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Neuroectodermal Tumors, Primitive

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Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunologic Factors

Immunosuppressive Agents

Interleukin-2

Mesna

Phase 1 dose escalation will utilize a 3+3 dose escalation design and will evaluate safety, feasibility, and preliminary efficacy of four cohort dose levels of CYNK-001 administered after a 6M IU subcutaneous dose of rhIL-2 for both IV and IC cycles. Up to 21 patients will be enrolled over 4 dosing cohorts in Phase 1.

To evaluate efficacy and safety of CYNK-001 administrations in recurrent GBM at maximum tolerated dose for IV and IC per Phase 1 outcome. No patients staggering will be implemented in phase 2a. DMC will review the phase 2a entirely

Phase 1 Lymphodepletion Days -5,-4 and -3 Cyclophosphamide 900 mg/m2, Fludarabine 30 mg/m2 and Mesna per SOC

IL 2 at 6M IU subcutaneous administration:

For IV cycle ( cycle1) rhIL2 will be administered on Days 1,3,5,8,9,11 and 15 . On days 1, 8 and 15 rhIL-2 will be administered 1 to 3 hours prior to CYNK-001 infusions For IC cycles rhIL2 will be administered 1 to 3 hours prior to each CYNK-001 IC dose.

CYNK-001 : for IV at 2.4 x10\^9 or 3.6 x10\^9 cells Days 1,8 and 15

Tumor resection will take place 7 to 14 day follow by first IC cycle ( Cycle 2) at 100 Million cells or 200 Million cells

IC cycles 3,4,5 once a week for three weeks , 28 days cycle at100 Million cells or 200 Million cells only for Phase 1 cohort 4 and Phase 2a

CYNK-001 systemic and Intra cavity administration

Adrian Kilcoyne, MD

A Phase 1/2a Open Label Multicenter, Non-Randomized, Trial to Assess the Safety and Efficacy of CYNK-001 in Combination with Recombinant Human Interleukin-2 in Adults with Recurrent Resection Eligible IDH1 wild-type Glioblastoma. For phase I portion, the study objectives to assess the safety and feasibility CYNK-001 in combination with rhIL2 of Intravenous (IV) infusion and Intracavitary (IC) administrations following tumor resection and to establish a maximum tolerated dose (MTD) and a Recommended Phase 2a Dose (RP2D) for IV and IC CYNK-001 administration. For Phase IIa, to evaluate efficacy and safety of CYNK-001 administrations in recurrent GBM as measured by Progression Free Survival at 6 months (PFS6M)

The study will contain two phases for the following objectives •The Phase 1 Dose Escalation will utilize a 3+3 dose escalation design and will evaluate safety, feasibility, and preliminary efficacy of four cohort dose levels of CYNK-001 administered after a 6M IU subcutaneous dose of rhIL-2 for both IV and IC cycles. Up to 21 patients will be enrolled over 4 dosing cohorts in Phase1 and 45 patients enrolled for phase IIa. Cohort 4 will be the safety run for Phase IIa. Cohort 4 in its entirety will be reviewed by the DMC prior to starting Phase 2a portion of this study. Phase 2a will continue to explore efficacy and safety of CYNK-001 in combination with rhIL2 in patients with recurrent resection eligible IDH1 wild-type glioblastoma.

CYNK-001 IV and IC in Combination With IL2 in Surgical Eligible Recurrent GBM With IDH-1 Wild Type

A Phase I/IIa Open Label Multicenter, Non-Randomized, Trial to Assess the Safety and Efficacy of CYNK-001in Combination With Recombinant Human Interleukin-2 in Adults With Recurrent Resection Eligible IDH1 Wild-type Glioblastoma

is defined as the time from the tumor resection until the date of death 9 and 12 months (PFS9 and PFS12) post tumor resection

is defined as the median 95% CIs time from the tumor resection until the date of death 9 and 12 months (PFS9 and PFS12) post tumor resection

is defined as the median as the 95%CI time from the tumor resection until the date of death.

is defined as the time from the tumor resection to the date of first documented disease progression determined in accordance with RANO(iRANO).

Defined as the proportion of subjects with best overall response of either complete response (CR) or partial response (PR)

To assess patient quality of life at baseline and post tumor resection surgery per the schedule of Events using EORTC QLQ C30 and EORTC QLQ BN 20 scale

NANO scale provides an objective clinician-reported outcome of neurologic function with high inter-observer agreement

any event not present prior to the initiation of the drug treatment

any untoward or unfavorable medical occurrence in patient during the clinical trial

Defined as the maximum dose safely administered intravenously or Intracavitary for the treatment of patients with GBM

Defined as the number of patients experience Adverse Events and severity

To evaluate CYNK-001 efficacy post tumor resection and survival within PFS6 Month

is defined as the time from the tumor resection to the date of first documented disease progression determined in accordance with RANO (and iRANO) or death due to any reason, whichever occurs first

is defined as the time from the tumor resection until the date of death at 6,9 and 12 months

