Breast Cancer, Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Carcinoma, Uterine Cancer, Cervical Cancer, Endometrial Cancer
Conditions
Keywords
Vigil, durvalumab, MEDI4736, PD-L1, anti PD-L1, immunotherapy, PD-L1 inhibitor, breast cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, uterine cancer, cervical cancer, endometrial cancer
Brief summary
In this study, the researchers want to learn more about Vigil and durvalumab in advanced women's cancers: 1) how much of Vigil in combination with durvalumab (MEDI4736) can be given with an acceptable level of side effects, 2) the effects of Vigil and durvalumab in combination (good and bad), 3) if Vigil will cause changes in cancer cells that may help durvalumab attack the cancer, and 4) whether or not Vigil and durvalumab will slow your cancer or stop your cancer from getting worse. Combining Vigil with durvalumab will allow the former to induce (or increase) the infiltration of activated T cells into tumors, and in addition, to enhance PD-L1 (programmed cell death ligand 1) expression. Consequently, the response rate of historically low or un-responsive cancer will be increased with the combination of Vigil and anti PD-L1.
Detailed description
This is an open label pilot study to evaluate the safety, tolerability, and efficacy of the combination of Vigil autologous tumor cell immunotherapy and durvalumab PD-L1 inhibitor in patients with locally advanced or metastatic women's cancers, inclusive, but not limited to breast, ovarian, cervical, uterine, fallopian, primary peritoneal, and endometrial regardless of the number of prior therapies. This will be a 2-part study. The first part will be a safety run-in comprised of 2 cohorts that will use a 3 + 3 design to determine the Vigil dose in Part 2. Patients in Cohort 1 will receive a low dose of Vigil (1x10\^6 cells/intradermal (ID) injection) in combination with durvalumab (1500 mg (if \> 30 kg) IV over 60 minutes) every 4 weeks. Patients in Cohort 2 will receive Vigil at 1x10\^7 cells/ID injection and durvalumab (1500mg (if \> 30 kg) IV over 60 minutes) every 4 weeks. If needed, patients in Cohort -1 will receive Vigil at 1x10\^5 cells/ID injection and durvalumab (1500mg (if \> 30 kg) IV over 60 minutes) every 4 weeks. The enrollment of the first two patients in each Cohort of Part 1 will be staggered by 2 weeks. In Part 2 of the study, patients meeting study eligibility criteria will receive Vigil at the dose determined in Part 1 and durvalumab (1500mg (if \> 30 kg) IV over 60 minutes) every 4 weeks. As of March 13, 2018, Part 2 of the study will not be initiated due to limited enrollment. Currently only patients who have Vigil immunotherapy available from Gradalis protocol CL-PTL-119 may be considered for the study. Radiological assessment of tumor response or alternative assessments of disease status should be performed at screening, Cycle 3 and every 2 cycle thereafter, and end of treatment (EOT) using RECIST 1.1 and investigator assessment as applicable. Tumor biopsy for correlative studies including but not limited to scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis should be obtained at tissue procurement and at Cycle 3, and optional biopsies thereafter if the patient has accessible tissue. Peripheral blood mononuclear cells (PBMC) for correlative studies should be obtained at pre-procurement if applicable, and prior to study regimen administration at Cycle 1, Cycle 3, Cycle 5 and EOT. Patient survival will be followed for 1 year after last dose of either Vigil or durvalumab.
Interventions
BIOLOGICALVigil
Vigil is made up of irradiated autologous tumor cells which have been electroporated ex vivo with the Vigil plasmid designed to suppress expression of both the TGFβ1 and TGFβ2 proteins while simultaneously expressing rhGMCSF protein.
DRUGDurvalumab
A human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody directed against programmed cell death ligand 1 (PD-L1)
Sponsors
Gradalis, Inc.
