PAINTER: Polymorphism And INcidence of Toxicity in ERibulin Treatment

Metastatic Breast Cancer Clinical Trial

Official title:

Multicenter, Interventional, Single-arm, Phase IV Study Evaluating Tolerability of Eribulin and Its Relationship With a Set of Polymorphisms in an Unselected Population of Female Patients With Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02864030
• Other study ID #: PAINTER01
• Status: Completed
• Phase: Phase 4
• Start date: May 2014
• Est. completion date: December 31, 2020

Study information

• Verified date: March 2021
• Source: Oncologia Medica dell'Ospedale Fatebenefratelli
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

On March 17th, 2011, the European Commission issued a marketing authorization valid throughout the European Union for Eribulin mesylate (Halaven; Eisai Limited), for the treatment of patients with locally advanced or metastatic breast cancer who have progressed after at least two chemotherapic regimens for advanced disease.

As the use of Eribulin will be widespread in this tumor setting, a better knowledge of its safety profile outside clinical trials is warranted.

Indeed the possibility to select patients at risk for developing Eribulin-induced neuropathy, will allow the exclusion from these treatment of those patients harbouring the specific single nucleotide polymorphism (SNP). Given that Eribulin toxicity often results in treatment discontinuation, the ability to anticipate which patients will experience severe toxicity could allow for either early intervention or even possibly for prophylactic therapy, or for selection of the patients to be treated.

Description:

This study is primarily aimed at surveying the tolerability profile of Eribulin in an unselected population of patients with metastatic breast cancer in relation to toxicities already described in clinical trials, and neurotoxicity in particular.

The secondary objectives of this trial include:

• To study the relationship between specific genetic polymorphism and incidence and severity of peripheral neuropathy

• To describe treatment efficacy in terms of duration of treatment and impact on survival.

All toxicities will be collected and classified according to National Cancer Institute Common Terminology criteria for Adverse Events (NCI CTCAE) version 4.0 and monitored during all the treatment period and up to 30 days after therapy discontinuation.

In particular, evaluation of incidence and outcome of any grade AEs already recorded in previous clinical trials will be collected, as follows:

• asthenia/fatigue,

• neutropenia,

• alopecia,

• nausea,

• peripheral neuropathy

• constipation

Any other unexpected AEs shall be evaluated likewise.

Patients must be followed for AEs until every ongoing Eribulin-related/unrelated toxicity and AE have been resolved, or the Investigator assesses them as "chronic" or "stable" or until the end of the trial, whichever comes first. For patients who will begin a new anticancer therapy after the last study drug administration, the AEs reporting period will end at the time the new treatment starts.

For the determination of polymorphisms, a routine blood collection of two tubes with 3-5 ml of blood be performed. The sample can be collected at any time during the participant's first two treatment cycles. Blood will be collected in a Vacutainer containing ethylendiaminetetraacetic acid (EDTA). Immediately after blood collection, tubes have to be inverted (at least five times) and then stored at - 20° C.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: December 31, 2020
• Est. primary completion date: December 31, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of metastatic breast cancer

• Previous treatment with anthracyclines and taxanes

• Patients who will start Eribulin or who have already received only the first dose (cycle 1, day 1) of Eribulin according to the approved indication

• Ability to comply with sample collection

• Patient has signed the study Informed Consent Form (ICF) and the specific Pharmacogenetic ICF.

• Absence of any contraindication to treatment

Exclusion Criteria:

• Previous treatment with Eribulin in a previous line of treatment

• Previous treatment with Eribulin off label

Related Conditions & MeSH terms

• Adverse Drug Event
• Breast Neoplasms
• Drug Toxicity
• Drug-Related Side Effects and Adverse Reactions
• Metastatic Breast Cancer
• Neurotoxicity
• Toxicity

Intervention

Drug:
• ERIBULIN MESYLATE
Eribulin mesylate will be administered according to the European Medicines Agency (EMA) and Italian Medicines Agency (AIFA) approved indications and schedule consists in 1.23 mg/m2 on day 1 and on day 8 of each cycle. Cycles will be repeated every 21 days until progression of disease, unacceptable toxicity, patient refusal or medical decision. The decision to treat patients with Eribulin is independent from the trial. Patients will be treated and managed according to clinical practice. The physician can choose any further line of treatment after disease progression with Eribulin.

