A First-in-Human Study of PRL3-ZUMAB

PRL-3 is involved in cellular processes driving metastasis, including cell proliferation, invasion, motility and survival and has been shown to be upregulated and overexpressed in cancer tissues, in contrast to low or no expression in most normal tissues. In mouse models of PRL3-positive gastric cancers, PRL3-ZUMAB, a first-in-class humanized antibody against PRL-3, has shown to reduce tumour growth and increase survival. In contrast, no response was seen in PRL3-negative gastric cancer mouse models, reflecting the exquisite target specificity of PRL3-ZUMAB.

Because PRL3-ZUMAB has produced little apparent toxicity in Good Laboratory Practice (GLP) toxicology studies, it is expected to have a favorable adverse event (AE) profile in humans. PRL3-ZUMAB has the potential to be an anti-tumor agent in the management of solid tumors. In this first-in-human study, the Phase Ia study will confirm safety, tolerability and establish evidence for anti-tumor activity in advanced, solid tumor patients in the dose expansion phase (Phase Ib).

• Rationale for Doses Selected: Administration of 50-150 μg PRL3-zumab/dose significantly reduced PRL-3-positive lung tumor burden in Balb/C nude mice metastatic tumor models (p = 0.044, Kruskal-Wallis test).

These results established the range of 50-150 ug PRL3-zumab/dose as sufficiently efficacious exposure levels for maximal suppression of PRL-3-positive tumors in rodents in this experimental setting. Importantly, this dose range did not cause any undesirable side effects - mice receiving these doses of PRL3-zumab displayed normal weight gain and physical activity, as compared to untreated mice. Based on these observations, the median dose of 100 ug PRL3-zumab/dose (i.e. approximately 4-5 mg/kg, depending on mice body weight between 20 to 25 g) was set as the pharmacologically active dose (PAD) in all subsequent animal treatment experiments. Assuming a PAD in rodent tumor models of 5 mg/kg, a PAD of around 0.4 mg/kg is expected in humans by converting this into the Minimal Anticipated Biologically Effect Level (MABEL) in humans by dividing by a factor of 12.3 (based on FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers).

In the monkey toxicokinetics study, PRL3-zumab was administered IV over 8 weeks at 2 week intervals. Dose amounts of 4 to 36 mg/kg (0 mg/kg for controls) were used. As the dose increased from 4 to 36 mg/kg, the systemic exposure (AUC0-168 and C0) to PRL3-zumab increased dose-proportionally on Day 1 and 57 and there was no marked drug accumulation for PRL3-zumab at any dose level. Therefore, the no observed adverse effect level (NOAEL) in the GLP toxicology study in cynomolgus monkeys for PRL3-zumab was considered to be 36 mg/kg/dose.

Using the standard safety factor of 1/10th of the NOAEL as the starting dose for humans yields a human dose of 3.6 mg/kg/dose. As this is a first-in-class compound and first-in-human study, the investigators have factored in a greater safety margin of an additional 1/10th of the starting dose,resulting in a final starting dose of 0.3 mg/kg/dose. Importantly, while this starting dose provides a 100-fold safety margin compared to the NOAEL, it is also within the estimated human PAD range (as determined from rodent studies).

The investigators will perform 3-fold escalations from 0.3 mg/kg to 6 mg/kg and will use the correlative PK and PDn data to guide further doses and to determine the maximum tolerated dose (MTD) and optimum biologic dose (OBD).

Taking into account the pharmacologically active dose (PAD) in mouse tumor models of 5 mg/kg, and converting this into the human effective dose (HED) by a factor of 12.3 (based on FDA Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers), a PAD of 0.4 mg/kg is expected for humans. Thus, the proposed final starting dose of 0.3 mg/kg/dose is indeed within the PAD range.

Before the start of each new dose cohort, a review of the adverse event profile and pharmacokinetics (where available) will be conducted by the investigators before dose escalation.

Once the MTD or OBD has been determined, the investigators will conduct the dose expansion part (phase Ib) of the study which will include PRL3-positive tumors.

• Rationale for Study Population: As this is a FIH study, the risk-benefit ratio of the drug is unknown. Therefore, the study population of patients with advanced solid tumors who no longer respond to standard therapy or for whom no standard therapy is available, would be appropriate for this study as they may benefit from treatment with PRL3-ZUMAB.
• Rationale for Study Design: This phase 1, open label, dose-escalation study of PRL3-ZUMAB will use titration from low doses to higher doses of PRL3-ZUMAB in order to assess the PK, PDn, and potential toxicities of the study drug in the target population, and to determine the MTD/OBD/ or recommended phase 2 dose (RP2D). The sample size employed is a minimally modified standard 3+3 cohort model commonly used in Phase I oncology studies. Once determined, the MTD/OBD/RP2D may be administered to an Expansion Cohort (Phase Ib) of subjects with advanced PRL-3 expressing cancer.