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

Primary Purpose

Malignant Pleural Mesothelioma

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Immunotherapy plus chemotherapy

Immunotherapy with cyclophosphamide plus chemotherapy

About this trial

This is an interventional treatment trial for Malignant Pleural Mesothelioma focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

University of California at San Francisco
H. Lee Moffitt Cancer Center
University of Chicago Medical Center
National Cancer Institute
University of Pennsylvania Abramson Cancer Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Immunotherapy plus chemotherapy

Immunotherapy with cyclophosphamide plus chemotherapy

Arm Description

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

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

Outcomes

Primary Outcome Measures

Number of Subjects Reporting Adverse Events

Count of subjects with incidences of adverse events.

Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay

Secondary Outcome Measures

Objective Tumor Response

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

Serum Mesothelin as Correlate of Therapeutic Response

Full Information

NCT ID

NCT01675765

First Posted

August 23, 2012

Last Updated

September 28, 2020

Sponsor

Aduro Biotech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT01675765

Brief Title

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

2. Study Status

Record Verification Date

September 2020

Overall Recruitment Status

Completed

Study Start Date

September 3, 2014 (Actual)

Primary Completion Date

September 5, 2018 (Actual)

Study Completion Date

August 19, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Aduro Biotech, Inc.

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

60 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Immunotherapy plus chemotherapy

Arm Type

Experimental

Arm Description

Arm Title

Immunotherapy with cyclophosphamide plus chemotherapy

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

Immunotherapy plus chemotherapy

Other Intervention Name(s)

CRS-207, Listeria, pemetrexed, cisplatin, ALIMTA, Platinol

Intervention Description

live attenuated double deleted Lm

Intervention Type

Biological

Intervention Name(s)

Immunotherapy with cyclophosphamide plus chemotherapy

Other Intervention Name(s)

CRS-207, Cytoxan, pemetrexed, cisplatin, ALIMTA, Platinol, Listeria

Intervention Description

live attenuated double deleted Lm

Primary Outcome Measure Information:

Title

Number of Subjects Reporting Adverse Events

Description

Count of subjects with incidences of adverse events.

Time Frame

From first study dose until 28 days after the final dose (an average of 44 weeks)

Title

Induction of Immune Response to Mesothelin by Enzyme-linked Immunosorbent Spot (ELISPOT) Assay

Time Frame

Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)

Secondary Outcome Measure Information:

Title

Objective Tumor Response

Description

Time Frame

Baseline to measured disease progression or death (up to 12 months or longer)

Title

Time to Progression

Time Frame

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

Title

Serum Mesothelin as Correlate of Therapeutic Response

Time Frame

Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Raffit Hassan, MD

Organizational Affiliation

National Cancer Institute (NCI)

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California at San Francisco

City

San Francisco

State/Province

California

ZIP/Postal Code

94115

Country

United States

Facility Name

H. Lee Moffitt Cancer Center

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

University of Chicago Medical Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60637

Country

United States

Facility Name

National Cancer Institute

City

Bethesda

State/Province

Maryland

ZIP/Postal Code

20892

Country

United States

Facility Name

University of Pennsylvania Abramson Cancer Center

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

22595054

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.

Results Reference

background

PubMed Identifier

31263030

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.

Results Reference

derived

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

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