TY - JOUR
T1 - 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
AU - Tao, Jessica J.
AU - Cangemi, Nicholas A.
AU - Makker, Vicky
AU - Cadoo, Karen A.
AU - Liu, Joyce F.
AU - Rasco, Drew W.
AU - Navarro, Willis H.
AU - Haqq, Christopher M.
AU - Hyman, David M.
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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 keymetabolic 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.
AB - 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 keymetabolic 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.
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U2 - 10.1158/1078-0432.CCR-19-1065
DO - 10.1158/1078-0432.CCR-19-1065
M3 - Article
C2 - 31068369
AN - SCOPUS:85072233671
SN - 1078-0432
VL - 25
SP - 5458
EP - 5465
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 18
ER -