Fallopian Tube Cancer, Ovarian Cancer, Primary Peritoneal Carcinoma
Conditions
Brief summary
Phase I study to establish safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy
Detailed description
This is a Phase I study evaluating the safety and feasibility of intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells in 4 cohorts with or without cyclophosphamide + fludarabine in a 3+3 dose escalation design. The DLT observation period is 28 days post CAR T cell infusion. The Maximum Tolerated Dose (MTD) is defined as the dose at which 0 or 1 DLT occurs in 6 evaluable subjects tested within the dose range of this study. Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine. Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.
Interventions
intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy.
DEVICEAlpha Folate Receptor expression test
Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational.
Sponsors
National Cancer Institute (NCI)
OvaCure Fundation
Alliance for Cancer Gene Therapy
Ovarian Cancer Alliance of Greater Cincinnati
University of Pennsylvania
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed persistent or recurrent stage II to IV high grade serous epithelial ovarian, fallopian tube or primary peritoneal carcinoma. Disease can be platinum-sensitive or platinum-resistant. 2. Failure of at least two prior chemotherapy regimens for advanced stage disease. Prior therapies against PD-1 or PDL-1 are permissible. 3. Confirmation of tumor aFR expression (≥70% of tumor cells with ≥2+ aFR staining). 4. Subjects must have measureable disease as defined by RECIST 1.1 criteria. 5. Patients with asymptomatic CNS metastases that have been treated and are off steroids are allowed. They must meet the following at the time of eligibility confirmation by physician-investigator: 1. No concurrent treatment for the CNS disease 2. No progression of CNS metastasis on brain MRI at screening 3. No evidence of leptomeningeal disease or cord compression 6. Patients ≥ 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: i. Absolute neutrophil count ≥ 1,000/μl ii. Platelets ≥75,000/μl iii. Hemoglobin ≥ 9 g/dL iv. Total bilirubin ≤ 2.0x the institutional normal upper limit unless secondary to bile duct obstruction by tumor v. Creatinine ≤ 1.5x the institutional normal upper limit vi. Albumin ≥2 vii. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤ 5x the institutional normal upper limit viii. Cardiac ejection fraction of ≥40% 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. Provides written informed consent. 11. Subjects of reproductive potential must agree to use acceptable birth control methods, as described in protocol Section 4.3.
Exclusion criteria
1. High grade serous ovarian, fallopian, or primary peritoneal cancer that is platinum refractory, defined as disease that has clinical or radiographic progression on platinum-based chemotherapy, as per the discretion of the treating physician. 2. Patients with symptomatic CNS metastases are excluded. 3. Participation in a therapeutic investigational study within 4 weeks prior to eligibility confirmation by physician-investigator, or anticipated treatment with another investigational product while on study. This refers to non-commercially approved investigational drugs different than those used in this protocol. 4. Active invasive cancer other than ovarian cancers. Patients with active non-invasive cancers (such as non-melanoma skin cancer, superficial cervical and bladder cancer) are not excluded. 5. HIV infection 6. Hepatitis B or hepatitis C infection 7. Active autoimmune disease requiring systemic immunosuppressive treatment equivalent to \>/= 10 mg of prednisone. Patients with autoimmune neurologic diseases (such as multiple sclerosis) will be excluded. 8. Patients with active and uncontrolled infection. 9. Planned concurrent treatment with systemic high dose corticosteroids. Patients may be on a stable low dose of steroids (\<10 mg daily equivalent of prednisone). Corticosteroids treatment as anti-emetic prophylaxis on the day of lymphodepleting chemotherapy administration is allowed per institutional guidance. The use of topical and/or inhaled steroids are not exclusionary. 10. Patients requiring supplemental oxygen therapy. 11. Prior therapy with lentiviral gene modified cells. 12. History of allergy or hypersensitivity to study product excipients (human serum albumin, DMSO, and Dextran 40). 13. Any ascites requiring therapeutic drainage within 4 weeks prior to eligibility confirmation by physician-investigator. 14. Pregnant or breastfeeding women. 15. Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the physician-investigator, would make the patient inappropriate for entry into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to 34 months | For this study, collection of adverse events will begin at the time of apheresis and will continue until the subject is off-study. |
| Manufacturing Feasibility | 8 weeks | Manufacturing feasibility is determined based on the manufacturing failures products. The number of manufactured products that do not meet release criteria for vector transduction efficiency, CART+ cell number, T cell purity, viability, and sterility will be determined and defined as manufacturing failures. |
| Clinical Feasibility | 8 weeks | Clinical feasibility is defined as the proportion of subjects enrolled on this protocol who do not receive MOv19-BBz CAR T cells. Reasons for this occurrence include rapid clinical deterioration or death, and subject withdrawal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 33 months | PFS will be evaluated up to 5 years post-infusion or until subjects initiate a cancer-related therapy |
| Overall Response Rates (ORR) | Up to 33 months | ORR is the proportion of subjects with a best response of CR or PR based on RECIST 1.1, as compared to baseline. ORR will be evaluated up to 5 years post-infusion or until subjects initiate a cancer-related therapy. |
| Overall Survival (OS) | Up to 33 months | Overall survival is defined as the time from the date of the infusion to the date of death due to any reason. OS will be evaluated up to 15 years post-infusion. |
Countries
United States
Participant flow
Pre-assignment details
35 Subjects were screen failure and were not assigned to a cohort.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo Cohort 1: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy.
