mesothelioma

NCT02303899 | Completed Phase 2

• 1 other identifier: ONC-2014-002
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

Brief Summary

This is a phase II, monocentric study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with MPM expressing PDGFR-beta and/or C-kit by Immunohistochemistry (IHC). Treatment will be done until disease progression, or patient refusal or withdrawal of patient consent, or unacceptable toxicity

Conditions

Mesothelioma, Malignant

Outcome Measures

Primary Outcomes (1)

• anti-tumor activity of Imatinib mesylate in combination with Gemcitabine

  assess the anti-tumor activity of Imatinib mesylate in combination with Gemcitabine, in terms of 3-months progression-free survival (PFS) rate

  12 weeks

Secondary Outcomes (4)

• anti-tumor activity of Imatinib mesylate in combination with Gemcitabine in terms of Response Evaluation Criteria In Solid Tumors (RECIST) criteria

  16 weeks

• anti-tumor activity of Imatinib mesylate in combination with Gemcitabine in terms of overall survival (OS).

  30 months

• safety profile of the combination according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3

  16 weeks

• molecular profile of patients

  baseline

Study Arms (1)

Gemcitabine & Imatinib mesylate

EXPERIMENTAL

Gemcitabine 1000 mg/m2, i.v., days 3 and 10 of a 21-days schedule; Imatinib mesylate 400 mg/die orally on days 1-5 and 8-12 of a 21-days schedule.

Drug: Gemcitabine; Drug: Imatinib mesylate

Interventions

Gemcitabine DRUG

infusion drug

Also known as: Gemzar

Gemcitabine & Imatinib mesylate

Imatinib mesylate DRUG

oral drug

Also known as: Glivec

Gemcitabine & Imatinib mesylate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of \> 18 years.
• Histologically proven malignant mesothelioma of the pleura or of the peritoneum, expressing PDGFR-beta and/or C-kit by immunohistochemistry.
• Locally advanced disease, unsuitable for curative surgical resection, or metastatic disease.
• Confirmed progression of the disease according to modified RECIST-criteria, documented after a pemetrexed-based chemotherapy.
• Eastern Cooperative Oncology group (ECOG) Performance Status of 0, 1 or 2.
• Life expectancy of at least 3 months.
• Written informed consent.

You may not qualify if:

• Co-existing tumors of different histologic origin, except non melanomatous localized skin cancer and/or in situ cervical carcinoma.
• A history of earlier tumors of different histologic origin being in complete remission for less than 5 years.
• Unresolved toxicity from prior antitumor treatment(s).
• Primary peritoneal mesothelioma.
• Any of the following abnormal baseline hematological values:
• Hb \< 9 g/dL
• White blood count (WBC) \< 3 x 109/L
• Neutrophils \< 1.5 x 109/L
• Platelets \< 100 x 109/L
• Serum bilirubin \> 2.5 mg/dL
• Alanine transaminase (ALAT) and Aspartate transaminase (ASAT) \> 3 x upper normal limit (UNL) (unless due to liver metastases)
• Serum creatinine \> 1.5 mg/dL.
• Symptomatic and/or unstable pre-existing brain metastases. To be enrolled in the study, subjects must have confirmation of stable disease by MRI or computer tomography (CT) scan within 4 weeks from day 1 of cycle 1 of treatment and have central nervous system (CNS) metastases well controlled by steroids, anti - epileptics or other symptom-relieving medications.
• Clinically relevant cardiovascular disease, i.e., myocardial infarction or other severe coronary artery diseases within the prior 6 months, cardiac arrythmia requiring medication, uncontrolled hypertension, overt cardiac failure or non compensated chronic heart disease in New York Heart Association (NYHA) class II or more.
• History of psychiatric disabilities, potentially interfering with the capability of giving adequate informed consent.

Sponsors & Collaborators

• Istituto Clinico Humanitas: lead

Study Sites (1)

Istituto Clinico Humanitas

Rozzano, MI, 20089, Italy

Location

Related Publications (26)

• Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.

  PMID: 12860938 BACKGROUND

• Ceresoli GL, Zucali PA, Favaretto AG, Grossi F, Bidoli P, Del Conte G, Ceribelli A, Bearz A, Morenghi E, Cavina R, Marangolo M, Parra HJ, Santoro A. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma. J Clin Oncol. 2006 Mar 20;24(9):1443-8. doi: 10.1200/JCO.2005.04.3190.

