Protocol Number: 09-C-0077

Title:

An Open-Label Clinical Trial of MORAb-009 in Combination with Pemetrexed and Cisplatin in Subjects with Mesothelioma

Number:

09-C-0077

Summary:

Background:

Mesothelin is a tumor differentiation antigen whose expression on normal human tissues is limited to mesothelia cells but is highly expressed in many cancers such as mesothelioma, pancreatic, ovarian and lung adenocarcinoma.

MORAb-009 is a high-affinity IgGl/k anti-mesothelin monoclonal antibody, whose safety was evaluated in a phase I clinical trial.

Pre-clinical studies show that MORAb-009 has increased activity in combination with chemotherapy.

Mesothelioma is an aggressive disease with median overall survival of 12.1 months with standard chemotherapy.

Objectives:

To determine the effect on progression-free survival of MORAb-009 plus premetrexed and cisplatin in the treatment of subjects with unresectable malignant pleural mesothelioma who have not received prior systemic therapy

To evaluate antitumor activity, as assessed by objective tumor response

To evaluate duration of response

To evaluate overall survival

To determine the safety and tolerability of MORAb-009 when administered with pemetrexed and cisplatin

Eligibility:

Adults, 18 years of age or older, with unresectable malignant pleural mesothelioma (epithelial or mixed subtypes with at least 75% epithelial content) who have not received prior systemic therapy.

Subjects must have measureable disease at screening as defined by EORTC Modified RECIST Criteria

Study Design:

This is a phasel II, multicenter, multinational, open-label, single-arm trial using a 2-stage design to evaluate efficacy and safety of MORAb-009 in combination with pemetrexed and cisplatin.

Treatment will be administered as below:

--MORAb:009: 5 mg/kg by IV infusion in 0.9% normal saline; administered on Day 1 and Day 8 of each 21-day cycle until disease progression.

--Premetrexed: 500 mg/m2 by IV infusion in 0.9% normal saline over 10 minutes; administered on Day 1 of each 21-day cycle for 6 to 12 cycles.

--Cisplatin: 75 mg/m2 by IV infusion in 0.9% normal saline over 2 hours; administered on Day 1 of each 21-day cycle for 6 to 12 cycles.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

Each subject must meet all of the following criteria to be enrolled in this clinical trial.

1. Female or male and greater than or equal to 18 years of age.

2. Life expectancy of at least 3 months.

3. Histologically confirmed unresectable MPM (epithelial or mixed subtypes of at least 75% epithelial content).

4. Measurable disease at Screening.

5. Karnofsky performance status of greater than or equal to 70% at Screening.

6. Other significant medical conditions must be well-controlled and stable in the opinion of the investigator for at least 30 days prior to Day 1.

7. Laboratory and clinical results within 2 weeks prior to Day 1 must be as follows:

--Absolute neutrophil count (ANC) greater than or equal to 1.5 x 10(9)/L

--Platelet count greater than or equal to 100 x 10(9)/L

--Hemoglobin greater than or equal to 9 g/dL

--Serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN)

--Aspartate transaminase (AST) less than or equal to 2.5 x ULN

--Alanine transaminase (ALT) less than or equal to 2.5 x ULN

--Alkaline phosphatase (ALK-P) less than or equal to 3 x ULN

--Serum creatinine less than or equal to 2.0 mg/dL

Subjects with liver function abnormalities greater than the ULN specified above are eligible only if, in the opinion of the investigator, they are due to disease obstruction of the bile ducts or metastatic disease.

Stenting to reduce liver functions to qualifying levels is permitted.

8. Calculated serum creatinine clearance greater than or equal to 60 mL/min using the Cockroft-Gault equation.

9. Female subjects of childbearing potential and all male subjects must be surgically sterile or consent to use a medically acceptable method of contraception throughout the trial.

10. Willing and able to provide written informed consent.

EXCLUSION CRITERIA:

Subjects who meet any of the following criteria will be excluded from the clinical trial.

1. Sarcomatous subtype of mesothelioma.

2. Prior systemic therapy or radiotherapy for mesothelioma; prior treatment with local radiotherapy for symptom control (ie, non-curative intent) is permitted.

3. Known central nervous system (CNS) tumor involvement.

4. Evidence of other active malignancy requiring treatment.

5. Clinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4 angina not well controlled by medication, or myocardial infarction within 6 months).

6. Active viral hepatitis or symptomatic human immunodeficiency virus (HIV) infection.

7. Clinically significant arrhythmias demonstrated on electrocardiogram (ECG).

(Note: Subjects with chronic atrial arrhythmia, ie, atrial fibrillation or paroxysmal supraventricular tachycardia [SVT], are eligible).

8. Active, serious systemic disease, including active bacterial or fungal infection.

9. Treatment within 3 months of the start of the trial with other immunomodulatory therapy (eg, interferons, immunoglobulin therapy, IL-1RA or systemic corticosteroids). Short term use of systemic corticosteroids, topical or intra-articular steroids is acceptable, subject to the judgment of the investigator.

10. Known hypersensitivity to any of the following: monoclonal antibodies or biologic therapy, pemetrexed or ingredients used in the formulation of pemetrexed, cisplatin or other platinum containing compounds.

11. Known allergy or hypersensitivity to oral and/or IV contrast agents, as required for the imaging studies included in this protocol.

12. Breast-feeding, pregnant, or likely to become pregnant during the clinical trial.

13. Unwillingness or inability to sign the trial informed consent form (ICF).

Special Instructions:

Currently Not Provided

Keywords:

Monoclonal Antibody

Chemotherapy

Pleural Mesothelioma

Recruitment Keyword(s):

Mesothelioma

Condition(s):

Mesothelioma

Investigational Drug(s):

MORAb-009

Investigational Device(s):

None

Intervention(s):

Drug: MORAb-009

Drug: Premetrexed

Drug: Cisplatin

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

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.

Thomas AM, Santarsiero LM, Lutz ER, Armstrong TD, Chen YC, Huang LQ, Laheru DA, Goggins M, Hruban RH, Jaffee EM. Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med. 2004 Aug 2;200(3):297-306.

Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005 Jul 30-Aug 5;366(9483):397-408.

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