FT516 and IL2 With Enoblituzumab for Ovarian Cancer
Condition: Ovarian Cancer; Fallopian Tube Adenocarcinoma; Primary Peritoneal Cavity Cancer
MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
Intervention: IP FT516; Enoblituzumab; IL-2
Intervention description: FT516 is an off-the-shelf cryopreserved NK cell product derived from an iPSC that was transduced with a high affinity, ADAM17 non-cleavable CD16 (Fc receptor) that maintains CD16 on the cell surface, which remains fully functional after NK cell activation; Enoblituzumab is an Fc-optimized monoclonal antibody that targets B7-H3 which is highly expressed on ovarian cancer. Enoblituzumab at 15 mg/kg IV, one day before lymphodepleting chemotherapy; IL-2 at 6 Million IU (3 Million IU/m2 if patient weight is <45 kg) is administered IP in 50 cc of room temperature D5W via peritoneal catheter directly after the FT-516 infusion is completed. Immediately following the IL-2, an additional 100 cc D5W flush is infused into the peritoneal cavity through the peritoneal catheter as rapidly as possible.
Intervention MeSH terms: Interleukin-2
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Intervention model description: This study is conducted in two consecutive stages with 5 cohorts. A minimum of 28 days must separate each cohort. Within a 3 patient cohort, a minimum of 14 days must separate the first and second patient. Stage 1 Step 1 uses a fast-track design (1 patient per cohort) with a minimum of 28 days between each patient until one of the following: a) 1st occurrence of a pre-defined adverse event at which point the study moves to Step 2. The cohort size increases from 1 to 3 patients with 2 additional patients added. Escalation in Step 2 continues until the 1st DLT at which point Stage 2 continual reassessment method (CRM) is activated. If Cohort 5 is completed with 10 patients enrolled at the MTD without a DLT, Stage 2 (CRM) is not used. b) The 1st occurrence of a DLT the study moves directly to Stage 2 (CRM) and Step 2 is not used. c) Cohort 5 is completed without a pre-defined AE or a DLT - neither Step 2 nor Stage 2 is used if a total of 10 patients are enrolled in Cohort 5.
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a single center Phase I clinical trial of FT516 administered intraperitoneally (IP)
      once a week for 3 consecutive weeks for the treatment of recurrent gynecologic cancers. As
      this is an early 1st in human study and the 1st intraperitoneal infusion of FT516, the safety
      of FT516 is confirmed prior to adding enoblituzumab as an intravenous infusion approximately
      1 week prior to the 1st dose of FT516 and every 3 weeks beginning on Day 22 (1 week after the
      last dose of FT516). Each dose of FT516 is followed directly by an IP infusion of
      interleukin-2 (IL-2) to facilitate natural killer (NK) cell survival. A short course of
      outpatient lymphodepletion chemotherapy is given prior to the 1st dose of FT516.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Recurrent epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer
             meeting one of the following minimal prior treatment requirement (no limit to the
             maximum number of prior treatments):

          -  Platinum Resistant: may receive FT516 as 2nd line (as 1st salvage therapy) with
             platinum resistant is defined as disease that has responded to initial chemotherapy
             but demonstrates recurrence within a relatively short period of time (< 6 months)
             following the completion of treatment.

          -  Platinum Sensitive: may receive FT516 as 3rd line therapy (as 2nd salvage therapy)
             with platinum sensitive is defined as the recurrence of active disease in a patient
             who has achieved a documented response to initial platinum-based treatment and has
             been off therapy for an extended period of time (≥ 6 months).

          -  Measurable disease per modified Response Evaluation Criteria in Solid Tumors, v1.1
             within the abdomen and pelvis assess within 42 days of the 1st FT516 infusion.
             Extra-peritoneal disease is permitted; however each lesion must be < 5 cm at the
             largest diameter.

          -  At least 18 years of age

          -  GOG Performance Status 0, 1, or 2

          -  Adequate organ function within 14 days of study registration (28 days for pulmonary
             and cardiac) defined as:

          -  Hematologic: platelets ≥ 75,000 x 10^9/L and hemoglobin ≥ 9 g/dL, unsupported by
             transfusions; absolute neutrophil count (ANC) ≥ 1000 x 10^9/L, unsupported by G-CSF or
             granulocytes

          -  Creatinine: Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m^2 per
             current institutional calculation formula

          -  Hepatic: AST and ALT ≤ 3 x upper limit of institutional normal

          -  Pulmonary Function: Oxygen saturation ≥ 90% on room air; PFT's required only if
             symptomatic or prior known impairment - must have pulmonary function >50% corrected
             DLCO and FEV1

          -  Cardiac Function: LVEF ≥ 40% by echocardiography, MUGA, or cardiac MRI; no clinically
             significant cardiovascular disease including any of the following: stroke or
             myocardial infarction within 6 months prior to first study treatment; unstable angina
             or congestive heart failure of New York Heart Association Grade 2 or higher

          -  Agrees to the placement of an intraperitoneal catheter before the 1st dose of study
             directed drug (chemotherapy or enoblituzumab - Cohort 4 and 5) and remains in place
             through Day 36 or longer if retreatment is planned

          -  Agrees to undergo a tumor biopsy if feasible at the time the catheter is placed and
             removed - Accessible tumor for biopsy is not required for eligibility.

          -  Washout period of at least 14 days after any standard of care tumor directed therapy
             prior to the first dose of investigational product (FT516 for Levels 1-3 or
             enoblituzumab for Levels 4-5)

          -  If history of brain metastases must be stable for at least 3 months after treatment -
             A brain CT scan or MRI is only be required in subjects with known brain metastases at
             the time of enrollment or in subjects with clinical signs or symptoms suggestive of
             brain metastases

          -  Must agree to and sign the consent for the companion Long-Term Follow-Up study (CPRC
             #2020LS072) to fulfill the FDA required 15 years of follow-up for a genetically
             modified cell product

          -  Voluntary written consent prior to the performance of any research related procedures

        Exclusion Criteria:

          -  Pregnant or breastfeeding or planning on becoming pregnant in the next 6 months. Woman
             of childbearing potential who still have a uterus and ovaries, must agree to use at
             effective contraception and must have a negative pregnancy test within 14 days of
             study enrollment.

          -  Any known condition that requires systemic immunosuppressive therapy (> 5mg prednisone
             daily or equivalent) during the FT516 dosing period (3 days before the 1st dose
             through 14 days after the last dose) - topical and inhaled steroids are permitted.

          -  Active autoimmune disease requiring systemic immunosuppressive therapy

          -  History of severe asthma and currently on chronic systemic medications (mild asthma
             requiring inhaled steroids only is eligible)

          -  Uncontrolled bacterial, fungal or viral infections with progression of clinical
             symptoms despite therapy

          -  Receipt of any investigational agent within 28 days prior to the first dose of
             investigational product (FT516 for Levels 1-3 or enoblituzumab for Levels 4-5)

          -  Live vaccine <6 weeks prior to start of lympho-conditioning

          -  Known allergy to the following FT516 components: albumin (human) or DMSO

          -  Any history of prior enoblituzumab administration

          -  Known history of HIV positivity or active hepatitis C or B - chronic asymptomatic
             viral hepatitis is allowed

          -  Presence of any medical or social issues that are likely to interfere with study
             conduct or may cause increased risk to patient