Phase I Study of the Prolactin Receptor Antagonist LFA102 in Metastatic Breast and Castration-Resistant Prostate Cancer

Abstract

Lessons learned: Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.

Background: Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.

Methods: Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.

Results: A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.

Conclusion: Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.

Trial registration: ClinicalTrials.gov NCT01338831.

Figure 1.

AUC_last and C_max increase with LFA102 dose in a relatively proportional manner. AUC_last (A) and C_max (B) results for individual patients in cycle 1. For each dose, parameter values (open symbols), least-square mean (black triangles), and 90% least-square means confidence interval (vertical bars) are shown. Serum LFA102 concentrations were measured up to day 28 of cycle 1 via dense sampling followed by trough concentration measurement in subsequent cycles. Concentration-time profiles show biexponential disposition typical for monoclonal antibodies. C_max and AUC_last increased in a relatively proportional manner with increasing LFA102 doses. Abbreviations: AUC_last, area under the last measurable concentration; C_max, maximum concentration observed.

Figure 2.

Serum prolactin levels rise with increasing doses of LFA102. Linear views of individual serum prolactin concentration-time profiles grouped by LFA102 dose group are shown. Individual patient serum prolactin increased after LFA102 administration.

Supplemental Figure 1.

(A): Linear view. (B): Semilogarithmic view.

Supplemental Figure 2.

Individual LFA102 concentration-time profiles by treatment group: semi-logarithmic view (cycle 1).

Supplemental Figure 3.

Geometric mean for fold change from baseline for serum prolactin versus time profiles by treatment group (cycle 1).

Supplemental Figure 4.

Correlation of maximum fold change from baseline serum prolactin with dose.

Supplemental Figure 5.

Correlation of serum prolactin exposure with baseline prolactin receptor expression, 60 mg/kg dose group. r² = .003; p = .7. Abbreviations: AUEC, area under the effect curve; PRLR, prolactin receptor.