Locations

Country	Name	City	State
Italy	Comprensorio sanitario di Bolzano	Bolzano
Italy	Istituti Ospitalieri di Cremona	Cremona
Italy	Azienda Ospedaliera S. Croce e Carle	Cuneo
Italy	A.O.U. Careggi	Firenze
Italy	A.O. Vito Fazzi	Lecce
Italy	Ospedale Civile di Legnano	Legnano
Italy	Oncologia Medica Ospedale Fatebenefratelli	Milano
Italy	ASL Salerno Presidio Ospedaliero Andrea Tortora	Pagani
Italy	Fondazione IRCCS Policlinico San Matteo di Pavia	Pavia
Italy	Azienda Ospedaliera di Piacenza	Piacenza
Italy	Fondazione Policlinico Tor Vergata	Roma
Italy	Istituto Nazionale Tumori "Regina Elena" Oncologia Medica A	Roma
Italy	Istituto Nazionale Tumori "Regina Elena" Oncologia medica B	Roma
Italy	Policlinico Universitario Agostino Gemelli	Roma
Italy	POliclinico Universitario Campus Bio-Medico	Roma
Italy	Azienda Ospedaliera Valtellina e Valchiavenna - Presidio di Sondrio	Sondrio
Italy	ASL di FRosinone Ospedale SS Trinità di Sora	Sora
Italy	A.O. Santa Maria di Terni	Terni
Italy	Ospedale di Treviglio	Treviglio
Italy	Azienda Ospedaliero-Universitaria Santa Maria della Misericordia	Udine

Sponsors (2)

Lead Sponsor	Collaborator
Oncologia Medica dell'Ospedale Fatebenefratelli	Mario Negri Institute for Pharmacological Research

Country where clinical trial is conducted

Italy, 

References & Publications (21)

Aogi K, Iwata H, Masuda N, Mukai H, Yoshida M, Rai Y, Taguchi K, Sasaki Y, Takashima S. A phase II study of eribulin in Japanese patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2012 Jun;23(6):1441-8. doi: 10.1093/annonc/mdr444. Epub 2011 Oct 11. — View Citation

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Cavaletti G, Alberti P, Marmiroli P. Chemotherapy-induced peripheral neurotoxicity in the era of pharmacogenomics. Lancet Oncol. 2011 Nov;12(12):1151-61. doi: 10.1016/S1470-2045(11)70131-0. Epub 2011 Jun 28. Review. — View Citation

Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. doi: 10.1016/S0140-6736(11)60070-6. Epub 2011 Mar 2. — View Citation

Cortes J, Vahdat L, Blum JL, Twelves C, Campone M, Roché H, Bachelot T, Awada A, Paridaens R, Goncalves A, Shuster DE, Wanders J, Fang F, Gurnani R, Richmond E, Cole PE, Ashworth S, Allison MA. Phase II study of the halichondrin B analog eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2010 Sep 1;28(25):3922-8. doi: 10.1200/JCO.2009.25.8467. Epub 2010 Aug 2. — View Citation

Goel S, Mita AC, Mita M, Rowinsky EK, Chu QS, Wong N, Desjardins C, Fang F, Jansen M, Shuster DE, Mani S, Takimoto CH. A phase I study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced solid malignancies. Clin Cancer Res. 2009 Jun 15;15(12):4207-12. doi: 10.1158/1078-0432.CCR-08-2429. Epub 2009 Jun 9. — View Citation

Guarneri V, Conte PF. The curability of breast cancer and the treatment of advanced disease. Eur J Nucl Med Mol Imaging. 2004 Jun;31 Suppl 1:S149-61. Epub 2004 Apr 24. Review. — View Citation

Hasmats J, Kupershmidt I, Rodríguez-Antona C, Su QJ, Khan MS, Jara C, Mielgo X, Lundeberg J, Green H. Identification of candidate SNPs for drug induced toxicity from differentially expressed genes in associated tissues. Gene. 2012 Sep 10;506(1):62-8. doi: 10.1016/j.gene.2012.06.053. Epub 2012 Jul 1. — View Citation

Johnson DC, Corthals SL, Walker BA, Ross FM, Gregory WM, Dickens NJ, Lokhorst HM, Goldschmidt H, Davies FE, Durie BG, Van Ness B, Child JA, Sonneveld P, Morgan GJ. Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol. 2011 Mar 1;29(7):797-804. doi: 10.1200/JCO.2010.28.0792. Epub 2011 Jan 18. — View Citation

Jordan MA, Kamath K, Manna T, Okouneva T, Miller HP, Davis C, Littlefield BA, Wilson L. The primary antimitotic mechanism of action of the synthetic halichondrin E7389 is suppression of microtubule growth. Mol Cancer Ther. 2005 Jul;4(7):1086-95. — View Citation

Kobayashi T, Ichiba T, Sakuyama T, Arakawa Y, Nagasaki E, Aiba K, Nogi H, Kawase K, Takeyama H, Toriumi Y, Uchida K, Kobayashi M, Kanehira C, Suzuki M, Ando N, Natori K, Kuraishi Y. Possible clinical cure of metastatic breast cancer: lessons from our 30-year experience with oligometastatic breast cancer patients and literature review. Breast Cancer. 2012 Jul;19(3):218-37. doi: 10.1007/s12282-012-0347-0. Epub 2012 Apr 25. Review. — View Citation

Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP. Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst. 2008 Dec 17;100(24):1780-91. doi: 10.1093/jnci/djn414. Epub 2008 Dec 9. Review. — View Citation

