Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma

Phase 1

Completed

Conditions: Malignant Pleural Mesothelioma

Interventions: Biological: Immunotherapy plus chemotherapy
Biological: Immunotherapy with cyclophosphamide plus chemotherapy

Registration Number: NCT01675765

Lead Sponsor: Aduro Biotech, Inc.

Brief Summary: This clinical trial will evaluate the safety and immune response of the sequential administration cancer vaccine CRS-207 (with or without cyclophosphamide) followed by standard of care chemotherapy (pemetrexed and cisplatin). CRS-207 is a weakened (attenuated) form of Listeria monocytogenes that has been genetically-modified to reduce its capacity to cause disease, while maintaining its ability to stimulate potent immune responses. CRS-207 has been engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be present at higher levels on certain tumor cells (such as mesothelioma) than on normal cells. Pemetrexed and cisplatin are the standard chemotherapy regimen to treat malignant pleural mesothelioma. This trial will evaluate whether giving CRS-207 cancer vaccine with chemotherapy will induce anti-tumor immune responses and/or objective tumor response.

Detailed Description: Up to 60 subjects will be enrolled in this study. Eligible subjects will receive 2 prime vaccinations of CRS-207 (1×10\^9 colony-forming units \[CFU\] given intravenously \[i.v.\] over 2 hours) (with or without cyclophosphamide) 2 weeks apart followed 2 weeks later by up to 6 cycles of pemetrexed and cisplatin 21 days apart. Three weeks after completion of chemotherapy, subjects will receive an additional 2 infusions (boost vaccinations) of CRS-207 3 weeks apart. Subjects will be followed every 8 weeks until disease progression by immune-related response criteria. Subjects who continue to meet dosing eligibility may receive additional CRS-207 (with or without cyclophosphamide) infusions (maintenance vaccinations) at each follow-up visit.

Study assessments include blood draws for safety and immune response monitoring and CT scans \[with optional fluorodeoxyglucose positron emission tomography (FDG-PET)\] or magnetic resonance imaging (MRI) to monitor disease status. In addition, optional tumor biopsies may be performed before, during and after treatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

Inclusion Criteria

Have histologically confirmed epithelial or biphasic MPM not amenable to potentially curative surgical resection (subjects with biphasic tumors that have a predominantly (≥50%) sarcomatoid component will be excluded)
Be at least 18 years of age
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Have an anticipated life expectancy of greater than 6 months
For women and men of childbearing potential, a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) must be used throughout the study period and for 28 days after their final vaccine administration. (A barrier method of contraception must be employed by all subjects [male and female], regardless of other methods.)
Be willing and able to give written informed consent, and be able to comply with all study procedures
Have adequate organ function as defined by specified laboratory values

Exclusion Criteria

A candidate for curative surgery
Surgery within 2 weeks prior to dosing
Prior radiotherapy or biologic therapy
Treatment with an investigational agent within 4 weeks before dosing
Prior systemic chemotherapy
Currently have or have history of certain study-specified heart, liver, kidney, lung, neurological, immune or other medical conditions
Documented and ongoing brain metastases
Have any evidence of hepatic cirrhosis or clinical or radiographic ascites
Have clinically significant and/or malignant pleural effusion
Known or suspected allergy or hypersensitivity to yeast or any other component of CRS-207 (e.g., glycerol), Platinol or platinum-containing compounds, or pemetrexed
Used any systemic steroids within 28 days of study treatment
Use more than 3 g/d of acetaminophen
An artificial (prosthetic) joint or other artificial implant or device that cannot be easily removed (with some exceptions for dental and breast implants and biliary stents and mediports)
Infection with HIV or hepatitis B or C at screening
Any immunodeficiency disease or immunocompromised state or active autoimmune disease or history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment
Be a woman who is pregnant or breastfeeding
Unable to avoid close contact with another individual known to be at high risk of listeriosis (e.g., newborn infant, pregnant woman, HIV-positive individual) during the course of CRS-207 treatment until completion of antibiotic regimen
Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient's ability to comply with study visits and procedures

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Immunotherapy plus chemotherapy	Immunotherapy plus chemotherapy	Weeks 1 and 3: CRS-207 (1 × 10\^9 CFU) Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m\^2) and cisplatin (75 mg/m\^2) Weeks 23 and 26: CRS-207 Maintenance Vaccinations: CRS-207 every 8 weeks (starting at Week 34) until disease progression
Immunotherapy with cyclophosphamide plus chemotherapy	Immunotherapy with cyclophosphamide plus chemotherapy	Weeks 1 and 3: cyclophosphamide (200 mg/m\^2), CRS-207 (1 × 10\^9 CFU) Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): pemetrexed (500 mg/m\^2) and cisplatin (75 mg/m\^2) Weeks 23 and 26: cyclophosphamide one day before CRS-207 Maintenance Vaccinations: cyclophosphamide one day before CRS-207 every 8 weeks (starting at Week 34) until disease progression

Primary Outcome Measures

Name	Time	Method
Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay	Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)
Number of Subjects Reporting Adverse Events	From first study dose until 28 days after the final dose (an average of 44 weeks)	Count of subjects with incidences of adverse events.

Secondary Outcome Measures

Name	Time	Method
Objective Tumor Response	Baseline to measured disease progression or death (up to 12 months or longer)	Objective tumor response was measured using modified Response Evaluation Criteria in Solid Tumors (mRECIST) for assessment of response in malignant pleural mesothelioma (MPM). Per mRECIST for target lesions and assessed by CT: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease, those who fulfilled the criteria for neither PR nor PD; Progressive Disease (PD), \>=20% increase in the sum of the longest diameter of target lesions.
Time to Progression	From date of randomization until date of documented progression (by modified RECIST or immune-related response criteria) or death, assessed up to 12 months or longer
Serum Mesothelin as Correlate of Therapeutic Response	Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)

Trial Locations

Locations (5): University of Chicago Medical Center
🇺🇸
Chicago, Illinois, United States
National Cancer Institute
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Bethesda, Maryland, United States
University of California at San Francisco
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San Francisco, California, United States
H. Lee Moffitt Cancer Center
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Tampa, Florida, United States
University of Pennsylvania Abramson Cancer Center
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Philadelphia, Pennsylvania, United States