Safety, Pharmacokinetics and Preliminary Efficacy of IL4-Rα Monoclonal Antibody AK120 in Both Healthy and Atopic Dermatitis Subjects: A Phase I, Randomized, Two-Part, Double-Blind, Placebo-Controlled, Dose-Escalation, First-In-Human Clinical Study.

INTRODUCTION: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two essential cytokines involved in the T helper 2 (Th2)-mediated inflammatory response to diseases, such as atopic dermatitis (AD). AK120 is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) directed against the IL-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. This mAb inhibits the signaling of the IL-4 and IL-13 cytokines. METHODS: The study consisted of two parts. Part 1 was a single ascending dose (SAD) study with five cohorts (receiving 15, 50, 150, 300 or 600 mg of AK120, respectively) of healthy subjects; part 2 was a multiple ascending dose (MAD) study with four cohorts (receiving AK120 at doses of 300 mg once every 2 weeks [Q2W], 300 mg once weekly [QW], 150 mg QW or 75 mg QW) of subjects with AD. A total of 81 subjects (40 in part 1, 41 in part 2) were enrolled in the study. RESULTS: The compound was safe and well tolerated in both a SAD up to 600 mg in healthy subjects and in a MAD from 75 to 600 mg in subjects with AD. The exposure of AK120 increased in an approximately dose-dependent manner upon subcutaneous dosing. The levels of the biomarkers serum thymus and activation-regulated chemokine ligand 17 (TARC/CCL17) and immunoglobulin E decreased from baseline after AK120 administration, indicating the inhibition of the IL-4/IL-13 signaling pathways. AK120 showed improved Eczema Area and Severity Index (EASI) scores, and the proportion of subjects with Investigator Global Assessment (IGA) score 0/1 increased after AK120 treatment. CONCLUSIONS: AK120 exhibited an acceptable safety profile in healthy and AD subjects, and showed preliminary efficacy. These findings support the continued investigation of AK120 for treating AD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT04256174.

A multicenter, randomized, open-label, 2-arm parallel study to compare the pharmacokinetics, safety and tolerability of AVT02 administered subcutaneously via prefilled syringe or autoinjector in healthy adults.

BACKGROUND: AVT02 is an adalimumab biosimilar, with bioequivalence previously established along with clinical similarity. This study assessed the pharmacokinetic (PK) similarity of a single dose of 100 mg/mL AVT02 administered via prefilled syringe (PFS) or autoinjector (AI). RESEARCH DESIGN AND METHODS: In this open-label, 2-arm, parallel-group study, healthy adults were randomized 1:1 to receive one 40 mg (100 mg/mL) dose of AVT02 subcutaneously via PFS (N = 102) or AI (N = 105). Primary PK parameters (Cmax, AUC0-t and AUC0-inf) were evaluated up to Day 64 of the study. Secondary PK parameters, safety, tolerability and immunogenicity were also assessed. RESULTS: The 90% CIs for the ratio of geometric least squares means were contained within the pre-specified 80-125% equivalence margins for the primary PK parameters, demonstrating bioequivalence of AVT02 when administered by PFS or AI. The incidence of treatment-emergent adverse events was comparable between the two groups, with a low frequency of injection site reactions observed. Immunogenicity profiles were also similar between the two groups. CONCLUSION: Bioequivalence was demonstrated for a single dose of AVT02 administered via PFS or AI. These results will help to increase availability of devices for patients, enabling treatment choice and flexibility.

A randomized, double-blind, 3-arm, parallel study assessing the pharmacokinetics, safety, tolerability and immunogenicity of AVT04, an ustekinumab candidate biosimilar, in healthy adults.

BACKGROUND: This study assessed pharmacokinetic (PK) similarity, safety, and immunogenicity of AVT04, a candidate biosimilar, compared with reference product (RP) ustekinumab (EU-approved and US-licensed Stelara®). METHODS: Healthy subjects (N = 298) were randomized 1:1:1 to receive one 45 mg dose of AVT04, EU-RP, or US-RP. The primary PK parameters were Cmax and AUC0-inf. PK similarity was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means were all contained within the prespecified margins of 80% and 125%. Additional PK parameters, including AUC0-t, were also assessed. Safety and immunogenicity were also assessed until Day 92. RESULTS: After pre-specified protein content normalization, the 90% CI for the ratio of geometric means for primary PK parameters were all contained within the pre-specified bioequivalence margins of 80% and 125%, supporting demonstration of PK similarity between AVT04 and both EU- and US-RP. Secondary PK parameters supported the analysis. Safety and immunogenicity profiles were comparable across all three treatment arms, although the study was not powered to detect small differences in these parameters. CONCLUSION: Results supported a demonstration of PK similarity between candidate biosimilar AVT04, US-RP and EU-RP. Similar safety and immunogenicity were also shown.Clinical trial registration: www.clinicaltrials.gov identifier is NCT04744363.

