NeoOPTIMIZE: Early Switching of mFOLFIRINOX or Gemcitabine/Nab-Paclitaxel Before Surgery for the Treatment of Resectable, Borderline Resectable, or Locally-Advanced Unresectable Pancreatic Cancer
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| ClinicalTrials.gov Identifier: NCT04539808 |
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Recruitment Status :
Recruiting
First Posted : September 7, 2020
Last Update Posted : February 10, 2022
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Sponsor:
OHSU Knight Cancer Institute
Collaborator:
Oregon Health and Science University
Information provided by (Responsible Party):
Charles D Lopez, OHSU Knight Cancer Institute
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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), or that has spread to nearby tissue or lymph nodes and cannot be removed by surgery (locally-advanced unresectable). 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Borderline Resectable Pancreatic Carcinoma Locally Advanced Unresectable Pancreatic Adenocarcinoma Resectable Pancreatic Ductal Adenocarcinoma Stage 0 Pancreatic Cancer AJCC v8 Stage I Pancreatic Cancer AJCC v8 Stage IA Pancreatic Cancer AJCC v8 Stage IB Pancreatic Cancer AJCC v8 Stage III Pancreatic Cancer AJCC v8 Stage IV Pancreatic Cancer AJCC v8 | Drug: Capecitabine Drug: Fluorouracil Drug: Irinotecan Hydrochloride Drug: Leucovorin Calcium Drug: Losartan Potassium Drug: Oxaliplatin Radiation: Radiation Therapy Procedure: Resection | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 60 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | 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/Locally Advanced Unresectable Pancreatic Cancer |
| Actual Study Start Date : | May 27, 2021 |
| Estimated Primary Completion Date : | January 15, 2024 |
| Estimated Study Completion Date : | October 5, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus related topics:
Pancreatic Cancer
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (mFOLFIRINOX, chemotherapy)
mFOLFIRINOX REGIMEN: Oxaliplatin intravenously (IV) over 2 hrs, leucovorin calcium IV over 2 hrs, and irinotecan hydrochloride IV over 90 minutes on day 1. Also receive fluorouracil IV over 46 hrs starting on day 1. Repeats every 14 days for up to 4 cycles. Those with response and no disease progression may receive an additional 2 months. GA REGIMEN: Those with disease progression or toxicity to mFOLFIRINOX switch to GA regimen comprising gemcitabine hydrochloride IV over 30-60 mins and nab-paclitaxel IV over 30-40 mins on days 1, 8, and 15. Repeats every 28 days for 2 cycles. LOSARTAN: Cycle 1 day 1, start losartan potassium orally once daily until end of RT. RT/SURGERY: Short-course RT for 10 fractions over 5 days weekly or long-course RT with 15-25 fractions over 5 days weekly along with oral capecitabine twice daily on Monday-Friday or fluorouracil IV over 5-7 days weekly until completion of RT. Patients then undergo surgery 1-4 weeks following RT |
Drug: Capecitabine
Given PO
Other Names:
Drug: Fluorouracil Given IV
Other Names:
Drug: Irinotecan Hydrochloride Given IV
Other Names:
Drug: Leucovorin Calcium Given IV
Other Names:
Drug: Losartan Potassium Given PO
Other Names:
Drug: Oxaliplatin Given IV
Other Names:
Radiation: Radiation Therapy Undergo short-course or long-course RT
Other Names:
Procedure: Resection Undergo surgical resection
Other Name: Surgical Resection |
Primary Outcome Measures :
- Proportion of participants with R0 resection [ Time Frame: Up to time of surgery ]Using the surgery analysis set, the proportion of participants with R0 resection will be estimated with exact 95% confidence interval.
Secondary Outcome Measures :
- Progression-free survival (PFS) NeoOPTIMIZE [ Time Frame: 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 ]Using the efficacy analysis set, the estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., gemcitabine/nab-paclitaxel [GA] or modified fluorouracil/irinotecan/leucovorin/oxaliplatin [mFOLFIRINOX] +/- radiation therapy [RT] [i.e., short- or long-course, or both RT modalities combined]) will be performed for PFS.
