A Double-blind, Randomised, Parallel Group, Phase III Study to Demonstrate Equivalent Efficacy and Comparable Safety of CT-P6 and Herceptin, Both in Combination with Paclitaxel, in Patients with Metastatic Breast Cancer.
Ethics Committee of Care Institute of Medical Sciences
Approved
Ethics Committee, Apollo Hospitals Enterprise Limited, Chennai
Approved
Hirabai Cowasji Jehangir Medical Research Institute & Jehangir Clinical Development Centre Ethics Committee,Jawaharlal Nehru Cancer Hospital & Research Centre
Approved
Indraprastha Apollo Hospital,Sarita Vihar, New Delhi
Approved
Institutional Ethics Committee , City Cancer Care , Vijayawada - Dr M Gopichand
Approved
Institutional Ethics Committee - B.P. Poddar Hospital and Medical Research Ltd.
Approved
Institutional Ethics Committee Acharya Harihara Regional Cancer Center
Approved
Institutional Ethics Committee, King George Hospital, Visakhapatnam
Approved
Institutional Review Board(IRB), Tata Memorial Hospital., Mumbai
Approved
Institutional Review Board, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi
Approved
Manipal University Ethics Committee, Manipal
Approved
MNJ Institute of Oncology & Regional Cancer Center Institutional Ethics Committee, Hyderabad
Approved
Radix Central Ethics Committee, Vijayawada - Dr DS Raju Naidu
Patients will be entered into this study only if they meet all of the following criteria:
1. Written and signed informed consent, obtained prior to starting any protocol-specific procedures.
2. Are females over 18 years of age.
3. Have pathologically confirmed, uni-dimensionally measurable metastatic breast cancer.
4. Have a strong Her-2 over-expression as described by a 3+ score by immunohistochemistry (IHC) or a positive fluorescence in-situ hybridisation (FISH) or chromogenic in-situ hybridisation (CISH) result.
5. Have target lesions outside prior radiation fields.
6. Have Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Have at least 4 weeks since last surgery or radiation therapy, with full recovery. Patients must have received no radiotherapy for the treatment of metastatic disease. However, patients who have received adjuvant radiotherapy as part of the treatment of early breast cancer are eligible if the last fraction of radiotherapy was administered at least 6 months prior to randomisation. Radiotherapy administered for the relief of metastatic bone pain other than the sole site of measurable diseases is allowed, but:
• no more than 25% of marrow-bearing bone should have been irradiated,
• the last fraction of radiotherapy should not have been administered within 4 weeks prior to randomisation,
• patients must have recovered from all treatment-related toxicities prior to randomisation.
8. Regarding trastuzumab treatment;
• Have never been treated with trastuzumab, or
• Prior trastuzumab and chemotherapy (taxane included) or trastuzumab alone as neoadjuvant/adjuvant treatment is discontinued >12 months prior to randomisation.
9. Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of randomised therapy. Prophylactic use of bisphosphonates in patients without bone diseases is not permitted, except for the treatment of osteoporosis.
10. Laboratory requirements, as defined below:
• Haematology:
Absolute neutrophil count (ANC): greater than or equal to 1,500/mm3 (1.5 x 109 cells per L)
Platelets: greater than or equal to 100,000/mm3 (100 x 109 cells per L)
Haemoglobin: greater than or equal to 9.0 g per dL
• Liver function:
Total bilirubin: Lessthan or equal to 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT): Lessthan or equal to 2.5 x ULN, or Lessthan or equal to 5.0 x ULN in the case of liver metastasis
• Renal function:
Serum creatinine: Lessthan or equal to 2 mg/dL
11. Are expected to survive for at least 6 months.
12. Are not pregnant and do not plan to become pregnant during the study. For females of childbearing potential, pregnancy tests must be performed via serum pregnancy test at baseline (within 7 days prior to starting study drug) and at the end of treatment. Further tests are only required if there is a suspicion of pregnancy. If sexually active, must be using at least one reliable method of contraception (e.g., a barrier method [condom or occlusive cap] with spermicidal foam/gel/film/cream/suppository, an intrauterine device [IUD] or intrauterine system [IUS], oral or injectable contraception, sterilisation of sole male partner, abstinence) throughout the study period and for 6 months after the last study drug treatment.
