Fallopian Tube Cancer, Lung Adenocarcinoma, Mesothelioma Peritoneum, Mesotheliomas Pleural, Ovarian Cancer, Peritoneal Carcinoma
Conditions
Brief summary
Phase I study to establish safety and feasibility of both intravenous administration and local delivery of lentiviral transduced huCART-meso cells with or without lymphodepletion.
Detailed description
This is a Phase I study evaluating the safety and feasibility of both intravenous administration and local delivery of lentiviral transduced huCART-meso cells with and without lymphodepleting chemotherapy. * Cohort 1 (N=3-6): will receive a single dose of 1-3x10\^7 huCARTmeso cells/m\^2 on day 0 without any conditioning chemotherapeutic regimen. * Cohort 2 (N=3-6): will receive a single dose of 1-3x10\^7 huCARTmeso cells/m\^2 on day 0, following a flat dose of 1 gram/m2 of cyclophosphamide administered 2-4 days prior to huCARTmeso cells (day -4 to day -2). * Cohort 3 (N=3-6): will receive a single dose of 1-3x10\^8 /m\^2 lentiviral transduced huCART-meso cells on day 0 without any conditioning chemotherapeutic regimen. \*\*Cohort 3 permanently closed\*\* * Cohort 4 subjects (N=3-6) will receive a single dose of 1-3x10\^8 /m\^2 lentiviral transduced huCART-meso cells on day 0, following a flat dose of 1 gram/m\^2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (day -4 to day -2). \*\*Cohort 4 permanently closed\*\* * Cohort 5 (N=up to 6): will receive a single dose of 1-3x10\^7 huCARTmeso cells/m\^2 on day 0 by intrapleural infusion (IP) through an indwelling pleural catheter without any conditioning chemotherapeutic regimen. The safety of this dose level has been established by Cohorts 1 and 2. * Cohort 6 (N=up to 6): will receive a dose of 1-3x10\^7 huCARTmeso cells/m\^2 via IV infusion on Day 0, following a flat dose of 1 gram/m\^2 of cyclophosphamide administered 2-4 days prior to huCART-meso cells (\ Day -4 to -2). This initial infusion may be followed by up to two additional IV infusions of huCART-meso cells at the same dose level, given between 21-42 days apart, if the subject meets eligibility to receive additional infusions. Cyclophosphamide will not be repeated prior to subsequent doses of huCART-meso cells. Enrollment into Cohort 6 will occur in parallel with Cohort 5. * Cohort 7 (N = up to 6): will receive a single dose of 1-3x10\^7 huCART-meso cells/m\^2 via intraperitoneal (i.p.) administration, following lymphodepleting chemotherapy with cyclophosphamide 300 mg/m\^2/day and fludarabine 30 mg/m\^2/day given over 3 days by intravenous infusion. Lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (+/- 1 day) prior to the 1st infusion of huCART-meso cells. This initial i.p. infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. The subject must meet eligibility to receive additional infusions. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of huCART-meso cells. The Maximum Tolerated Dose (MTD) is defined as the dose at which 0-1 DLT occurs in 6 evaluable subjects tested within the dose range of this study. The maximum tolerated dose has been established as 1-3x10\^7 huCARTmeso cells/m\^2. Adverse events will be collected and evaluated during the protocol specified adverse event reporting period
Interventions
BIOLOGICALhuCART-meso cells
Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion..
