Phase I Trial of huA33 Plus Chemotherapy in Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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Although treatment for metastatic colorectal cancer has improved significantly over the recent years, it still remains a significant health problem representing the leading cancer by incidence in the United States of America. In the search for new therapies, monoclonal antibodies have been developed to specifically target human colon cancer cells. huA33 is an antibody that reacts with the A33 antigen which is produced by colorectal cancers. Prior studies have shown that administration of the huA33 antibody may delay the growth of tumor cells producing the specific antigen. Oxaliplatin and 5-fluorouracil (5-FU) are cytotoxic agents which are considered as standard treatment in metastatic colorectal cancer. Leucovorin (folinic acid) is a vitamin which enhances the effect of 5-FU. Eligible patients with advanced colorectal cancer will receive huA33 10 mg/m2 by intravenous (IV) infusion weekly for twelve weeks. Starting on Study Day 15 (week 3), 5-FU, leucovorin, and oxaliplatin will be administered every 2 weeks for 10 weeks. Patients will be evaluated weekly for toxicity. Blood samples will be obtained every week for hematology and serum biochemistry analysis and for determination of human anti-human antibodies (HAHA). In patients with measurable disease, tumors will be assessed by the appropriate scan at baseline and at the end of the thirteen week cycle. The primary objective of this study is to assess the safety of huA33 + 5-FU + leucovorin + oxaliplatin. The secondary objective is to measure the immunogenicity of huA33 when given in combination with 5-FU plus leucovorin and oxaliplatin and to document tumor responses.

Detailed Description
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Purpose of the Research Study: huA33 is an antibody that reacts with the A33 antigen which is produced by colorectal cancers. Prior studies have shown that application of the huA33 antibody may delay the growth of tumor cells producing the respective antigen. Oxaliplatin and 5-FU are cytotoxic agents which are considered as standard treatment in metastatic colorectal cancer. Leucovorin is a vitamin which enhances the effect of 5-FU. The primary purpose of this study is to determine whether the combination huA33 plus oxaliplatin, 5-FU and leucovorin is safe and what side effects occur. Description of Research Procedures: The first step is to determine whether or not patients are eligible for participation in the study. Apart from general blood tests and x-ray studies needed, this involves testing with regard to some special requirements: Three tests of stool to determine if it is positive for blood. Women of childbearing age must have a negative pregnancy test. If patients ever had a treatment with similar substances like huA33 before, a blood sample needs to be tested for antibodies that may have developed against huA33. After eligibility is established, huA33 will be administered intravenously over a period of 30 minutes once a week at a dose of 10 mg/m2. Starting on day 15 and continuing every second week, oxaliplatin, 5-FU and leucovorin are administered. Oxaliplatin and leucovorin will be given as infusions over 2 hours. Afterwards patients will receive a bolus infusion of 5-FU intravenously followed by an infusion of 5-FU over 22 hours. The doses of oxaliplatin will be 85mg/m2, leucovorin 200mg/m2, 400mg/m2 of 5-FU as a bolus infusion and 600mg/m2 as a continuous infusion. A complete treatment cycle consists of 12 weekly treatment days. Patients will have an interview with their doctor and a physical examination before the first day of treatment and before each therapy. Standard blood tests as well as special blood tests to measure a possible reaction of the immune system to the huA33 antibody will be done weekly and before the treatment is started. The amount of blood to be drawn will be 20-30 ml during one cycle of the study. X-rays and/or CT scans to measure the extent of the disease will be done at the start and at week 13, which is considered to be the first day of the next cycle. Patients may continue with this treatment for up to 2 cycles.

Official Title
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Phase I Trial of huA33 Plus 5-fluorouracil (5-FU), Leucovorin and Oxaliplatin in Patients With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: 5-Fluorouracil
* Drug: Leucovorin
* Drug: huA33


