Adedigbo Fasanmade

Pharmacokinetic Properties of Infliximab in Children and Adults with Crohn's Disease: A Retrospective Analysis of Data from 2 Phase III Clinical Trials

BACKGROUND Infliximab is a chimeric monoclonal antibody against TNFα. The pharmacokinetic (PK) properties of infliximab have been studied in several adult patient populations, but a literature search identified no reported comparative population PK properties of this drug in pediatric patients. OBJECTIVES The current analysis applied population PK techniques to compare data on the PK properties of infliximab in pediatric and adult patients with moderately to severely active Crohns disease (CD) from 2 Phase III studies. METHODS This analysis used serum infliximab concentration data from 692 patients (112 children, 580 adults; age range, 6-76 years) from 2 Phase III clinical studies (REACH [A Randomized, Multicenter, Open-Label Study to Evaluate the Safety and Efficacy of Anti-TNF-α Chimeric Monoclonal Antibody in Pediatric Subjects with Moderate-to-Severe Crohns Disease] and ACCENT I [A Crohns Disease Clinical Trial Evaluating Infliximab in a New, Long-term Treatment Regimen]). PK models were developed separately for children, adults, and a combination of both. The combined population was used for establishing important covariates of infliximab PK properties in the combined CD population. Exploratory simulations using combined PK and covariate data were performed to expand the interpretation of the results in children. RESULTS Based on the findings, in a typical child (who, based on the median values in REACH, weighs 42 kg, has a baseline serum albumin concentration [SAC] 3.8 mg/dL, and has not developed antibodies to infliximab [ATIs]) who is receiving infliximab and an immunomodulator, PK estimates (typical value [SE]) were as follows: clearance (CL), 5.43 (0.15) mL/kg/d; V(d) in the central compartment (V(1)), 54.2 (1.15) mL/kg; V(d) in the peripheral compartment (V(2)), 29.2 (2.03) mL/kg; and intercompartmental clearance (Q), 3.52 (0.71) mL/kg/d. Corresponding properties in a typical adult (weight, 68 kg; SAC, 4.1 mg/dL) were CL, 5.39 (0.13) mL/kg/d; V(1), 52.7 (0.49) mL/kg; V(2), 19.0 (1.53) mL/kg; and Q, 2.15 (0.39) mL/kg/d. V(2) decreased as body weight increased, predicting a possible undercompensation for exposure with infliximab dosing per kg weight in lower-weight individuals. In pediatric and adult patients, CL was higher in those in whom ATIs developed or who had low baseline SAC. Concurrent immunomodulator use (purine antimetabolites or methotrexate) was associated with a 14% decrease in CL. In the pediatric and adult patients, observed trough serum infliximab concentrations, median infliximab t(1/2) (in children, 13.2 days; and in adults, 12.4 days), and exploratory PK simulations predicted infliximab PK properties to be comparable between children and adults. CONCLUSIONS Infliximab PK properties appeared to be comparable between pediatric and adult patients with CD. Specifically, in this select population using nonlinear mixed effects modeling, infliximab CL increased as SAC decreased. CL also increased with ATI formation but decreased with immunomodulator coadministration. Although weight affects infliximab PK properties (total CL and total Vd increased with total body weight while per kg CL and Vd decrease with total body weight), age was not found to influence infliximab PK in the age range tested (6-76 years).

Population Pharmacokinetics of Infliximab in Patients With Ankylosing Spondylitis

The population pharmacokinetics of infliximab were characterized in patients with active ankylosing spondylitis (n =274). Serum infliximab concentration data, from a 2‐year period, were analyzed using NONMEM. A 2‐compartment linear pharmacokinetic model was chosen to describe the pharmacokinetic characteristics of infliximab in serum. Population estimates (typical value ± standard error) were obtained from the final covariate model: clearance (CL: 0.273 ± 0.007 L/day), volume of distribution in the central compartment (V1: 3.06 ± 0.057 L), intercompartment clearance (Q: 1.72 ± 0.48 L/day), and volume of distribution in the peripheral compartment (V2:2.94 ± 0.17 L). Interindividual variability for CL and V1 was 34.1% and 17.5%, respectively. White blood cell count at baseline and the antibody‐to‐infliximab status were significant covariates to CL; body surface area and sex were significant covariates to V1. The CL for patients with a positive antibody‐to‐infliximab status was estimated to be 41.9% to 76.7% higher than for the remaining patients. Other covariates (baseline disease activity and the concomitant medication use of prednisolone, omeprazole, nonsteroidal anti‐inflammatory drugs, or analgesics) did not affect infliximab pharmacokinetics. The development of antibodies to infliximab was associated with accelerated infliximab clearance and may represent a potential underlying mechanism for an inadequate response, or loss of response, to infliximab treatment.

