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Antineoplastic Agents, Immunological

Folinic Acid

Folate

Vitamin B9

Cetuximab 500mg/m² + irinotecan\* 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 2800 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles

FOLFOXIRI + Cetuximab

Irinotecan\* 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 2800 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles

FOLFOXIRI

Yanhong Deng, M.D.

PURPOSE:

A primary aim of phase II FOCULM study is to explore whether cetuximab in combination with FOLFOXIRI as first treatment could improve surgical conversion in patients with KRAS/NRAS wild-type, unresectable liver - only metastases of colorectal cancer. The first secondary aim is to evaluate the safety and tolerability of the chemotherapy of FOLFOXIRI plus Cetuximab targeted therapy regimen in this patient population.

Secondary aims include determination of objective response rate, progression free survival, quality of life and time to recurrence for patients undergoing complete resection and/or ablation of liver.

Patients will be randomized to two therapy groups:

Experimental arm A: Chemotherapy with FOLFOXIRI + Cetuximab Standard arm B: Chemotherapy with FOLFOXIRI

FOLFOXIRI With or Without Cetuximab as First-line Treatment of Patients With Non-resectable Liver - Only Metastatic Colorectal Cancer

A Phase II Study to Evaluate the Surgical Conversion Rate in Patients Receiving FOLFOXIRI +/- Cetuximab for Unresectable Wild-Type KRAS/NRAS Colorectal Cancer With Metastases Confined to the Liver

Number of patients with adverse events and severity according to NCI CTC 4.0

Time from date of randomization until the date of first documented progression or date of death from any cause, whichever came first.

Time from date of complete resection and/or ablation of liver until first recurrence

scores according to EORTC QLQ-C30 scoring manual

Sun Yat-sen University

Associate professor

Bevacizumab

Angiogenesis Inhibitors

Growth Inhibitors

Bevacizumab 5mg/kg + irinotecan\* 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 2800 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle until PD or resectability or to max. 12 cycles

FOLFOXIRI + Bevacizumab

BACKGROUND:

For patients with liver-limited metastatic colorectal cancer (mCRC), complete resection of liver metastases is the only potentially curative treatment. The current goal of medical treatment for colorectal cancer with initially unresectable liver metastases is to maximize the rate of secondary resection and prolong overall survival (OS). A strong correlation was found between response rate and secondary resection rate of metastases, and the triple drugs combination of infusional 5-fluorouracil/leucovorin (5-FU/LV), irinotecan, and oxaliplatin (FOLFOXIRI) was recommended can be used in selected patients with potentially resectable metastases in order to improve response rate and make resection more possible. The addition of a anti-VEGFs monoclonal antibody such as bevacizumab to chemotherapy has been shown to increase response rate, resection rate and improve OS in the first-line treatment of mCRC patients. The efficacy and safety of bevacizumab in addition to triplet drugs were previously tested in OLIVIA trial, the resection rate of liver metastases of 49% was reported, and the response rate was 81%; most common grade 3-4 adverse events was neutropenia. On the basis of such promising results, we conducted the present randomized study to explore whether FOLFOXIRI plus bevacizumab compared with FOLFOXIRI alone as first-line treatment could improve radical resectability in patients with RAS mutation-type, unresectable liver-only metastatic colorectal cancer.

OBJECTIVE:

The primary objective of the FOBULM study is to evaluate the efficacy of FOLFOXIRI plus bevacizumab compared to FOLFOXIRI alone in patients with initially unresectable liver-limited RAS mutation-type mCRC.

Secondary objectives are safety and tolerability of the treatment, efficacy in terms of objective response rate (ORR), OS, progression free survival (PFS), quality of life and an assessment of biomarkers for predictive response and prognosis.

OVERVIEW OF TRIAL DESIGN

This FOCULM trial is a a two-arm, multicenter, open labelled, prospective, randomized phase II studies. Eligible patients with initially unresectable liver-limited mCRC will be randomised 1:1 to receive either FOLFOXIRI plus bevacizumab or FOLFOXIRI alone.

