Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer.

BACKGROUND: MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody-drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). PATIENTS AND METHODS: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3-3.2 mg/kg) or weekly (Q1W, 0.8-1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. RESULTS: Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. CONCLUSIONS: DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. CLINICAL TRIAL NUMBER: NCT01335958.

Preclinical studies to predict the disposition of Apo2L/tumor necrosis factor-related apoptosis-inducing ligand in humans: characterization of in vivo efficacy, pharmacokinetics, and safety.

Apo2L/TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a member of the tumor necrosis factor gene family known to induce apoptosis in a number of cancer cell lines and may have broad-spectrum activity against human malignancies. These studies have evaluated the potency of recombinant soluble human Apo2L/TRAIL in a mouse xenograft model and the disposition and safety of Apo2L/TRAIL in rodents and nonhuman primates. Mice with established COLO205 tumors were given daily i.v. injections of Apo2L/TRAIL (30-120 mg/kg/day). Control tumors doubled in size every 2 to 3 days, while time to tumor doubling in the treatment groups was significantly longer and related to dose (14-21 days). For pharmacokinetic studies, Apo2L/TRAIL was given as an i.v. bolus to mice (10 mg/kg), rats (10 mg/kg), cynomolgus monkeys (1, 5, and 50 mg/kg), and chimpanzees (1 and 5 mg/kg). Apo2L/TRAIL was rapidly eliminated from the serum of all species studied. Half-lives were approximately 3 to 5 min in rodents and approximately 23 to 31 min in nonhuman primates. Allometric scaling provided estimates of Apo2L/TRAIL kinetics in humans, suggesting that on a milligram per kilogram basis, doses significantly lower than those used in xenograft studies could be effective in humans. Apo2L/TRAIL clearance was highly correlated with glomerular filtration rate across species, indicating that the kidneys play a critical role in the elimination of this molecule. Safety evaluations in cynomolgus monkeys and chimpanzees revealed no abnormalities associated with Apo2L/TRAIL exposure. In conclusion, these studies have characterized the disposition of Apo2L/TRAIL in rodents and primates and provide information that will be used to predict the pharmacokinetics of Apo2L/TRAIL in humans.

Vitamin A intake affects the contribution of chylomicrons vs. retinol-binding protein to milk vitamin A in lactating rats.

To investigate the influence of vitamin A intake on the contribution of chylomicrons vs. holo retinol-binding protein to milk vitamin A, female rats were fed diets containing either 10 (n = 6) or 50 micromol vitamin A/kg body (n = 4) during pregnancy and through d 13 of lactation. [3H]Vitamin A was incorporated into each diet beginning on d 6 of lactation. Vitamin A concentrations on d 13 were significantly higher in dam liver (x 3), pup liver (x 2.6), milk (x 2.5) and mammary tissue (x 1.3) in rats consuming the higher level of vitamin A. In both groups, vitamin A specific activities in plasma and milk reached apparent plateaus by 2.33 d after addition of [3H]vitamin A to the diets. Vitamin A specific activity in milk was higher than in plasma at all times in both groups. The estimated minimum contribution of chylomicrons to milk vitamin A was 32 +/- 3% in rats fed the lower level of vitamin A vs. 52 +/- 10% at the higher level (P = 0.014). We concluded that dietary vitamin A, like triglycerides, may be directed to mammary tissue during lactation for preferential secretion into milk; thus, increasing vitamin A intakes will increase the contribution of dietary vitamin A to milk. In contrast to milk, mammary tissue vitamin A turns over very slowly.

Mobilization of vitamin A stores in rats after administration of 2,3, 7,8-tetrachlorodibenzo-p-dioxin: a kinetic analysis.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant that prevents the normal accumulation of vitamin A in liver and causes increased excretion of vitamin A. To determine what alterations in vitamin A metabolism occur first in response to TCDD treatment, we administered TCDD (7.0 microg/kg b.w. ) orally to rats that had received a nonperturbing (tracer) iv dose of [(3)H]vitamin A-labeled plasma (n = 3) or lymph (n = 3) 21 days earlier. Within a few days after TCDD administration, fraction of the injected radiolabel in plasma, which had been in a terminal slope when plotted on a semilog scale, increased and remained elevated until the experiment was terminated (day 42). At that time, liver vitamin A levels were 65% lower in TCDD-perturbed rats than in controls. Using model-based compartmental analysis and compartmental models developed previously for control rats (S. K. Kelley et al., 1998, Toxicol. Sci, 44:1-13), we determined the minimal changes needed to account for the perturbation in plasma [(3)H] tracer responses after TCDD administration. We determined that the effects of TCDD could be explained by adjusting the value of one fractional transfer coefficient corresponding to the mobilization of vitamin A from large, slowly turning-over pools. We speculate that this change corresponds to an increased fractional rate of retinyl ester hydrolysis, and that it precedes the TCDD-associated increased irreversible utilization and excretion of vitamin A.

Plasma retinol is a major determinant of vitamin A utilization in rats.

