Clinical Pharmacokinetics (PK) of Anti-MUC16 Antibody-Drug Conjugates (ADCs), DMUC5754A, in Patients with Platinum-Resistant Ovarian Cancer: Results from Phase I study

ABSTRACT

Jian Xu1*, Priya Agarwal1, Ola Saad1, Liu J2, Moore K3, Burris H A4, Eric W. Humke1, Kirsten Achilles Poon1, Sandhya Girish1

(1) Genentech, Inc., South San Francisco, CA; (2) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (3) University of Oklahoma Health Sciences Center, Oklahoma City, OK; (4) Harvard Medical School, Boston, MA

Objectives: MUC16 is a transmembrane glycoprotein that is overexpressed on ovarian cancer cells; the blood level of a soluble form of MUC16, carbohydrate antigen 125 (CA125), is also increased in the majority of advanced ovarian cancer patients. [1-4]. Conjugation of a highly potent cytotoxic drug to a MUC16-specific monoclonal antibody represents a novel approach to the treatment of ovarian cancer. DMUC5754A is an antibody drug conjugate (ADC) containing the potent anti-mitotic agent monomethyl auristatin E (MMAE) conjugated to a humanized IgG1 anti-MUC16 monoclonal antibody via a protease labile linker. A Phase I study is ongoing in platinum-resistant ovarian cancer patients to assess the safety, efficacy and pharmacokinetics of DMUC5754A (0.3-3.2 mg/kg) given every 3 weeks (Q3W). Here, we discuss the pharmacokinetics of DMUC5754A on patients from this study as well as the impact of circulating CA125 on exposure. Methods: In this study, serum/plasma samples were obtained from all patients at multiple time points. Three major analytes, including total antibody (unconjugated and conjugated antibody) (Tab), free MMAE and antibody conjugated MMAE (acMMAE), were quantified for the pharmacokinetic (PK) analysis. PK parameters for multiple analytes were assessed by standard non-compartmental analysis. Serum CA125 levels were measured at several time points and compared with PK exposure parameters by visual inspection. Results: After DMUC5754A administration, PK linearity was evaluated by PK parameters. Within the tested dose range, the systemic exposure of acMMAE and Tab increased nonlinearly. The mean Tab and acMMAE clearance ranged from 12.56 to 29.37 mL/day/kg, and 19.00 to 44.37 mL/day/kg, respectively. The median half-life for Tab, acMMAE and free MMAE was 1.5 to 5.6 days, 1.7 to 4.9 days, and 2.4 to 3.9 days, respectively. Accumulation of these three analytes is not expected. At 2.4 mg/kg, clearance (CL) was ~16 mL/day/kg (Tab) and ~26 mL/day/kg (acMMAE). The steady state volume of distribution (Vss) for both analytes (acMMAE and Tab) was ~84-89 mL/kg. Exposure of free MMAE at 2.4 mg/kg was ~54 ng/ml•day (AUCinf) and ~7 ng/mL (Cmax – achieved 2-3 days post-dose). CA125 levels in this study ranged up to ~7178 U/mL. At the dose of 2.4 mg/kg, there were no differences in exposure and PK parameters between patients with high and low pre-dose CA 125 levels. Conclusions: In this ongoing Phase I study with platinum-resistant ovarian cancer patients, nonlinear PK of acMMAE and Tab has been observed in the dose range of 0.3 to 3.2 mg/kg. Circulating CA125 data to date suggested no impact on the PK at 2.4 mg/kg, the potential clinically relevant dose. Systemic free MMAE concentrations have been low and consistent with other MMAE containing ADCs either approved or in clinical development.

•  First in Human Phase 1 Study Design: Platinum-Resistant Ovarian Cancer (PROC) as shown in Figure 1.

•  In this study, pharmacokinetic samples for total antibody (unconjugated and conjugated antibody) (Tab), free MMAE and

antibody conjugated MMAE (acMMAE) were collected at pre-specified time points and were evaluated using a validated ELISA assay for Tab, a validated LC-MS/MS assay for acMMAE, and a validated LC-MS/MS assay for free MMAE in ovarian cancer patients.

•  Non-compartmental pharmacokinetics parameters for DMUC5754A total antibody, acMMAE, and free MMAE were calculated by WinNonlin Enterprise (Pharsight Corporation) and were estimated from samples collected after the first dose of DMUC5754A during Cycle 1.

•  Serum CA125 levels were measured at several time points and the impact of CA125 on PK exposure parameters was assessed by plotting with visual inspection.

•  DMUC5754A is an antibody drug conjugate (ADC) with toxin of MMAE, and conjugated antibody specially targets MUC16 overexpressed ovarian cancer cells.

•  CA125 is useful to monitor ovarian cancer disease response or progression, but is also circulating form of extracellular domain of MUC16. Thus, CA125 is the soluble antigen to DMUC5754A.

•  Understanding CA125 impact is important to help dose optimization in current and future studies. •  A ongoing Phase I is to evaluate the safety, efficacy and pharmacokinetics of DMUC5754A in platinum-resistant ovarian cancer

patients.