FOLFOXIRI With or Without Bevacizumab as First-line Treatment for Unresectable Liver-only Metastatic Colorectal Cancer Patients With RAS Mutation-type

A Phase II Study to Evaluate the Surgical Conversion Rate in Patients With RAS Mutation-type Receiving FOLFOXIRI +/- Bevacizumab for Unresectable Colorectal Liver-Limited Metastases

Defined as the proportion of patients who had a curative liver treatment following protocol treatment, i.e., liver metastases that can be radical resected with or without ablation with no postoperative evidence of residual malignant disease.

The grade of toxicity will be assessed using the NCI common toxicity criteria, version 4.0.

CR + PR rate will be assessed according to the RECIST version 1.1 guidelines.

Estimated from the date of randomization to death from any cause.

Time measured from the day of randomization to the date of first documented progression, or death from any cause.

Scores according to EORTC QLQ-C30 scoring manual

Gland and Hormone Related Diseases

Rare Diseases

Pancreatic Neoplasms

Neoplastic Processes

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Gastrointestinal Agents

Pancrelipase

Pancreatin

Patients with pancreatic cancer and low-volume liver metastasis

Patients will undergo pancreaticoduodenectomy, or the Whipple procedure, which involves removal of the head of the pancreas, the duodenum, and a portion of the stomach, as well as the gallbladder and a portion of the bile duct.

The patient will also undergo a Hepatectomy, the surgical resection or removal of all or part of the liver or Microwave Ablation (MWA) if determined by the surgeon to be the best course of care.

Hepatic Resection or Ablation with Pancreaticoduodenectomy

Sabino Zani, MD

The purpose of this study is to demonstrate the feasibility of an aggressive multimodal approach among patients with stage IV pancreatic cancer (PAC) with isolated, low-volume hepatic metastasis (LVHM). We will evaluate and describe the surgical and overall outcomes of an initial cohort of subjects who undergo pancreatectomy and hepatic resection/ablation for PAC with LVHM. The end of study results will be reviewed by the Hepatiobiliary Multidisciplinary Conference (HDMC) and Surgery Audit Committee (SAC) to determine the appropriateness of adding this treatment arm for patients with oligometastatic metastatic pancreatic cancer.

This is a small interventional pilot study that will be conducted as a single-site study at Duke University Health System (DUHS). All subjects with pancreatic cancer and low-volume liver metastases (\< or = 3 lesions) who meet criteria for pancreatic and liver resection will be offered the opportunity to participate. Potential subjects will be referred by the Medical Oncology physicians at Duke if they feel like the patient would be suitable for this study. We anticipate enrolling 15 subjects to include 10 evaluable subjects in the analysis.

Any subject who consents to the study will proceed with primary resection, including pancreaticoduodenectomy or distal pancreatectomy, and liver resection/ablation of the metastases.

Screening will include a medical record review, standard of care CT scan/MRI, clinical evaluation including physical, vitals, height weight and routine blood tests.

Preoperative data such as sex, race, age at resection, ASA class, race, body mass index (BMI), pretreatment staging, CA 19-9 (missing in open PD), tumor size (cm), and neoadjuvant therapy (no; yes), time to initiation and completion will also be captured.

Perioperative data like date of surgery, OR time, ASA class, intra-operative transfusion requirements, fluid administration, EBL, operative complications (including but not limited to infection, bleeding, need for re-operation, thrombus, pancreatic leak, bile leak, liver failure, nutritional data like use of TPN and tube feedings, and length of stay will be collected.

Post-operative data regarding re-admission and surveillance data for oncologic outcomes such as re-operation, final pathology margin status, nodal status, and postoperative CA 19-9, as well as DFS and OS, including date of death if applicable, during the provided follow up period.

