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

Jessica J. Tao, Nicholas A. Cangemi, Vicky Makker, Karen A. Cadoo, Joyce F. Liu, Drew W. Rasco, Willis H. Navarro, Christopher M. Haqq, David M. Hyman

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)5458-5465
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number18
DOIs
StatePublished - Sep 15 2019
Externally publishedYes

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Granulosa Cell Tumor
Activins
Ovarian Neoplasms
Growth Differentiation Factor 2
Neoplasms
Cachexia
Hemorrhage
Safety
Clinical Trials, Phase I
Epistaxis
Maximum Tolerated Dose
Follicle Stimulating Hormone
Fatigue
Therapeutics
Pharmacokinetics
Ligands
Muscles
Growth
activin A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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. / Tao, Jessica J.; Cangemi, Nicholas A.; Makker, Vicky; Cadoo, Karen A.; Liu, Joyce F.; Rasco, Drew W.; Navarro, Willis H.; Haqq, Christopher M.; Hyman, David M.

In: Clinical Cancer Research, Vol. 25, No. 18, 15.09.2019, p. 5458-5465.

Research output: Contribution to journalArticle

Tao, Jessica J. ; Cangemi, Nicholas A. ; Makker, Vicky ; Cadoo, Karen A. ; Liu, Joyce F. ; Rasco, Drew W. ; Navarro, Willis H. ; Haqq, Christopher M. ; Hyman, David M. / 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. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 18. pp. 5458-5465.
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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 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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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.

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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