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Pharmacology: Pharmacodynamics: Mechanism of action: Trastuzumab binds with high affinity and specificity to an epitope located in the extracellular sub-domain IV of HER2 present juxtaposed to the cell membrane region. Binding of trastuzumab to HER2 inhibits HER2 signalling and prevents the proteolytic cleavage of its extracellular domain, leading to an inhibition of proliferation of HER2 overexpressing human tumor cells both in-vitro and in-vivo. Trastuzumab is also known to carry out its function in-vitro via an immune effector mechanism, ADCC (antibody-dependent cell-mediated cytotoxicity), by binding to HER2 overexpressing cancer cells in the presence of NK cells.
Clinical Efficacy and Safety: Clinical Trial of Vivitra in Indian Patients: In a clinical trial conducted in 102 female patients with HER2+ metastatic breast cancer, received four cycles of trastuzumab (loading dose 8 mg/kg intravenous infusion on day 1 and subsequently 6 mg/kg intravenous infusion every three weekly) and paclitaxel (175 mg/m2 intravenous infusion every three weekly). Sixty seven patients received CHL's Trastuzumab (Vivitra) and thirty five patients received Reference Trastuzumab. The pharmacokinetics, efficacy, safety and immunogenicity were evaluated in Test and Reference groups.
Efficacy conclusions: Objective Response Rate (ORR): Patients were evaluated for Objective Response Rate based on RECIST 1.1 criteria. Response rate was based on sum of Complete response (CR) and partial response (PR) at the end of the study.
The Objective Response Rate (ORR) at the end of study (21 days after last dose i.e. Cycle 4) was 71.0% (44 out of 62 patients) in Test group (Vivitra) and 64.5% (20 out of 31 patients) in Reference group. There was no statistical significant difference (p>0.05) observed between test group and reference group based on ORR. (See Tables 2 and 3.)
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Click on icon to see table/diagram/imageWith respect to immunogenicity, among 102 patients with metastatic breast cancer, only two patients in test group and one patient in reference group tested positive for human anti-human antibody (HAHA) based on enzyme-linked immunosorbent assay (ELISA) method. These three samples were found to be negative in drug neutralization. Therefore, all the patients in both arms were negative for neutralizing anti-drug antibody. Overall, the occurrence of human anti-Human antibody (HAHA) in both the treatment groups was similar both in terms of prevalence and its drug neutralizing ability.
Safety conclusions: Most of the reported AEs were of mild to moderate category in both the treatment groups. Overall, test product and reference product were well tolerated and safety profile of the test product and reference product were comparable during the study.
Pharmacokinetics: Pharmacokinetic study conclusion: Pharmacokinetics of CHL's Trastuzumab (Vivitra) was determined in patients of metastatic breast cancer in a comparative study.
Summary of key pharmacokinetic parameters (primary endpoints) of CHL's Trastuzumab (Vivitra) and reference product observed during the study is described in Table 4 as follows: See Table 4.
Click on icon to see table/diagram/imageFor the log transformed trastuzumab data, the 90% confidence intervals about the ratio of the Test geometric mean to Reference geometric mean are within the 80% to 125% limits for Cmax (86.48%; 102.18%) and AUC0-168hrs (87.50%; 107.74%). Based on these results CHL's Trastuzumab (Vivitra) and Reference product are bioequivalent in pharmacokinetics.
Additionally AUCt (µg·hr/mL), Tmax (hours) and t1/2 (hours) were also evaluated for the test and reference products and found to be comparable.
Toxicology: Preclinical Safety Data of CHL's Trastuzumab: Preclinical studies for CHL's Trastuzumab (Vivitra) were performed as per GLP standards. The rationale for dose selection was based on human therapeutic dose of 4 mg/kg and all doses were calculated to animal doses based on body surface area. Toxicological studies included independent acute toxicity studies in mice and rats by intravenous route of administration as well as Repeated dose toxicity studies (comparative) by intravenous route comprising weekly dosing schedule over a period of four weeks was performed in rats and rabbits. Local tolerance evaluation was a part of repeated dose toxicity studies.
In acute studies, CHL's Trastuzumab (Vivitra) revealed a good safety margin in terms of mortality over the acute dose of 400 mg/kg in mice & 200 mg/kg in rats by intravenous and were approximately 8x of the human equivalent dose. No mortality, apparent signs of toxicity, adverse changes in body weights and gross pathological lesions were noticed in both mice and rats when compared to vehicle control groups.
Comparative study comprising of repeated weekly intravenous administration of CHL's Trastuzumab (Vivitra) and reference product was conducted over a period of four weeks at dose levels of 25, 62.5 & 125 mg/kg in rats and 12.5, 31.25 & 62.5 mg/kg in rabbits. The selected dose levels were 1x, 2.5x & 5x of the human equivalent dose. A recovery group was maintained for a period of two weeks at 5x of the human equivalent dose. Vehicle control groups were maintained with main study & recovery groups. An approved reference (originator) product was used at 1x of the human equivalent dose. No mortality occurred in both rats and rabbits. No adverse changes were noticed during detailed clinical examination, body weight and feed intake determinations, hematological, biochemical, organ weight estimations, bone marrow examination and gross or histopathological evaluation. No any differences were noticed in these studies from reference (originator) product in both rats and rabbits. No any delayed toxicity was noticed during treatment free recovery period of two weeks. The immunogenic response in CHL's trastuzumab (Vivitra) treated groups were comparable to that of reference (originator) product treated group. NOAEL was considered to be more than 5x of human equivalent dose (125 mg/kg in rats and 62.5 mg/kg in rabbits) by weekly intravenous administration over a period of four weeks.
Thus, the overall pre-clinical profile of CHL's Trastuzumab is found to be comparable to reference originator product and considered to be safe at the recommended dose in humans.