To ensure accurate and complete incorporation of medical data, a database of perioperative outcomes will be prospectively maintained during the subject's hospital stay and for the first 3 months following surgery. Duke University is a member of the National Surgical Quality Improvement Program (NSQIP), with 100% participation in Hepatopancreaticobiliary (HPB) procedures. As such, all preoperative data and 30-day outcomes are collected by a fully trained Surgical Clinical Reviewer and are available within our electronic medical record (EMR). NSQIP provides a robust, audited dataset that has been validated to optimize the accuracy of data collection, substantially reducing the cost and resource requirements of data extraction. Following this 30-day period, data will be collected at regularly scheduled clinic visits, which typically occur weekly until 6-12 weeks post-surgery, then 3-4 months for the first year, and every 6 months thereafter and stored in a local, REDCap database.

Subjects' medical records will be continually reviewed for surgical complications and for overall survival (date of subject death).

Hepatic Resection for Metastatic Pancreatic Cancer

Number of deaths within 90 days of operation

Number of days in the hospital post-surgery

Number of patients readmitted to the hospital post-operatively

Length of time to treatment after surgery

Amount of blood loss during surgery in milliliters

Duke University

mFOLFOX7 (5-FU, leucovorin, oxaliplatin) + cetuximab

500 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles. Cetuximab dose will be escalated by 100 mg/m2 every 2 weeks to a maximum dose of 800 mg/m2 if, at the time of retreatment, skin rash is less than or equal to grade 1, diarrhea is grade 0 (defined as less than or equal to 3 stools per day over baseline), and the patient is not experiencing any other greater than or equal to grade 2 toxicity attributed to cetuximab.

cetuximab

3000 mg/m2 IV continuous infusion over 46 hours every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.

5-FU

85 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.

oxaliplatin

400 mg/m2 IV every two weeks on days 1, 15, 29, and 43 of each 56 day cycle, for a total of 3 cycles.

leucovorin

Norman Wolmark, MD

FC-6 is a Phase II, multi-center clinical trial for patients with unresectable, wild-type K-RAS, colorectal cancer with metastases confined to the liver. Liver metastases must be determined by FC-6 criteria to be unresectable, and the colorectal cancer (CRC) tumor (primary or metastatic) must be found to be wild-type K-RAS. Patients with mutant K-RAS tumors are ineligible. K-RAS testing can be done through the local hospital or a tumor sample can be submitted to the FC-6 central lab (Esoterix Clinical Trial Services).

A primary aim of this study is to evaluate the surgical conversion rate using cytotoxic combination chemotherapy and biologic therapy with cetuximab, a monoclonal antibody targeted against the epidermal growth factor receptor. A second primary aim is to evaluate the safety and tolerability of a chemotherapy/targeted therapy regimen in this patient population. Secondary aims include determination of clinical response rate, recurrence-free survival for patients undergoing complete resection and/or ablation of liver metastases, and overall survival.

All patients will receive the FC-6 study treatment regimen every 2 weeks during each 8-week cycle for a total of 3 cycles.

Baseline imaging of the chest, abdomen, and pelvis will be performed. CT scan or MRI of the abdomen will be performed after 1 cycle of neoadjuvant therapy to assess clinical response and resectability of liver metastases. If liver metastases are not deemed to be resectable at this assessment, but tumor assessment demonstrates stable disease or partial response, therapy will continue with re-assessment for clinical response and resectability after Cycle 2 and, if necessary, after Cycle 3.

After a minimum of 1 cycle of therapy, patients who meet the guidelines for resection of liver metastases will undergo liver metastasectomy (tumor resection and/or ablation) as soon as judged technically feasible by the hepatic surgeon in order to minimize chemotherapy damage to the liver and morbidity from surgery. At the investigator's discretion, the chemotherapy and cetuximab regimen may be continued for 1 additional treatment given at least 2 weeks before the planned date of surgery. This additional treatment, if given, will not be considered to be part of the 3 study therapy cycles.

