First-in-Human Phase I Study of the Activin A Inhibitor, STM 434, in Patients with Granulosa Cell Ovarian Cancer and Other Advanced Solid Tumors

Abstract

Purpose: STM 434 is a soluble receptor ligand trap targeting activin A, a protein in the TGFβ family that plays important roles in growth, differentiation, and cancer cachexia. This study evaluated the safety, antitumor activity, and metabolic effects of STM 434 in a first-in-human, multicenter, phase I clinical trial (NCT02262455).

Patients and methods: Patients with advanced solid tumors were enrolled in 8 dose cohorts ranging from 0.25 mg/kg every 4 weeks to 8 mg/kg every 2 weeks via a 3 + 3 dose-escalation design. The primary endpoint was maximum tolerated dose (MTD). Secondary endpoints included safety, pharmacokinetics, and response. As activin A is implicated in metabolism and muscle function, changes in key metabolic parameters, including lean body mass and 6-minute walk test, were serially measured.

Results: Thirty-two patients were treated on study. The most common treatment-related adverse events were fatigue (41%) and mucocutaneous bleeding complications including epistaxis (34%) and gingival bleeding (22%), likely related to off-target inhibition of bone morphogenetic protein 9 (BMP9). STM 434 treatment resulted in the expected follicle-stimulating hormone level decreases in most patients and in metabolic parameter changes, including an increase in total lean body mass and 6-minute walk test distance. No responses were observed in the 30 evaluable patients, but the stable disease rate in patients with granulosa cell ovarian cancer was 10 of 12 (80%).

Conclusions: Although no direct antitumor efficacy was documented, potentially clinically meaningful dose-related metabolic effects, including treatment of cancer cachexia, were observed that support further exploration of activin A inhibitors that limit BMP9 blockade.See related commentary by Bonilla and Oza, p. 5432.

Conflict of interest statement

CONFLICTS OF INTEREST:

DM: consultant: Atara Biotherapeutics, Chugai Pharma, Cytom X Therapeutics, Boehringer Ingelheim, AstraZeneca, Puma Biotechnology, LOXO. CH, WH: employment, stock ownership: Atara Biotherapeutics. VM: consultant: Eisai. KC: Research Funding: AstraZeneca. DR: consultant: Eli Lilly, Boehringer Ingelheim; research funding: Abbvie, Ascentage, Asana, Celgene, Constellation, FivePrime, GSK, Eisai, Macrogenics, Merck; travel, accommodations, expenses: Takeda, Asana. JT, NC, JL: no disclosures.

©2019 American Association for Cancer Research.

Figures

Figure 1:. STM 434: Dose escalation cohorts (3+3 design)

Schema depicting the dose escalation design of the first-in-human, phase I clinical trial of STM 434. Abbreviations: Q2W, every 2 weeks; Q4W, every 4 weeks.

Figure 2:. Pharmacokinetics of STM 434

Exposure to STM 434, as measured by the maximum concentration (Cmax) and area under the concentration-time curve from 0 to 336 hours (AUC 0–336 hr) and 320–1448 hours (AUC 320–1448 hr) appears to increase in a linear manner with doses from 0.25 mg/kg to 8 mg/kg. Abbreviations: Q2W, every 2 weeks; Q4W, every 4 weeks.

Figure 3:. Greatest change in target lesions and duration of therapy

A) Waterfall plotting showing the greatest change in target lesions by RECIST v1.1 criteria. Only patients with baseline and at least one post-baseline assessment of target lesion are included. Two patients in the efficacy population are not included in this figure. Colors (shown in legend) represent the different dose cohorts. Asterisks indicate that the tumor type is granulosa ovarian. B) Swimmer plot showing duration of therapy for the 32 patients who received STM 434.

Figure 4:. Pharmacodynamic and metabolic response to therapy

A) Mean absolute change in FSH compared to baseline. B) Mean percent change in total lean body mass (LBM) compared to baseline. C) Mean absolute change in 6 Minute Walk Test Distance (6MWD) in meters.