Mir O, Alexandre J, Tran A, Durand JP, Pons G, Treluyer JM, Goldwasser F. Relationship between GSTP1 Ile(105)Val polymorphism and docetaxel-induced peripheral neuropathy: clinical evidence of a role of oxidative stress in taxane toxicity. Ann Oncol. 2009 Apr;20(4):736-40. doi: 10.1093/annonc/mdn698. Epub 2009 Feb 17. — View Citation

Mukohara T, Nagai S, Mukai H, Namiki M, Minami H. Eribulin mesylate in patients with refractory cancers: a Phase I study. Invest New Drugs. 2012 Oct;30(5):1926-33. doi: 10.1007/s10637-011-9741-2. Epub 2011 Sep 2. — View Citation

Okouneva T, Azarenko O, Wilson L, Littlefield BA, Jordan MA. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther. 2008 Jul;7(7):2003-11. doi: 10.1158/1535-7163.MCT-08-0095. — View Citation

Sissung TM, Mross K, Steinberg SM, Behringer D, Figg WD, Sparreboom A, Mielke S. Association of ABCB1 genotypes with paclitaxel-mediated peripheral neuropathy and neutropenia. Eur J Cancer. 2006 Nov;42(17):2893-6. Epub 2006 Sep 6. — View Citation

Sucheston LE, Zhao H, Yao S, Zirpoli G, Liu S, Barlow WE, Moore HC, Thomas Budd G, Hershman DL, Davis W, Ciupak GL, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Livingston RB, Albain KS, Hayes DF, Ambrosone CB. Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). Breast Cancer Res Treat. 2011 Dec;130(3):993-1002. doi: 10.1007/s10549-011-1671-3. Epub 2011 Jul 16. — View Citation

Swain SM, Arezzo JC. Neuropathy associated with microtubule inhibitors: diagnosis, incidence, and management. Clin Adv Hematol Oncol. 2008 Jun;6(6):455-67. Review. — View Citation

Tan AR, Rubin EH, Walton DC, Shuster DE, Wong YN, Fang F, Ashworth S, Rosen LS. Phase I study of eribulin mesylate administered once every 21 days in patients with advanced solid tumors. Clin Cancer Res. 2009 Jun 15;15(12):4213-9. doi: 10.1158/1078-0432.CCR-09-0360. Epub 2009 Jun 9. — View Citation

Towle MJ, Salvato KA, Budrow J, Wels BF, Kuznetsov G, Aalfs KK, Welsh S, Zheng W, Seletsky BM, Palme MH, Habgood GJ, Singer LA, Dipietro LV, Wang Y, Chen JJ, Quincy DA, Davis A, Yoshimatsu K, Kishi Y, Yu MJ, Littlefield BA. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 2001 Feb 1;61(3):1013-21. — View Citation

Vahdat LT, Pruitt B, Fabian CJ, Rivera RR, Smith DA, Tan-Chiu E, Wright J, Tan AR, Dacosta NA, Chuang E, Smith J, O'Shaughnessy J, Shuster DE, Meneses NL, Chandrawansa K, Fang F, Cole PE, Ashworth S, Blum JL. Phase II study of eribulin mesylate, a halichondrin B analog, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2009 Jun 20;27(18):2954-61. doi: 10.1200/JCO.2008.17.7618. Epub 2009 Apr 6. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The European Organization for research and treatment of cancer Quality of Life Questionnaire EORTC QLQ - C30	This is a kind of assessment to evaluate the quality of life of cancer patients during Eribulin treatment using unique measurements that share a common Unit of Measure	Trough study completion, an average of 1 year
Other	Breast Cancer-Specific Quality of Life Questionnaire QlQ - BR23	This is a kind of assessment to evaluate the quality of life during Eribulin treatment using unique measurements that share a common Unit of Measure	Trough study completion, an average of 1 year
Primary	Incidence, time of onset, severity and duration of all Adverse Events (AEs) experienced during treatment with Eribulin (any grade)	All toxicities and their grade will be reported according to Common Terminology criteria for Adverse Events (CTCAE) v4.0, especially the most common AEs reported in previous clinical studies (asthenia/fatigue, neutropenia, alopecia, nausea, peripheral neuropathy and constipation) but also other possible unexpected toxicities.	Trough study completion, an average of 1 year
Primary	Association between a set of selected polymorphisms and the onset of any grade peripheral neuropathy	The association between a set of selected polymorphisms and the onset of all grades peripheral neuropathy will be investigated using blood samples collected at the time of treatment initiation.	Trough study completion, an average of 1 year
Primary	Treatment tolerability	Treatment tolerability will also be described in terms of dose intensity and dose schedule maintenance.	Trough study completion, an average of 1 year
Primary	DOT (Duration Of Treatment)	DOT will be calculated for each patient from the date of start of Eribulin treatment to the date of last Eribulin administration for any cause (i.e. progression of disease, unacceptable toxicity, patient refusal or physician decision).	Trough study completion, an average of 1 year
Primary	OS (Overall Survival)	OS will be calculated from the date of start of therapy to the date of death.	Trough study completion, an average of 1 year