Patient case: 48-year-old female with melanoma; genetic feature: tumor cells with >50% membranous PD-L1 expression

Clinical trial: Pilot Study of Durvalumab (MEDI4736) in Combination With Vigil™ in Advanced Breast Cancer

Summary: Combining Vigil™ with Durvalumab (MEDI4736) will allow Vigil™ to 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 unresponsive PD-L1 negative cancer to Durvalumab (MEDI4736) will reach a level similar to that achieved in PD-L1 positive cancer.

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 (programmed cell death ligand 1) inhibitor in patients with PD-L1 negative locally advanced or metastatic triple negative breast cancer (TNBC), regardless of the number of prior therapies. PD-L1 negative tumor status is defined as < 1% membranous PD-L1 staining with antihuman PDL1 rabbit monoclonal antibody SP263 (Ventana, Tucson, AZ) of neoplastic cells.
  Patients undergoing a standard surgical procedure (e.g., tumor biopsy, palliative resection, thoracentesis of malignant pleural effusion) will have tumor tissue procured for manufacture of Vigil™ vaccine. 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. 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. 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, Cohort -1 will be used which 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.
  Three to six weeks after tissue procurement has occurred eligibility will be reconfirmed by the study site. Subjects must begin the study regimen within 6 weeks of tissue procurement. Radiological assessment of tumor response should be performed at screening, Cycle 3 and every 2nd cycle thereafter, and end of treatment (EOT) using RECIST 1.1 and investigator assessment. Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 and PD-L1 expression analysis should be obtained at tissue procurement and at Cycle 3. Peripheral blood mononuclear cells (PBMC) for correlative studies should be obtained at pre-procurement, and prior to study regimen administration at Cycle 1, Cycle 3, Cycle 5 and EOT. Patient survival will be followed for 1 year after treatment initiation.

Eligibility: 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 triple negative breast cancer (TNBC) that is locally advanced or metastatic for which the projected response rate to Durvalumab is 10% or less.
  -  Female patients age ≥ 18 years
  -  No prior Vigil immunotherapy
  -  No prior PD-1 or PD-L1 inhibitor therapy including Durvalumab
  -  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.
  -  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
  -  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 (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) 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 mm3)
  2. Platelets > 100 × 10^9/L (100,000 per mm3)
  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
  -  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 Exclusion Criteria:
  -  Concurrent enrollment in another clinical study, unless it is an observational (noninterventional) clinical study or the follow-up period of an interventional study.
  -  Medical condition requiring any form of chronic systemic immunosuppressive therapy (steroid or other) except physiologic replacement doses of hydrocortisone or equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily for < 30 days duration.
  -  Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent.
  -  Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 5 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers are allowed if definitively resected.
  -  History of brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 4 months.
  -  Any documented history of autoimmune disease with exception of Type 1 diabetes on stable insulin regimen, hypothyroidism on stable dose of replacement thyroid medication, vitiligo, or asthma not requiring systemic steroids (unless within the protocol allowed doses).
  -  Known history of allergies or sensitivities to gentamicin, Durvalumab, or any excipient.
  -  History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
  -  Known HIV or acute or chronic Hepatitis B or C infection.
  -  History of pneumonitis or interstitial lung disease.
  -  History of organ transplant that requires therapeutic immunosuppression
  -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
  -  History of Peptic Ulcer Disease or gastritis
  -  History of primary immunodeficiency
  -  History of leptomeningeal carcinomatosis
  -  Known history of previous clinical diagnosis of tuberculosis
  -  Previous allogeneic bone marrow transplant
  -  Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  -  Previous enrollment in the present study
  Study Enrollment Exclusion Criteria:
  -  Any anti-neoplastic therapy between tissue procurement for vaccine manufacture and start of study therapy. Limited field of radiation for palliation greater than 3 weeks prior of the first dose of study treatment is allowed:
  1. Provided the lung is not in the radiation field
  2. Provided irradiated lesion(s) cannot be used as target lesions
  -  Receipt of live, attenuated vaccine within 30 days prior to the first dose of Vigil ™ Durvalumab. NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 180 days after the last dose of both drugs.
  -  Post-surgery complication that in the opinion of the treating investigator would interfere with the patient's study participation or make it not in the best interest of the patient to participate
  -  Participation in another clinical study with an investigational product during the last 3 weeks
  -  Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction
  -  Female subjects who are pregnant, breast-feeding or of reproductive potential who are not employing an effective method of birth control defined in the protocol (section 7.6)
  -  Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Relevance to patient case: not relevant