A First-in-Human, Phase I, Multicenter, Open-Label, Dose-Escalation Study of PCA062: An Antibody–Drug Conjugate Targeting P-Cadherin, in Patients With Solid Tumors

Author:

Duca Matteo1ORCID,Lim Darren Wan-Teck2ORCID,Subbiah Vivek3ORCID,Takahashi Shunji4,Sarantopoulos John5,Varga Andrea6,D'Alessio Joseph A.7,Abrams Tinya7,Sheng Qing78,Tan Eugene Youchin9,Rosa Maria Santos10,Gonzalez-Maffe Juan10,Sand-Dejmek Janna10,Fabre Claire10,Martin Miguel11ORCID

Affiliation:

1. 1S.C. Oncologia Medica 1, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.

2. 2Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

3. 3Division of Cancer Medicine & Division of Pediatrics, The University of MD Anderson Cancer Center, Houston, Texas.

4. 4Department of Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan.

5. 5Institute for Drug Development, Mays Cancer Center at University of Texas Health San Antonio MD Anderson Cancer Center, San Antonio, Texas.

6. 6Drug Development Department, Institut de Cancérologie Gustave Roussy, Villejuif, France.

7. 7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.

8. 8Allorion Therapeutics, Natick, Massachusetts.

9. 9Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

10. 10Novartis Pharma AG, Basel, Switzerland.

11. 11Department of Medicine, Hospital General Universitario Gregorio Marañón, Complutense University, Madrid, Spain.

Abstract

Abstract This first-in-human (FIH), phase I, multicenter, open-label study was conducted to characterize the safety, tolerability, pharmacokinetics, and preliminary efficacy, and to establish the MTD/recommended dose for expansion (RDE) of PCA062 in patients with solid tumors. Adult patients with any solid tumor type and having a documented P-cadherin–positive tumor were enrolled; exceptions to P-cadherin positivity requirement were head and neck squamous cell carcinomas (HNSCC) and esophageal squamous cell carcinoma (ESCC). Dose escalation was guided by an adaptive Bayesian logistic regression model with escalation with overdose control to determine the MTD/RDE. Forty-seven patients were treated at 10 different dose levels of PCA062, ranging from 0.4 to 5.0 mg/kg every 2 weeks administered as a 1-hour intravenous infusion. All enrolled patients discontinued the treatment; primary reason for discontinuation was progressive disease (78.7%). All 47 patients experienced at least one AE, of which 32 patients had a grade ≥3 AE and 37 patients experienced AEs suspected to be study drug related. The MTD of PCA062 was 3.6 mg/kg every 2 weeks and thrombocytopenia was reported as a DLT that was attributed to the known toxicities of the DM1 payload with no P-cadherin–related toxicities. Pharmacokinetics was proportional, and no patients developed antidrug antibodies, suggesting adequate exposure at the doses tested. One patient of 47 achieved a partial response and there was no correlation between tumor P-cadherin expression and clinical efficacy. Because of limited antitumor activity at the MTD level, Novartis has terminated clinical development of PCA062 (NCT02375958).

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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