Perioperative MVT-5873, a Fully Human Monoclonal Antibody Against a CA 19-9 Epitope, for Operable CA 19-9 Producing Pancreatic Cancers, Cholangiocarcinomas, and Metastatic Colorectal Cancers

Study Overview
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Brief Summary
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Background: Gastrointestinal tumors have a molecule called carbohydrate antigen 19-9 (CA19-9) in the tumors and blood. The agent MVT-5873 was designed to block this molecule. Researchers want to test how safe it is to give this agent to people before and after surgery to remove a tumor. They want to learn the highest dose tolerated. They want to see if getting the agent at surgery helps slow down the disease. Objective: To test the safety of giving MVT-5873 at surgery to remove cancer and see if it slows the progression of the disease. Eligibility: Adults at least 18 years old with certain cancers and certain blood CA19-9 levels Design: Participants will be screened with: Medical history Physical exam Blood and heart tests Scans Review of normal activities Review of tumor sample Pregnancy test A few days before surgery, participants will get a dose of the study agent. They will get it through a small plastic tube in a vein over about 2 hours. Participants will sign a separate consent and have the surgery. A sample of the tumor and normal liver will be removed for research. For 1-2 weeks after surgery, participants will recover in intensive care then regular care at the hospital. They will be monitored and treated throughout the stay. After leaving the hospital, participants will get the study agent every week for 1 month. Then they will get it every other week for 2 months. They will repeat screening tests at study visits and at a follow-up visit. That will be about 5 weeks after the last dose.

Detailed Description
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Background: Resections to remove tumors in the liver, bile ducts and pancreas are rarely curative, and patients frequently succumb to disease recurrence in the ensuing months to year(s) after the operation. Standard adjuvant therapies, which typically begin 6-12 weeks after surgery, offer little demonstrable decreases in the rates of tumor recurrence. The concept and implementation of immediate perioperative therapy has not been evaluated given the serious concerns related to healing and recovery with standard cytotoxic chemotherapy and newer targeted agents. A significant percentage of metastatic colorectal cancers, and primary tumors of the pancreas and bile ducts express Sialyl Lewis, an epitope on the well-established tumor marker, Carbohydrate antigen 19-9 (CA19-9). MVT-5873, a fully human antibody against Sialyl Lewis, has displayed antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) in vitro, potentiated chemotherapeutic efficacy in mouse models and demonstrated efficacy in Phase 1 trials of patients with advanced inoperable Hepato-pancreato-biliary (HPB) cancers. MVT-5873 is well tolerated as a single agent; moderate elevations in aspartate aminotransferase (AST)/alanine aminotransferase (ALT) appear to be dose-limiting. Patients with resectable Sialyl Lewis-expressing cancers represent an ideal population to explore the use of perioperative MVT-5873 given moderate level of CA 19-9 elevations, and the potential for extension of recurrence-free survival. Objectives: Document the safety of perioperative MVT-5873 in patients undergoing pancreas and liver resections. Determine if perioperative MVT-5873 can decrease 1-year recurrence rates for patients with operable CA 19-9-producing cancers. Eligibility: Histologically or cytologically confirmed adenocarcinoma of the Colon (metastatic to liver) Pancreas Bile Ducts (Cholangiocarcinoma) Serum CA19-9 levels greater than the upper limit of normal, but less than 2500. Disease amenable to complete surgical extirpation. Design: -Pre-operative one-time treatment with MVT-5873, resection to remove all demonstrable disease in the liver, bile ducts and pancreas, and continuing MVT-5873 mono-therapy until off treatment criteria are met.

Official Title
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Perioperative MVT-5873, a Fully Human Monoclonal Antibody Against a CA 19-9 Epitope, for Operable CA 19-9 Producing Pancreatic Cancers, Cholangiocarcinomas, and Metastatic Colorectal Cancers

Conditions
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Colon Cancer, Pancreatic Cancer, Cholangiocarcinoma, Metastatic Colon Carcinoma, Liver Metastasis

