Clinical trial NCT01675765: Safety and Efficacy of Listeria in Combination With Chemotherapy as Front-line Treatment for Malignant Pleural Mesothelioma
Official title: A Phase 1B Study to Evaluate the Safety and Induction of Immune Response of CRS-207 in Combination With Pemetrexed and Cisplatin as Front-line Therapy in Adults With Malignant Pleural Mesothelioma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malignant Pleural Mesothelioma
Keywords: Cancer
Cancer vaccine
Listeria monocytogenes
Listeria-based vaccines
Pemetrexed
Cisplatin
T regulatory cells
Mesothelin
Malignant Pleural Mesothelioma
Chemotherapy
Standard of care
Naive
Front-line
Immunotherapy
MPM
Lead sponsor: Aduro Biotech, Inc.
Sponsor class: INDUSTRY
First posted: 2012-08-30
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Subjects Reporting Adverse Events
timeFrame: From first study dose until 28 days after the final dose (an average of 44 weeks)
measure: Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay
timeFrame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)
Secondary outcomes:
measure: Objective Tumor Response
timeFrame: Baseline to measured disease progression or death (up to 12 months or longer)
measure: Time to Progression
timeFrame: 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
measure: Serum Mesothelin as Correlate of Therapeutic Response
timeFrame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California at San Francisco
state: California
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Bethesda
country: United States
facility: National Cancer Institute
state: Maryland
city: Philadelphia
country: United States
facility: University of Pennsylvania Abramson Cancer Center
state: Pennsylvania
Study officials:
affiliation: National Cancer Institute (NCI)
name: Raffit Hassan, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le DT, Dubenksy TW Jr, Brockstedt DG. Clinical development of Listeria monocytogenes-based immunotherapies. Semin Oncol. 2012 Jun;39(3):311-22. doi: 10.1053/j.seminoncol.2012.02.008.
citation: Hassan R, Alley E, Kindler H, Antonia S, Jahan T, Honarmand S, Nair N, Whiting CC, Enstrom A, Lemmens E, Tsujikawa T, Kumar S, Choe G, Thomas A, McDougall K, Murphy AL, Jaffee E, Coussens LM, Brockstedt DG. Clinical Response of Live-Attenuated, Listeria monocytogenes Expressing Mesothelin (CRS-207) with Chemotherapy in Patients with Malignant Pleural Mesothelioma. Clin Cancer Res. 2019 Oct 1;25(19):5787-5798. doi: 10.1158/1078-0432.CCR-19-0070. Epub 2019 Jul 1.