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

Study Overview
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Brief Summary
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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
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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.

Official Title
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S1313, A Phase IB/II Randomized Study of Modified FOLFIRINOX + Pegylated Recombinant Human Hyaluronidase (PEGPH20) Versus Modified FOLFIRINOX Alone in Patients With Good Performance Status Metastatic Pancreatic Adenocarcinoma

Conditions
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Metastatic Pancreatic Adenocarcinoma

Intervention / Treatment
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* Drug: PEGPH20
* Drug: Oxaliplatin
* Drug: Leucovorin
* Drug: Irinotecan
* Drug: 5-fluorouracil


Participation Criteria
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Eligibility Criteria
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Patients must have newly diagnosed, untreated metastatic histologically or cytologically documented pancreatic adenocarcinoma; patients must not have known history of brain metastases Patients must have measurable metastatic disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; CT scans or MRIs must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) Patients must not have had any prior treatment with oxaliplatin or irinotecan within 3 years prior to registration; patients must not have had prior chemotherapy in metastatic setting; prior abdominal radiation therapy is not allowed Patients must have a Zubrod performance status of 0-1 Absolute neutrophil count (ANC) >= 1,500/mcL Platelets >= 100,000/mcL Hemoglobin >= 9 g/dL Total bilirubin =< institutional upper limit of normal (IULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 2.5 X IULN in the absence of liver metastases or =< 5.0 x IULN with liver metastasis Serum albumin >= 3 g/dL Serum creatinine =< ULN within 14 days prior to registration OR calculated creatinine clearance > 50 ml/min; the serum creatinine value used in the calculation must have been obtained within 14 days prior to registration Patients must have international normalized ratio (INR) =< 1.2 within 14 days prior to registration; patients must not be receiving warfarin for therapeutic use, have history of cerebrovascular accident (CVA), history of transient ischemic attack (TIA) requiring intervention or treatment, pre-existing carotid artery disease requiring intervention or treatment, or current use of megestrol acetate (use within 10 days of registration) Patients must not be receiving chronic treatment (equivalent of prednisone > 10 mg/day) with systemic steroids or other immuno-suppressive agent Patients must not have liver disease such a cirrhosis, chronic active hepatitis or chronic persistent hepatitis Patients must not have active bleeding or a pathological condition that is associated with a high risk of bleeding Patients with a known history of human immunodeficiency virus (HIV) must not be on active treatment for HIV Patients must have no non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with protocol therapy No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of reproductive potential if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, effective contraception also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures Patients must have tumor (paraffin block or slides) available for submission and be willing to submit tumor and blood samples Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system Patients planning to enroll in the phase I portion of this study must first have a slot reserved in advance of the registration; all site staff will use OPEN to create a slot reservation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Phase II: mFOLFIRINOX<br>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 5-fluorouracil (5-FU) IV over 46 hours on days 2-4. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: Oxaliplatin<br>* 85 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: NSC-266046;Drug: Leucovorin<br>* 400 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: leucovorin calcium;Drug: Irinotecan<br>* 180 mg/m^2, on Day 2, IV over 1.5 hours<br>* Other names: NSC-616348;Drug: 5-fluorouracil<br>* 2,400 mg/m^2, Days 2-4, IV over 46 hours<br>* Other names: NSC-19893;|
| Experimental: Phase II: mFOLFIRINOX + PEGPH20<br>Patients receive pegylated recombinant human hyaluronidase (PEGPH20) IV over 10 minutes on day 1 and oxaliplatin, leucovorin calcium, irinotecan hydrochloride, and 5-fluorouracil (5-FU) as in Arm I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. | Drug: PEGPH20<br>* 3 ug/kg on Day 1, IV over 15 minutes<br>* Other names: Pegylated Recombinant Human Hyaluronidase;Drug: Oxaliplatin<br>* 85 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: NSC-266046;Drug: Leucovorin<br>* 400 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: leucovorin calcium;Drug: Irinotecan<br>* 180 mg/m^2, on Day 2, IV over 1.5 hours<br>* Other names: NSC-616348;Drug: 5-fluorouracil<br>* 2,400 mg/m^2, Days 2-4, IV over 46 hours<br>* Other names: NSC-19893;|
| Experimental: Phase I<br>PEGPH20, 3 ug/kg on Day 1 and Day 3/4, IV over 15 minutes; Oxaliplatin, 85 mg/m^2, on Day 2, IV over 2 hours; Leucovorin, 400 mg/m^2, on Day 2, IV over 2 hours; Irinotecan, 180 mg/m^2, on Day 2, IV over 1.5 hours; 5-fluorouracil (5-FU), 2,400 mg/m^2, Days 2-4, IV over 46 hours | Drug: PEGPH20<br>* 3 ug/kg on Day 1, IV over 15 minutes<br>* Other names: Pegylated Recombinant Human Hyaluronidase;Drug: Oxaliplatin<br>* 85 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: NSC-266046;Drug: Leucovorin<br>* 400 mg/m^2, on Day 2, IV over 2 hours<br>* Other names: leucovorin calcium;Drug: Irinotecan<br>* 180 mg/m^2, on Day 2, IV over 1.5 hours<br>* Other names: NSC-616348;Drug: 5-fluorouracil<br>* 2,400 mg/m^2, Days 2-4, IV over 46 hours<br>* Other names: NSC-19893;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With mFOLFIRINOX | Assess safety of mFOLFIRINOX in combination with PEGPH20 and select the optimal dose of PEGPH20 for the Phase II portion. MTD of PEGPH20 in combination with mFOLFORINOX was evaluated by testing decreasing doses of PEGPH20 from 3mcg/kg on Day 1 and Day 3/4, to 3mcg/kg on Day 1 only and to 1.6 mcg/kg on Day 1 only. MTD reflects the highest dose that had a dose-limiting toxicity (DLT) rate of ≤ 17%. DLTs were defined as treatment regimen related: grade ≥ 3 non-hematologic toxicity; grade 4 absolute neutrophil count (ANC) anemia or thrombocytopenia; grade 4 ANC lasting > 7 days; grade ≥ 3 febrile neutropenia; grade ≥ 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), total bilirubin, and creatinine; delay in starting the 2nd cycle of mFOLFIRINOX by > 2 weeks due to drug related toxicity. DLT were graded using the NCI CTCAE version 4. Note: the third and lowest dose level was not reached. | 2 cycles of 14 days | 
| Phase II: Overall Survival | Time from date of registration to date of death due to any cause. Participants last known to be alive are censored at date of last contact. Assessed using the logrank test. | From date of registration to date of death due to any cause, assessed up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) (Phase II) | Time from date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause. Participants last known to be alive without report of progression are censored at date of last contact. | From date of registration to date of death due to any cause, assessed up to 3 years | 
| Objective Tumor Response Rate (Confirmed and Unconfirmed, Complete and Partial) | Objective tumor response rate (complete response, unconfirmed complete response, partial response, unconfirmed partial response) in patients with measurable disease were assessed in each arm and compared between arms using Chi-squared test. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions | Up to 3 years | 
| Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Adverse Events (AEs) are reported by CTCAE Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care activities of daily living e.g. bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden. Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to adverse event | Duration of treatment and follow up until death or 3 years post registration |