Clinical trial NCT02953184: Marched Pair Study Conventional Doxorubicin(DOX) Versus Pegylated Liposomal Doxorubicin(PLD) Neoadjuvant Chemotherapy
Official title: Marched Pair Study of the Standard Chemotherapy 4doxorubicin Plus Cyclophosphamide(AC) 60 + 4 Docetaxel Protocol Versus 4 PLD C35+4 Docetaxel in Neoadjuvant Chemotherapy of Breast Cancer
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Antineoplastic Combined Chemotherapy Protocols
Keywords: neoadjuvant chemotherapy
Pegylated liposomal doxorubicin
breast cancer
Lead sponsor: Jilin University
Sponsor class: OTHER
First posted: 2016-11-02
Enrollment: 160
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The regimen PLD plus cyclophosphamide 4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in phase II CAPRICE) will be used as experimental group. The regimen will be compared to the standard treatment of doxorubicin plus cyclophosphamide(AC) 4 cycles followed by paclitaxel or docetaxel 4 cycles\[noted in National Comprehensive Cancer Network (NCCN) guideline\].

Detailed description: Purpose :Anthracycline based chemotherapy regimen is the milestone on the treatment of breast cancer . A sequential protocol, using docetaxel or Paclitaxel after an anthracycline-based combination is primary treatment for high-risk breast cancer .Despite its efficient antitumor activity profile, the use of conventional anthracycline in clinical practice is limited due to it's the risk of cardiac toxicity. The meta analysis show that subclinical cardiotoxicity was 17.9% whereas the incidence of clinically overt cardiotoxicity was 6.3%. Overall cardiovascular events occurred in 10.6%(Lotrisone , Am J Cardiol. 2013).Many patients have healed from breast cancer while they are snatched lives because of heart issue from chemotherapy using anthracycline. There are a lot of clinical trials exploring the possibilities of chemotherapy regimen without anthracycline ,however the recent result has shown anthracycline is indispensible for the patients whose axillary nodes are involved or triple negative breast cancer (ASCO 2016 ).So our target is to find a kind of anthracycline which is of equal efficiency with conventional anthracycline while less cardiac toxicity. Pegylated Liposomal Doxorubicin(PLD) is a novel kind of anthracycline. It distributes into cardiac cells lowly and releases Doxorubicin (DOX) slower to avoid peak plasma concentration, so it is of significant less cardiotoxicity compared to free DOX. It also achieve non-inferior efficacy at 50mg/m2 to conventional anthracycline in Metastatic Breast Cancer (MBC).( M. E. R. O'Brien, ,Annals of Oncology,2004;).

PLD 35mg/m2 in combination with paclitaxel showed an overall response rate of 71% ,tolerating toxicity of the skin(3% hand-foot syndrome)and rare cardiac event( H. Gogas1, Annals of Oncology, 2002;Gil-Gil , Breast Cancer Res Treat. 2015)However, There are a crucial question is to know if 35mg/m2 PLD has equivalent efficacy with less cardiac toxicity compared with 60 mg/m2 DOX in adjuvant chemotherapy for all patients.

The regimen PLD plus cyclophosphamide 4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in phase II CAPRICE)will be used as experimental group. The regimen will be compared to the standard treatment of doxorubicin plus cyclophosphamide (AC)4 cycles followed by paclitaxel or docetaxel 4 cycles(noted in NCCN guideline).

Condition Intervention Phase

Individualized Chemotherapy Drug: Pegylated Liposomal Doxorubicin(PLD) Drug: Doxorubicin(DOX)

Drug: Cyclophosphamide Drug: docetaxel or Paclitaxel Phase 2

Study Type: Interventional Study Design: Allocation: assignment based on patients desire Endpoint Classification: Safety/Efficacy Study Intervention Model: Marched pair Parallel Assignment Masking: Open Label Primary Purpose: Treatment

Eligibility criteria: Inclusion Criteria:

* Patient with histological proof of invasive cancer, whose clinical tumor diameter is \> 2 cm, or \< 2 cm, but Axillary lymphnodes are involved .There is no metastatic Imaging findings.
* Stage II,III tumor, non-metastatic, grade II - III
* Performance Status = 0-1 World Health Organization (WHO).
* Patient non pretreated for breast cancer.
* Patient without cardiac pathology and without anthracyclines contra-indication (assessed by normal ejection fraction).
* Normal haematological, renal and hepatic functions : platelets \> 100. 109 /l, Hb \> 10 g/dl, normal bilirubin serum , Aspartate transaminase(ASAT) and Alanine Aminotransferase(ALAT) \< 2,5 Upper Limit of Normal (ULN), alkaline phosphatases \< 2,5 ULN, creatinin \< 140 µmol/l or creatinin clearance \> 60 ml/min
* Written informed consent dated and signed by the patient

Exclusion Criteria:

* All other breast cancers than those described in inclusion criteria, in particular inflammatory and/or neglected (T4b or T4d) forms.
* Patient presenting with intraduct cancer in situ.(DCIS)
* Grade I well differentiated tumor.
* Non measurable lesion, in the two diameters, whatever radiological methods used.
* Patient already operated for breast cancer or having had primary axillar node dissection.
* Patient presenting with cancer in other system.
* Any psychological, familial, sociological or geographical condition that may potentially hamper compliance with the study protocol and follow up schedule, assessed with the patient prior to registration in the trial

Primary outcomes:
measure: improvement of pathological complete response（PCR)
timeFrame: at th 26th weeks of treatment since recruitment (after 8 cycles of neoadjuvant chemotherapy when the patient will undergo surgery)
Secondary outcomes:
measure: Tolerance according to Common Terminology Criteria Adverse Events (CTCAE) Version 4.0
timeFrame: at 3rd ,6th,9th,12th, 15 ,18,21,24th weeks since recruitment (after each cycle of chemotherapy) ; half year ,1 year , one and half year ,two years since recruitment
measure: Clinical Response Rate
timeFrame: at 3rd ,6th,9th,12th, 15 ,18,21,24th weeks since recruitment （after each cycle of chemotherapy）
Other outcomes:
Locations:
city: Changchun
country: China
facility: First Hospital of Jilin University
state: Jilin
Study officials:
affiliation: The First Hospital of Jilin University
name: Aiping Shi, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Peto R, Davies C, Godwin J, Gray R, Pan HC, Clarke M, Cutter D, Darby S, McGale P, Taylor C, Wang YC, Bergh J, Di Leo A, Albain K, Swain S, Piccart M, Pritchard K. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012 Feb 4;379(9814):432-44. doi: 10.1016/S0140-6736(11)61625-5. Epub 2011 Dec 5.
citation: Lotrionte M, Biondi-Zoccai G, Abbate A, Lanzetta G, D'Ascenzo F, Malavasi V, Peruzzi M, Frati G, Palazzoni G. Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity. Am J Cardiol. 2013 Dec 15;112(12):1980-4. doi: 10.1016/j.amjcard.2013.08.026. Epub 2013 Sep 25.
citation: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. doi: 10.1200/JCO.2008.18.4028. Epub 2009 Feb 9.
citation: Gogas H, Papadimitriou C, Kalofonos HP, Bafaloukos D, Fountzilas G, Tsavdaridis D, Anagnostopoulos A, Onyenadum A, Papakostas P, Economopoulos T, Christodoulou C, Kosmidis P, Markopoulos C. Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group. Ann Oncol. 2002 Nov;13(11):1737-42. doi: 10.1093/annonc/mdf284.
citation: Gil-Gil MJ, Bellet M, Morales S, Ojeda B, Manso L, Mesia C, Garcia-Martinez E, Martinez-Janez N, Mele M, Llombart A, Pernas S, Villagrasa P, Blasco C, Baselga J. Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study. Breast Cancer Res Treat. 2015 Jun;151(3):597-606. doi: 10.1007/s10549-015-3415-2. Epub 2015 May 16.
citation: O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. doi: 10.1093/annonc/mdh097.