Sponsors
National Institutes of Health (NIH)
Tmunity Therapeutics, a wholly owned subsidiary of Kite Pharma (a Gilead company)
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed cancer (one of the following): 1. Cohorts 1-4 and Cohort 6 participants: \*\*Note: Cohorts 3 and 4 permanently closed\*\* * Metastatic or recurrent lung adenocarcinoma. * Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal carcinoma or fallopian tube carcinoma * Malignant pleural and peritoneal mesothelioma (histologically confirmed epithelial) 2. Cohort 5 participants: \*\*Note: As of 1-Feb-2021 lung adenocarcinoma patients are no longer being enrolled in this trial\*\* * Metastatic or recurrent lung adenocarcinoma with documented pleural effusion * Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal carcinoma or fallopian tube carcinoma with documented pleural effusion * Malignant pleural and peritoneal mesothelioma (histologically confirmed epithelial) with documented pleural effusion 3. Cohort 7 patients: * Persistent or recurrent serous epithelial ovarian cancer or primary peritoneal carcinoma or fallopian tube carcinoma with evidence of ascites * Malignant peritoneal mesothelioma (histologically confirmed epithelial) 2. CRITERIA HAS BEEN RETIRED 3. Failure of at least one prior standard of care chemotherapy for advanced stage disease. ALLOWANCE FOR PRIOR PD-1 or PDL-1 THERAPIES REMOVED. 4. Patients must have measurable disease as defined by RECIST 1.1 criteria or modified RECIST criteria (mesothelioma only). 5. Subjects with asymptomatic CNS metastases that have been treated (and are off steroids for the treatment of CNS disease) are allowed. They must meet the following at the time of enrollment: 1. No concurrent treatment for the CNS disease 2. No progression of CNS metastasis on MRI at screening scans 3. No evidence of leptomeningeal disease or cord compression 6. Subjects ≥ 18 years of age. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. Satisfactory organ and bone marrow function as defined by the following: * Absolute neutrophil count ≥ 1,000/μl * Platelets ≥75,000/μl * Hemoglobin ≥ 8 g/dL * Direct bilirubin ≤ 2.0 mg/dl unless secondary to bile duct obstruction by tumor or Gilbert's syndrome with a direct bilirubin of less that 3.0 mg/dl is allowed. * Creatinine ≤ 1.5x the institutional normal upper limit * Albumin ≥ 2 * Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5x the institutional normal upper limit * Cardiac ejection fraction of ≥40% as measured by resting echocardiogram, with no clinically significant pericardial effusion. 9. Blood coagulation parameters: PT such that international normalized ratio (INR) is ≤ 1.5 and a PTT ≤ 1.2 time the upper limit of normal unless the patient is therapeutically anti-coagulated for history of cancer-related thrombosis and has stable coagulation parameters. 10. Provide written informed consent. 11. Subjects of reproductive potential must agree to use acceptable birth control methods.
Exclusion criteria
1. Sarcomatoid and biphasic mesothelioma. 2. Known leptomeningeal carcinomatosis or spinal cord compression. Screening for this is not required unless suspicious symptoms. 3. Subjects with symptomatic CNS metastases are excluded. 4.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 7 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 7 years | Progression is defined using RECIST V1.1 - at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered progression. |
| Overall Survival | 7 years | — |
| Objective Response Rate | Month 6 | Objective response rate is the proportion of subjects in the efficacy-evaluable set with radiologically confirmed measurable disease at baseline, who achieved partial response (PR) or better after infusion as determined by RECIST 1.1. Missing or non-evaluable time points will not be included. Per RECIST 1.1, a complete response is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
United States
Participant flow
Pre-assignment details
Protocol specifies that a consented participant is an enrolled participant. 65 participants were consented. Of these, 34 were ineligible and 31 were eligible. Of the 31 eligible, one participant was never assigned to a cohort. This participant was withdrawn prior to assignment due to disease progression. The remaining 30 participants are detailed below.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Single dose of 1-3x10\^7 huCARTmeso cells/m\^2
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 3 |
| Cohort 2 Cyclophosphamide 1 gram/m\^2 administered 2-4 days prior to a single dose of 1-3x10\^7 huCARTmeso cells/m\^2
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 3 |
| Cohort 3 PERMANENTLY CLOSED
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 2 |
| Cohort 4 PERMANENTLY CLOSED
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 0 |
| Cohort 5 Single dose of 1-3x10\^7 huCART-meso cells/m\^2 day 0 by intrapleural infusion (IP) through an indwelling pleural catheter without any conditioning chemotherapeutic regimen.
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 6 |
| Cohort 6 Cyclophosphamide 1 gram/m\^2 administered 2-4 days prior to dose of 1-3x10\^7 huCART-meso cells/m\^2 via IV infusion on Day 0. This initial infusion may be followed by up to two additional IV infusions of huCART-meso cells at the same dose level, given approximately 21-42 days apart, if the subject meets eligibility to receive additional infusions. Cyclophosphamide will not be repeated prior to subsequent doses of huCART-meso cells.
