NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable or Borderline Resectable Pancreatic Cancer

NeoOPTIMIZE: An Open-Label, Phase II Trial to Assess the Efficacy of Adaptive Switching of FOLFIRINOX or Gemcitabine/Nab-Paclitaxel as a Neoadjuvant Strategy for Patients With Resectable and Borderline Resectable Pancreatic Cancer

Sponsors

Lead Sponsor: OHSU Knight Cancer Institute

Collaborator: Oregon Health and Science University

Source OHSU Knight Cancer Institute
Brief Summary

This phase II trial evaluates whether early switching from modified fluorouracil/irinotecan/leucovorin/oxaliplatin (mFOLFIRINOX) chemotherapy regimen to a combination of gemcitabine and nab-paclitaxel (GA) before surgery is effective in treating patients with pancreatic cancer that can be surgically removed (resectable or borderline resectable). Chemotherapy drugs, such as fluorouracil, irinotecan, leucovorin, oxaliplatin, gemcitabine, and nab-paclitaxel 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. The study will also evaluate the drug losartan in combination with mFOLFIRINOX or GA.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine the rate of margin-negative (R0) resection following treatment using NeoOPTIMIZE adaptive therapy (i.e., mFOLFIRINOX alone, or switch to GA).

SECONDARY OBJECTIVES:

I. To determine the progression-free survival (PFS) of participants that received NeoOPTIMIZE adaptive therapy (i.e., mFOLFIRINOX, or switch to GA).

II. To determine the PFS of participants that received NeoOPTIMIZE adaptive therapy, and preoperative radiation therapy (RT).

III. To determine the disease-free survival (DFS) of participants that received NeoOPTIMIZE adaptive therapy (i.e., mFOLFIRINOX, or switch to GA).

IV. To determine the DFS of participants that received NeoOPTIMIZE adaptive therapy, and preoperative RT.

V. To determine the overall survival (OS) of participants that received NeoOPTIMIZE adaptive therapy.

VI. To determine the OS of participants that received NeoOPTIMIZE adaptive therapy, and preoperative RT.

VII. To assess the surgical complications of participants that undergo surgical resection after receiving NeoOPTIMIZE adaptive therapy, and preoperative RT.

VIII. To assess 30-day post-operative mortality that undergo surgical resection after receiving NeoOPTIMIZE adaptive therapy and preoperative RT.

IX. To assess safety of NeoOPTIMIZE adaptive therapy.

EXPLORATORY OBJECTIVES:

I. To monitor changes in CA19-9 levels.

OUTLINE:

mFOLFIRINOX REGIMEN: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and irinotecan hydrochloride IV over 90 minutes on day 1. Patients also receive fluorouracil IV over 46 hours starting on day 1. Treatment with mFOLFIRINOX repeats every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo disease restaging (re-stage I). Patients with radiographic response and no disease progression receive mFOLFIRINOX for an additional 2 months (approximately 4 cycles). Patients then undergo second re-staging (re-stage II).

GA REGIMEN: After re-stage I, patients with disease progression or toxicity to mFOLFIRINOX (per assessment of the treating physician) switch to receive the GA regimen comprising gemcitabine hydrochloride IV over 30-60 minutes and nab-paclitaxel IV over 30-40 minutes on days 1, 8, and 15. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo second re-staging (re-stage II).

LOSARTAN: Starting cycle 1 day 1, patients also receive losartan potassium orally (PO) once daily (QD) until completion of RT in the absence of disease progression or unacceptable toxicity.

RT/SURGERY: Patients with no vascular tumor involvement at re-stage II, undergo surgery 1-4 after completion of chemotherapy. Patients with resolution of tumor contact with pancreatic vasculature at re-stage II, undergo short-course RT to receive a total of 10 fractions over 5 days weekly (Monday-Friday). Patients with tumor vessel involvement that is persistent at re-stage II, undergo long-course RT to receive a total of 15-25 fractions over 5 days weekly (Monday-Friday), and receive capecitabine PO twice daily (BID) on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks after completion RT.

After completion of study treatment, patients are followed up at 30 days, every 3 months for 6 months, and then every 6 months for up to 2 years.

