Safety Study of ²¹²Pb-TCMC-Trastuzumab Radio Immunotherapy

Breast Neoplasms Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01384253
• Other study ID #: AREVAMED01
• Status: Completed
• Phase: Phase 1
• First received: June 27, 2011
• Last updated: September 29, 2016
• Start date: July 2011
• Est. completion date: July 2016

Study information

• Verified date: September 2016
• Source: Areva Med LLC
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: July 2016
• Est. primary completion date: October 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

1. At least 19 years of age.

2. Life expectancy is greater than three months.

3. Female subjects of child-bearing potential must have negative serum pregnancy test.

4. If not surgically sterile, male and female patients of child-bearing potential must use double barrier contraception (e.g., hormonal; intrauterine device; barrier).

5. 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.

6. 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.

7. Disease must be predominantly intra-abdominal and should include documented peritoneal studding or positive peritoneal washings.

8. Able and willing to sign an informed consent form.

Exclusion Criteria:

1. ECOG performance status greater than 3.

2. 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.

3. 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.

4. Liver only metastases.

5. 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

6. Breast-feeding woman.

7. 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.

8. 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.

9. Wash out period of less than one week from last palliative dose of radiotherapy.

10. 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

11. 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).

12. Prior whole abdomen radiation therapy exceeding 4Gy, intraperitoneal radionuclide therapy, bone marrow transplant, or stem cell transplant.

13. 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.

14. Detectable human anti-human antibody (HAHA) if there is any history of monoclonal antibody exposure.

15. Iodine allergy if the patient is unwilling to accept radiation to the thyroid from uptake of radionuclide without blocking.

16. Allergy to furosemide if the patient is unwilling to accept radiation risk without these agents and alternative is not feasible.

17. History of cumulative anthracycline therapy exceeding 200 mg/m² for doxorubicin or comparable low dose of other anthracyclines.

Study Design

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Neoplasms
• Neoplasms
• Ovarian Neoplasms
• Pancreatic Neoplasms
• Peritoneal Neoplasms
• Stomach Neoplasms

Intervention

Other:
• ²¹²Pb-TCMC-Trastuzumab
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.

Biological:
• trastuzumab
4 mg/kg.

Locations

Country	Name	City	State
United States	University Of Alabama at Birmingham	Birmingham	Alabama
United States	UCSD Moores Cancer Center	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Areva Med LLC

Country where clinical trial is conducted

United States, 

References & Publications (2)

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 a radioimmunotherapy with 212Pb-TCMC-trastuzumab. J Nucl Med. 2014 Oct;55(10):1636-42. doi: 10.2967/jnumed.114.143842. Epub 2014 Aug 25. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Yes
Secondary	Immunogenicity: To characterize the human immune response against ²¹²Pb-TCMC-Trastuzumab given via IP infusion.		Assessed at six weeks visit	No
Secondary	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.	No
Secondary	Pharmacokinetics: To determine the plasma pharmacokinetics and assess the extent of exit of radioactivity from the peritoneal cavity by ?-camera imaging.		Up to 3 days post-injection	No

External Links

•   AREVA Med's website
•   University of Alabama at Birmingham Department of Oncology Clinical Research