Marched Pair Study Conventional Doxorubicin(DOX) Versus Pegylated Liposomal Doxorubicin(PLD) Neoadjuvant Chemotherapy

Jilin University

Status and phase: Unknown; Phase 2

Conditions: Antineoplastic Combined Chemotherapy Protocols

Treatments: Procedure: Sentinel Lymph Node Biopsy（SLNB）; Drug: Taxotere; Drug: Dexrazoxane (DZR); Drug: Pegylated Liposomal Doxorubicin; Drug: vitamin B; Drug: Cyclophosphamide; Drug: Doxorubicin; Procedure: Breast Conserved Surgery; Procedure: Modified Radical Mastectomy

Study type: Interventional

Funder types: Other

Identifiers

NCT02953184

2016yx238

Details and patient eligibility

About

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].

Full 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

Enrollment: 160 estimated patients

Sex: Female

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

160 participants in 2 patient groups

conventional Doxorubicin plus C-T

Active Comparator group

Description:

AC-T regimen 8 cycles ,60mg/M2 conventional Doxorubicin will be used as active comparator. four cycles of Doxorubicin plus 600mg/m2 Cyclophosphamide every three weeks followed 4 cycles of 100mg/m2 Taxotere, every three weeks for one cycle.Dexrazoxane (DZR)will be used for protecting cardiac toxicity.Patients will undergo Modified Radical Mastectomy or Breast Conserved Surgery or Axillary Lymph Node Dissection(ALND) or Sentinel Lymph Node Biopsy（SLNB） after 8 cycles of chemotherapy

Treatment:

Procedure: Modified Radical Mastectomy

Procedure: Breast Conserved Surgery

Drug: Doxorubicin

Drug: Cyclophosphamide

Drug: Dexrazoxane (DZR)

Drug: Taxotere

Procedure: Sentinel Lymph Node Biopsy（SLNB）

PLD plus C -T

Experimental group

Description:

Pegylated Liposomal Doxorubicin(PLD) plus Cyclophosphamide followed Taxotere 8 cycles.35mg/M2 PLD will be used as experimental medicine. four cycles of PLD plus 600mg/m2 Cyclophosphamide every three weeks followed 4 cycles of 100mg/m2 Taxotere , every three weeks for one cycle.Vitamin B will be used for protecting hand-foot syndrome(HFS).Patients will undergo Modified Radical Mastectomy or Breast Conserved Surgery or Axillary Lymph Node Dissection(ALND) or Sentinel Lymph Node Biopsy（SLNB） after 8 cycles of chemotherapy

Treatment:

Procedure: Modified Radical Mastectomy

Procedure: Breast Conserved Surgery

Drug: vitamin B

Drug: Cyclophosphamide

Drug: Pegylated Liposomal Doxorubicin

Drug: Taxotere

Procedure: Sentinel Lymph Node Biopsy（SLNB）