Overall Status Not yet recruiting
Start Date October 5, 2020
Completion Date October 5, 2025
Primary Completion Date January 15, 2024
Phase Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Proportion of participants with R0 resection Up to time of surgery
Secondary Outcome
Measure Time Frame
Progression-free survival (PFS) NeoOPTIMIZE From the start of neoadjuvant therapy (day 1) to the time of tumor progression, or death due to any cause, assessed up to 24 months
PFSNeoOPTIMIZE + pre-operative (preop)-RT From the start of neoadjuvant therapy (day 1) to the time of tumor progression, or death due to any cause, assessed up to 24 months
Disease-free survival (DFS) NeoOPTIMIZE From the date of surgery to the time of tumor progression, or death due to any cause, assessed up to 24 months
DFSNeoOPTIMIZE + preop-RT From the date of surgery to the time of tumor progression, or death due to any cause, assessed up to 24 months
Overall survival (OS) NeoOPTIMIZE From the start of neoadjuvant therapy (day 1) to death due to disease, assessed up to 24 months
OSNeoOPTIMIZE + preop-RT From the start of neoadjuvant therapy (day 1) to death due to disease, assessed up to 24 months
Proportion of participants with peri- and post-operative complications Up to 30 days after surgery
Proportion of participants that die within 30 days of surgery At 30 days post-surgery
Incidence of grade >= 3 toxicities Up to 90 days after last dose of protocol-directed therapy
Enrollment 40
Condition
Intervention

Intervention Type: Drug

Intervention Name: Capecitabine

Description: Given PO

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Drug

Intervention Name: Fluorouracil

Description: Given IV

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Drug

Intervention Name: Irinotecan Hydrochloride

Description: Given IV

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Drug

Intervention Name: Leucovorin Calcium

Description: Given IV

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Drug

Intervention Name: Losartan Potassium

Description: Given PO

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Drug

Intervention Name: Oxaliplatin

Description: Given IV

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Radiation

Intervention Name: Radiation Therapy

Description: Undergo short-course or long-course RT

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Intervention Type: Procedure

Intervention Name: Resection

Description: Undergo surgical resection

Arm Group Label: Treatment (mFOLFIRINOX, chemotherapy)

Other Name: Surgical Resection

Eligibility

Criteria:

Inclusion Criteria:

- Ability to understand and the willingness to sign a written informed consent document

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

- Cytologic or histologic proof pancreatic ductal carcinoma is required prior to study entry

- If a biopsy (e.g., endoscopic ultrasound [EUS]-guided fine needle aspiration [FNA]) is planned per standard of care, the participant may be asked to consent to the additional collection of tumor tissue for research

- No evidence of metastatic disease as determined by chest computed tomography (CT) scan, abdomen/pelvis computed tomography (CT) scan (or magnetic resonance imaging [MRI] with gadolinium and/or manganese) within 6 weeks of study entry

- Diagnostic staging laparoscopy is not required for study eligibility

- If staging laparoscopy is planned per standard of care, the participant may be asked to consent to the collection of tumor tissue for research

- At time of screening, per National Comprehensive Cancer Network (NCCN) criteria, must have either:

- Resectable pancreatic ductal adenocarcinoma (PDAC), defined as no arterial tumor contact (celiac axis [CA], superior mesenteric artery [SMA], or common hepatic artery [CHA]), or

- Node positive disease as defined by CT, MRI, or EUS imaging, or

- Borderline resectable PDAC, defined as:

- For tumors of the head or uncinate process:

- Solid tumor contact with the superior mesenteric vein (SMV) or portal vein of > 180 degrees with contour irregularity of the vein or thrombosis of the vein, but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction

- Solid tumor contact with the inferior vena cava

- Solid tumor contact with the common hepatic artery without extension to the celiac axis or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction

- Solid tumor contact with the SMA =< 180 degrees

- Solid tumor contact with variable anatomy (e.g., accessory right hepatic artery, replaced right hepatic artery, replaced common hepatic artery, and the origin of replaced or accessory artery), and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning

- For tumors of the body/tail:

- Solid tumor contact with the celiac axis of =< 180 degrees

- Solid tumor contact with the celiac axis >180 degrees without involvement of the aorta and with an intact and uninvolved gastroduodenal artery, thereby permitting a modified Appleby procedure (although some members of the consensus committee preferred this criterion to be in the unresectable category)

- Must be deemed fit to undergo planned curative resection as determined by institutional standards

- No history of previous chemotherapy for pancreatic cancer

- Baseline systolic blood pressure (BP) > 100 mm Hg

- Hemoglobin > 9 g/dL with no blood transfusion within 28 days of starting treatment (at time of registration and within 4 weeks prior to initiating study therapy)

- Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (> 1000 cells/mm^3) (at time of registration and within 4 weeks prior to initiating study therapy)

- May be waived on a case-by-case basis for patient populations recognized to have normal baseline values below this level

- Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (at time of registration and within 4 weeks prior to initiating study therapy)

- Creatinine =< 1.5 mg/dL OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min/1.73 m^2 for participants with creatinine levels > 1.5 x institutional upper limit of normal (ULN) (at time of registration and within 4 weeks prior to initiating study therapy)

- Creatinine clearance should be calculated per institutional standard. For participants with a baseline calculated creatinine clearance below normal institutional laboratory values, a measured baseline creatinine clearance should be determined. Individuals with higher values felt to be consistent with inborn errors of metabolism will be considered on a case-by-case basis

- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); or =< 2 x ULN or 2 down-trending values for individuals who have undergone biliary stenting (at time of registration and within 4 weeks prior to initiating study therapy)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN, OR two consecutive down-trending values for individuals who have undergone biliary stenting (at time of registration and within 4 weeks prior to initiating study therapy)

- Female participants of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to initiating study therapy. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

- Female participants of childbearing potential agree to use adequate methods of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy

- Participants of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year without an alternative medical cause

- Male participants must agree to use an adequate method of contraception starting with the first dose of study therapy through 30 days after the last dose of study therapy

- Male patients must use a condom during treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male participant should also use a highly effective form of contraception if they are of childbearing potential

- Participants currently receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) will remain eligible for study participation. In such cases, losartan will not be assigned as part of the study intervention. These participants will continue to receive their ACE inhibitor or ARB per standard-of-care. The ACE inhibitor or ARB type should be recorded as a concomitant medication (including dose and frequency)

Exclusion Criteria:

- History of previous chemotherapy, targeted/biologic therapy, or radiation therapy for the treatment of their PDAC

- Evidence of metastasis to distant organs (liver, peritoneum, lung, others)

- Any other active malignancy or prior history of malignancy with less than a 90% cure rate in the judgement of the investigators

- Medical co-morbidities that are deemed to make risk of surgery unacceptably high as determined by institutional standards

- Personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest

- Recent major surgery (excluding laparoscopy) within 4 weeks prior to starting study treatment. Minor surgery within 2 weeks of starting study treatment. Patients must be recovered from effects of surgery

- Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy [hormone replacement therapy is acceptable]), not otherwise allowed in this study

- Participants receiving any other study agents

- Participants with a history of hypersensitivity reactions to study agents or their excipients

- Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 30 days after the last dose of trial therapy

- Psychiatric illness/social situations, or any condition that, in the opinion of the investigator, would: interfere with evaluation of study treatment or interpretation of participant safety or study results, or substantially increase risk of incurring adverse events (AEs), or compromise the ability of the patient to give written informed consent

- Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Charles D Lopez Principal Investigator OHSU Knight Cancer Institute
Location
Facility: Contact: Investigator: OHSU Knight Cancer Institute Charles D. Lopez 503-494-8321 [email protected] Charles D. Lopez Principal Investigator
Location Countries

United States

Verification Date

August 2020

Responsible Party

Type: Principal Investigator

Investigator Affiliation: OHSU Knight Cancer Institute

Investigator Full Name: Charles D Lopez

Investigator Title: Principal Investigator

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (mFOLFIRINOX, chemotherapy)

Type: Experimental

Description: See Detailed Description.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov