Eryaspase With Modified FOLFIRINOX in Advanced Pancreatic Ductal Adenocarcinoma

Study Overview
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Brief Summary
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This will be a single-arm, multi-center, open-label phase 1 study. The standard 3+3 design will be used to determine the maximum tolerated dose (MTD) from 4 possible dose levels of Eryaspase in combination with mFOLFIRINOX. We hypothesize that the addition of Eryaspase to FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin) will be safe and demonstrate preliminary signs of efficacy in patients with advanced pancreatic cancer. Safety assessments include adverse events, physical examination abnormalities, vital signs, and clinical laboratory tests (including blood chemistry, hematology, and coagulation panel).

Detailed Description
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This is an open-label, multicenter, Phase 1 study of Eryaspase combination with FOLFIRINOX in patients with locally advanced or metastatic pancreatic adenocarcinoma. Subjects will undergo screening in order to determine eligibility. The study will use a standard 3+3 method of dose escalation. Patients will be enrolled in cohorts of 3. Four dose levels are planned and include 25, 50, 75, and 100 mg of Eryaspase with reduced dose irinotecan. Subjects will be assigned to a dose level in the order of study entry with at least a 3-day stagger in enrollment between individual subjects. With the 3+3 design to be employed, doses are not escalated unless all patients receiving the current dose have been observed for at least 6 weeks and dose-limiting toxicities (DLTs) have been reported. The MTD is defined as the highest dose level where at most 1 of 6 patients experience a dose limiting toxicity (DLT). Three patients will be treated at dose level 0. If 0/3 experience a DLT, 3 new patients will be enrolled at the next higher dose level. If 1/3 experience a DLT, 3 additional patients will be enrolled at the same dose level. If 1/6 patients experience a DLT at any dose level except the highest dose level, 3 new patients will be enrolled at the next higher dose level; if 1/6 patients at the highest dose level experience a DLT, it will be deemed the MTD and the trial will stop. As soon as 2 patients experience a DLT at a given dose level, that dose will be concluded to be above the MTD, dose escalation will cease and 3 new patients will be enrolled at the next lower dose level. If 6 patients were previously treated at that lower dose, the study will halt and that lower dose will be declared the MTD. A subject who withdraws from the escalation phase of the study for reasons other than a DLT will be replaced. FOLFIRINOX treatment will be given on Day 1 and 15 of the 4 weeks cycle and continued until unacceptable toxicity or disease progression, for a maximum of 12 cycles. Subjects will receive a single intravenous administration of Eryaspase on Day 1 and 15 of 4-weeks cycle. The study visits are day 1, 8, 15, 22, during cycle 1 and day 1 and 15 during subsequent cycles with a 4-week follow-up period after the end of treatment. Subjects who show at least stable disease based on RECIST 1.1 at the end of the 12-week period (Day 85) are eligible for the continuation of FOLFIRINOX plus eryaspase treatment until disease progression or unacceptable toxicity.

Official Title
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A Phase I Dose Escalation Study of Eryaspase in Combination With Modified FOLFIRINOX in Locally Advanced and Metastatic Pancreatic Ductal Adenocarcinoma

Conditions
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Locally Advanced Pancreatic Ductal Adenocarcinoma, Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Biological: Eryaspase
* Drug: FOLFIRINOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be able to understand and willing to sign an IRB approved written informed consent document. Patient must have histologically or cytologically confirmed pancreatic adenocarcinoma, which is locally advanced, unresectable, or metastatic. Patient must have received no previous surgery, chemotherapy, radiotherapy or investigational therapy for the treatment of locally advanced or metastatic disease. If a patient has had adjuvant/neoadjuvant therapy for localized disease, tumor recurrence or disease progression must have occurred no sooner than 6 months after completing the last dose of the aforementioned therapies. Patient must have radiographically measurable disease according to RECIST 1.1 Patient must be > 18 years of age. Patient must have a life expectancy of >= 3 months. Patient must have an ECOG performance status ≤ 1. Patient must have normal bone marrow and organ function as defined below: Absolute neutrophil count >=1,500/mcl Platelets >=100,000/mcl Hemoglobin >=9.0 g/dL Serum Albumin >=3.0 g/dL Creatinine should be below the upper limit of normal OR Creatinine clearance (eGFR) >=60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Plasma antithrombin III >= 65%, fibrinogen >= 150 mg/dL, international normalized ratio (INR) ≤ 1.5, and partial thromboplastin time (PTT) ≤ institutional ULN. Total bilirubin ≤ 1.5x institutional ULN Patients who have had a stent placed for biliary obstruction can be included in the study. Female subject of childbearing potential must have a negative urine or serum pregnancy test. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Male subjects with a female partner of childbearing potential must agree to use two adequate methods or a barrier method plus a method of contraception Exclusion Criteria: Evidence of neuroendocrine tumor, duodenal adenocarcinoma, or ampullary adenocarcinoma. History of other malignancy ≤ 3 years ago, with the exception of basal cell or squamous cell carcinoma of the skin, which were treated with local resection only or carcinoma in situ of the cervix of ductal carcinoma in situ. Receiving any other investigational agents 28 days prior to the screening process. Patient with evidence of brain metastases. Such patients must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. History of allergic reactions attributed to compounds of similar chemical or biologic composition to asparaginase, 5FU, oxaliplatin, or irinotecan. Any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection , symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, any clinically active malabsorption syndrome, inflammatory bowel disease, any condition that increases the risk of severe irinotecan gastrointestinal toxicity, or psychiatric illness/social situations that would limit compliance with study requirements Has an active autoimmune disease, or a documented history of autoimmune disease or syndrome that requires steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Has had an allogeneic tissue/solid organ transplant. Has received or will receive a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain live virus are permitted Has known active Hepatitis B or C. Patient is pregnant and/or breastfeeding. Known to be HIV-positive on combination antiretroviral.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation of Eryaspase in combination with FOLFIRINOX
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Eryaspase plus FOLFIRINOX<br>Eryaspase will be administered on day 1 and 15 of a 4 week cycle (intravenous infusion) in dose escalating/reduction depending on the cohort the patient is assigned to mFOLFIRINOX dosing will include 5-fluorouracil 2400 mg/m² over 46 hours, oxaliplatin 85 mg/m², Irinotecan 150 mg/m² (intravenous infusion) on Day 1 and 15 of the 4 weeks cycle for a maximum of 12 cycles. | Biological: Eryaspase<br>* intravenous administration of Eryaspase, starting dose 75 units/kg, dose escalation to 100 units/kg, dose reduction 50 units/kg and 25 units/kg<br>Drug: FOLFIRINOX<br>* intravenous administration of FOLFIRINOX<br>* Other names: 5-fluorouracil, oxaliplatin, Irinotecan, leucovorin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Grade 3 or 4 adverse events | The number and percentage of all subjects who experience adverse events (AEs), serious adverse events (SAEs), or abnormal laboratory results according to NCI CTCAE Version 5.0, that occur after Cycle 1, Day 1 will be reported. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | Estimated | 2 years | 
| progression-free survival (PFS) | Summarized | 2 years | 
| overall survival (OS) | Summarized | 2 years |