Absence of Adverse Effects in Cynomolgus Macaques Treated with CNTO 95, a Fully Human Anti-αv Integrin Monoclonal Antibody, Despite Widespread Tissue Binding

Purpose: CNTO 95 is a fully human anti-αv integrin monoclonal antibody that inhibits macaque and rodent angiogenesis and inhibits human tumor growth in rodents. The purpose of these studies was to evaluate the preclinical safety of long-term administration of CNTO 95 in cynomolgus macaques. Experimental Design: The in vitro binding profiles of CNTO 95 to human and macaque tissues and the in vivo binding to macaque tissues was evaluated by immunohistochemistry. The preclinical safety of CNTO 95 (10 and 50 mg/kg, i.v.) was evaluated in macaques treated once per week for up to 6 months. Safety was evaluated by clinical observations, ophthalmic and physical examinations (including heart rate, blood pressure, and electrocardiogram), clinical pathology (including coagulation parameters), and comprehensive anatomic pathology. The effect of CNTO 95 (50 mg/kg, i.v.) on incisional wound healing was evaluated in macaques. Results: The tissue binding studies showed that CNTO 95 bound with mild to moderate intensity to macaque and human endothelial cells, epithelial cells, and vascular smooth muscle cells in most normal tissues examined. CNTO 95 showed strong to intense staining to the positive control tissue, human placenta. Despite the widespread binding to normal tissues, treatment of cynomolgus macaques with CNTO 95 produced no signs of toxicity and no histopathologic changes in any of the tissues examined (including ovaries and bone growth plates). CNTO 95 did not impair wound healing. Conclusion: These studies show that CNTO 95 is safe and, unlike some other angiogenesis inhibitors, does not seem to inhibit normal physiologic angiogenesis.

Phase I Study of the Investigational Anti-Guanylyl Cyclase Antibody-Drug Conjugate TAK-264 (MLN0264) in Adult Patients with Advanced Gastrointestinal Malignancies.

Purpose: To assess the safety, tolerability, and preliminary antitumor activity of the investigational anti–guanylyl cyclase C (GCC) antibody–drug conjugate TAK-264 (formerly MLN0264) in adult patients with advanced gastrointestinal malignancies. Experimental Design: Adult patients with GCC-expressing gastrointestinal malignancies (H-score ≥ 10) were eligible for inclusion. TAK-264 was administered as a 30-minute intravenous infusion once every 3 weeks for up to 17 cycles. Dose escalation proceeded using a Bayesian continual reassessment method. At the maximum tolerated dose (MTD), 25 patients with metastatic colorectal cancer were enrolled in a prespecified dose expansion cohort. Results: Forty-one patients were enrolled, including 35 (85%) with metastatic colorectal cancer. During dose escalation (0.3–2.4 mg/kg), four of 19 patients experienced dose-limiting toxicities of grade 4 neutropenia; the MTD was determined as 1.8 mg/kg. Patients received a median of two cycles of TAK-264 (range, 1–12); nine received ≥four cycles. Common drug-related adverse events (AEs) included nausea and decreased appetite (each 41%), fatigue (32%), diarrhea, anemia, alopecia, and neutropenia (each 27%); grade ≥3 AEs included neutropenia (22%), hypokalemia, and febrile neutropenia (each 7%). Peripheral neuropathy was reported in four (10%) patients. Pharmacokinetic data showed approximately dose proportional systemic exposure and a mean plasma half-life of around 4 days, supporting the dosing schedule. Overall, 39 patients were response-evaluable; three experienced durable stable disease; and one with gastric adenocarcinoma had a partial response. GCC expression did not appear to correlate with treatment duration. Conclusions: These findings suggest that TAK-264 has a manageable safety profile, with preliminary evidence of potential antitumor activity in specific gastrointestinal malignancies. Further investigation is underway. Clin Cancer Res; 22(20); 5049–57. ©2016 AACR.

Abstract CT117: A phase II trial of TAK-264, a novel antibody-drug conjugate (ADC), in patients with pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC)

