Safety Study of ²¹²Pb-TCMC-Trastuzumab Radio Immunotherapy

NCT01384253 | Completed Phase 1 DMC

• 1 other identifier: AREVAMED01
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

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.

Conditions

Breast Neoplasms; Peritoneal Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• 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

Study Arms (1)

Phase I: Dose escalation

EXPERIMENTAL

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; Biological: trastuzumab

Interventions

²¹²Pb-TCMC-Trastuzumab OTHER

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.

Phase I: Dose escalation

trastuzumab BIOLOGICAL

4 mg/kg.

Also known as: Herceptin

Phase I: Dose escalation

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Orano Med LLC: lead

Study Sites (2)

University Of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

UCSD Moores Cancer Center

San Diego, California, United States

Location

Related Publications (2)

• Meredith RF, Torgue J, Azure MT, Shen S, Saddekni S, Banaga E, Carlise R, Bunch P, Yoder D, Alvarez R. Pharmacokinetics and imaging of 212Pb-TCMC-trastuzumab after intraperitoneal administration in ovarian cancer patients. Cancer Biother Radiopharm. 2014 Feb;29(1):12-7. doi: 10.1089/cbr.2013.1531. Epub 2013 Nov 14.

  PMID: 24229395 BACKGROUND

• Meredith R, Torgue J, Shen S, Fisher DR, Banaga E, Bunch P, Morgan D, Fan J, Straughn JM Jr. Dose escalation and dosimetry of first-in-human alpha radioimmunotherapy with 212Pb-TCMC-trastuzumab. J Nucl Med. 2014 Oct;55(10):1636-42. doi: 10.2967/jnumed.114.143842. Epub 2014 Aug 25.

  PMID: 25157044 BACKGROUND

Related Links

• University of Alabama at Birmingham Department of Oncology Clinical Research

MeSH Terms

Conditions

Breast Neoplasms; Peritoneal Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

Interventions

Trastuzumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Abdominal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Peritoneal Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Pancreatic Diseases; Gastrointestinal Neoplasms; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ruby F Meredith, M.D., Ph.D.

  University of Alabama at Birmingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 27, 2011
• First Posted: June 29, 2011
• Study Start: July 1, 2011
• Primary Completion: October 1, 2015
• Study Completion: July 1, 2016
• Last Updated: September 30, 2016

Record last verified: 2016-09

Locations

US (2)