AstraZeneca
Mary Crowley Medical Research Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Tissue Procurement Inclusion Criteria: * Ability to understand and the willingness to sign a written informed consent document for tissue harvest * Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Histologically or cytologically confirmed diagnosis of women's cancer, inclusive, but not limited to breast, ovarian, fallopian tube, primary peritoneal, uterine, cervical, endometrial, that is locally advanced or metastatic for which the projected response rate to durvalumab is 15% or less. * Female patients age ≥ 18 years * No prior Vigil immunotherapy * Treatment-naïve or refractory (no response to checkpoints) / resistant (initial response but relapse) to PD-1 or PD-L1 inhibitor therapy * ECOG Performance Status ≤ 1 * Estimated survival ≥ 6 months * Planned standard of care surgical procedure (e.g., tumor biopsy or palliative resection or thoracentesis) and expected availability of a cumulative mass of \ 10-30 grams tissue (golf-ball size) or pleural fluid estimated volume ≥ 500mL (must be primary tap) for immunotherapy manufacture. * One lesion not previously irradiated nor intended for vaccine manufacture, which can be biopsied with minimal invasion and measurable at baseline as per RECIST 1.1 guidelines (performed prior to biopsy) or 2 lesions not previously irradiated nor intended for vaccine manufacture, one of which can be biopsied with minimal invasion and the other of which is measurable at baseline as per RECIST 1.1 guidelines. If the only such target lesion has previously been irradiated it must have shown unequivocal evidence of disease progression following completion of radiation therapy. Alternative methods of disease assessment, e.g. measurement of tumor markers or ascites/pleural fluid, may be considered by the Sponsor on a case-by-case basis. * Provision of tumor tissue sample (archived or fresh) to allow for PD-L1 expression analysis Study Enrollment Inclusion Criteria: * Successful manufacturing of at least 4 vials of Vigil. * Ability to understand and the willingness to sign a written informed consent document * Willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. * Estimated survival of ≥ 6 months * Provision of tumor tissue sample (archived or fresh) in a quantity sufficient to allow for PD-L1 expression analysis (if not already obtained during tissue procurement under this protocol), and after entry, a portion of Vigil harvested tissue * If female of childbearing potential, has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a negative serum test will be required for study entry. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, complete hysterectomy, or surgery for gynecological cancer) or postmenopausal (defined as 12 months with no menses without an alternative medical cause). * Adequate organ and bone marrow function as defined below: 1. Absolute neutrophil count (ANC) \> 1.5 × 10\^9/L (1500 per mm\^3) 2. Platelets \> 100 × 10\^9/L (100,000 per mm\^3) 3. Hemoglobin ≥ 9.0 g/dL (5.59 mmol/L) 4. Creatinine clearance (CrCL) \> 50 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance: Females: CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85 / 72 × serum creatinine (mg/dL) 5. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of hemolysis or hepatic pathology) who will be allowed in consultation with their physician. 6. AST and ALT ≤ 2.5 × ULN in patients with no liver metastasis 7. AST or ALT ≤ 5 × ULN in patients with liver metastasis 8. TSH within institutional limits. If TSH is greater or less than institutional limits patients may participate if their T4 is within normal limits (WNL); patients may be on a stable dose of replacement thyroid medication; dose adjustments are allowed if needed. * Subject has recovered to CTCAE Grade 1 or better from all adverse events associated with prior therapy or surgery 1. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade \> 2 or better 2. Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the IPs may be included (e.g., hearing loss) after consultation with the Medical Monitor * Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) prior to tissue procurement and at least 21 days prior to the first dose of study drug (at least 21 days prior to the first dose of study drug for subjects who have received prior TKIs \[e.g., erlotinib, gefitinib and crizotinib\] and within 6 week for nitrosourea or mitomycin C). (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period may be required.)
Exclusion criteria
Tissue Procurement
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of treatment-emergent AEs of Vigil + Durvalumab | Up to 90 days after last dose of study treatment | The safety evaluation will include collection of AEs, SAEs and changes from baseline in laboratory evaluations, vital signs, ECGs and physical exams. AEs will be graded according to the NCI CTCAE v4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (ORR) | Up to 12 months after start of study treatment | The ORR will be estimated in patients with measurable disease, along with its exact binomial 95% confidence interval. |
| Disease status | Up to 12 months after start of study treatment | Disease status will be summarized based on tumor markers or ascites/pleural fluid in patients with non-measurable disease |
| IFNγ-ELISPOT conversion rate (negative to positive) during on-study treatment | 12 weeks after start of study treatment | — |
Countries
United States
Outcome results
None listed