  PMID: 16549838 BACKGROUND

• Castagneto B, Botta M, Aitini E, Spigno F, Degiovanni D, Alabiso O, Serra M, Muzio A, Carbone R, Buosi R, Galbusera V, Piccolini E, Giaretto L, Rebella L, Mencoboni M. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM). Ann Oncol. 2008 Feb;19(2):370-3. doi: 10.1093/annonc/mdm501. Epub 2007 Dec 20.

  PMID: 18156144 BACKGROUND

• Santoro A, O'Brien ME, Stahel RA, Nackaerts K, Baas P, Karthaus M, Eberhardt W, Paz-Ares L, Sundstrom S, Liu Y, Ripoche V, Blatter J, Visseren-Grul CM, Manegold C. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008 Jul;3(7):756-63. doi: 10.1097/JTO.0b013e31817c73d6.

  PMID: 18594322 BACKGROUND

• Ceresoli GL, Zucali PA, Gianoncelli L, Lorenzi E, Santoro A. Second-line treatment for malignant pleural mesothelioma. Cancer Treat Rev. 2010 Feb;36(1):24-32. doi: 10.1016/j.ctrv.2009.09.003. Epub 2009 Oct 29.

  PMID: 19879055 BACKGROUND

• Pietras K, Ostman A, Sjoquist M, Buchdunger E, Reed RK, Heldin CH, Rubin K. Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors. Cancer Res. 2001 Apr 1;61(7):2929-34.

  PMID: 11306470 BACKGROUND

• Pietras K, Rubin K, Sjoblom T, Buchdunger E, Sjoquist M, Heldin CH, Ostman A. Inhibition of PDGF receptor signaling in tumor stroma enhances antitumor effect of chemotherapy. Cancer Res. 2002 Oct 1;62(19):5476-84.

  PMID: 12359756 BACKGROUND

• Pietras K, Stumm M, Hubert M, Buchdunger E, Rubin K, Heldin CH, McSheehy P, Wartmann M, Ostman A. STI571 enhances the therapeutic index of epothilone B by a tumor-selective increase of drug uptake. Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3779-87.

  PMID: 14506171 BACKGROUND

• Garlepp MJ, Leong CC. Biological and immunological aspects of malignant mesothelioma. Eur Respir J. 1995 Apr;8(4):643-50.

  PMID: 7664867 BACKGROUND

• Langerak AW, van der Linden-van Beurden CA, Versnel MA. Regulation of differential expression of platelet-derived growth factor alpha- and beta-receptor mRNA in normal and malignant human mesothelial cell lines. Biochim Biophys Acta. 1996 Feb 7;1305(1-2):63-70. doi: 10.1016/0167-4781(95)00196-4.

  PMID: 8605252 BACKGROUND

• Pogrebniak HW, Lubensky IA, Pass HI. Differential expression of platelet derived growth factor-beta in malignant mesothelioma: a clue to future therapies? Surg Oncol. 1993 Aug;2(4):235-40. doi: 10.1016/0960-7404(93)90012-n.

  PMID: 8252214 BACKGROUND

• Klominek J, Baskin B, Hauzenberger D. Platelet-derived growth factor (PDGF) BB acts as a chemoattractant for human malignant mesothelioma cells via PDGF receptor beta-integrin alpha3beta1 interaction. Clin Exp Metastasis. 1998 Aug;16(6):529-39. doi: 10.1023/a:1006542301794.

  PMID: 9872600 BACKGROUND

• Sawyers C. Targeted cancer therapy. Nature. 2004 Nov 18;432(7015):294-7. doi: 10.1038/nature03095.

  PMID: 15549090 BACKGROUND

• Shih AH, Holland EC. Platelet-derived growth factor (PDGF) and glial tumorigenesis. Cancer Lett. 2006 Feb 8;232(2):139-47. doi: 10.1016/j.canlet.2005.02.002. Epub 2005 Aug 31.

  PMID: 16139423 BACKGROUND

• Yu J, Ustach C, Kim HR. Platelet-derived growth factor signaling and human cancer. J Biochem Mol Biol. 2003 Jan 31;36(1):49-59. doi: 10.5483/bmbrep.2003.36.1.049.

