A Trial of Atezolizumab and Vigil in Patients With Advanced Gynecological Cancers

The clinical trial was intended as a companion study to protocol CL-PTL-119 (VITAL study; NCT 02346747). Subjects who had tumor harvested at surgery and Vigil successfully manufactured, but then were ineligible for randomization onto the VITAL study or previously randomized to placebo, and also in subjects who have recurrent ovarian cancer were offered the opportunity to participate in this protocol. The trial was a multi-center, randomized, 3-part, open label study of Vigil, the checkpoint inhibitor atezolizumab and the combination of the two agents, in subjects with treatment refractory or recurrent epithelial ovarian cancer, or other gynecological cancers (i.e., cervical, uterine).

Part 1 was a safety run-in cohort and intervention (Vigil plus atezolizumab) was combined. The first 3 subjects registered in the trial were assigned to Part 1.

Part 2 was conducted after Part 1 participants completed combination therapy without dose-limiting toxicity. The purpose of Part 2 was to determine if Vigil given first then in sequence with atezolizumab would enhance immunotherapeutic anticancer activity. The overall efficacy of administration sequence was assessed.

Eligible subjects were randomized to receive two cycles of Vigil alone (n= 11) or two cycles of atezolizumab alone (n=10), followed by combination treatment with both of the agents.

Part 3 was an expansion cohort to allow subjects who completed all cycles of Part 2 to continue on atezolizumab alone, after Cycle 12. In this study, only 1 subject from Part 2 received additional treatment with atezolizumab. Pre-approval by sponsor was required by the sponsor before allowing subjects to continue treatment with atezolizumab in Part 3.

Subjects remained on treatment until disease progression or death or product toxic effect. Disease progression was determined radiographically by local investigators using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).

Part 1, radiological assessment of tumor response was performed at baseline and every third cycle thereafter. Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis was obtained at tissue procurement and at any time after the end of cycle 3. Whole blood for correlative studies (immune function) was obtained at baseline, prior to study agent administration at the start of cycle 3 and every third cycle thereafter.

Part 2, radiological assessment of tumor response was performed at baseline, at the end of cycle 2 of single agent therapy, and every third cycle thereafter. Tumor biopsy for correlative studies including scoring of tumor infiltrating lymphocyte (TIL) and PD-1 / PD-L1 expression analysis was obtained at tissue procurement, prior to the start of combination therapy and at any time after the end of cycle 3. Whole blood for correlative studies (immune function) was obtained at baseline, prior to study agent administration at the start of cycle 3 (the first cycle of combination therapy) and every third cycle thereafter.

Part 3 schedule of assessments continued from Part 2 in which the following was assessed every third cycle: radiological assessments, tumor biopsy (if available), and whole blood collection for correlative studies.

The safety evaluation included recording of AEs and SAEs, and changes from baseline in laboratory evaluations, vital signs, electrocardiograms, and physical examinations.

Treatment was administered on an outpatient basis. A study cycle is defined as 21 days (3 weeks). Treatment was allowed to continue unless documented disease progression, discontinuation for toxicity, withdrawal of consent, or meeting other criteria for withdrawal from study. After progression, participants were contacted annually for three years for documentation of survival status information.

Tissue Procurement Inclusion Criteria:

Subjects will be eligible for tissue procurement for the Vigil manufacturing process, if they meet all of the following criteria:

• Histologically confirmed Stage IIIb, IIIc or IV high-grade papillary serous, clear cell, or endometrioid ovarian, fallopian tube or primary peritoneal carcinoma
• Age ≥ 18 years.
• Estimated survival ≥ 6 months.
• ECOG Performance Status ≤ 1
• Metastatic disease
• 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.
• Tumor intended for immunotherapy manufacture is not embedded in bone and does not contain luminal tissue (e.g. bowel, ureter, bile duct).
• 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:

• 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.
• 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.
• Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 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.
• Known HIV or chronic Hepatitis B or C infection.
• Known history of allergies or sensitivities to gentamicin.
• 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.
• 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:

• Successful manufacturing of at least 4 vials of Vigil.
• One of the following:

• 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.
• Recurrent ovarian cancer.
• Randomized on Protocol CL-PTL-119 and were subsequently unblinded at recurrence and were assigned to the placebo arm.
• ECOG performance status (PS) ≤ 1 (or ≤ 2 due to carcinoid syndrome).
• Estimated survival ≥ 6 months.
• Measureable per RECIST 1.1 or evaluable disease.
• Adequate organ and bone marrow function as defined below:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10e9/L (1500 per mm^3)
• Platelets >100 × 10e9/L (100,000 per mm^3)
• Hemoglobin ≥9.0 g/dL (5.59 mmol/L)
• 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)

• 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.
• AST and ALT ≤2.5 × ULN in patients with no liver metastasis
• AST or ALT ≤5 × ULN in patients with liver metastasis
• 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 (or ≤ 2 due to carcinoid syndrome).
• Pre-existing motor or sensory neurologic pathology or symptoms must be recovered to CTCAE Grade 2 or better
• 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
• 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.
• Ability to understand and the willingness to sign a written informed protocol specific consent.
• 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.
• Palliative radiotherapy is permitted provided:

• More than 3 weeks have elapsed between the end of radiotherapy and the first dose of study therapy, AND
• 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:

• Participation in another clinical study with an investigational product within the last 3 weeks prior to study start.
• Receipt of steroid therapy within the 2 weeks of the first dose of study therapy.
• 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.
• 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.
• Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia'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. Effective contraception is required for women receiving atezolizumab for 5 months after the last dose.
• Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results.
• 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.
• Receipt of any anti-cancer therapy between tissue procurement on CL-PTL-126 and first dose of study drug.