This trial was a randomized, double-blind, single-dose, 2-arm, parallel-group study in healthy adult male volunteers conducted at a single clinical pharmacology unit (CPU) (Fig. 1). Analyses included a total of 36 healthy male subjects (n = 18 per treatment group) who were randomized 1:1 to receive either an IV infusion of ABP 980 (6 mg/kg) plus pertuzumab (420 mg) combined in a single 250-mL infusion bag or trastuzumab RP (6 mg/kg) plus pertuzumab (420 mg) combined in a single 250-mL infusion bag given over 60 min. Investigational product (IP) was administered on day 1 after predose baseline procedures were completed. Subjects remained in the CPU for at least 24 h after dosing for safety evaluations and PK assessments. They were discharged on day 2 after the 24-h study procedures were completed (at their discretion, investigators could keep subjects in the CPU longer if needed for additional safety monitoring reasons [i.e., potential infusion reaction]). Subjects returned to the CPU on days 3, 5, 9, 15, 22, 29, 36, 43, 50, 64, and 92 (end-of-study [EOS] visit) for safety evaluations and PK assessments. Safety analyses included analyses of AEs and serious adverse events (SAEs), 12-lead ECGs, echocardiograms, local tolerability, and ADAs.
All procedures were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The final study protocol was approved by an Institutional Review Board and Independent Ethics Committee.
Study subjects were healthy male adults between 18 and 45 years of age. All subjects were required to meet the study inclusion criteria and provide signed informed consent during the 28 to 2 days prior to dosing. Inclusion criteria included but were not limited to body mass index of 18.0–30.0 kg/m2; normal or clinically acceptable physical examination including but not limited to urinalysis, vital signs, and electrocardiogram (ECG); and the ability to communicate effectively with study personnel. Exclusion criteria included but were not limited to men with pregnant partners or not taking measured precautions to prevent pregnancy in partners; history of a clinically significant disorder or condition that could pose a risk to the subject safety or interference with the study; history or presence of conditions known to interfere with the distribution, metabolism, or excretion of drugs; potentially interfering medications or investigational drugs including prior exposure to trastuzumab RP, biosimilars of trastuzumab RP or pertuzumab, or compounds with similar mechanisms of action.
Subjects were randomized after eligibility was confirmed and predose assessments were completed (Fig. 1). Each subject was tracked by a unique 11-digit subject identification number assigned in sequential order.
Investigational products (IPs)
IV infusion bags contained 150 mg of ABP 980 or trastuzumab RP (provided in vials of 21 mg/mL upon reconstitution) and 420 mg of pertuzumab (provided in 14 mL vials of 30 mg/mL each). The IPs were stored in their original container at 2 – 8 °C. Once prepared for IV infusion, ABP 980 plus pertuzumab and trastuzumab RP plus pertuzumab were similar in appearance. The unblinded study site pharmacist matched the appropriate unique infusion bag number to the subject’s randomization group code. Except for an unblinded study monitor if needed, all further study personnel, biostatisticians, and data managers were blinded to treatment assignment for the duration of the study.
Primary and secondary endpoints
The primary endpoints were safety and immunogenicity. Safety was determined by treatment-emergent AEs as well as clinical laboratory tests, 12-lead ECGs, echocardiograms, physical examinations, local tolerability, and vital signs. The Common Technology Criteria for Adverse Events (CTCAE) classification was used to categorize the severity of AEs. Immunogenicity was determined by the incidence of ADAs. Secondary endpoints were PK parameters (for ABP 980, trastuzumab RP, and pertuzumab), including: area under the serum concentration–time curve from time 0 to infinity (AUCinf), maximum observed serum concentration (Cmax), clearance (CL), terminal phase half-life (t1/2), time at which the maximum serum concentration was observed (tmax), terminal elimination rate constant (λz), area under the serum concentration–time curve from time 0 to the time of the last quantifiable concentration (AUClast), and last measurable serum concentration (Clast).
A 4-mL sample of blood was collected for the measurement of incidence of ADAs on day 1 at baseline prior to dosing and at day 92/EOS. A validated electrochemiluminescence-based bridging immunoassay was used to detect antibodies capable of binding to ABP 980 and which utilized the Meso Scale Discovery platform that followed a two-tiered approach consisting of a screening assay and a specificity assay. Samples were assessed for anti-ABP 980 and anti-trastuzumab RP binding antibodies. Only those samples that tested positive for binding antibodies were further tested for neutralizing antibodies.
A 4-mL sample of blood was collected for PK measurement at predose, at 0.5 min before dose, at end of infusion, at 2, 3, 4, 5, 6, 8, and 24 h after the start of the infusion, at each return visit to the CPU (days 3, 5, 9, 15, 22, 29, 36, 43, 50, and 64), and at EOS day 92 (Fig. 1). Serum concentrations were determined using a validated electrochemiluminescent assay.
Descriptive data summaries were tabulated by treatment for all endpoints. Categorical outcomes were summarized by number and percent of subjects falling into each category. The sample size of 18 subjects per arm was considered sufficient to provide descriptive safety data. Assuming a 15% incidence rate for an AE in each arm, the sample size of 18 subjects provides approximately 95% chance of observing at least one AE in each arm. PK parameters were estimated using non-compartmental methods and actual sampling times.