Safety and QoL of Trastuzumab With Lapatinib or Chemiotherapy in MBC and HER2+ Patients Refractory to Anti HER2 Therapies

Metastatic Breast Cancer Clinical Trial

Official title:

A Randomised, Multicentre, Open-label Phase II Trial Investigating Activity of Chemotherapy and Lapatinib and Trastuzumab in Patients With HER2-positive Metastatic Breast Cancer (MBC) Refractory to Anti HER2 Therapies

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02238509
• Other study ID #: GIM12-TYPHER
• Secondary ID: 2013-005044-29
• Status: Recruiting
• Phase: Phase 2
• First received: September 9, 2014
• Last updated: June 14, 2016
• Start date: November 2014
• Est. completion date: October 2017

Study information

• Verified date: June 2016
• Source: Consorzio Oncotech
• Contact: Clinical Research Technology
• Phone: 0039089301545
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

Recent clinical studies have shown that the combination of lapatinib and trastuzumab has superior antitumor activity compared to either single drug in both neoadjuvant and metastatic setting and is well tolerated. According to this evidence, the combination of lapatinib and trastuzumab today offers a valid chemotherapy-free option, primarily for patients with pre-treated HER2-positive MBC

Description:

The present study is designed to determine the efficacy and safety profile of the combination of lapatinib and trastuzumab (plus endocrinetherapy in ER-positive breast cancer) versus trastuzumab and chemotherapy in heavily pretreated patient population with HER2-positive MBC and to investigate the predictive role of cfDNA for detection of HER2 gene amplification on patients' outcome. The presence of circulating free DNA (cfDNA) for detection of HER2 gene amplification was associated with worse prognosis and seems to allow early response evaluation. However, many aspects of the role of cfDNA detection in patients undergoing molecular target agents such as trastuzumab or lapatinib are not well described. With the availability of improved and standardized techniques for cfDNA detection, it should now be possible to examine several of these important questions within a prospective multicenter study and a striking potential of cfDNA for detection of HER2 gene amplification might enable a more individual and optimized antimetastatic therapy inpatients with cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 154
• Est. completion date: October 2017
• Est. primary completion date: October 2017
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histological or cytological confirmed and documented adenocarcinoma of the breast with metastatic disease

• The original tumour specimen must be HER2 IHC 3+ positive or, in case of IHC 2+

• Age =18

• Life expectancy of >12 weeks

• ECOG PS 0-1

• Measurable disease as defined by RECIST1.1 criteria

• All patients must have received prior anthracycline-and taxane-based regimens as well as trastuzumab based regimens in either the adjuvant or the metastatic setting. Patients must have been already treated with at least one line of the anti HER2 inhibitor therapy lapatinib for their metastatic breast cancer. A maximum of three previous lines of anti-HER-2 therapies in the metastatic setting are allowed.

• Adequate haematological function as defined by: ANC 1.5 x 109/L, platelet count 100 x 109/L, haemoglobin 10 g/dL.

• Adequate renal function, as defined by: creatinine 1.5 x UNL

• Adequate hepatobiliary function, as defined by the following baseline liver function tests: total serum bilirubin 1.5 upper normal limit (UNL); alanine amino transferase (ALT), aspartate amino transferase (AST) 2.5xUNL; alkaline phosphatase (AP) 2.5xUNL; if total alkaline phosphatase (AP) > 2.5xUNL, alkaline phosphatase liver fraction must be 2.5xUNL

• Adequate contraception for all fertile patients

• Negative pregnancy test.

• Postmenopausal women fulfilling any of the NCCN criteria may be included.

• Left ventricular ejection fraction (LVEF) =50% during a baseline period of 28 days, as determined by either echocardiography (ECHO) or multi gated acquisition (MUGA) scan.