•  In this ongoing Phase I study with platinum-resistant ovarian cancer patients, nonlinear PK of acMMAE and Tab has been observed in the dose range of 0.3 to 3.2 mg/kg.

•  Circulating CA125 data to date suggested no impact on the PK at 2.4 mg/kg, the potential clinically relevant dose.

•  Systemic free MMAE concentrations have been low and consistent with other MMAE containing ADCs either approved or in clinical development.

• Yulei Wang, Walter Darbonne for Biomarker and Marija Milojic Blair for Assay support. • All members in MUC16 project team.

BACKGROUND

METHODS

RESULTS & DISCUSSION

CONCLUSIONS

Dose (mg/kg) N Cmax AUCinf

t1/2 (day)

CL (mL/day/kg)

Vss (mL/kg)

Total Antibody (ug/mL) (ug/mL⋅day) 0.3   3   6.65  (12.9%)   11.52  (46.5%)   1.51  (41.6%)   29.37  (36.8%)   45.43  (46.5%)  0.6   3   16.60  (30.0%)   29.10  (22.1%)   1.40  (60.0%)   21.37  (23.2%)   44.00  (24.1%)  1.2   3   22.47  (13.5%)   81.43  (60.8%)   4.05  (93.9%)   20.49  (73.6%)   75.90  (34.1%)  1.8   3   35.47  (3.4%)   101.97  (14.6%)   5.63  (29.5%)   17.90  (14.0%)   83.37  (15.5%)  2.4   28   42.10  (21.0%)   179.01  (37.3%)   5.47  (47.2%)   15.64  (45.9%)   89.44  (29.9%)  3.2   3   71.43  (20.2%)   270.33  (29.5)   4.08  (11.4%)   12.56  (29.8%)   61.23  (36.2%)  

acMMAE (ng/mL) (ng/mL⋅day) 0.3   3   93.30  (32.4%)   132.50  (40.5%)   1.71  (51.6%)   44.37  (33.5%)   79.07  (18.0%)  0.6   3   225.67  (19.0%)   305.00  (29.0%)   3.00  (11.7%)   37.20  (30.8%)   62.37  (22.2%)  1.2   3   337.33  (13.7%)   711.33  (39.1%)   4.00  (55.2%)   34.27  (47.8%)   95.07  (32.9%)  1.8   3   617.67  (10.6%)   1004.00  (13.4%)   3.79  (27.1%)   32.30  (13.5%)   81.10  (3.7%)  2.4   29   859.69  (25.2%)   1786.79  (29.8%)   4.90  (32.7%)   26.22  (32.5%)   83.87  (28.4%)  3.2   3   1220.00  (4.6%)   2953.33  (22.2%)   3.01  (54.6%)   19.90  (19.7%)   68.00  (23.9%)  

Free MMAE (ng/mL) (ng/mL⋅day) 0.3   3   0.68  (23.9%)   4.33  (32.5%)   3.09  (18.8%)  

Note: Mean (%CV);

Median (%CV) for half-life

0.6   3   2.03  (50.1%)   10.19  (37.6%)   2.49  (24.0%)  1.2   3   2.84  (21.2%)   19.17  (16.6%)   3.86  (21.2%)  1.8   3   4.70  (40.5%)   32.30  (51.9%)   3.81  (19.7%)  2.4   28   6.76  (59.2%)   54.32  (74.0%)   3.07  (28.4%)  3.2   3   20.03  (74.7%)   234.33  (85.5%)   2.37  (14.3%)  

Table 1. Summary of PK Parameters for Each Analyte in Cycle 1

Figure 5. Predose CA125 Level vs. Cmax or AUC in Cycle 1

Figure 4. Histogram of Predose CA125 Levels in Cycle 1

•  Recommended Phase 2 Dose (RP2D): 2.4 mg/kg Q3W based on Maximum Tolerated Dose (MTD) •  At RP2D: Serum concentration-time profiles similar between total antibody and acMMAE •  At RP2D: Minimal accumulation for both acMMAE and total antibody •  No Impact of Predose CA125 on PK Exposure: Cmax and AUC in Cycle 1 •  No Impact of Predose CA125 on acMMAE PK Profile at RP2D

ACKNOWLEDGEMENTS

American Conference on Pharmacometrics (ACoP) Fort Lauderdale, FL, May 12 - 15, 2013

Figure 1.

Figure 2 Pharmacokinetic Profiles for Each Analyte (Cycle 1).

•  Exposure increased with the increase of dose

•  Similar exposure between escalation 2.4 mg/kg cohort and expansion 2.4 mg/kg cohort

•  Approximately linear PK of free MMAE

•  Nonlinearity of PK of total Antibody and acMMAE

Figure 3. PK Profiles at RP2D (2.4 mg/kg, Q3W) in Cycle 1

Total 42 patients with predose CA125 levels in cycle 1 •  12 pts with >1000 U/mL

a)

b)

High: 3230 ~7177 U/mL Low: 100.1 ~525.4 U/mL

Figure 6. Selected PK Profiles with High or Low Cycle 1 Predose CA125 levels at RP2D (a. logX; b logY)