Non-childbearing potential is defined as:
- aged ≥50 years and naturally amenorrhoeic for at least 1 year (Amenorrhoea following cancer therapy does not rule out childbearing potential), or
- premature ovarian failure confirmed by a specialist gynaecologist, or
- previous bilateral salpingo-oophorectomy or hysterectomy, or
- XY genotype, Turner’s syndrome, uterine agenesis.
ExclusionCriteria
Details
1. Have received prior chemotherapy for metastatic breast cancer.
2. Current clinical or radiographic evidence of central nervous system (CNS) metastases. A computerised tomography (CT) or magnetic resonance imaging (MRI) scan of the brain is mandatory in cases of clinical suspicion of brain metastases within 21 days of randomisation. Eligible patients must be asymptomatic and cannot be receiving steroids.
3. Are receiving concurrent immunotherapy or hormonal therapy.
4. Have a history of congestive heart failure (CHF) of any New York Heart Association (NYHA) criterion, or serious cardiac arrhythmia requiring treatment (except for atrial fibrillation and/or paroxysmal supraventricular tachycardia). 5. Have an abnormal LVEF (≤50%) at baseline, as determined by either two-dimensional echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan. If the patient is randomised, the same method of LVEF assessment, ECHO or MUGA, must be used throughout the study.
6. History of myocardial infarction within 6 months before randomisation.
7. Current uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or unstable angina.
8. Have severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
9. Have had a prior malignancy within the last 5 years that might affect breast cancer diagnosis or assessment.
10. Have had prior mediastinal irradiation (except internal mammary-node irradiation for the present breast cancer).
11. Have received cumulative doses of anthracycline exceeding 360 mg/m2 of body surface area for doxorubicin, 720 mg/m2 for epirubicin, 120 mg/m2 for mitoxantrone, 90 mg/m2 for idarubicin, or the equivalent of 360 mg/m2 of doxorubicin for other anthracyclines such as liposomal doxorubicin. If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
12. Have received stem-cell support for chemotherapy.
13. Have a history of hypersensitivity to the trastuzumab or to drugs with similar chemical structures, or to any of the excipients, or to murine proteins.
14. Have a history of severe hypersensitivity reaction to paclitaxel, or to any of the excipients.
15. At study entry, have an absolute neutrophil count ≤1,500/L or platelet count ≤100,000/L.
16. At study entry, have haemoglobin level ≤9 g/dL.
17. At study entry, have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >2.5 x upper limit of normal (ULN) (>5 x ULN in patients with liver metastases), or serum (total) bilirubin >1.5 x ULN.
18. At study entry, have a serum creatinine level >2.0 mg/dL 19. Have any other medical or psychiatric condition that could compromise study participation.
20. Have received treatment with any other investigational drug in the last 30 days before study entry, or within less than five half-lives after receiving the previous investigational drug.
21. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
22. Are pregnant or a nursing mother.
23. Have a history or suspicion of unreliability, poor cooperation or non-compliance with medical treatment.
24. Have any concurrent disease or condition that, in the opinion of the investigator, would make the patient unsuitable for participation in the study.
25. Have previously been enrolled in this study.
Overall response rate, ORR (complete response [CR] or partial response [PR]) at 6 months, as assessed by Response Evaluation Criteria In Solid Tumours (RECIST) 1.1.
Efficacy: TTP (Time to progression), time to response and PFS by RECIST 1.1, the proportion of patients without progression or death due to disease at 1 year, and change in target lesion size.
Pharmacokinetics: CtroughSS, Trough concentration before any dose (Ctrough), Maximum concentration (Cmax), Peak to trough fluctuation ratio (PTF).
This is a double blind, randomised, comparator controlled, parallel group study. A total of 383 patients with Her-2-positive metastatic breast cancer will be enrolled to evaluate efficacy, safety and PK of CT-P6 and Herceptin. Patients will receive CT-P6 or Herceptin at an initial dose of 8 mg/kg, then at a dose of 6 mg/kg every 3 weeks. All patients will also receive paclitaxel (175 mg/m2) in 3-week cycles. The primary endpoint will be reached at 6 months (8 treatment cycles), although treatment will continue until disease progression, death, or discontinuation. From India we had recruited 83 subjects from 16 sites. First subject was randomized on 5 Oct 2010. All the subjects had completed the study and we had terminated 13 sites and remaining 3 sites will be terminated by end of March 2015From India we had recruited 83 subjects from 16 sites. First subject was randomized on 5 Oct 2010. All the subjects had completed the study and we had terminated 13 sites and remaining 3 sites will be terminated by end of March 2015.