FT516 and IL2 With Enoblituzumab for Ovarian Cancer

Phase 1

Completed

Conditions: Ovarian Cancer
Fallopian Tube Adenocarcinoma
Primary Peritoneal Cavity Cancer

Interventions: Drug: IP FT516
Drug: IL-2
Drug: Enoblituzumab

Registration Number: NCT04630769

Lead Sponsor: Masonic Cancer Center, University of Minnesota

Brief 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.

Detailed Description: FT516 is an off the shelf product comprised of allogeneic natural killer (NK) cells, expressing high-affinity non-cleavable CD16 (FT516). Enoblituzumab is an Fc-optimized monoclonal antibody that targets B7-H3 which is highly expressed on ovarian cancer. Based on data showing that within the ovarian cancer tumor microenvironment surface expression of CD16a on NK cells is diminished, the researchers hypothesize that the FT516 cellular product containing a non-cleavable CD16 will bypass the low CD16 expression issue and maximize NK cell cytotoxicity. Enoblituzumab is an Fc optimized humanized IgG1 monoclonal antibody that binds to B7-H3 (CD276). B7-H3 is an inhibitory immune checkpoint molecule that is widely expressed by a number of different tumor types and may play a key role in regulating the immune response. It is therefore hypothesized that the combination of FT516 with enoblituzumab will maximize NK cell cytotoxicity in patients with ovarian cancer.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Monotherapy: IP FT516 at 9 x 10^7 cells/dose on Day 1, 8, and 15	IL-2	-
Monotherapy: IP FT516 at 3 x 10^8 cells/dose on Day 1, 8, and 15	IL-2	-
Safe dose (MTD-1) from 1st 3 levels + IV enoblituzumab on Day -6	IL-2	-
Highest dose (MTD) from 1st 3 levels + IV enoblituzumab on Day -6	IL-2	-
Highest dose (MTD) from 1st 3 levels + IV enoblituzumab on Day -6	IP FT516	-
Monotherapy: IP FT516 at 9 x 10^7 cells/dose on Day 1, 8, and 15	IP FT516	-
Monotherapy: IP FT516 at 3 x 10^8 cells/dose on Day 1, 8, and 15	IP FT516	-
Monotherapy: IP FT516 at 9 x 10^8 cells/dose on Day 1, 8, and 15	IP FT516	-
Safe dose (MTD-1) from 1st 3 levels + IV enoblituzumab on Day -6	IP FT516	-
Monotherapy: IP FT516 at 9 x 10^8 cells/dose on Day 1, 8, and 15	IL-2	-
Highest dose (MTD) from 1st 3 levels + IV enoblituzumab on Day -6	Enoblituzumab	-
Safe dose (MTD-1) from 1st 3 levels + IV enoblituzumab on Day -6	Enoblituzumab	-

Primary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events	28 Days Post FT516 infusion	DLT is defined as any treatment emergent toxicity at least possibly related to the study treatment meeting one of the following criteria based on CTCAE v5 within 28 days (14 days for ascites) of the 1st FT516 infusion (for Cohort 4 and 5, DLT assessment starts with enoblituzumab and continues for 28 days after 1st FT516): Grade 3 organ toxicity (pulmonary, hepatic, renal, or neurologic) not pre-existing and lasting more than 72 hours , Any non-hematologic Grade 4 or 5 toxicity, Neutrophil count decreased ≥ Grade 4 that persists at Day 28 despite use of growth factor support ,Grade 3 abdominal pain lasting more than 4 consecutive days and not controlled by standard analgesics, Grade 3 or greater ascites within 14 days after FT516 administration in patients who had no ascites or Grade 1 ascites at enrollment and is not attributable to disease progression
Number of Participants Experiencing Adverse Events	28 days after first dose of FT516 or 28 days after last dose of Enoblituzumab (arm 4 and 5 only)	Number of participants experiencing adverse events related to FT516

Secondary Outcome Measures

Name	Time	Method
Number of Participants Experiencing Progression Free Survival	1 year from the first dose of FT516	Number of participants experiencing progression free survival at 1 year from the first dose of FT516
Number of Participants Experiencing Overall Survival	1 year from the first dose of FT516	Number of participants experiencing overall survival at 1 year from the first dose of FT516