Clinical trial NCT01413451: Amatuximab for High Mesothelin Cancers
Official title: A Single-Dose Pilot Study of Radiolabeled Amatuximab (MORAb-009) in Mesothelin Over Expressing Cancers
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: EARLY_PHASE1
Conditions: Carcinoma, Pancreatic Ductal
Mesothelioma
Ovarian Neoplasms
Carcinoma, Non-Small-Cell Lung
Keywords: Monoclonal IgG Antibody
Biodistribution
Pharmacokinetics
HACA
Safety
Mesothelioma
Ovarian Cancer
Pancreatic Duct Cancer
Non-Small Cell Lung Cancer
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-08-10
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

- Amatuximab is a cancer treatment drug that targets mesothelin. High levels of this substance are found on some kinds of tumor cells. Lab studies have shown that amatuximab helps the immune system to kill cells that have high levels of mesothelin. However, more research is needed to determine how safe and effective amatuximab is for treating tumors with high levels of mesothelin.

Objectives:

- To assess the safety and effectiveness of amatuximab in treating tumors with high levels of mesothelin.

Eligibility:

- Individuals at least 18 years of age who have a type of cancer that overexpresses mesothelin.

Design:

* Participants will be screened with a medical history and physical exam. They will also have blood tests and tumor assessment studies.
* Participants will have two intravenous doses of amatuximab several hours apart. Researchers will monitor them closely and do frequent blood draws. On the same day and also within 48 hours of the second dose, participants will have imaging studies. These studies will measure how well the amatuximab is working against the cancer.
* Participants will have a third imaging study of the cancer about 1 week after the infusions.
* Participants will have a followup visit 2 weeks after receiving amatuximab. This visit will require blood samples. Four weeks after receiving the drug, researchers will review patients symptoms or side effects. This interview can be done in person or by phone.

Detailed description: Background:

* Amatuximab is a high-affinity monoclonal IgG antibody raised against human mesothelin.
* Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane glycoprotein thought to be involved in tumor metastasis
* Mesothelin is over-expressed in many cancers

Objectives:

-The primary objective is to determine the biodistribution of radiolabeled amatuximab in tumor and nontumor tissues in subjects with mesothelin over-expressing cancers including mesothelioma, pancreatic, ovarian, and non small cell lung cancer.

Eligibility:

* Female or male subjects greater than or equal to 18 years of age;
* Histologically confirmed mesothelin-expressing cancer;
* Transaminases less than or equal to 3 times ULN for mesothelioma, non small cell lung and ovarian cancer;
* Transaminases less than or equal to 5 times ULN for pancreatic cancer with known liver metastasis.

Design:

* This is a single-center, single-dose, open-label, pilot study of MORAb-009 in approximately 20 subjects with mesothelin expressing tumors.
* Indium-radiolabeled MORAb-009 (5mCi) will be administered.
* Serial single photon emission-computerized tomography imaging will be performed to determine binding to tumor and nontumor tissue.
* Subjects will be observed closely for safety and possible development of anti-MORAb-009 antibodies.
* Pharmacokinetics of radiolabeled antibody will be determined with imaging over time.

Eligibility criteria: * INCLUSION CRITERIA:
* Female or male subjects, greater than or equal to 18 years of age.
* Histologically-confirmed diagnosis of pancreatic adenocarcinoma, mesothelioma, mesothelin-positive ovarian cancer, or NSCLC. A new biopsy is not required; the diagnostic biopsy sample will be sufficient. IHC confirmation of mesothelin-positivity is not necessary for pancreatic adenocarcinoma and mesothelioma as nearly 100% of pancreatic adenocarcinomas and mesotheliomas express mesothelin. Mesothelin expression in ovarian cancer and NSCLC will be tested by IHC and any degree of positivity (1+, 2+, or 3+) will be accepted.
* Subjects are required to have measurable disease that has progressed through prior therapy and that includes a non-hepatic lesion for imaging that is greater than or equal to 1.5 cm, as defined by Modified Response Evaluation Criteria in Solid Tumors (RECIST).
* Eastern Cooperative Oncology Group (ECOG) performance status or 0, 1, or 2.
* Female subjects of childbearing potential and all male subjects are required to consent to use a medically acceptable method of contraception throughout the study period and for 30 days after amatuximab administration. A barrier method of contraception is required.
* Laboratory and clinical results within the 2 weeks prior to Day of Infusion as follows:

