ts as compared to younger patients in both those receiving treatment for metastatic disease inStudies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in studydesign of the 4 studies of trastuzumab in adjuvant treatment of breast cancer preclude a determination ofwhether the toxicity profile of trastuzumab in older patients is different from younger patients. The reported
clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) oftrastuzumab treatment in older patients is different from that observed in patients < 65 years of age formetastatic disease and adjuvant treatment.
In Study 7 (metastatic gastric cancer), of the 294 patients treated with trastuzumab, 108 (37%) were 65years of age or older, while 13 (4.4%) were 75 and over. No overall differences in safety oreffectiveness were observed.
10 OVERDOSAGE
There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have notbeen tested.
11 DESCRIPTION
Trastuzumab-anns is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinityto the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2.
Trastuzumab-anns is produced by recombinant DNA technology in a mammalian cell (Chinese HamsterOvary) culture containing the antibiotic geneticin. Geneticin is not detectable in the final product.
KANJINTI (trastuzumab-anns) for injection is a sterile, white to pale yellow, preservative-free lyophilizedpowder with a cake-like appearance, for intravenous administration.
Each multiple-dose vial of KANJINTI delivers 420 mg trastuzumab-anns, 381.8 mg α,α-trehalose dihydrate,9.5 mg L-histidine HCl monohydrate, 6.1 mg L-histidine, and 1.7 mg polysorbate 20. Reconstitution with 20 mLof the appropriate diluent (BWFI or SWFI) yields a solution containing 21 mg/mL trastuzumab-anns thatdelivers 20 mL (420 mg trastuzumab-anns), at a pH of approximately 6. If KANJINTI is reconstituted withSWFI without preservative, the reconstituted solution is considered single-dose.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which isstructurally related to the epidermal growth factor receptor. Trastuzumab products have been shown, inboth in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpressHER2.
Trastuzumab products are mediators of antibody-dependent cellular cytotoxicity (ADCC). In vitro,trastuzumab product-mediated ADCC has been shown to be preferentially exerted on HER2overexpressing cancer cells compared with cancer cells that do not overexpress HER2.
12.2 Pharmacodynamics
Cardiac Electrophysiology
The effects of trastuzumab on electrocardiographic (ECG) endpoints, including QTc interval duration, were eva luated in patients with HER2 positive solid tumors. Trastuzumab had no clinically relevant effecton the QTc interval duration and there was no apparent relationship between serum trastuzumabconcentrations and change in QTcF interval duration in patients with HER2 positive solid tumors.
12.3 Pharmacokinetics
The pharmacokinetics of trastuzumab was eva luated in a pooled population pharmacokinetic (PK) modelanalysis of 1,582 subjects with primarily breast cancer and metastatic gastric cancer (MGC) receivin |
