Malignant Pleural Mesothelioma
Conditions
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
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.
Interventions
BIOLOGICALImmunotherapy plus chemotherapy
live attenuated double deleted Lm
BIOLOGICALImmunotherapy with cyclophosphamide plus chemotherapy
live attenuated double deleted Lm
Sponsors
Aduro Biotech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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 plus chemotherapy: live attenuated double deleted Lm | 38 |
| 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
Immunotherapy with cyclophosphamide plus chemotherapy: live attenuated double deleted Lm | 22 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Clinical progression | 3 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Progressive disease | 4 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Immunotherapy Plus Chemotherapy | Immunotherapy With Cyclophosphamide Plus Chemotherapy |
|---|---|---|---|
| Age, Customized <65 years | 15 Participants | 9 Participants | 6 Participants |
| Age, Customized >=65 years | 45 Participants | 29 Participants | 16 Participants |
| Body Mass Index | 26.473 kg/m^2 STANDARD_DEVIATION 4.3498 | 26.702 kg/m^2 STANDARD_DEVIATION 4.3292 | 26.076 kg/m^2 STANDARD_DEVIATION 4.4584 |
| Body Surface Area | 1.935 m^2 STANDARD_DEVIATION 0.2148 | 1.982 m^2 STANDARD_DEVIATION 0.223 | 1.852 m^2 STANDARD_DEVIATION 0.1756 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 59 Participants | 37 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 172.28 cm STANDARD_DEVIATION 8.359 | 174.51 cm STANDARD_DEVIATION 8.295 | 168.41 cm STANDARD_DEVIATION 7.102 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 58 Participants | 36 Participants | 22 Participants |
| Sex: Female, Male Female | 9 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 51 Participants | 34 Participants | 17 Participants |
| Weight | 78.77 kg STANDARD_DEVIATION 15.271 | 81.63 kg STANDARD_DEVIATION 16.203 | 73.83 kg STANDARD_DEVIATION 12.34 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 38 | 0 / 22 |
| other Total, other adverse events | 38 / 38 | 22 / 22 |
| serious Total, serious adverse events | 15 / 38 | 11 / 22 |
Outcome results
Primary
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)
Population: Immune response to mesothelin was not assessed.
Primary
Number of Subjects Reporting Adverse Events
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)
Population: Safety Analysis Set (all participants who received \>= 1 dose of study treatment)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Immunotherapy Plus Chemotherapy | Number of Subjects Reporting Adverse Events | 38 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Number of Subjects Reporting Adverse Events | 22 Participants |
Secondary
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 frame: Baseline to measured disease progression or death (up to 12 months or longer)
Population: Safety analysis set: all enrolled subjects who received at least one dose of study treatment and had measurable disease.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Immunotherapy Plus Chemotherapy | Objective Tumor Response | Partial Response | 19 Participants |
| Immunotherapy Plus Chemotherapy | Objective Tumor Response | Progressive Disease | 1 Participants |
| Immunotherapy Plus Chemotherapy | Objective Tumor Response | Stable Disease | 14 Participants |
| Immunotherapy Plus Chemotherapy | Objective Tumor Response | Not Assessable | 1 Participants |
| Immunotherapy Plus Chemotherapy | Objective Tumor Response | Complete Response | 1 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Objective Tumor Response | Not Assessable | 0 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Objective Tumor Response | Complete Response | 0 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Objective Tumor Response | Partial Response | 11 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Objective Tumor Response | Stable Disease | 8 Participants |
| Immunotherapy With Cyclophosphamide Plus Chemotherapy | Objective Tumor Response | Progressive Disease | 2 Participants |
Secondary
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)
Population: Predictive value of serum mesothelin was not assessed.
Secondary
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
Population: Time to progression was not assessed.