A phase Ib study of the combination regorafenib with PF-03446962 in patients with refractory metastatic colorectal cancer (REGAL-1 trial)

• Published in: Cancer chemotherapy and pharmacology 2019-10, Vol.84 (4), p.909-917
• Main Authors: Clarke, Jeffrey Melson, Blobe, Gerard C., Strickler, John H., Uronis, Hope Elizabeth, Zafar, S. Yousuf, Morse, Michael, Dropkin, Evan, Howard, Leigh, O’Neill, Margot, Rushing, Christel N., Niedzwiecki, Donna, Watson, Hollie, Bolch, Emily, Arrowood, Christy, Liu, Yingmiao, Nixon, Andrew B., Hurwitz, Herbert I.
• Format: Article
• Language: English
• Subjects: Activin; Activin Receptors, Type II - antagonists & inhibitors; Angiogenesis; Anorexia; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Back pain; Cancer; Cancer Research; Clinical Trial Report; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dehydration; Diarrhea; Dose-Response Relationship, Drug; Drug Monitoring - methods; Drug-Related Side Effects and Adverse Reactions - diagnosis; Drug-Related Side Effects and Adverse Reactions - etiology; Early Termination of Clinical Trials; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Enzyme-linked immunosorbent assay; Female; Humans; Kinases; Male; Maximum Tolerated Dose; Medical treatment; Medicine; Medicine & Public Health; Metastases; Metastasis; Middle Aged; Monoclonal antibodies; Nausea; Neoplasm Staging; Oncology; Pain; Patients; Pharmacology/Toxicology; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects; Phenylurea Compounds - pharmacokinetics; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - pharmacokinetics; Targeted cancer therapy; Toxicity
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-019-03916-0

Purpose This study aimed to evaluate the maximum tolerated dose (MTD) and recommended phase II dose (RPTD), as well as the safety and tolerability of PF-03446962, a monoclonal antibody targeting activin receptor like kinase 1 (ALK-1), in combination with regorafenib in patients with refractory metastatic colorectal cancer. Methods The first stage of this study was a standard “3 + 3” open-label dose-escalation scheme. Cohorts of 3–6 subjects were started with 120 mg of regorafenib given PO daily for 3 weeks of a 4 week cycle, plus 4.5 mg/kg of PF-03446962 given IV every 2 weeks. Doses of both drugs were adjusted according to dose-limiting toxicities (DLT). Plasma was collected for multiplexed ELISA analysis of factors related to tumor growth and angiogenesis. Results Seventeen subjects were enrolled, of whom 11 were deemed evaluable. Seven subjects were enrolled at dose level 1, and four were enrolled at level − 1. Overall, three DLTs were observed during the dose-escalation phase: two in level 1 and one in level − 1. A planned dose-expansion cohort was not started due to early termination of the clinical trial. Common adverse events were infusion-related reaction, fatigue, palmar-plantar erythrodysesthesia syndrome, abdominal pain, dehydration, nausea, back pain, anorexia, and diarrhea. One subject achieved stable disease for 5.5 months, but discontinued treatment due to adverse events. Conclusions The regimen of regorafenib and PF-03446962 was associated with unacceptable toxicity and did not demonstrate notable clinical activity in patients with refractory metastatic colorectal cancer.