A randomized, adaptive design, double-blind, 3-arm, parallel study assessing the pharmacokinetics and safety of AVT02, a high-concentration (100 mg/mL) Adalimumab biosimilar, in healthy adult subjects (ALVOPAD FIRST).

BACKGROUND: This study (ALVOPAD FIRST) assessed bioequivalence, safety, and immunogenicity of AVT02, an adalimumab biosimilar, compared with reference product adalimumab (EU- and US-approved Humira®). METHODS: Healthy subjects (N = 392) were randomized 1:1:1 to receive one 40 mg dose of AVT02, EU-reference product, or US-reference product subcutaneously. An interim analysis was planned when ~30 subjects per arm had completed the study, to optimize final sample size. The primary PK parameters were Cmax, AUC0-t, and AUC0-inf. Bioequivalence was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means for the primary pharmacokinetic (PK) parameters were all contained within the prespecified margins of 80% and 125%. Safety and immunogenicity were assessed until Day 64. RESULTS: The 90% CI for the ratio of geometric means for the primary PK parameters, based on Fisher's Combination test analysis, were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence between AVT02 and both EU- and US-reference product. The safety and immunogenicity profiles were comparable across all three treatment arms. CONCLUSION: PK bioequivalence was supported between AVT02, US-licensed- and EU-approved-reference product adalimumab. Similar safety and immunogenicity were also demonstrated. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03849313).

A randomized, single-blind, Phase I trial (INVICTAN-1) assessing the bioequivalence and safety of BI 695502, a bevacizumab biosimilar candidate, in healthy subjects.

OBJECTIVES: This Phase I trial (INVICTAN®-1) evaluated three-way bioequivalence and safety of BI 695502 a bevacizumab biosimilar candidate, and reference product bevacizumab from two sources (US-approved Avastin®, Genentech; EU-approved Avastin, Roche). METHODS: Healthy male subjects (N = 91) were randomized 1:1:1 to receive a single intravenous infusion of 1 mg/kg of BI 695502 or US- or EU-approved Avastin. An interim analysis was planned when ~50% of subjects were evaluable for the primary end point to determine if the prespecified criteria for bioequivalence were achieved; if demonstrated, the study could be stopped early. The primary end point was area under the concentration-time curve (AUC) of the analyte in plasma from time zero extrapolated to infinity (AUC0-∞). Other pharmacokinetic (PK) parameters, safety, and in vitro binding affinity were also evaluated. RESULTS: The interim analysis demonstrated three-way bioequivalence for all comparisons. The confidence intervals around the geometric mean ratios of the primary and secondary PK parameters were within the predefined acceptance ranges. Study drugs were well tolerated with no clinically relevant differences in safety. CONCLUSION: BI 695502 and US- and EU-approved Avastin showed three-way bioequivalence with similar safety profile. CLINICAL TRIAL REGISTRATION: NCT01608087.

Efficacy of an integrated continuing medical education (CME) and quality improvement (QI) program on radiation oncologist (RO) clinical practice.

PURPOSE: There has been little radiation oncologist (RO)-specific research in continuing medical education (CME) or quality improvement (QI) program efficacy. Our aim was to evaluate a CME/QI program for changes in RO behavior, performance, and adherence to department protocols/studies over the first 12 months of the program. METHODS AND MATERIALS: The CME/QI program combined chart audit with feedback (C-AWF), simulation review AWF (SR-AWF), reminder checklists, and targeted CME tutorials. Between April 2003 and March 2004, management of 75 patients was evaluated by chart audit with feedback (C-AWF) and 178 patients via simulation review audit (SR-AWF) using a validated instrument. Scores were presented, and case management was discussed with individualized educational feedback. RO behavior and performance was compared over the first year of the program. RESULTS: Comparing the first and second 6 months, there was a significant improvement in mean behavior (12.7-13.6 of 14, p = 0.0005) and RO performance (7.6-7.9 of 8, p = 0.018) scores. Protocol/study adherence significantly improved from 90.3% to 96.6% (p = 0.005). A total of 50 actions were generated, including the identification of learning needs to direct CME tutorials, the systematic change of suboptimal RO practice, and the alteration of deficient management of 3% of patients audited during the program. CONCLUSION: An integrated CME/QI program combining C-AWF, SR-AWF, QI reminders, and targeted CME tutorials effectively improved targeted RO behavior and performance over a 12-month period. There was a corresponding increase in departmental protocol and study adherence.

