A Trial of Atezolizumab and Vigil in Patients With Advanced Gynecological Cancers
Condition: Advanced Gynecological Cancers; Ovarian Cancer; Cervical Cancer; Uterine Cancer
MeSH terms: Ovarian Neoplasms; Uterine Cervical Neoplasms; Uterine Neoplasms
Intervention: Vigil; Atezolizumab
Intervention description: The Vigil vaccine 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.; Atezolizumab was prepared and administered at the FDA approved dose and schedule as described in the U.S. Package Insert (USPI). The initial dose was administered over one hour and if well tolerated, subsequent infusions may have been administered over 30 minutes.
Atezolizumab in formulation F03 (1200 mg per vial) was administered in 250 mL 0.9% NaCl IV infusion bags and infusion lines equipped with 0.2 μm in-line filters.
Intervention MeSH terms: Atezolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This was a 3 part study. Parts 1 and 3 did not involve randomization. In part 2, eligible participants were randomized to receive two cycles of either Vigil alone or Atezolizumab alone, then followed by combination treatment with the two agents.
Masking: None (Open Label)
Enrollment: 25.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Stage IIIb; Stage IV; Ovarian Cancer; Cervical Cancer; Uterine Cancer; Immunotherapy

Summary:

      The clinical trial was a companion study to protocol CL-PTL-119 (A Randomized, Double-Blind,
      Placebo-Controlled Phase 2 Trial of Vigil Engineered Autologous Tumor Cell Immunotherapy in
      Subjects with Stage IIIb-IV Ovarian Cancer in Clinical Complete Response following Surgery
      and Primary Chemotherapy (VITAL) NCT02346747). Participants who had investigational product
      (Vigil) successfully made but were not eligible to enroll onto the VITAL study or previously
      randomized to placebo were given the opportunity to participate in this protocol. The main
      goal of this clinical trial was to determine the safety of combining Vigil therapy with
      atezolizumab.
    

Eligibility criteria:

        Tissue Procurement Inclusion Criteria:

        Subjects will be eligible for tissue procurement for the Vigil manufacturing process, if
        they meet all of the following criteria:

          1. Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous, clear
             cell, or endometrioid ovarian, fallopian tube or primary peritoneal carcinoma

          2. Age ≥ 18 years.

          3. Estimated survival ≥ 6 months.

          4. ECOG Performance Status ≤ 1

          5. Metastatic disease

          6. Planned standard of care surgical procedure (e.g., tumor biopsy or palliative
             resection or thoracentesis) and expected availability of a cumulative soft-tissue mass
             of ~10-30 grams tissue ("grape" to "golf-ball" size) or ascites fluid estimated volume
             ≥ 500mL (from a primary or secondary paracentesis, yielding in a high volume of tumor
             cells) for immunotherapy manufacture.

          7. Tumor intended for immunotherapy manufacture is not embedded in bone and does not
             contain luminal tissue (e.g. bowel, ureter, bile duct).

          8. Ability to understand and the willingness to sign a written informed protocol specific
             consent for tissue harvest or a parental/guardian informed consent and pediatric
             assent when appropriate.

        Tissue Procurement Exclusion Criteria:

        Subjects meeting any of the following criteria are not eligible for tissue procurement for
        the Vigil manufacturing:

          1. 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.

          2. Known history of other malignancy unless having undergone curative intent therapy
             without evidence of that disease for ≥ 3 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.

          3. Brain metastases unless treated with curative intent (gamma knife or surgical
             resection) and without evidence of progression for ≥ 2 months.

          4. 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.

          5. Known HIV or chronic Hepatitis B or C infection.

          6. Known history of allergies or sensitivities to gentamicin.

          7. 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.

          8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) less than 21 days prior to tissue
             procurement.

        Study Enrollment Inclusion Criteria:

        Subjects will be eligible for registration into the trial if they meet all of the following
        inclusion criteria:

          1. Successful manufacturing of at least 4 vials of Vigil.

          2. One of the following:

               1. Failure to meet the eligibililty criteria for Protocol CL-PTL-119 due to i)
                  histology of ovarian cancer and failure to achieve a complete clinical response
                  following primary debulking surgery and standard paclitaxel/carboplatin therapy
                  OR, ii) a histologic diagnosis of another gynecologic malignancy which is not
                  ovarian cancer.

               2. Recurrent ovarian cancer.

               3. Randomized on Protocol CL-PTL-119 and were subsequently unblinded at recurrence
                  and were assigned to the placebo arm.

          3. ECOG performance status (PS) ≤ 1 (or ≤ 2 due to carcinoid syndrome).

          4. Estimated survival ≥ 6 months.

          5. Measureable per RECIST 1.1 or evaluable disease.

          6. Adequate organ and bone marrow function as defined below:

               1. Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L (1500 per mm^3)

               2. Platelets >100 × 10e9/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

          7. Subject has recovered to CTCAE Grade 1 or better from all adverse events associated
             with prior therapy or surgery (or ≤ 2 due to carcinoid syndrome).

          8. Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to
             CTCAE Grade 2 or better

          9. Patients with irreversible toxicity that is not reasonably expected to be exacerbated
             by the IPs (Vigil and/or atezolizumab) may be included (e.g., hearing loss) after
             consultation with the Principal Investigator

         10. Subjects who are not rendered surgically sterile as a result of surgery for ovarian
             cancer, must have, 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.

         11. Ability to understand and the willingness to sign a written informed protocol specific
             consent.

         12. 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.
             Patients must have fully recovered from chemotherapy associated toxicities prior to
             starting treatment on this protocol.

         13. Palliative radiotherapy is permitted provided:

               1. More than 3 weeks have elapsed between the end of radiotherapy and the first dose
                  of study therapy, AND

               2. The irradiated lesion(s) (unless measurable progression after irradiation) cannot
                  be used as target lesions.

        Study Enrollment Exclusion Criteria:

        In addition to the procurement exclusion, subjects (both with Vigil manufactured and
        undergoing procurement) will NOT be eligible for study registration and enrollment if
        meeting any of the following criteria:

          1. Participation in another clinical study with an investigational product within the
             last 3 weeks prior to study start.

          2. Receipt of steroid therapy within the 2 weeks of the first dose of study therapy.

          3. Live vaccine used for the prevention of infectious disease administered < 30 days
             prior to the start of study therapy. NOTE: Subjects, if enrolled, should not receive
             live vaccine during the study and for 5 months after the last dose of atezolizumab.

          4. Post-surgery complication that in the opinion of the treating investigator would
             interfere with the subject's study participation or make it not in the best interest
             of the subject to participate.

          5. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
             electrocardiograms (ECGs) using Fridericia's Correction.

          6. 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. Effective
             contraception is required for women receiving atezolizumab for 5 months after the last
             dose.

          7. Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results.

          8. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
             endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies, other investigational agent) less than 21 days prior to the first dose of
             study drug or less than 6 weeks for nitrosourea or mitomycin C.

          9. Receipt of any anti-cancer therapy between tissue procurement on CL-PTL-126 and first
             dose of study drug.