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 TGFb 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 þ 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

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer

“…In patients with advanced‐stage EOC, the performance status at baseline and at 3 months after adjuvant chemotherapy were associated OS, suggesting the relevance of optimal supportive care during cancer therapy . Lifestyle therapy and pharmacotherapy may also offer benefits for the management of body composition in patients with EOC; however, their effectiveness for advanced‐stage EOC remains unclear. Hence, future studies are warranted to determine if the effects of body composition on survival outcomes are both causal and, more importantly, reversible through intervention for advanced‐stage EOC.…”

Activin A: an emerging target for improving cancer treatment?

“…It has recently become the first activin receptor-based drug to gain regulatory approval by the FDA for the treatment of anemia associated with βthalassemia. Another ActRIIB-based ligand trap targeting activin A, STM 434, was recently tested in a phase I study with 32 patients suffering from gynecological and other solid tumors [118]. It achieved an increase in total lean body mass and improvements in a walking test indicative of successful treatment of cachexia.…”

“…A signals. On the other hand, it increases the risk of unwanted side effects as exemplified by the clinical study with the ActRIIB-based ligand trap STM 434, in which mucocutaneous bleeding was most likely caused by interaction with BMP9 [118]. In addition, the lack of specificity of clinically used targeting agents also makes it difficult to dissect how much of an observed response can be attributed to inhibition of activin A versus other related cytokines.…”

“…Another area where activin A inhibition could benefit cancer patients is the treatment of cancer-associated cachexia, muscle wasting, bone loss and anemia. Indeed, clinical trials with sotatercept and STM 434 have shown the potential of activin A inhibition to improve anemia and cachexia in patients [94,118]. In recent years, high levels of circulating activin A were shown to predict a shorter overall survival for an increasing number of cancer types.…”

Prostate tumor–derived GDF11 accelerates androgen deprivation therapy–induced sarcopenia

“…Act-RIIB-Fc treatment of castrated adult mice blocked sarcopenia and fat gain (16). Unfortunately, during clinical trials, ActRIIB-Fc induced vascular adverse events, including telangiectasias and mucocutaneous bleeding, likely due to off-target bone morphogenetic protein 9 (BMP9) signaling blockade (23)(24)(25). Better understanding of the mechanism of ADT-induced obese frailty in the context of PrCa may enable development of more selective therapies to preserve muscle mass and strength (26,27).…”