Bioequivalence, safety and immunogenicity of BI 695501, an adalimumab biosimilar candidate, compared with the reference biologic in a randomized, double-blind, active comparator phase I clinical study (VOLTAIRE®-PK) in healthy subjects.

BACKGROUND: This Phase I study (VOLTAIRE®-PK) aimed to evaluate three-way pharmacokinetic similarity (bioequivalence), safety, and immunogenicity of BI 695501 (a Humira® [adalimumab] biosimilar candidate) compared with US- and EU-approved Humira in healthy male subjects. METHODS: Subjects (N = 327) were randomized 1:1:1 to receive one 40-mg subcutaneous dose of BI 695501, US- or EU-approved Humira; safety was assessed for 70 days. Bioequivalence was evaluated using the average bioequivalence method to test if the 90% confidence intervals (CIs) of the geometric means (BI 695501 vs US- and EU-approved Humira) for the primary end points were within prespecified acceptance ranges (80-125%). Immunogenicity was assessed using a sensitive bridging method. RESULTS: Bioequivalence between BI 695501 and US- and EU-approved Humira was demonstrated with the 90% CIs of the ratios of all primary end points: Cmax, AUC0-inf, pred and AUC0-tz being within the prespecified acceptance ranges of 80-125%. Concentration vs time profiles were similar as were the time course and frequency of immunogenic responses. All study drugs showed similar safety and tolerability results. CONCLUSIONS: Three-way bioequivalence of BI 695501 to US- and EU-approved Humira was demonstrated; safety and immunogenicity results of the three study drugs were also similar. CLINICAL TRIAL REGISTRATION: 2013-003722-84 (EudraCT) and NCT02045979.

Patient preference for radiotherapy fractionation schedule in the palliation of painful bone metastases.

PURPOSE: The radiotherapeutic management of painful bone metastases is controversial, with several institutional and national guidelines advocating use of single-fraction radiotherapy. We aimed to determine patient choice of fractionation schedule after involvement in the decision-making process by use of a decision board. PATIENTS AND METHODS: Advantages and disadvantages of two fractionation schedules (24 Gy in six fractions v 8 Gy in one fraction) used in the randomized Dutch Bone Metastasis Study were discussed with patients using a decision board. Patients were asked to choose a fractionation schedule, to give reasons for their choice, and to indicate level of satisfaction with being involved in decision making. RESULTS: Sixty-two patients were entered. Eighty-five percent (95% confidence interval, 74% to 93%) chose 24 Gy in six fractions over 8 Gy in one fraction (P <.0005). Variables including age, sex, performance status, tumor type, pain score, and paying class were not significantly related to patient choice. Multiple fractionation was chosen for lower re-treatment rates (92%) and fewer fractures (32%). Single-fraction treatment was chosen for cost (11%) and convenience (89%). Eighty-four percent of patients expressed positive opinions about being involved in the decision-making process. CONCLUSION: Decision board instruments are feasible and acceptable in an Asian population. The vast majority of patients preferred 24 Gy fractionated radiotherapy compared with a single fraction of 8 Gy. These results indicate the need for further research in this important area and serve to remind both clinicians and national or institutional policy makers of the importance of individual patient preference in treatment decision making.

Design of an internationally accredited radiation oncology resident training program incorporating novel educational models.

PURPOSE: Our primary aim was to design a new, internationally accredited, comprehensive radiation oncology (RO) training program for Singaporean residents that satisfied the needs of stake holders and incorporated published evidence. METHODS AND MATERIALS: The evidence-based method included Medline literature review and broad-based training needs assessment. RESULTS: Literature review revealed few studies describing or evaluating RO resident training programs. Our program was designed by incorporating available published research and stakeholder views determined by the training needs assessment. The program includes novel evidence-based educational methods, including individually negotiated learning contracts, a mentor program, logbooks, task-based learning, tutorials, and formative plus summative assessments. The content and structure is consistent with most United States, United Kingdom, and Royal Australian and New Zealand College of Radiologist (RANZCR) guidelines, with resident evaluation via RANZCR examinations. The RANZCR accredited the program in January 2002. CONCLUSION: We recommend institutions or countries introducing or revising RO resident training programs use an evidence-based approach, addressing the needs of stake holders (determined by a comprehensive training needs assessment) and incorporating published research. Novel educational methods may be considered in RO training. This new Singapore program is the first to achieve international accreditation by the RANZCR. It is clear that additional research in the design and evaluation of RO resident training programs is required.

