Safety Study of ²¹²Pb-TCMC-Trastuzumab Radio Immunotherapy

Study Overview
=================
Brief Summary
-----------------
Monoclonal antibodies can transport and deliver radioactive elements capable of releasing sufficient amounts of energy to destroy tumor cells. In this clinical trial, we will study alpha particle radio immunotherapy using lead-212 (²¹²Pb), an isotope with a short path length targeted to malignant cells by the trastuzumab antibody, as a potential treatment for metastatic diseases. This Phase I trial is designed to determine the toxicity profile of ²¹²Pb-TCMC-Trastuzumab, its dose-limiting toxicities, and its anti-tumor effects in patients with HER-2 positive intraperitoneal cancers.

Official Title
-----------------
Phase I Trial of Intraperitoneal ²¹²Pb-TCMC-Trastuzumab for HER-2 Expressing Malignancy

Conditions
-----------------
Breast Neoplasms, Peritoneal Neoplasms, Ovarian Neoplasms, Pancreatic Neoplasms, Stomach Neoplasms

Intervention / Treatment
-----------------
* Other: ²¹²Pb-TCMC-Trastuzumab
* Biological: trastuzumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: At least 19 years of age. Life expectancy is greater than three months. Female subjects of child-bearing potential must have negative serum pregnancy test. If not surgically sterile, male and female patients of child-bearing potential must use double barrier contraception (e.g., hormonal; intrauterine device; barrier). Patients with HER-2 expressing tumors (e.g., ovarian, pancreatic, colon, gastric, endometrial, or breast) with measurable or non-measurable disease for which no standard therapy is available. HER-2 amplification by fluorescent in situ hybridization or HER-2 score of at least at least 1+ by Immunohistochemistry in more than 10% of the cells. Alternatively, HER-2 serum levels greater than 15ng/mL by ELISA. Disease must be predominantly intra-abdominal and should include documented peritoneal studding or positive peritoneal washings. Able and willing to sign an informed consent form. Exclusion Criteria: ECOG performance status greater than 3. Any serious active disease or co-morbid condition that, in the opinion of the investigator, may interfere with the safety or the compliance with the study. Poor bone marrow reserve as defined by absolute neutrophil count less than 1.5 x 10³/cmm or platelets less than 100 x 10³/cmm within two weeks prior to initiation of treatment. Liver only metastases. Poor organ function as defined by one of the following: Total bilirubin greater than 1.5 upper limits of normal (ULN) Aspartate aminotransferase (AST), alanine aminotransferase (ALT) greater than 2.5 ULN or greater than 5 ULN in case of documented liver metastasis Serum creatinine greater than ULN, except if calculated creatinine clearance greater than 60 mL/min Urine Protein/Creatinine Ratio greater than 1 on morning spot urinalysis or proteinuria greater than 500 mg/24 h Breast-feeding woman. No resolution of all specific toxicities (excluding alopecia) related to any prior anticancer therapy to Grade 2 according to the National Cancer Institute common terminology criteria for adverse events (NCI CTCAE) v.4.03 or nausea and vomiting to Grade 3 and uncontrolled with anti-emetics. Wash out period of less than three weeks from previous anti-tumor therapy or any investigational treatment (and less than six weeks in case of prior nitroso-urea and or mitomycin C treatment) of scheduled date of administration. Wash out period of less than one week from last palliative dose of radiotherapy. Any other severe underlying medical conditions that could impair the ability to participate in the study or the interpretation of its results related to the investigational product such as: Patients with abnormal cardiac function defined by a left ventricular ejection fraction (LVEF) less than 50% by echocardiogram (ECHO) or multi gated acquisition (MUGA) scan Patients with previous history of acute cardiac failure Clinical symptoms of bowel obstruction, evidence of rectosigmoid bowel involvement on exam, or transmural bowel wall involvement on computed tomography (CT) or magnetic resonance imaging (MRI). Prior whole abdomen radiation therapy exceeding 4Gy, intraperitoneal radionuclide therapy, bone marrow transplant, or stem cell transplant. History of Human Immunodeficiency Virus (HIV) antibody by enzyme-linked immunosorbent assay (ELISA) or negative by Western blot (if ELISA is positive) or hepatitis B surface antigen (HBsAg) because of the potential for added toxicity from the radiolabeled antibody among patients infected with these viruses. Detectable human anti-human antibody (HAHA) if there is any history of monoclonal antibody exposure. Iodine allergy if the patient is unwilling to accept radiation to the thyroid from uptake of radionuclide without blocking. Allergy to furosemide if the patient is unwilling to accept radiation risk without these agents and alternative is not feasible. History of cumulative anthracycline therapy exceeding 200 mg/m² for doxorubicin or comparable low dose of other anthracyclines.

Ages Eligible for Study
-----------------
Minimum Age: 19 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Dose escalation<br>In preparation for the study, patients screened and eligible will have a peritoneal catheter placed and the evening prior to the injection of the labeled antibody will receive furosemide. Herceptin will be administered IV followed by a single IP infusion of ²¹²Pb-TCMC-Trastuzumab. Serial sampling of blood, urine, and dosimetry will be performed following treatment to determine the toxicity, pharmacokinetics, immunogenicity, and antitumor effects. | Other: ²¹²Pb-TCMC-Trastuzumab<br>* The starting dose level will be 200 μCi/m² of ²¹²Pb-TCMC-Trastuzumab. Three to six patients will be treated at each dose level, and dose escalation will proceed if no more than 1 out of 6 patients in a cohort experiences dose limiting toxicity. Six patients will be treated at the maximum tolerated dose.<br>Biological: trastuzumab<br>* 4 mg/kg.<br>* Other names: Herceptin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: To measure the number of participants who experience adverse events after intraperitoneal (IP) administration of ²¹²Pb-TCMC-Trastuzumab. | Adverse events considered dose limiting toxicity: Grade 3 elevations of ALP, bilirubin, ALT, or AST lasting ≥7 days Grade 3 elevations of serum creatinine within 6 weeks of treatment Grade 2 elevations of serum creatinine lasting ≥7 days that occur after 6 weeks Grade 3 proteinuria Any other Grade 3 or 4 non-hematologic toxicity Grade 4 neutropenia lasting ≥7 days or febrile neutropenia of any duration Grade 3 thrombocytopenia that fails to recover to ≤ Grade 2 at 6 weeks Grade 4 thrombocytopenia lasting ≥7 days or thrombocytopenia accompanied by bleeding | Assessed periodically during study treatment follow-up, up to five years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity: To characterize the human immune response against ²¹²Pb-TCMC-Trastuzumab given via IP infusion. |  | Assessed at six weeks visit | 
| Anti-tumor effects: To monitor for anti-tumor effects as assessed by physical examination, radiographic imaging, and tumor marker studies. |  | Assessed after six and twelve weeks, and then at twelve-week intervals until progression. | 
| Pharmacokinetics: To determine the plasma pharmacokinetics and assess the extent of exit of radioactivity from the peritoneal cavity by γ-camera imaging. |  | Up to 3 days post-injection | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HER2+, HER-2 positive, intraperitoneal, intra-abdominal, Lead 212, Radio Immunotherapy, Alpha particle, Antibodies, Immunoglobulins, Antibodies, Monoclonal, Immunologic Factors, Physiological Effects of Drugs, Pharmacologic Actions, RIT