Celularity Incorporated

Neoplasm Metastasis

Cohort 1A ( recurrent GBM) will receive CYNK-001 at a dose of 1.2 x 10\^9 cells intravenous ( IV) on Days 0, 7, and 14 and will include up to 6 subjects. The subjects will be followed for a 42 day DLT period from the initial CYNK-001 infusion (or 28 days after the last dose). No other treatment interventions are planned between the last day of CYNK-001. In the event of DLTs, Cohort 1C ( recurrent GBM dose-De escalation) will receive CYNK-001 at a dose of 600 x 10\^6 cells (IV) on Days 0, 7, 14, and will include up to 6 subjects who will be followed for a 42-day DLT period from the initial CYNK-001 infusion (or 28 days after the last dose. Cohort 1B (surgical cohort) will receive CYNK-001 at the maximum safe dose (MSD) (either 1.2x10\^9 cells or 600x10\^6 cells) (IV) at Days 0, 7, 14, and will include up to 6 subjects. The tumor resection surgery will be performed after the last CYNK-001 infusion during the DLT period.

The cohort 2A or cohort 2C (recurrent GBM) IT route of administration can be started only after the safety results were acceptable from the completion of cohort 1A or Cohort 1C (IV route of administration). The Treatment Period for the IT cohorts will begin with having the Ommaya catheter placement per institutional policy, which is planned to occur within one week prior to the CYNK-001 administration on Day 0. Cohort 2A will be treated with CYNK-001 IT at 200 x 10\^6 ± 50 x 10\^6 cells IT on Day 0, 7 and 14 includes up to 6 recurrent GBM subjects Cohort 2C ( dose de-escalation) will be treated with CYNK-001 200 x 106 ± 50 x 106 cells IT on Day 0, and Day 7 ( only two days dosing) and include up to 6 recurrent GBM subjects. Cohort 2B ( the surgical IT cohort) will be treated with CYNK-001 at the maximum safe dose ( MSD) (either 200 x 10\^6 ± 50 x 10\^6 cells on Days 0, 7 and 14 or at 200 x 10\^6 ±50x10\^6 cells on Days 0 and 7) and include up to 6 surgical GBM subjects

Planned Starting dose dor IV 1.2x10\^9 cells/dose

CYNK001-IV

Planned starting dose for IT 200 x10\^6 +/- 50 x10\^6 cells dose

CYNK001-IT

Sharmila Koppisetti, MD

This study will find the maximum safe dose (MSD) or maximum tolerated dose (MTD) of CYNK-001 which are NK cells derived from human placental CD34+ cells and culture-expanded. CYNK-001 cells will be given after lymphodepleting chemotherapy for the systemic cohort (IV) (intravenous). The intratumoral cohort (IT) will not be giving lymphodepletion. The safety of this treatment will be evaluated, and researchers want to learn if NK cells will help in treating recurrent glioblastoma multiforme.

2 modalities Systemic vs Intratumoral. For systemic experimental: Cyclophosphamide at Day -3 followed by CYNK-001. On Days 0, 7, and 14. Experimental IntraTumoral, Ommaya placement surgery 7 days prior to CYNK-001 administrations at Days 0, 7 and 14

Natural Killer Cell (CYNK-001) IV Infusion or IT Administration in Adults With Recurrent GBM

A Phase I Study of Human Placental Hematopoietic Stem Cell Derived Natural Killer Cells (CYNK-001) in Adults With Recurrent Glioblastoma Multiforme (GBM)

Defined as the maximum dose safely administered intravenously or Intratumoral for the treatment of patients with GBM.

Defined as the number and Severity of Adverse Events

Defined as duration from first observation of partial response (PR) or better to the date of disease progression per RANO criteria

Defined as date of the first CYNK-001 infusion to the date of disease progression per RANO Response Criteria or death (regardless of cause of death), whichever comes first

Defined as the date of the first CYNK-001 infusion to the date of disease progression per RANO Response Criteria, with deaths from causes other than progression censored

Defined as the date of the first CYNK-001 infusion to the date of death

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CYNK-001 IV and IC in Combination With IL2 in Surgical Eligible Recurrent GBM With IDH-1 Wild Type	NCT05218408	Astrocytoma, Gr... Glioblastoma Giant Cell Glio... Glioblastoma Mu...	CYNK-001 system...	18 Years -	Celularity Incorporated
Natural Killer Cell (CYNK-001) IV Infusion or IT Administration in Adults With Recurrent GBM	NCT04489420	Astrocytoma, Gr... Giant Cell Glio... Glioblastoma Mu... Cyclophosphamid... Immunosuppressi... Immunologic Fac... Physiological E... Molecular Mecha... Antiviral Agent... Anti-infective ... Analgesics, Non... Analgesics Sensory System ... Peripheral Nerv...	CYNK001-IV CYNK001-IT	18 Years -	Celularity Incorporated
CYNK-001 IV and IC in Combination With IL2 in Surgical Eligible Recurrent GBM With IDH-1 Wild Type	NCT05218408	Astrocytoma, Gr... Glioblastoma Giant Cell Glio... Glioblastoma Mu...	CYNK-001 system...	18 Years -	Celularity Incorporated

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