- PFSNeoOPTIMIZE + pre-operative (preop)-RT [ Time Frame: 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 ]Using the efficacy analysis set, the estimated distribution of the PFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT [i.e., short- or long-course, or both RT modalities combined]) will be performed for PFS.
- Disease-free survival (DFS) NeoOPTIMIZE [ Time Frame: From the date of surgery to the time of tumor progression, or death due to any cause, assessed up to 24 months ]Using the surgery analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. Using the efficacy analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT [i.e., short- or long-course, or both RT modalities combined]) will be performed for DFS.
- DFSNeoOPTIMIZE + preop-RT [ Time Frame: From the date of surgery to the time of tumor progression, or death due to any cause, assessed up to 24 months ]Using the efficacy analysis set, the estimated distribution of the DFS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT [i.e., short- or long-course, or both RT modalities combined]) will be performed for DFS.
- Overall survival (OS) NeoOPTIMIZE [ Time Frame: From the start of neoadjuvant therapy (day 1) to death due to disease, assessed up to 24 months ]Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX +/- RT [i.e., short- or long-course, or both RT modalities combined]) will be performed for OS.
- OSNeoOPTIMIZE + preop-RT [ Time Frame: From the start of neoadjuvant therapy (day 1) to death due to disease, assessed up to 24 months ]Using the efficacy analysis set, the estimated distribution of the OS will be plotted using Kaplan Meier curves and reported with median survival and 95% confidence intervals if available. When feasible, sub-group analyses for the different treatment regimens (i.e., GA or mFOLFIRINOX] +/- RT [i.e., short- or long-course, or both RT modalities combined]) will be performed for OS.
- Proportion of participants with peri- and post-operative complications [ Time Frame: Up to 30 days after surgery ]Peri- and post-operative complications occurring within 30 days following surgery will be categorized per the Clavien-Dindo classification system. Using the surgery analysis set, the proportion of participants with peri- and post-operative complications occurring within 30 days following surgery.
- Proportion of participants that die within 30 days of surgery [ Time Frame: At 30 days post-surgery ]The proportion of 30-day post-operative mortality will be estimated and reported with two-sided exact 95% confidence intervals. If necessary, the proportion of 30-day post-operative mortality may be estimated from the Kaplan Meier product limit method.
- Incidence of grade >= 3 toxicities [ Time Frame: Up to 90 days after last dose of protocol-directed therapy ]The incidence of grade >= 3 toxicities per Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0 will be determined using the safety analysis set. The exact 95% confidence interval will be reported with the point estimate of toxicity rate. Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA version 21.1) preferred term and system organ class and a preferred term. The severity of the adverse events (AE) will be assessed by National Cancer Institute (NCI) CTCAE v 5.0 criteria. Descriptive statistics using the safety analysis set will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, serious adverse events (SAEs), treatment-related SAEs, and AEs leading to discontinuation per CTCAE v 5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria.
Other Outcome Measures:
- CA19-9 serum levels (U/ml) [ Time Frame: Baseline up to 24 months ]Using the safety analysis set, the levels of CA19-9 will be descriptively reported (across all participants).
- Proportion of LAPC participants with R0 resection [ Time Frame: From the start of neoadjuvant therapy (day 1) to time of surgery ]Will be estimated with exact 95% confidence interval.
- PFSNeoOPTMIZE for LAPC cohort [ Time Frame: From the start of neoadjuvant therapy (day 1) to time of tumor progression, or death due to any cause (up to 24 months from start of study treatment) ]Results will be qualitatively described when statistical measures are not feasible.
- PFSNeoOPTMIZE + preop-RT for LAPC subset [ Time Frame: From the start of neoadjuvant therapy (day 1) to time of tumor progression, or death due to any cause (up to 24 months from start of study treatment) ]Results will be qualitatively described when statistical measures are not feasible.