  * Absolute neutrophil count (ANC): greater than or equal to 1.5 times 10(9)/L
  * Platelet count: greater than or equal to 75 times 10(9)/L
  * Hemoglobin: greater than or equal to 9 g/dL
  * Serum bilirubin: less than or equal to 1.5 mg/dL
  * Aspartate transaminase (AST): less than or equal to 3 x upper limit of normal (ULN) (less than or equal to 5 ULN acceptable for pancreatic patients with known liver metastasis only)
  * Alanine transaminase (ALT) less than or equal to 3 times upper limit of normal (ULN) (less than or equal to 5 ULN acceptable for pancreatic patients with known liver metastasis only)
  * Alkaline Phosphatase less than or equal to 5 times ULN
  * Serum creatinine less than or equal to 1.5 mg/dL
* Subjects are required to be willing and able to provide written informed consent.

EXCLUSION CRITERIA:

* Subjects are ineligible to participate in this study if any of the following criteria are met:

  * Known allergy or hypersensitivity to monoclonal antibodies;
  * Prior treatment with amatuximab;
  * Prior treatment with SS1(dsFv)PE38 (SS1P);
  * Known brain metastases;
  * Known prosthetic devices that would prohibit imaging of lesion of interest due to radiographic artifact;
  * Evidence of other active malignancy requiring treatment;
  * Clinically significant heart disease (e.g., congestive heart failure of New York Heart Association Class III or IV, angina not well controlled by medication, or myocardial infarction within 6 months);
  * ECG demonstrating clinically significant arrhythmias. Subjects with chronic atrial arrhythmia, (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia), are eligible;
  * Active serious systemic disease, including active bacterial or fungal infection within 2 weeks before study entry;
  * Active viral hepatitis or symptomatic human immunodeficiency virus (HIV) infection;
  * Treatment within 3 months with immunomodulatory therapy (e.g., interferons, immunoglobulin therapy, Interleukin 1 receptor antagonist (IL-1RA) or systemic corticosteroids). Short-term systemic corticosteroids or topical or intra-articular steroids are acceptable, at the discretion of the Investigator;
  * Chemotherapy, biologic therapy, radiation therapy or immunotherapy within 3 weeks prior to dosing with amatuximab;
  * Breast-feeding, pregnant, or likely to become pregnant during the study.

Primary outcomes:
measure: Biodistribution of radiolabelled amatuximab in tumor and nontumor tissues.
measure: Tumor
measure: Background ratio of maximum counts
Secondary outcomes:
measure: CTCAE V.4 events
measure: Observation of HACA
measure: PKs
measure: Antibody uptake vs. IHC mesothelin expression
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Raffit Hassan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hassan R, Ebel W, Routhier EL, Patel R, Kline JB, Zhang J, Chao Q, Jacob S, Turchin H, Gibbs L, Phillips MD, Mudali S, Iacobuzio-Donahue C, Jaffee EM, Moreno M, Pastan I, Sass PM, Nicolaides NC, Grasso L. Preclinical evaluation of MORAb-009, a chimeric antibody targeting tumor-associated mesothelin. Cancer Immun. 2007 Dec 19;7:20.
citation: Hassan R, Ho M. Mesothelin targeted cancer immunotherapy. Eur J Cancer. 2008 Jan;44(1):46-53. doi: 10.1016/j.ejca.2007.08.028. Epub 2007 Oct 22.
citation: Gubbels JA, Belisle J, Onda M, Rancourt C, Migneault M, Ho M, Bera TK, Connor J, Sathyanarayana BK, Lee B, Pastan I, Patankar MS. Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Mol Cancer. 2006 Oct 26;5(1):50. doi: 10.1186/1476-4598-5-50.