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 8 |
| Cohort 7 Cyclophosphamide 300 mg/m\^2/day and fludarabine 30 mg/m\^2/day given over 3 days by IV infusion followed by a single dose of 1-3x10\^7 huCART-meso cells/m\^2 via intraperitoneal (i.p.) administration. Lymphodepleting chemotherapy will be scheduled such that the last day of chemotherapy is 3 days (+/- 1 day) prior to the infusion of huCART-meso cells. This initial i.p. infusion may be followed by up to two additional infusions of huCART-meso cells via intravenous (IV) administration at the same dose level, given between 21-42 days apart. The subject must meet eligibility to receive additional infusions. Lymphodepleting chemotherapy will not be repeated prior to additional infusions of huCART-meso cells.
huCART-meso cells: Intravenous administration or local delivery of lentiviral transduced huCART-meso cells in 7 cohorts with or without lymphodepletion.. | 8 |
| Total | 30 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 3 | Cohort 5 | Cohort 6 | Cohort 7 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 1 Participants | 6 Participants | 6 Participants | 6 Participants | 24 Participants |
| Age, Continuous | 59.5 years | 62.3 years | 68.1 years | 61.1 years | 59.7 years | 63.0 years | 61.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 2 Participants | 2 Participants | 6 Participants | 8 Participants | 8 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 2 Participants | 6 Participants | 8 Participants | 6 Participants | 26 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 2 participants | 6 participants | 8 participants | 8 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 7 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 2 / 2 | 0 / 0 | 2 / 2 | 4 / 6 | 6 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 2 / 2 | 0 / 0 | 2 / 2 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 2 / 2 | 0 / 0 | 1 / 2 | 4 / 6 | 6 / 6 |
Outcome results
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03
Time frame: 7 years
Population: Cohort 4 closed prematurely.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 3 Participants |
| Cohort 2 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 3 Participants |
| Cohort 3 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 2 Participants |
| Cohort 4 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 0 Participants |
| Cohort 5 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 2 Participants |
| Cohort 6 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 6 Participants |
| Cohort 7 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.03 | 6 Participants |
Secondary
Objective Response Rate
Objective response rate is the proportion of subjects in the efficacy-evaluable set with radiologically confirmed measurable disease at baseline, who achieved partial response (PR) or better after infusion as determined by RECIST 1.1. Missing or non-evaluable time points will not be included. Per RECIST 1.1, a complete response is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. A partial response is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: Month 6
Population: Cohort 4 was permanently closed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Objective Response Rate | 0 percentage of participants |
| Cohort 2 | Objective Response Rate | 0 percentage of participants |
| Cohort 3 | Objective Response Rate | 0 percentage of participants |
| Cohort 5 | Objective Response Rate | 0 percentage of participants |
| Cohort 6 | Objective Response Rate | 0 percentage of participants |
| Cohort 7 | Objective Response Rate | 0 percentage of participants |
Secondary
Overall Survival
Time frame: 7 years
Population: Cohort 4 was prematurely closed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Overall Survival | 14.6 weeks |
| Cohort 2 | Overall Survival | 129.6 weeks |
| Cohort 3 | Overall Survival | 57.9 weeks |
| Cohort 5 | Overall Survival | 65.2 weeks |
| Cohort 6 | Overall Survival | 81.1 weeks |
| Cohort 7 | Overall Survival | 22 weeks |
Secondary
Progression-free Survival
Progression is defined using RECIST V1.1 - at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: the appearance of one or more new lesions is also considered progression.
Time frame: 7 years
Population: Cohort 4 was permanently closed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Progression-free Survival | 8.1 weeks |
| Cohort 2 | Progression-free Survival | 7 weeks |
| Cohort 3 | Progression-free Survival | 7.6 weeks |
| Cohort 5 | Progression-free Survival | 13.5 weeks |
| Cohort 6 | Progression-free Survival | 14.1 weeks |
| Cohort 7 | Progression-free Survival | 12.3 weeks |