• Signed, written informed consent

Exclusion Criteria:

• History of persistent Grade = 2 hematologic toxicity resulting from previous systemic therapy

• Current peripheral neuropathy of NCI-CTCAE, Version 3.0, Grade = 3 at randomization

• History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma

• Bone-only disease, unless a measurable lesion is evident as determined by RECIST v1.1

• Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. ve

• Blastic bone lesions are non-measurable.

• Uncontrolled hypertension (systolic >150 mm Hg and/or diastolic >100 mm Hg) or clinically significant (i.e. active) cardiovascular disease.

• Current dyspnoea at rest due to complications of advanced malignancy, or other diseases that require continuous oxygen therapy.

• Inadequate organ function, evidenced by the following laboratory results within 28 days prior to randomization.

• Current severe, uncontrolled systemic disease

• Major surgical procedure or significant traumatic injury within 28 days prior to study treatment start or anticipation of the need for major surgery during the course of study treatment

• History of receiving any investigational treatment within 28 days of randomization

• Current known infection with HIV, HBV, or HCV

• Receipt of IV antibiotics for infection within 14 days of randomization

• Known hypersensitivity to any of the study drugs

• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

• Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medications

• Concurrent interventional or non-interventional studies

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Lapatinib
ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose).
• Trastuzumab
ARM A: oral lapatinib 1,000 mg daily in combination with intravenous trastuzumab 6mg/kg q3wks (after the initial 8 mg/kg loading dose).

Locations

Country	Name	City	State
Italy	A.O.U. Ospedali Riuniti Umberto I	Ancona
Italy	Centro di Riferimento Oncologico	Aviano
Italy	Policlinico S. Orsola Malpighi	Bologna
Italy	Ospedale Centrale di Bolzano	Bolzano
Italy	Presidio Ospedaliero `Antonio Perrino	Brindisi
Italy	A.O.R.N.A.S. Garibaldi Nesima di Catania	Catania
Italy	Humanitas Centro Catanese di Oncologia	Catania
Italy	Azienda Ospedaliera S. Anna	Como
Italy	Ospedale `F. Spaziani`	Frosinone
Italy	I.R.C.C.S. A.O.U. San Martino	Genova
Italy	Ospedale Civile di Guastalla	Guastalla
Italy	Ospedale Vito Fazzi	Lecce
Italy	Ospedale di Lugo - AUSL della Romagna	Lugo
Italy	Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori	Meldola
Italy	Ospedale Niguarda Ca' Granda	Milano
Italy	A.O. San Gerardo	Monza
Italy	AORN "A. Cardarelli"	Naples
Italy	Istituto Nazionale Tumori - IRCCS "Fondazione G.Pascale"	Napoli
Italy	Policlinico SUN	Napoli
Italy	Università degli Studi di Napoli "Federico II"	Napoli
Italy	A.R.N.A.S. Ospedale Civico e Benfratelli	Palermo
Italy	Ospedale S. Maria della Misericordia	Perugia
Italy	Azienda Ospedaliera Santa Maria degli Angeli	Pordenone
Italy	Ospedale di Ravenna	Ravenna
Italy	Arcispedale S. Maria Nuova Azienda Ospedaliera di Reggio Emilia	Reggio Emilia
Italy	Ospedale Infermi di Rimini	Rimini
Italy	Istituto Regina Elena per lo studio e la cura dei tumori	Roma
Italy	Policlinico Universitario Campus Biomedico	Roma
Italy	Ospedale G. Da Procida	Salerno
Italy	Ospedale Civile di Sassari SS Annunaziata	Sassari
Italy	Ospedale `SS. Trinità`	Sora
Italy	Azienda Ospedaliera S.Maria di Terni	Terni
Italy	A.O.U. San Giovanni Battista di Torino	Torino
Italy	A.O.U. Santa Maria della Misericordia di Udine	Udine
Italy	A.O. Ospedale di Circolo e Fondazione Macchi	Varese
Italy	Ospedale Sacro Cuore Don Calabria	Verona

Sponsors (2)

Lead Sponsor	Collaborator
Consorzio Oncotech	Clinical Research Technology

Country where clinical trial is conducted

Italy, 

References & Publications (15)

Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. doi: 10.1200/JCO.2008.21.4437. Epub 2010 Feb 1. — View Citation

Clemens M, Eidtmann H, Nitz U, Niederle N, du Bois A, Grischke EM, Hinke A, von Minckwitz G. Trastuzumab single-drug therapy after failure of cytotoxic treatment for metastatic breast cancer. Onkologie. 2010;33(8-9):425-30. doi: 10.1159/000318144. Epub 2010 Jul 27. — View Citation

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. Erratum in: N Engl J Med. 2007 Apr 5;356(14):1487. — View Citation

Jagiello-Gruszfeld A, Tjulandin S, Dobrovolskaya N, Manikhas A, Pienkowski T, DeSilvio M, Ridderheim M, Abbey R. A single-arm phase II trial of first-line paclitaxel in combination with lapatinib in HER2-overexpressing metastatic breast cancer. Oncology. 2010;79(1-2):129-35. doi: 10.1159/000318043. Epub 2010 Nov 22. — View Citation

Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009 Nov 20;27(33):5538-46. doi: 10.1200/JCO.2009.23.3734. Epub 2009 Sep 28. — View Citation

Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett. 2006 Feb 8;232(2):123-38. Review. — View Citation

Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006 May;3(5):269-80. Review. — View Citation

Page K, Hava N, Ward B, Brown J, Guttery DS, Ruangpratheep C, Blighe K, Sharma A, Walker RA, Coombes RC, Shaw JA. Detection of HER2 amplification in circulating free DNA in patients with breast cancer. Br J Cancer. 2011 Apr 12;104(8):1342-8. doi: 10.1038/bjc.2011.89. Epub 2011 Mar 22. — View Citation

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. — View Citation

Rusnak DW, Lackey K, Affleck K, Wood ER, Alligood KJ, Rhodes N, Keith BR, Murray DM, Knight WB, Mullin RJ, Gilmer TM. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther. 2001 Dec;1(2):85-94. — View Citation

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. — View Citation

Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005 Nov 1;23(31):7811-9. — View Citation

von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. doi: 10.1016/j.ejca.2011.06.021. Epub 2011 Jul 7. — View Citation

Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers--role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13(6):R121. doi: 10.1186/bcr3067. Epub 2011 Nov 28. — View Citation

Wu Y, Amonkar MM, Sherrill BH, O'Shaughnessy J, Ellis C, Baselga J, Blackwell KL, Burstein HJ. Impact of lapatinib plus trastuzumab versus single-agent lapatinib on quality of life of patients with trastuzumab-refractory HER2+ metastatic breast cancer. Ann Oncol. 2011 Dec;22(12):2582-90. doi: 10.1093/annonc/mdr014. Epub 2011 Mar 15. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Clinical Benefit Rate	To evaluate clinical benefit rate (CBR) for patients treated with lapatinib and trastuzumab and for patients treated with trastuzumab and chemotherapy. CBR is defined as: confirmed complete response (CR) plus partial response (PR) at any time, plus stable disease (SD) for 24 weeks	Clinical Benefit Rate is defined as confirmed complete response plus partial response at any time, plus stable disease up to 24 weeks	No
Secondary	Progression free survival	Second-line progression-free survival, defined as the time from first dosing to the first documented disease progression or death from any cause, whichever occurs first.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months	No
Secondary	Overall Survival	OS is defined as the time from first dosing in second line to death from any cause.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months	No
Secondary	Safety and tolerability	Safety of second line treatment will be evaluated by the frequency of AEs and SAEs, cardiac events, clinically significant abnormal laboratory tests, vital signs, and ECOG PS. All patients who received at least one dose of study treatment will be included in the safety analysis.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months	Yes
Secondary	Quality of life	QoL and symptom control will be assessed using the FACT-B questionnaire.	Patients enrolled will receive study medication until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever comes first, assessed up to 36 months	No