  PMID: 12542975 BACKGROUND

• Johnson MD, Okedli E, Woodard A, Toms SA, Allen GS. Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells. J Neurosurg. 2002 Sep;97(3):668-75. doi: 10.3171/jns.2002.97.3.0668.

  PMID: 12296652 BACKGROUND

• Porta C, Mutti L, Tassi G. Negative results of an Italian Group for Mesothelioma (G.I.Me.) pilot study of single-agent imatinib mesylate in malignant pleural mesothelioma. Cancer Chemother Pharmacol. 2007 Jan;59(1):149-50. doi: 10.1007/s00280-006-0243-4. Epub 2006 Apr 25. No abstract available.

  PMID: 16636799 BACKGROUND

• Roberts F, Harper CM, Downie I, Burnett RA. Immunohistochemical analysis still has a limited role in the diagnosis of malignant mesothelioma. A study of thirteen antibodies. Am J Clin Pathol. 2001 Aug;116(2):253-62. doi: 10.1309/XL6K-8E62-9FLD-V8Q8.

  PMID: 11488073 BACKGROUND

• George D. Platelet-derived growth factor receptors: a therapeutic target in solid tumors. Semin Oncol. 2001 Oct;28(5 Suppl 17):27-33.

  PMID: 11740804 BACKGROUND

• Taylor JR, Brownlow N, Domin J, Dibb NJ. FMS receptor for M-CSF (CSF-1) is sensitive to the kinase inhibitor imatinib and mutation of Asp-802 to Val confers resistance. Oncogene. 2006 Jan 5;25(1):147-51. doi: 10.1038/sj.onc.1209007.

  PMID: 16170366 BACKGROUND

• Mathy A, Baas P, Dalesio O, van Zandwijk N. Limited efficacy of imatinib mesylate in malignant mesothelioma: a phase II trial. Lung Cancer. 2005 Oct;50(1):83-6. doi: 10.1016/j.lungcan.2005.04.010.

  PMID: 15951053 BACKGROUND

• Bertino P, Porta C, Barbone D, Germano S, Busacca S, Pinato S, Tassi G, Favoni R, Gaudino G, Mutti L. Preliminary data suggestive of a novel translational approach to mesothelioma treatment: imatinib mesylate with gemcitabine or pemetrexed. Thorax. 2007 Aug;62(8):690-5. doi: 10.1136/thx.2006.069872. Epub 2007 Feb 20.

  PMID: 17311837 BACKGROUND

• Bertino P, Piccardi F, Porta C, Favoni R, Cilli M, Mutti L, Gaudino G. Imatinib mesylate enhances therapeutic effects of gemcitabine in human malignant mesothelioma xenografts. Clin Cancer Res. 2008 Jan 15;14(2):541-8. doi: 10.1158/1078-0432.CCR-07-1388.

  PMID: 18223230 BACKGROUND

• George S, Desai J, Paul Eder J, Manola J, Ryan DP, Appleman LJ, Demetri GD. Selective kinase inhibition with daily imatinib intensifies toxicity of chemotherapy in patients with solid tumours. Eur J Cancer. 2006 May;42(7):864-70. doi: 10.1016/j.ejca.2005.12.010. Epub 2006 Feb 28.

  PMID: 16503137 BACKGROUND

• Ali Y, Lin Y, Gharibo MM, Gounder MK, Stein MN, Lagattuta TF, Egorin MJ, Rubin EH, Poplin EA. Phase I and pharmacokinetic study of imatinib mesylate (Gleevec) and gemcitabine in patients with refractory solid tumors. Clin Cancer Res. 2007 Oct 1;13(19):5876-82. doi: 10.1158/1078-0432.CCR-07-0883.

  PMID: 17908982 BACKGROUND

• Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol. 2004 Feb;15(2):257-60. doi: 10.1093/annonc/mdh059.

  PMID: 14760119 BACKGROUND

Related Links

• 27\) National Cancer Institute. Common toxicity criteria manual, version 3.0, July 16, 2003.

MeSH Terms

Conditions

Mesothelioma, Malignant

Interventions

Gemcitabine; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Mesothelioma; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines

Study Officials

• Armando Santoro, MD

  Istituto Clinico Humanitas

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 19, 2014
• First Posted: December 1, 2014
• Study Start: November 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2017
• Last Updated: January 22, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)