Evaluation of a radiotherapy protocol based on INT0116 for completely resected gastric adenocarcinoma.

PURPOSE: With the results of the INT0116 study, adjuvant radiochemotherapy has become the standard treatment after complete resection of gastric adenocarcinoma. However, the implementation of radiotherapy (RT) remains a concern. In response, consensus guidelines on RT technique have been published. Our objective was to measure the inter- and intraclinician variability in RT field delineation using conventional two- (2D) and three-dimensional (3D) techniques. METHODS AND MATERIALS: Between 1999 and 2003, five radiation oncologists (ROs) treated 45 patients with completely resected, gastric adenocarcinoma using postoperative radiochemotherapy (INT0116). Two cases were included in this study (Patient 1 had cardia and Patient 2 had antral disease). Standardized vignettes (with surgical and pathologic findings) and preoperative and postoperative imaging for each case were developed. Each RO designed AP-PA fields for each patient (2D planning) on two separate occasions. This was repeated using a 3D planning technique. RESULTS: Patient 1 had a mean field area of 250.2 cm(2) (SD 12.0) and 227.9 cm(2) (SD 26.5) using 2D and 3D planning, respectively (p = 0.03). The mean clinical target volume (CTV) volume was 468.3 cm(3) (SD 65.9). Patient 1 had a significantly greater inter- than intra-RO variation for the field area designed with 3D planning; however, no difference occurred with 2D planning or CTV contouring. Patient 2 had a mean field area of 234.8 cm(2) (SD 33.1) and 226.8 cm(2) (SD 19.3) using 2D and 3D planning, respectively (p = 0.5). The mean CTV was 729.4 cm(3) (SD 67.3). For Patient 2, the inter-RO variability was significantly greater than the intra-RO variability for the field area using both 2D and 3D planning, and no difference was seen for the CTV. Composite beam's-eye-view plots revealed that the superior, inferior, and right lateral borders proved to be most contentious. CONCLUSION: Despite published guidelines and a departmental protocol, significant variations in the RT field areas were seen among ROs for both 2D and 3D planning. However, in general, CTV contouring was reproducible. Because 3D-RT hinges on accurate target identification, caution should be exercised before migrating to 3D planning for postoperative gastric cancer.

The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial.

BACKGROUND: Metastatic bone disease (MBD) is a frequent complication in patients with breast cancer and is associated with significant morbidity. This study assessed the pharmacokinetics, efficacy, and safety of odanacatib, a selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD. PATIENTS AND METHODS: Women with breast cancer and MBD were randomized 2:1 (double-blind) to oral odanacatib 5 mg daily for 4 weeks or intravenous (I.V.) zoledronic acid (ZA) 4 mg given once at study initiation. Plasma samples were collected for pharmacokinetic analysis. Bone resorption was assessed by measuring urinary N-telopeptide of type I collagen corrected for creatinine (uNTx; primary objective, pmol BCE/µmol creatinine). Adverse events (AEs) were monitored throughout the 4-week study and up to 14 days after last dose. RESULTS: A total of 43 patients (mean age, 60 years) received odanacatib (n = 29) or ZA (n = 14); 40 patients completed 4 weeks of treatment. The mean percent change in uNTx values at week 4 was -77% (95% CI, -82 to -71; odanacatib) and -73% (95% CI, -80 to -62; ZA). Mean (standard deviation) plasma concentration of odanacatib was 511.7 (202.9) nM; the range was 63.7-844.8 nM. The most common AEs were nausea, vomiting, headache, and bone pain, which were generally not attributed to study drug. CONCLUSION: Odanacatib suppressed uNTx similarly to ZA after 4 weeks of treatment in women with breast cancer and MBD. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.

A comparison of RANZCR and Singapore-designed radiation oncology practice audit instruments: how does reproducibility affect future approaches to revalidation?