Intervention / Treatment
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* Drug: MVT-5873
* Procedure: pancreatectomy or hepatectomy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Subjects must have histologically or cytologically confirmed diagnoses of adenocarcinoma in one of the following scenarios: Primary tumors of the pancreas Primary tumors of the bile duct and ampulla Metastatic colorectal cancers to the liver Subjects must have disease resectable with a standard pancreatectomy (pancreaticoduodenectomy or distal pancreatectomy) or liver resection. Subjects may have received prior therapy, including neoadjuvant regimens. Subjects must have serum Carbohydrate antigen 19-9 (CA 19-9) elevations greater than the upper limit of normal but less than 2500 U/mL. Age greater than or equal to 18 years. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 Subjects must have adequate organ and marrow function as defined below: leukocytes >3,000/mcL absolute neutrophil count >1,500/mcL platelets >90,000/mcL For subjects with Periampullary cancers that require a pancreaticoduodenectomy for complete tumor extirpation: total bilirubin <10 upper limit of normal (ULN)* Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamate-pyruvate transaminase (SGPT) <5 X institutional upper limit of normal creatinine <1.5X institutional upper limit of normal Subjects with periampullary cancers typically present with biliary obstruction resulting in significant abnormalities in liver function tests that do not reflect liver dysfunction. These values normalize after tumor removal. They can be normalized pre-operatively with biliary stenting, but several large studies have demonstrated an increase in infectious complications with drainage. As such, a practice standard has been to avoid stenting until bilirubin level rises above 10 X ULN. For subjects with liver tumors (cholangiocarcinoma or metastatic colorectal cancer) requiring a hepatectomy for complete tumor extirpation: total bilirubin <2.5 X institutional upper limit of normal* AST(SGOT)/ALT(SGPT) <5 X institutional upper limit of normal* creatinine <1.5X institutional upper limit of normal Liver abnormalities in this range are consistent with parenchymal destruction from the tumor. For subjects with pancreas tumors that require a distal pancreatectomy for extirpation: total bilirubin <1.5 X institutional upper limit of normal* AST(SGOT)/ALT(SGPT) <2 X institutional upper limit of normal* creatinine <1.5X institutional upper limit of normal Liver abnormalities in this range are consistent with pancreas cancer destruction from the tumor. The effects of MVT-5873 (HuMab-5B1) on the developing human fetus are unknown. For this reason, women of child-bearing 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 and for 3 months after completion of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Ability of subject to understand and the willingness to sign a written informed consent document. Subjects must agree to co-enrollment on the tissue collection protocol 13C0176, Tumor, Normal Tissue and Specimens from Patients Undergoing Evaluation or Surgical Resection of Solid Tumors. EXCLUSION CRITERIA: Presence of disease outside the confines of a standard operation for subjects with periampullary cancers (pancreatic and cholangiocarcinoma). Presence of disease outside the liver for subjects with intrahepatic/hilar cholangiocarcinoma or metastatic colorectal cancer, other than a primary tumor for subjects with metastatic colorectal cancer. Subjects who are receiving any other investigational agents. Fewer than 28 days (or 5 half-lives for systemic agents, whichever is shorter) from the last day of prior anticancer therapy, including chemotherapy, hormonal, investigational, and or biological therapies and irradiation. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. -Active concurrent malignancies within the last five years other than the primary tumor in subjects with metastatic colorectal cancer, basal or squamous cell skin carcinoma or non- medullary thyroid carcinoma. Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects of the MVT-5873. Because there is an unknown but potential Subjects with active, Hepatitis B or C infection because of the potential for increased liver toxicity given the damaging effects of the virus. Allergic to chimeric, humanized or human antibodies. Received live vaccine within 4 weeks prior to first date of study intervention. Infection requiring hospitalization or herpes zoster treatment within 2 weeks prior to the first date of study intervention. Long-term infectious diseases (tuberculosis, fungal infections) active within 2 years prior to the first date of study intervention.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 - Pre-operative Escalation Doses of MVT-5873 (HuMab-5B1)<br>Pre-operative escalation doses of MVT-5873, pancreatectomy or hepatectomy and post-operative MVT-5873 treatment | Drug: MVT-5873<br>* 1 mg/kg or 3 mg/kg for pre-operative dose, 1 mg/kg during post-operative period<br>* Other names: HuMab-5B1;Procedure: pancreatectomy or hepatectomy<br>* Pancreatectomy or hepatectomy<br>|
| Experimental: Cohort 2 - Pre-operative Recommended Dose (RD) of MVT-5873 (HuMab-5B1)<br>Pre-operative RD of MVT-5873, pancreatectomy or hepatectomy and post-operative MVT-5873 treatment | Drug: MVT-5873<br>* 1 mg/kg or 3 mg/kg for pre-operative dose, 1 mg/kg during post-operative period<br>* Other names: HuMab-5B1;Procedure: pancreatectomy or hepatectomy<br>* Pancreatectomy or hepatectomy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Disease Recurrence At 1 Year | Disease recurrence is defined as new disease measurable on computed tomography (CT)/magnetic resonance imaging (MRI) that was not present on the baseline CT/MRI. | 1 year | 
| Number of Grade 3-5 Adverse Events Related and/or Not Related to Drug | Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse events. | Date treatment consent signed to date off study, approximately 29 months and 11 days, and 22 months and 21 days for cohort 1 and cohort 2 respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Define Disease Free Survival (DFS) for Participants Treated With Preoperative MVT-5873 | Disease free survival is defined as resection day of surgery Day 0 (D0) until the time of documented clinical recurrence (radiographically or pathologically). In the absence of a knowable time of recurrence, time of death will be used as a surrogate. Clinical recurrence is cancer that has recurred during which the cancer could not be detected. This is judged on computed tomography (CT) or magnetic resonance imaging (MRI) as compared to the scan obtained after surgery and completion of the study drug. | An average of 15.17 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Well Tolerated Agent, Pancreas and Liver Resections, Recurrence-Free Survival