- DFSNeoOPTMIZE for LAPC cohort [ Time Frame: From date of surgery to time of tumor progression, or death due to any cause (up to 24 months from start of study treatment) ]Results will be qualitatively described when statistical measures are not feasible.
- DFSNeoOPTMIZE + preop-RT for LAPC subset [ Time Frame: From date of surgery to time of tumor progression, or death due to any cause (up to 24 months from start of study treatment) ]Results will be qualitatively described when statistical measures are not feasible.
- OSNeoOPTMIZE for LAPC cohort [ Time Frame: From the start of neoadjuvant therapy (day 1) to death due to any cause, assessed up to 24 months from start of study treatment ]Results will be qualitatively described when statistical measures are not feasible.
- OSNeoOPTMIZE + preop-RT for LAPC subset [ Time Frame: From the start of neoadjuvant therapy (day 1) to death due to any cause, assessed up to 24 months from start of study treatment ]Results will be qualitatively described when statistical measures are not feasible.
- Proportion of LAPC participants with peri- and post-operative complications [ Time Frame: From date of surgery to within 30 days from date of surgery ]Assessed per the Clavien-Dindo classification system. Results will be qualitatively described when statistical measures are not feasible.
- Proportion of LAPC participants who die within 30 days of surgery [ Time Frame: From date of surgery to 30 days post-surgery ]Results will be qualitatively described when statistical measures are not feasible.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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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
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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
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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
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Borderline resectable PDAC, defined as:
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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
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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)
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Locally-advanced, unresectable disease as defined by NCCN guidelines as follows:
- Tumors of the head with SMA >= 180 degrees, or any celiac abutment, unreconstractable SMV or portal occlusion, or aortic invasion or encasement
- Tumors of the body with SMA or celiac encasement 180 degrees, unreconstractable SMV or portal occlusion, or aortic invasion
- Tumors of the tail with SMA or celiac encasement >= 180 degrees
- Irrespective of location, all tumors with evidence of nodal metastasis outside of the resection field that are considered unresectable
- Must be deemed fit to undergo planned curative resection as determined by institutional standards
- No history of previous chemotherapy for pancreatic cancer. At the discretion of the principal investigator (PI), patient that have received no more than 1 month of systemic chemotherapy (e.g., mFOLFIRINOX), per standard of care, for the treatment of their PDAC may be eligible to participate
- 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)
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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)
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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
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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 (other than no more than one cycle of standard systemic 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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04539808
Locations
| United States, Oregon | |
| OHSU Knight Cancer Institute | Recruiting |
| Portland, Oregon, United States, 97239 | |
| Contact: Charles D. Lopez 503-494-8321 lopezc@ohsu.edu | |
| Principal Investigator: Charles D. Lopez | |
Sponsors and Collaborators
OHSU Knight Cancer Institute
Oregon Health and Science University
Investigators
| Principal Investigator: | Charles D Lopez | OHSU Knight Cancer Institute |
| Responsible Party: | Charles D Lopez, Principal Investigator, OHSU Knight Cancer Institute |
| ClinicalTrials.gov Identifier: | NCT04539808 |
| Other Study ID Numbers: |
STUDY00021614 NCI-2020-06277 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) STUDY00021614 ( Other Identifier: OHSU Knight Cancer Institute ) |
| First Posted: | September 7, 2020 Key Record Dates |
| Last Update Posted: | February 10, 2022 |
| Last Verified: | February 2022 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Adenocarcinoma Pancreatic Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Digestive System Neoplasms Neoplasms by Site Endocrine Gland Neoplasms Digestive System Diseases Pancreatic Diseases Endocrine System Diseases Calcium, Dietary Leucovorin Folic Acid |
Fluorouracil Capecitabine Oxaliplatin Irinotecan Camptothecin Losartan Calcium Levoleucovorin Calcium-Regulating Hormones and Agents Physiological Effects of Drugs Bone Density Conservation Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Antimetabolites, Antineoplastic Antineoplastic Agents |