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

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.

• PEGPH20 (Drug), also known as Pegylated Recombinant Human Hyaluronidase: 3 ug/kg on Day 1, IV over 15 minutes
• Oxaliplatin (Drug), also known as Eloxatin, NSC-266046: 85 mg/m\^2, on Day 2, IV over 2 hours
• Leucovorin (Drug), also known as leucovorin calcium: 400 mg/m\^2, on Day 2, IV over 2 hours
• Irinotecan (Drug), also known as CPT-11, NSC-616348: 180 mg/m\^2, on Day 2, IV over 1.5 hours
• 5-fluorouracil (Drug), also known as 5-FU, Adrucil, NSC-19893: 2,400 mg/m\^2, Days 2-4, IV over 46 hours

Primary outcomes

• Phase I: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With mFOLFIRINOX [2 cycles of 14 days]: 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.
• Phase II: Overall Survival [From date of registration to date of death due to any cause, assessed up to 3 years]: 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.

Secondary outcomes

• Progression Free Survival (PFS) (Phase II) [From date of registration to date of death due to any cause, assessed up to 3 years]: 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.
• Objective Tumor Response Rate (Confirmed and Unconfirmed, Complete and Partial) [Up to 3 years]: 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
• 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]: 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

Other outcomes

• Cancer Antigen (CA) 19-9 Levels [Within 2 years of the end of the study]: Explore correlation of maximum decrease in CA 19-9 levels to maximum decrease in CA 19-9 levels with overall survival, progression-free survival and response.
• Plasma Expression of Hyaluronan (HA) [Within 2 years of end of study]
• Tumor Expression of HA [Within 2 years of end of study]

Sex: All, ages: 18 Years to 75 Years

* 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

Participant flow

Outcome results

• Phase I: Maximum Tolerated Dose (MTD) of PEGPH20 in Combination With mFOLFIRINOX (Primary), Number, ug/kg: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 3; All Phase 1 Participants 3
• Phase II: Overall Survival (Primary), Median, months: Phase II: mFOLFIRINOX 14.4 (9.2 to 18.0); Phase II: mFOLFIRINOX + PEGPH20 7.7 (4.5 to 10.7) (p <0.01)
• Progression Free Survival (PFS) (Phase II) (Secondary), Median, months: Phase II: mFOLFIRINOX 6.2 (3.7 to 10.2); Phase II: mFOLFIRINOX + PEGPH20 4.3 (2.4 to 5.8) (p 0.01)
• Objective Tumor Response Rate (Confirmed and Unconfirmed, Complete and Partial) (Secondary), Number, percent of participants: Phase II: mFOLFIRINOX 45 (32 to 58); Phase II: mFOLFIRINOX + PEGPH20 33 (20 to 45)
• Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs (Secondary), Number, Participants: Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 and Day 3/4 0; Phase I: mFOLFIRINOX + PEGPH20, 3 ug/kg on Day 1 Only 0; Phase II: mFOLFIRINOX 1; Phase II: PEGPH20 + mFOLFIRINOX 3
• Cancer Antigen (CA) 19-9 Levels (Other pre specified)
• Plasma Expression of Hyaluronan (HA) (Other pre specified)
• Tumor Expression of HA (Other pre specified)

Adverse events

Time frame: Duration of treatment and follow up until death or 3 years post registration

Serious adverse events by term

5 more terms not shown.

Other adverse events by term

142 more terms not shown.

54 more sites not listed.

• Results publication: 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. Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313. J Clin Oncol. 2019 May 1;37(13):1062-1069. doi: 10.1200/JCO.18.01295. Epub 2019 Feb 28. PMID 30817250

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form (PDF, 2017-07-28)

• Ramesh K Ramanathan, M.D., Study chair, Virginia G. Piper Cancer Center

NIH grants: U10CA180888