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

SWOG S1313

Ramesk 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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1062-1069
Number of pages8
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume37
Issue number13
DOIs
StatePublished - May 1 2019

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Hyaluronoglucosaminidase
Adenocarcinoma
Hyaluronic Acid
Survival
irinotecan
oxaliplatin
Pancreatic Neoplasms
Medical Futility
Enoxaparin
Leucovorin
Combination Drug Therapy
Fluorouracil
Neoplasms
Odds Ratio
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma : SWOG S1313. / Ramanathan, Ramesk K; McDonough, Shannon L.; Philip, Philip A.; Hingorani, Sunil R.; Lacy, Jill; Kortmansky, Jeremy S.; Thumar, Jaykumar; Chiorean, E. Gabriela; Shields, Anthony F.; Behl, Deepti; Mehan, Paul T.; Gaur, Rakesh; Seery, Tara; Guthrie, Katherine A.; Hochster, Howard S.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 37, No. 13, 01.05.2019, p. 1062-1069.

Research output: Contribution to journalArticle

Ramanathan, RK, McDonough, SL, Philip, PA, Hingorani, SR, Lacy, J, Kortmansky, JS, Thumar, J, Chiorean, EG, Shields, AF, Behl, D, Mehan, PT, Gaur, R, Seery, T, Guthrie, KA & Hochster, HS 2019, 'Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313', Journal of clinical oncology : official journal of the American Society of Clinical Oncology, vol. 37, no. 13, pp. 1062-1069. https://doi.org/10.1200/JCO.18.01295
Ramanathan, Ramesk K ; McDonough, Shannon L. ; Philip, Philip A. ; Hingorani, Sunil R. ; Lacy, Jill ; Kortmansky, Jeremy S. ; Thumar, Jaykumar ; Chiorean, E. Gabriela ; Shields, Anthony F. ; Behl, Deepti ; Mehan, Paul T. ; Gaur, Rakesh ; Seery, Tara ; Guthrie, Katherine A. ; Hochster, Howard S. / Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma : SWOG S1313. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019 ; Vol. 37, No. 13. pp. 1062-1069.
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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.",
author = "Ramanathan, {Ramesk K} and McDonough, {Shannon L.} and Philip, {Philip A.} and Hingorani, {Sunil R.} and Jill Lacy and Kortmansky, {Jeremy S.} and Jaykumar Thumar and Chiorean, {E. Gabriela} and Shields, {Anthony F.} and Deepti Behl and Mehan, {Paul T.} and Rakesh Gaur and Tara Seery and Guthrie, {Katherine A.} and Hochster, {Howard S.}",
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T1 - Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma

T2 - SWOG S1313

AU - Ramanathan, Ramesk K

AU - McDonough, Shannon L.

AU - Philip, Philip A.

AU - Hingorani, Sunil R.

AU - Lacy, Jill

AU - Kortmansky, Jeremy S.

AU - Thumar, Jaykumar

AU - Chiorean, E. Gabriela

AU - Shields, Anthony F.

AU - Behl, Deepti

AU - Mehan, Paul T.

AU - Gaur, Rakesh

AU - Seery, Tara

AU - Guthrie, Katherine A.

AU - Hochster, Howard S.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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