Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313.

Abstract

PURPOSE:

Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC).

MATERIALS AND METHODS:

Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS).

RESULTS:

PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm.

CONCLUSION:

Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

• Authors: Ramesh K Ramanathan, Shannon L McDonough, Philip A Philip, Sunil R Hingorani, Jill Lacy, Jeremy S Kortmansky, Jaykumar Thumar, E Gabriela Chiorean, Anthony F Shields, Deepti Behl, Paul T Mehan, Rakesh Gaur, Tara Seery, Katherine A Guthrie, Howard S Hochster
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 13 Pg. 1062-1069 (05 01 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 30817250 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• folfirinox
• Oxaliplatin
• Irinotecan
• Hyaluronic Acid
• Hyaluronoglucosaminidase
• PEGPH20
• Leucovorin
• Fluorouracil

Topics

• Adenocarcinoma (blood, drug therapy)
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Humans
• Hyaluronic Acid (blood)
• Hyaluronoglucosaminidase (administration & dosage, adverse effects)
• Immunohistochemistry
• Irinotecan (administration & dosage, adverse effects)
• Leucovorin (administration & dosage, adverse effects)
• Male
• Middle Aged
• Neoplasm Metastasis
• Oxaliplatin (administration & dosage, adverse effects)
• Pancreatic Neoplasms (blood, drug therapy, pathology)
• Survival Rate