MOv19-BBz CAR T cells: intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy.
Alpha Folate Receptor expression test: Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational. | 3 |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo Cohort 2: (n= 3 to 6 subjects): Single infusion of 1-3x107 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
MOv19-BBz CAR T cells: intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy.
Alpha Folate Receptor expression test: Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational. | 3 |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo Cohort 3: (n=3 to 6 subjects): Single infusion of 1-3x108 lentivirally transduced MOv19-BBz CAR T cells on day 0 beginning 3 days (+/- 1 day) after lymphodepleting chemotherapy with cyclophosphamide + fludarabine.
MOv19-BBz CAR T cells: intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy.
Alpha Folate Receptor expression test: Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational. | 5 |
| Cohort-1: Without Chemo;Only if Dose De-escalation Required Cohort -1: (n= 3 to 6 subjects): Single Infusion of 1-3x106 /m2 lentivirally transduced MOv19-BBz CAR T cells on day 0 without lymphodepleting chemotherapy. Up to 6 subjects will be infused in Cohort -1 with ≤ 1 DLT/6 subjects to establish the MTD.
MOv19-BBz CAR T cells: intraperitoneally administered lentiviral transduced MOv19-BBz CAR T cells with or without cyclophosphamide + fludarabine as lymphodepleting chemotherapy.
Alpha Folate Receptor expression test: Patients will first be pre-screened for alpha folate receptor expression. The test for alpha folate receptor expression is a laboratory developed test+, developed and conducted by the Hospital of the University of Pennsylvania Pathology and Laboratory Medicine lab to determine subject eligibility. This test is not an approved FDA device and its use is investigational. | 0 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 3 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Cohort 2: MOv19-BBz CAR T Cells After Chemo | Cohort 3: MOv19-BBz CAR T Cells After Chemo | Cohort-1: Without Chemo;Only if Dose De-escalation Required | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 4 Participants | 0 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 5 Participants | 0 Participants | 11 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 5 participants | — | 11 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 5 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 2 / 3 | 3 / 5 | 0 / 0 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 4 / 5 | 0 / 0 |
| serious Total, serious adverse events | 1 / 3 | 2 / 3 | 4 / 5 | 0 / 0 |
Outcome results
Primary
Clinical Feasibility
Clinical feasibility is defined as the proportion of subjects enrolled on this protocol who do not receive MOv19-BBz CAR T cells. Reasons for this occurrence include rapid clinical deterioration or death, and subject withdrawal.
Time frame: 8 weeks
Population: No participants were enrolled in cohort -1. Thirty five (35) participants were enrolled in the study but they screen failed and did not receive MOv19-BBz CAR T cell.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Clinical Feasibility | 0 Participants who didn't receive CART cel |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Clinical Feasibility | 0 Participants who didn't receive CART cel |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Clinical Feasibility | 2 Participants who didn't receive CART cel |
Primary
Manufacturing Feasibility
Manufacturing feasibility is determined based on the manufacturing failures products. The number of manufactured products that do not meet release criteria for vector transduction efficiency, CART+ cell number, T cell purity, viability, and sterility will be determined and defined as manufacturing failures.
Time frame: 8 weeks
Population: No participants were enrolled in cohort -1
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Manufacturing Feasibility | 0 Product manufacture failures |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Manufacturing Feasibility | 0 Product manufacture failures |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Manufacturing Feasibility | 0 Product manufacture failures |
Primary
Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0
For this study, collection of adverse events will begin at the time of apheresis and will continue until the subject is off-study.
Time frame: Up to 34 months
Population: No participants were enrolled in cohort 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 3 Participants |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 3 Participants |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 3 Participants |
| Cohort-1: Without Chemo;Only if Dose De-escalation Required | Number of Study Subjects With Treatment-related Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | 0 Participants |
Secondary
Overall Response Rates (ORR)
ORR is the proportion of subjects with a best response of CR or PR based on RECIST 1.1, as compared to baseline. ORR will be evaluated up to 5 years post-infusion or until subjects initiate a cancer-related therapy.
Time frame: Up to 33 months
Population: No participants were enrolled in Cohort -1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Overall Response Rates (ORR) | 0 Participants |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Overall Response Rates (ORR) | 0 Participants |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Overall Response Rates (ORR) | 0 Participants |
| Cohort-1: Without Chemo;Only if Dose De-escalation Required | Overall Response Rates (ORR) | 0 Participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from the date of the infusion to the date of death due to any reason. OS will be evaluated up to 15 years post-infusion.
Time frame: Up to 33 months
Population: No participants were enrolled in Cohort -1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Overall Survival (OS) | 187 Days |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Overall Survival (OS) | 163 Days |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Overall Survival (OS) | 136 Days |
Secondary
Progression-free Survival (PFS)
PFS will be evaluated up to 5 years post-infusion or until subjects initiate a cancer-related therapy
Time frame: Up to 33 months
Population: No participants were enrolled in Cohort -1
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: MOv19-BBz CAR T Cells Without Chemo | Progression-free Survival (PFS) | 42 Days |
| Cohort 2: MOv19-BBz CAR T Cells After Chemo | Progression-free Survival (PFS) | 80 Days |
| Cohort 3: MOv19-BBz CAR T Cells After Chemo | Progression-free Survival (PFS) | 21 Days |