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Up to three dosing cohorts of CYNK-001 given on Day 2 or Days 2, 7, 14 post ASCT. Once MTD has been determined, the Expansion cohort will commence.

CYNK-001 is an allogeneic off the shelf cell therapy enriched for CD56+/CD3- NK cells expanded from human placental CD34+ cells.

CYNK-001

Adrian Kilcoyne, MD

This study will find the maximum tolerated dose (MTD) of CYNK-001 which contain NK cells derived from human placental CD34+ cells and culture-expanded. CYNK-001 cells will be given post Autologous Stem Cell Transplant (ASCT). The safety of this treatment will be evaluated, and researchers will want to learn if NK cells will help in treating Multiple Myeloma.

The study will utilize a 3+3 open label design, and will enroll up to three dosing cohorts of CYNK-001 given on Day 2 or Days 2, 7, 14 post ASCT. Once MTD has been determined, the Expansion cohort will commence.

Natural Killer Cell (CYNK-001) Infusions in Adults With Multiple Myeloma

A Phase I Study of Human Placental Hematopoietic Stem Cell Derived Natural Killer Cells (CYNK 001) in Multiple Myeloma Patients Following Autologous Stem Cell Transplant in the Front-line Setting.

Safety Assessment of Dose-Limiting Toxicity (DLT)

Celularity Incorporated

Analgesics

All Drugs and Chemicals

Antineoplastic Agents

Anti-Inflammatory Agents

Coagulants

Antirheumatic Agents

Bortezomib

Hemostatics

Anti-Inflammatory Agents, Non-Steroidal

Enzyme Inhibitors

Vorinostat

Analgesics, Non-Narcotic

Histone Deacetylase Inhibitors

Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1-14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Four 100 mg capsules vorinostat taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

1.3 mg/m2 of bortezomib by IV push, on Days 1, 4, 8, and 11 of each 21-day treatment cycle.

bortezomib

Four placebo capsules taken orally, once daily, on Days 1 through 14 of each 21-day treatment cycle.

placebo to vorinostat

Medical Director

Study of the efficacy and safety of bortezomib administered in combination with vorinostat in patients with relapsed or refractory multiple myeloma. Histone deacetylases (HDAC) facilitate gene transcription by modulating the uncoiling of chromatin. HDAC function is dysregulated in hematologic and solid malignancies, and this dysregulation may result in over-expression of oncogenes. Thus, inhibition of HDACs may result in anti-cancer effects. HDAC inhibitors, like vorinostat, represent a new class of antitumor agents that have the ability to induce antiproliferative effects including cyto-differentiation, cell cycle growth arrest or apoptosis in various cancer cell lines. Several studies have investigated the in vitro antimyeloma activity of vorinostat in combination with bortezomib and have demonstrated that vorinostat may act synergistically with bortezomib to modulate tumor cell growth. Mitsiades et al have shown that vorinostat enhances the sensitivity of bortezomib. Pei et al found that exposure of human multiple myeloma cell lines \& patient-derived multiple myeloma cells to bortezomib and vorinostat resulted in synergistic interactions as a result of: (1) Interruption of NF-kB \& related signaling pathways (JNK, XIAP, Mcl-1, etc.) (2) Inhibition of Hsp90 (3)Induction of ER stress signal and (4) acetylation of Dynein/disruption of aggresome function/formation, salvage for ubiquitinated proteins. In addition a marked increase in mitochondrial injury, caspase activation, and apoptosis was also observed. Bortezomib is indicated for the treatment of patients with multiple myeloma. Two Phase I dose-ranging studies of a regimen combining vorinostat and bortezomib among patients with relapsed as well asend-stage, refractory multiple myeloma have been conducted. These studies enrolled a total of 57 patients. In these studies, administration of vorinostat with standard doses of bortezomib resulted in responses in 20/45 (44%) evaluable patients (Weber et al 2007, Badros et al 2007). The purpose of the present study is to definitively evaluate the clinical activity of vorinostat in combination with bortezomib inpatients with multiple myeloma.

Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)

An International, Multicenter, Randomized, Double-Blind Study of Vorinostat (MK-0683) or Placebo in Combination With Bortezomib in Patients With Multiple Myeloma

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Progression-free survival was measured from the start of the treatment to the time when the criteria for progression was met or death due to any cause (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. Grades come from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Per protocol, clinical and laboratory AEs are presented as a combined total for each grade.

Overall survival was measured from the start of the treatment to death due to any cause. Overall Survival is represented as the number of deaths per 100-person- months and was computed by dividing the number of participants with an event of death that occurred during the study follow-up period by the total duration of follow-up (in 100 months) for all the participants in each cohort since participants had different lengths of follow-up.

Time to progression was measured from the start of the treatment to the time when the criteria for progression was met or death due to myeloma (whichever is first recorded). Response to study therapy was assessed using European Blood and Marrow Transplantation Group (EBMT) Criteria. A stratified Cox proportional hazards model was used with Efron's likelihood approximation to account for ties in event times.

Objective response rate was measured as the proportion of patients who achieved a confirmed partial response or better during the course of the study. Response to study therapy was assessed using EBMT Criteria and confirmed by Independent Adjudication Review.

Merck Sharp & Dohme LLC

Adverse events were reported for the All Participants as Treated Population that included all randomized participants who received at least one dose of study treatment.

Participants will receive vorinostat four 100 mg capsules (400 mg total) orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Vorinostat + Bortezomib

Participants will receive four placebo capsules orally 0-30 minutes after a meal on Days 1 through 14 of a 21-day treatment cycle and bortezomib 1.3 mg/m\^2 by intravenous injection on Days 1, 4, 8, and 11 of a 21-day treatment cycle.

Placebo + Bortezomib

Total

Age, Continuous

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Senior Vice President, Global Clinical Development

Cox model stratified by myeloma stage at enrollment, history of a bone marrow transplant, and number of prior treatment regimens, with a single treatment covariate.

The analysis population includes all randomized participants.

Progression-Free Survival (PFS)

Grade 3

Grade 4

Grade 5

The analysis population includes all randomized participants who received ≥1 dose of study medication.

Number of Participants With Grade 3-5 Clinical or Laboratory Adverse Events (AEs)

Overall Survival

Time to Progression

Objective Response Rate

Overall Study

Neoplasm Metastasis

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Cyclophosphamide

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

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
Natural Killer Cell (CYNK-001) Infusions in Adults With Multiple Myeloma	NCT04309084	Multiple Myelom... Neoplasm, Plasm... Neoplasms by Hi... Neoplasms Hemostatic Diso... Vascular Diseas... Cardiovascular ... Paraproteinemia... Blood Protein D... Hematologic Dis... Hemorrhagic Dis... Lymphoprolifera... Immunoprolifera... Immune System D... Antineoplastic ... Analgesics, Non... Analgesics Sensory System ... Peripheral Nerv... Physiological E...	CYNK-001	18 Years - 75 Years	Celularity Incorporated
Study of Vorinostat (MK-0683) or Placebo, in Combination With Bortezomib in Participants With Multiple Myeloma (MK-0683-088 AMN)	NCT00773747	Multiple Myelom...	Vorinostat bortezomib placebo to vori...	18 Years -	Merck Sharp & Dohme LLC
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

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