TAK-264 (formerly MLN0264) is a novel ADC consisting of a human monoclonal antibody that specifically targets GCC, the potent microtubule disrupting agent monomethyl auristatin E (MMAE), and a linker. GCC is selectively expressed in the gastrointestinal (GI) tract, and its expression is maintained through the spectrum of adenoma and carcinoma in the colorectum as well as the pancreas. A Phase 1 clinical trial has demonstrated a manageable safety profile and clinical activity of TAK-264 in patients with pancreatic and gastric carcinomas (NCT01577758). The primary objective of this Phase 2, open-label, non-randomized, multicenter study was to evaluate the overall response rate (ORR; complete response + partial response [PR]), safety, and tolerability of TAK-264 in previously treated adult patients with advanced or metastatic pancreatic adenocarcinoma expressing GCC. Here we report the findings from the interim analysis (IA). Per protocol, the IA was required to show objective responses in at least 2/12 patients with a defined GCC level to continue the second part of this study. Patients aged ?18 years with advanced or metastatic pancreatic adenocarcinoma expressing GCC (confirmed histologically by immunohistochemistry with an H score of ?10) who had received ?1 prior treatment, were eligible for inclusion. TAK-264 1.8 mg/kg was administered as a single 30 minute intravenous infusion on day 1 of a 21-day cycle for up to 1 year or until disease progression or unacceptable toxicity. At data cut-off (October 5, 2015), 43 patients had been enrolled. The median age was 61 years (range, 44-81). Participating patients had metastatic disease and received a median of 3 prior therapies (range, 1-8), with a median time since initial diagnosis of 16.6 months (range, 6-51). Of the 38 patients in the response-evaluable population, the ORR was 3% (PR, n = 1) and 9 patients (24%) had stable disease. A total of 28 (74%) patients experienced progressive disease. All patients received at least 1 dose of TAK-264 and were included in the safety population. The most common adverse events (AE) reported in ?15% of patients were abdominal pain (47%), nausea (37%), fatigue (35%), constipation and decreased appetite (each 28%), vomiting and neutropenia (each 26%), asthenia (21%), and dehydration (16%). Grade ?3 neutropenia, including febrile neutropenia, was reported in 7 (16%) and 2 (5%) patients, respectively. Grade ?3 GI AE included abdominal pain (9%), dyspepsia and vomiting (each 5%), and diarrhea (2%). Overall, a limited number of patients with GCC-positive pancreatic adenocarcinoma showed a modest clinical benefit from treatment with an ADC exploiting MMAE. The correlation between GCC levels and clinical outcomes is being explored. Based on the IA, these data do not support continuation of this study. Citation Format: Khaldoun Almhanna, David Wright, Teresa Macarulla Mercade, Jean-Luc Van Laethem, Antonio Cubillo Gracian, Carmen Guillen-Ponce, Jason Faris, Carolina Muriel Lopez, Richard Hubner, Johanna Bendell, Alain Bols, Jaime Feliu Batlle, Naureen Starling, Peter Enzinger, Devalingham Mahalingham, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic. A phase II trial of TAK-264, a novel antibody-drug conjugate (ADC), in patients with pancreatic adenocarcinoma expressing guanylyl cyclase C (GCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT117.

Abstract CT107: Phase II trial of TAK-264 in previously treated patients (pts) with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expression guanylyl cyclase C (GCC)

Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA Gastric cancer is the third-leading cause of cancer-related deaths worldwide. Outcomes of current treatment regimens remain unsatisfactory, particularly in pts with advanced gastric cancer. TAK-264 is a novel drug conjugate consisting of a human monoclonal antibody that specifically targets GCC, which is expressed in approximately 70% of gastric cancers, linked to the potent microtubule disrupting agent monomethyl auristatin E. In the first-in-human Phase 1 study ([NCT01577758][1]) evaluating the safety of TAK-264, preliminary signals of clinical activity were reported in pts with gastric, gastroesophageal, and pancreatic carcinoma. The primary objective of this Phase 2 open-label, non-randomized, multicenter study ([NCT02202759][2]) was to evaluate the overall response rate (ORR; complete response + partial response) of adult pts with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction. Here we report the findings from the Interim Analysis (IA). Pts aged ?18 years with histologically-confirmed metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction, who were GCC-positive as demonstrated by immunohistochemistry with an H score ?10 and who had received ?1 prior therapy were eligible for inclusion. TAK-264 1.8 mg/kg was administered as a single 30-minute intravenous infusion on day 1 of a 21-day cycle until disease progression or unacceptable toxicity occurred. Pts were evaluated for a response every 2 cycles. At data cut-off (October 1, 2015), 37 pts had been enrolled (81% male), of which 36 (97%) pts were response-evaluable. The median age at baseline was 63 years (range, 31-81) and the median time from the initial diagnosis was 19.7 months (range, 5-76). Pts had received a median of 3 prior therapies (range, 1-7). Of the 36 pts in the response-evaluable population, the ORR was 6% (2 pts) and stable disease was observed in 15 (42%) pts. Progressive disease was experienced by 19 (53%) pts. All pts received at least one dose of TAK-264 and were included in the safety population. Common adverse events (AEs) observed in ?15% of pts included nausea (49%), fatigue (30%), decreased appetite and asthenia (each 27%), constipation and vomiting (each 22%), peripheral edema (19%), and diarrhea and anemia (each 16%). Diarrhea and neutropenia were the most prevalent Grade ?3 AEs, (each 5%). Other Grade ?3 gastrointestinal AEs included dysphagia, nausea and decreased appetite (each 1%). Results from the current IA suggest that few pts with GCC-positive metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction experienced limited clinical benefit with TAK-264 treatment. The correlation between GCC levels and clinical outcomes is being explored. Based on the IA, these data do not support continuation of the study. Citation Format: Khaldoun Almhanna, Maria Luisa Limon Miron, David Wright, Antonio Cubillo Gracian, Richard Hubner, Jean-Luc Van Laethem, Carolina Muriel Lopez, Maria Alsina, Federico Longo Munoz, Johanna Bendell, Wells Messersmith, Huyuan Yang, Adedigbo Fasanmade, Hadi Danaee, Thea Kalebic. Phase II trial of TAK-264 in previously treated patients (pts) with metastatic or recurrent adenocarcinoma of the stomach or gastroesophageal junction expression guanylyl cyclase C (GCC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT107. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01577758&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02202759&atom=%2Fcanres%2F76%2F14_Supplement%2FCT107.atom