Physician competency assessment requires the use of validated methods and instruments. The Royal Australian and New Zealand College of Radiologists (RANZCR) developed a draft audit form to be evaluated as a competency assessment instrument for radiation oncologists (ROs) in Australasia. We evaluated the reliability of the RANZCR instrument as well as a separate The Cancer Institute (TCI) Singapore-designed instrument by having two ROs perform an independent chart review of 80 randomly selected patients seen at The Cancer Institute (TCI), Singapore. Both RANZCR and TCI Singapore instruments were used to score each chart. Inter- and intra-observer reliability for both audit instruments were compared using misclassification rates as the primary end-point. Overall, for inter-observer reproducibility, 2.3% of TCI Singapore items were misclassified compared to 22.3% of RANZCR items (P < 0.0001, 100.00% confidence that TCI instrument has less inter-observer misclassification). For intra-observer reproducibility, 2.4% of TCI Singapore items were misclassified compared to 13.6% of RANZCR items (P < 0.0001, 100.00% confidence that TCI instrument has less intra-observer misclassification). The proposed RANZCR RO revalidation audit instrument requires further refinement to improve validity. Several items require modification or removal because of lack of reliability, whereas inclusion of other important and reproducible items can be incorporated as demonstrated by the TCI Singapore instrument. The TCI Singapore instrument also has the advantage of incorporating a simple scoring system and criticality index to allow discrimination between ROs and comparisons against future College standards.

Cultural attitudes to cancer management in traditional South-East Asian patients.

Cultural differences might influence patients' attitudes to decision-making for cancer management. In a Western medical system promoting shared decision-making and patient autonomy, the effects of traditional South-East Asian cultural and religious attitudes might provoke confusion for both the patient and health-care provider. Especially in oncology, these beliefs might influence patients' perceptions of diagnosis, symptoms, interventions and approaches to death. For the clinician, the potential conflicts in patient disclosure and discussion of diagnosis are evident, as well as patient avoidance of certain interventions. This review article explores the background and interpretation of cultural aspects experienced by Australasian-trained oncologists working in Singapore. Explanations of traditional health beliefs of South-East Asian patients are outlined, and provide a perspective for oncologists managing similar patients within Australasia's multicultural community.

A study of complications arising from different methods of anesthesia used in high-dose-rate brachytherapy for cervical cancer.

The purpose of this report is to review the complications related to different methods of anesthesia for high-dose-rate (HDR) brachytherapy for cervical carcinoma. All patients diagnosed with cervical cancer between 1999 and 2002 treated with 3-channel HDR brachytherapy were entered. Complications due to anesthesia for each fraction of brachytherapy were graded using the Common Toxicity Criteria. Eighty-four fractions of brachytherapy were delivered to 18 patients: 19 fractions with patients under general anesthesia (GA), 41 with patients under topical anesthesia and sedation, 5 with patients under paracervical nerve block, and 19 with patients under conscious sedation. Thirteen complications were reported: 12 related to GA and 1 due to paracervical nerve block. Of complications due to GA, 7 were grade 1 and 5 were grade 2. The complication due to paracervical nerve block (seizure) was grade 3. GA had significantly more complications than topical anesthesia or conscious sedation (both P < 0.001). HDR brachytherapy for cervical cancer under GA has significantly more complications than other methods. Given the increasing use of fractionated 3-channel brachytherapy, further investigation of risks and benefits of anesthetic techniques is required.

Adjuvant high-dose rate brachytherapy after chemoradiation for treatment of early T-stage nasopharyngeal carcinoma.

The local control of nasopharyngeal carcinoma after conventional radiotherapy has historically been suboptimal. Recently, investigators have reported improved outcomes for this patient population with the use of combined chemoradiotherapy. The purpose of this analysis of our prospective treatment protocol was to evaluate the additional value of high-dose rate intracavitary brachytherapy (HDRIB) on the disease response, local control, and survival. Between March 1999 and January 2001, 16 patients with newly diagnosed locally advanced (stage III and IV) nasopharyngeal carcinoma were treated prospectively at the Radiation Oncology Department of the National University Hospital of Singapore. All patients were staged according to the AJCC (1997) Staging System and had early T stages (T1 and T2). Treatments included concurrent external beam radiotherapy (EBRT) and chemotherapy as follows: 66 Gy to the primary tumor in conventional fractionation with cisplatin based concurrent chemotherapy followed by adjuvant cisplatin and 5-fluorouracil (5-FU) chemotherapy. Ten Gy of HDRIB in 2 weekly fractions were delivered after the completion of EBRT to all 16 patients. All patients were evaluable for treatment response, local control, survival, and toxicity analysis. The median follow-up for the whole group of patients was 18 months (range: 10-34 months). All patients obtained pathologic complete response at the primary site at 4 months after the completion of the treatment. At the time of this analysis, 15 (93.8%) patients are alive with no evidence of disease. One patient (6.2%) developed locoregional recurrence in the neck at 9 months, and distant metastasis at 11 months after the completion of treatment. Our experience has shown adjuvant HDRIB after concurrent chemoradiation offers encouraging disease response, local control, and survival. A prospective study is being planned to further evaluate the role of adjuvant HDRIB after concurrent chemoradiation on treatment outcome.