S1313, PEGPH20 in Treating Patients With Newly Diagnosed Metastatic Pancreatic Cancer

Brief summary public domain (ClinicalTrials.gov)

This partially randomized phase I/II trial studies the side effects and best dose of pegylated recombinant human hyaluronidase (PEGPH20) when given together with combination chemotherapy and to see how well they work compared with combination chemotherapy alone in treating patients with newly diagnosed pancreatic cancer that has spread to other places in the body. Pegylated recombinant human hyaluronidase may help chemotherapy drugs work better by making tumor cells more sensitive to the drugs. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether combination chemotherapy is more effective with or without pegylated recombinant human hyaluronidase in treating pancreatic cancer.

Detailed description public domain (ClinicalTrials.gov)

PRIMARY OBJECTIVES: I. To assess the safety of modified leucovorin calcium, fluorouracil, irinotecan hydrochloride and oxaliplatin (mFOLFIRINOX) in combination with PEGPH20 and select the optimal dose of PEGPH20 for the phase II portion in patients with metastatic pancreatic adenocarcinoma. (Phase I) II. To assess the overall survival of patients with metastatic pancreatic adenocarcinoma treated with mFOLFIRINOX + PEGPH20 compared to those treated with mFOLFIRINOX alone. (Phase II) SECONDARY OBJECTIVES: I. To assess progression free survival (PFS) in patients receiving mFOLFIRINOX with PEGPH20 and patients receiving mFOLFIRINOX alone in this patient population. II. To assess objective tumor response (confirmed and unconfirmed, complete and partial) in patients with measurable disease treated with mFOLFIRINOX with PEGPH20 and patients receiving mFOLFIRINOX alone in this patient population. III. To determine the frequency, severity, and tolerability of adverse events of mFOLFIRINOX with PEGPH20. TERTIARY OBJECTIVES: I. To explore the correlation of maximum decrease in cancer antigen (CA) 19-9 levels and time to maximum decrease in CA 19-9 levels with overall survival, progression-free survival and response. II. To explore the correlation of plasma hyaluronan (HA) and tumor expression of HA with overall survival, progression-free survival and response. OUTLINE: This is a phase I, dose de-escalation study of pegylated recombinant human hyaluronidase followed by a randomized phase II study. PHASE I: Patients receive pegylated recombinant human hyaluronidase intravenously (IV) over 10 minutes on day 1\*; oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 1.5 hours on day 2; and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 1.5 hours on day 2, and fluorouracil IV over 46 hours on days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive pegylated recombinant human hyaluronidase IV over 10 minutes on day 1\* and oxaliplatin, leucovorin calcium, irinotecan hydrochloride, and fluorouracil as in Arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. \*NOTE: Some patients also receive pegylated recombinant human hyaluronidase on day 3 or 4 of courses 1 and 2. After completion of study treatment, patients are followed up for 3 years.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Phase I: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With mFOLFIRINOX [2 cycles of 14 days]. Number, ug/kg. Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 (n=6): 3; All Phase 1 Participants (n=11): 3.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Phase II: Overall Survival [From date of registration to date of death due to any cause, assessed up to 3 years]. Median, months (95% Confidence Interval). Phase II: mFOLFIRINOX (n=56): 14.4 (9.2 to 18.0); Phase II: mFOLFIRINOX + PEGPH20 (n=55): 7.7 (4.5 to 10.7). Analysis, Phase II: mFOLFIRINOX vs Phase II: mFOLFIRINOX + PEGPH20: Hazard Ratio (HR) 2.07 (95% CI 1.28 to 3.34); p=<0.01; Regression, Cox; superiority.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression Free Survival (PFS) (Phase II) [From date of registration to date of death due to any cause, assessed up to 3 years]. Median, months (95% Confidence Interval). Phase II: mFOLFIRINOX (n=56): 6.2 (3.7 to 10.2); Phase II: mFOLFIRINOX + PEGPH20 (n=55): 4.3 (2.4 to 5.8). Analysis, Phase II: mFOLFIRINOX vs Phase II: mFOLFIRINOX + PEGPH20: Hazard Ratio (HR) 1.74 (95% CI 1.14 to 2.66); p=0.01; Regression, Cox; superiority.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Objective Tumor Response Rate (Confirmed and Unconfirmed, Complete and Partial) [Up to 3 years]. Number, percent of participants (95% Confidence Interval). Phase II: mFOLFIRINOX (n=56): 45 (32 to 58); Phase II: mFOLFIRINOX + PEGPH20 (n=55): 33 (20 to 45).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs [Duration of treatment and follow up until death or 3 years post registration]. Number, Participants. Abdominal pain: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 1; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 3. Acute kidney injury: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 1; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 0. Alanine aminotransferase increased: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 1; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 1; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 3. Alkaline phosphatase increased: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 1; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 2. Anemia: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 4; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 2. Anorexia: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 2; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 3. Arthralgia: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 1. Ascites: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 1. Aspartate aminotransferase increased: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 1; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 0. Blood bilirubin increased: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 1; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 0; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 1. Creatinine increased: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 0; Phase II: mFOLFIRINOX (n=54): 1; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 0. Dehydration: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 (n=5): 1; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only (n=6): 1; Phase II: mFOLFIRINOX (n=54): 7; Phase II: PEGPH20 + mFOLFIRINOX (n=51): 4. Depression: Phase I: mFOLFIRINOX + P