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients will be eligible for enrollment if they fulfill all of the following criteria: Metastatic colorectal cancer. Histologically or cytologically proven colorectal cancer. Expected survival of at least 4 months. Not more than 2 different pretreatment regimens. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Within the 2 weeks prior to the first dose of huA33, the following vital laboratory parameters: Lab Parameter Range Neutrophil count ≥ 1.5 x 10E9/L Platelet count ≥ 150 x 10E9/L Serum bilirubin ≤ 2 mg/dL Creatinine clearance >50 ml/ min Age ≥ 18 years. Able and willing to give valid written informed consent. Exclusion Criteria: Patients will be excluded from the study for any of the following reasons: Untreated active metastatic disease to the central nervous system defined as new or enlarging lesions on CT or MRI. Surgery or radiotherapy of brain metastases within 3 months prior to the first dose of huA33. Metastatic disease involving > 50% of liver volume. Other serious illnesses, eg, serious infections requiring antibiotics, bleeding disorders. Chemotherapy, radiation therapy, or immunotherapy within 4 weeks prior to first dosing (6 weeks for nitrosoureas). Previous treatment with oxaliplatin. Previous treatment with huA33 monoclonal antibody or antibody fragment. a. Positive huA33 HAHA titer - defined as greater than 3 standard deviations above the mean patient normal range by Biacore analysis. Concomitant treatment with systemic corticosteroids. Topical or inhalational corticosteroids are permitted. Known HIV, Hepatitis B or C positivity. Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study. Lack of availability of the patient for clinical and laboratory follow-up assessment. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing. Pregnancy or breastfeeding. Women of childbearing potential: Refusal or inability to use effective means of contraception.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: huA33 antibody plus chemotherapy<br>huA33 was administered intravenously over a period of 30 minutes once a week at a dose of 10 mg/m2 for 12 weeks. Starting on day 15 and continuing every second week, oxaliplatin, 5-fluorouracil (5-FU) and leucovorin were also administered. Oxaliplatin and leucovorin were given as infusions over 2 hours. Afterwards, patients received a bolus infusion of 5-FU intravenously followed by an infusion of 5-FU over 22 hours. The doses of oxaliplatin were 85mg/m2, leucovorin 200mg/m2, 400mg/m2 of 5-FU as a bolus infusion and 600mg/m2 as a continuous infusion. A complete treatment cycle consisted of 12 weeks. Patients were eligible to receive an additional cycle in the absence of dose-limiting toxicity (DLT), immunogenicity (huA33 human anti-human antibodies {HAHA}) and disease progression. | Drug: Oxaliplatin<br>* Oxaliplatin was administered at 85 mg/m2 on day 2 of every 2 week regimen.<br>* Other names: Eloxatin;Drug: 5-Fluorouracil<br>* The dose of 5-FU was 400 mg/m2 IV bolus followed by continuous IV infusion at 600 mg/m2 over 22 hours on day 2 and day 3 of every 2 week regimen.<br>* Other names: 5-FU;Drug: Leucovorin<br>* Leucovorin was administered at a dose of 200mg/m2 on day 2 and day 3 of every 2 week regimen.<br>* Other names: folinic acid;Drug: huA33<br>* huA33 was administered intravenously over a period of 30 minutes once a week at a dose of 10 mg/m2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Measured by the Number of Patients With Treatment Emergent Adverse Events (TEAEs), Grade 3 TEAEs, TEAEs Resulting in Death, TEAEs Related to Treatment and Serious TEAEs in Patients With Metastatic Colorectal Cancer. | Patients were evaluated weekly for toxicity. Blood samples were obtained every week for hematology and serum biochemistry analysis. All adverse events, which occurred after the signing of informed consent were documented in the case report form. Toxicity was evaluated according to the National Cancer Institute CTCAE Scale (Version 3.0). All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 13.1 and classified by MedDRA system organ class (SOC) and preferred term. Treatment emergent adverse events (TEAEs) are any adverse events occurring or worsening after the first administration of study drug. | up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of huA33 as Measured by the Number of Patients With Human Anti-human Antibodies (HAHA) When Given huA33 Together With Oxaliplatin and 5-FU Plus Leucovorin in Patients With Metastatic Colorectal Cancer. | Serum samples were taken at baseline and prior to each administration of huA33.The samples were analyzed by surface plasmon resonance technology using a BIACORE 2000 instrument. All sera were analyzed at the end of the study. Patient serum was considered HAHA positive if the response unit (RU) value at a serum dilution of 1:100 exceeded a cutoff value, defined as the mean inter-patient baseline RU value + 3x the standard deviation (SD) of negative control sera at a serum dilution of 1:100. Results were reported as either positive or negative. | up to 26 weeks | 
| Tumor Response in Patients With Metastatic Colorectal Cancer Receiving huA33, Oxaliplatin and 5-FU Plus Leucovorin. | Tumor response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) (Therasse P et al. J Natl Cancer Inst 92: 205-216 2000) at baseline and at the end of each cycle. Per RECIST, target lesions were categorized as follows: complete response (CR): disappearance of all target lesions; partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria. | up to 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer, huA33, antibody, chemotherapy