We studied relationships among vitamin A intake, liver levels of vitamin A, plasma retinol concentrations and the irreversible utilization of vitamin A. To supplement existing data, we first used model-based compartmental analysis to determine vitamin A utilization and other kinetic parameters in male Sprague-Dawley rats that had adequate liver vitamin A stores ( approximately 9000 nmol) and were fed a diet containing low levels of vitamin A. Plasma retinol kinetics were monitored for 43 d after administration of [3H]retinol-labeled plasma to rats consuming approximately 23 (Group 1, n = 6) or approximately 4.2 (Group 2, n = 6) nmol vitamin A/d. Data for plasma tracer vs. time and for tracer lost irreversibly by the end of the experiment, were fit to a three-compartment model in which plasma retinol exchanges with vitamin A in two kinetically distinct extravascular compartments. Irreversible utilization rates ( approximately 41 nmol/d) were similar to those for rats that are in vitamin A balance, suggesting that, when liver vitamin A stores are adequate, utilization rate is not decreased to compensate for a low vitamin A intake. Multiple linear regression analysis was then used to relate these and previously collected data (total, 62 rats) on vitamin A intake (4. 2-49 nmol/d), plasma retinol concentration (1.4-2.5 micromol/L) and liver vitamin A level (1.2-11,000 nmol) to vitamin A utilization (disposal rate, 4.2-68 nmol/d). A significant relationship (R2(adj) = 0.93) was found for the equation [disposal rate (nmol/d) = -0.720 (nmol/d) + 0.844 (d-1).(plasma retinol; nmol) + 0.00139 (d-1).(liver vitamin A; nmol) + 0.220.(vitamin A intake; nmol/d)]. Plasma retinol accounted for 92% of the variability in disposal rate (vs. 5% for liver vitamin A and 3% for vitamin A intake). We conclude that plasma retinol is a main determinant of the irreversible utilization of vitamin A in rats with low to moderate vitamin A intake.

Plasma thyroid hormone kinetics are altered in iron-deficient rats.

Iron deficiency anemia is associated with lower plasma thyroid hormone concentrations in rodents and, in some studies, in humans. The objective of this project was to determine if plasma triiodothyronine (T3) and thyroxine (T4) kinetics were affected by iron deficiency. Studies were done at a near-thermoneutral temperature (30 degrees C), and a cool environmental temperature (15 degrees C), to determine plasma T3 and T4 kinetics as a function of dietary iron intake and environmental need for the hormones. Weanling male Sprague-Dawley rats were fed either a low Fe diet [iron-deficient group (ID), <5 microg/g Fe] or a control diet [control group (CN), 35 microg/g Fe] at each temperature for 7 wk before the tracer kinetic studies. An additional ID group receiving exogenous thyroid hormone replacement was also used at the cooler temperature. For T4, the disposal rate was >60% lower (89 +/- 6 vs. 256 +/- 53 pmol/h, P < 0.001) in ID rats than in controls at 30 degrees C, and approximately 40% lower (192 +/- 27 vs. 372 +/- 26 pmol/h, P < 0.01) in ID rats at 15 degrees C. Exogenous T4 replacement in a cohort of ID rats at 15 degrees C normalized the T4 concentration and the disposal rate. For T3, the disposal rate was significantly lower in ID rats in a cool environment (92 +/- 11 vs. 129 +/- 11 pmol/h, P < 0.01); thyroxine replacement again normalized the T3 disposal rate (126 +/- 12 pmol/h). Neither liver nor brown fat thyroxine 5'-deiodinase activities were sufficiently different to explain the lower T3 disposal rates in iron deficiency. Thus, plasma thyroid hormone kinetics in iron deficiency anemia are corrected by simply providing more thyroxine. This suggests a central regulatory defect as the primary lesion and not peripheral alterations.

Use of model-based compartmental analysis to study effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on vitamin A kinetics in rats.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic, widespread environmental contaminant that has dramatic adverse effects on the metabolism of vitamin A. We used model-based compartmental analysis to investigate sites and quantitative impacts of TCDD on vitamin A kinetics in rats given on oral loading dose of TCDD in oil (3.5 micrograms/kg) followed by weekly maintenance doses (0.7 microgram/kg) or oil only. [3H]Retinol in its plasma transport complex (experiment 1) of lymph containing chylomicrons labeled mainly with [3H]retinyl esters (experiment 2) were administered i.v., and tracer kinetics in plasma, liver, carcass, urine, and feces were measured for up to 42 days. TCDD treatment caused significant reductions in liver vitamin A levels and significant changes in tracer kinetics and tracer excretion. A four-compartment model was used to fit tracer data for experiment 1; for experiment 2, compartments were added to describe the metabolism of newly absorbed vitamin A. The compartmental models predict that TCDD caused a slight delay in plasma clearance (via an increased recycling to plasma), and in liver processing, of chylomicron-derived vitamin A. Models for both experiments predict that TCDD exposure did not affect the fractional uptake of plasma retinol from the rapidly turning-over extravascular pool, but it doubled the fractional transfer of recycled retinol from slowly turning-over pools of vitamin A to plasma. The residence time for vitamin A was reduced by 70% in TCDD-treated rats, transfer into urine and feces was tripled, and vitamin A utilization rates were significantly increased. Since our results do not indicate that retinol esterification is inhibited, we hypothesize that some of the significant effects of TCDD on vitamin A metabolism result from increased catabolism and mobilization of vitamin A from slowly turning-over pools (especially the liver).

A survey of human resources in managed care organizations.

Although managed health care is increasing exponentially in the United States, minimal published information exists regarding the human resources needed to perform various managed care activities. This article reports on the results of a national survey of managed care organizations regarding the quantitative use of nurse and physician reviewers and the type of activities being performed.