The surgical goal is to perform a curative (R0) resection and/or ablation. If curative surgery was performed and if only 1 or 2 cycles of therapy were administered before surgery, postoperative therapy using the same regimen will resume 4-6 weeks following surgery to complete 3 cycles of study treatment. Following discontinuation of study therapy, all patients who undergo R0 resection (with or without ablation) will be followed every 3 months for the first 2 years on the study and then every 6 months for years 3 through 5.

Further therapy for patients who do not undergo R0 resection/ablation will be at the investigator's discretion. These patients will only be followed for vital status every 12 months for the remainder of the 5-year period following study entry.

A total sample size of 60 patients will be enrolled in the FC-6 trial.

A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver

A Phase II Study to Determine the Surgical Conversion Rate in Patients Receiving Neoadjuvant mFOLFOX7 + Cetuximab for Unresectable Wild-Type K-RAS Colorectal Cancer With Metastases Confined to the Liver

19 participants experienced at least one adverse event. There were a total of 95 adverse events reported. (Note: multiple occurrences of the same adverse event in one individual are counted only once.) Refer to the Adverse Events section for specifics. The Other Adverse Events section lists only those events occurring above 5% frequency.

The percentage of patients alive at 18 months.

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by PET/CT, CT scan, MRI or spiral CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective clinical Response Rate (cRR) = CR + PR during the 3 preoperative cycles, among the treated patients.

Bristol-Myers Squibb

NSABP Foundation Inc

Treatment

Age, Continuous

Sex/Gender, Customized

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Diana Gosik, Director Department of Site and Study Management

All 20 patients were included in this outcome measure.

The Percentage of Patients Who Had a Curative (R0) Liver Metastasectomy Following Protocol Treatment, i.e., Metastatic Disease That Can be Completely Resected and/or Ablated With no Postoperative Evidence of Residual Malignant Disease (R0 Resection).

Reported Adverse Events.

Overall Survival (OS). Time From Study Entry Until Death From Any Cause.

Objective Clinical Response Rate (cRR). Measureable Lesions That Can be Accurately Measured in at Least One Dimension With Conventional Radiologic Techniques or Spiral CT.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
FOLFOXIRI With or Without Cetuximab as First-line Treatment of Patients With Non-resectable Liver - Only Metastatic Colorectal Cancer	NCT02063529	Metastatic Colo...	FOLFOXIRI + Cet... FOLFOXIRI	18 Years - 65 Years	Sun Yat-sen University
FOLFOXIRI With or Without Cetuximab as First-line Treatment of Patients With Non-resectable Liver - Only Metastatic Colorectal Cancer	NCT02063529	Metastatic Colo...	FOLFOXIRI + Cet... FOLFOXIRI	18 Years - 65 Years	Sun Yat-sen University
FOLFOXIRI With or Without Cetuximab as First-line Treatment of Patients With Non-resectable Liver - Only Metastatic Colorectal Cancer	NCT02063529	Metastatic Colo...	FOLFOXIRI + Cet... FOLFOXIRI	18 Years - 65 Years	Sun Yat-sen University
FOLFOXIRI With or Without Bevacizumab as First-line Treatment for Unresectable Liver-only Metastatic Colorectal Cancer Patients With RAS Mutation-type	NCT02350530	Metastatic Colo...	FOLFOXIRI + Bev... FOLFOXIRI	18 Years - 70 Years	Sun Yat-sen University
Hepatic Resection for Metastatic Pancreatic Cancer	NCT02892305	Pancreatic Neop... Neoplasm Metast... Liver Metastase...	Hepatic Resecti...	18 Years - 90 Years	Duke University
A Study With Neoadjuvant mFOLFOX7 Plus Cetuximab to Determine the Surgical Conversion Rate for Unresectable Colorectal Cancer With Metastases Confined to the Liver	NCT00803647	Metastatic Colo...	cetuximab 5-FU oxaliplatin leucovorin	18 Years -	NSABP Foundation Inc

Spots Global Cancer Trial Database for liver ablation