A phase I study of acapatamab, a half-life extended, PSMA-targeting bispecific T-cell engager for metastatic castration-resistant prostate cancer Journal Article
| Authors: | Dorff, T.; Horvath, L. G.; Autio, K.; Bernard-Tessier, A.; Rettig, M. B.; Machiels, J. P.; Bilen, M. A.; Lolkema, M. P.; Adra, N.; Rottey, S.; Greil, R.; Matsubara, N.; Tan, D. S. W.; Wong, A.; Uemura, H.; Lemech, C.; Meran, J.; Yu, Y.; Minocha, M.; McComb, M.; Penny, H. L.; Gupta, V.; Hu, X.; Jurida, G.; Kouros-Mehr, H.; Janát--Amsbury, M. M.; Eggert, T.; Tran, B. |
| Article Title: | A phase I study of acapatamab, a half-life extended, PSMA-targeting bispecific T-cell engager for metastatic castration-resistant prostate cancer |
| Abstract: | Purpose: Safety and efficacy of acapatamab, a prostate-specific membrane antigen (PSMA) x CD3 bispecific T-cell engager were evaluated in a first-in-human study in metastatic castration-resistant prostate cancer (mCRPC). Patients and Methods: Patients with mCRPC refractory to androgen receptor pathway inhibitor therapy and taxane-based chemotherapy received target acapatamab doses ranging from 0.003 to 0.9 mg in dose exploration (seven dose levels) and 0.3 mg (recommended phase II dose) in dose expansion intravenously every 2 weeks. Safety (primary objective), pharmacokinetics, and antitumor activity (secondary objectives) were assessed. Results: In all, 133 patients (dose exploration, n 1⁄4 77; dose expansion, n 1⁄4 56) received acapatamab. Cytokine release syndrome (CRS) was the most common treatment-emergent adverse event seen in 97.4% and 98.2% of patients in dose exploration and dose expansion, respectively; grade ≥ 3 was seen in 23.4% and 16.1%, respectively. Most CRS events were seen in treatment cycle 1; incidence and severity decreased at/beyond cycle 2. In dose expansion, confirmed prostate-specific antigen (PSA) responses (PSA50) were seen in 30.4% of patients and radiographic partial responses in 7.4% (Response Evaluation Criteria in Solid Tumors 1.1). Median PSA progression-free survival (PFS) was 3.3 months [95% confidence interval (CI): 3.0–4.9], radiographic PFS per Prostate Cancer Clinical Trials Working Group 3 was 3.7 months (95% CI: 2.0–5.4). Acapatamab induced T-cell activation and increased cytokine production several-fold within 24 hours of initiation. Treatment-emergent antidrug antibodies were detected in 55% and impacted serum exposures in 36% of patients in dose expansion. Conclusions: Acapatamab was safe and tolerated and had a manageable CRS profile. Preliminary signs of efficacy with limited durable antitumor activity were observed. Acapatamab demonstrated pharmacokinetic and pharmacodynamic activity. ©2024 American Association for Cancer Research. |
| Keywords: | adult; controlled study; treatment outcome; aged; major clinical study; clinical trial; drug tolerability; fatigue; drug safety; hypertension; hypophosphatemia; antineoplastic agents; nuclear magnetic resonance imaging; follow up; antineoplastic agent; cancer grading; cd8+ t lymphocyte; t lymphocyte; t-lymphocytes; prostate specific antigen; metabolism; interleukin 2; progression free survival; pharmacodynamics; anemia; tumor volume; nausea; vomiting; incidence; interleukin 10; interleukin 12p70; interleukin 13; interleukin 1beta; interleukin 4; interleukin 8; dexamethasone; bone pain; antineoplastic activity; pathology; lymphocytopenia; prostate-specific antigen; alanine aminotransferase; aspartate aminotransferase; hospitalization; prostate specific membrane antigen; disease severity; gamma interferon; immunogenicity; cd4+ t lymphocyte; interleukin 6; phase 1 clinical trial; corticosteroid; cytokine release; autoimmune disease; half life time; androgen deprivation therapy; atrial fibrillation; life expectancy; electrocardiogram; t lymphocyte activation; half-life; pharmacokinetics; race; platelet count; tumor necrosis factor; vital sign; castration resistant prostate cancer; androgen receptor antagonist; cytokine release syndrome; response evaluation criteria in solid tumors; androgen receptor antagonists; humans; human; male; article; prostatic neoplasms, castration-resistant; metastatic castration resistant prostate cancer; electrochemiluminescence; ecog performance status; acapatamab |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 8 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-04-15 |
| Start Page: | 1488 |
| End Page: | 1500 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-23-2978 |
| PUBMED: | 38300720 |
| PROVIDER: | scopus |
| PMCID: | PMC11395298 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
