Neoplasms

Symptoms and General Pathology

All Conditions

Blood and Lymph Conditions

Rare Diseases

Neoplasm Metastasis

Leukemia

Hematologic Neoplasms

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Neoplasm, Residual

Hematologic Diseases

Neoplasms by Histologic Type

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Interleukin-2

Antineoplastic Agents, Alkylating

Cyclophosphamide + Fludarabine prior to CYNK-001 on Days 0, 7, and 14; CYNK-001 at 3 varying dose levels.

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

CYNK-001

Cherie Daly, MD

Michael Maris, MD

Hongtao Liu, MD, PhD

James McCloskey, MD

Eunice Wang, MD

Joseph Jurcic, MD, PhD

Lauren Harrison, MSN

Mitchell Cairo, MD

Amir Steinberg, MD

William Donnellan, MD

Melissa Cabrera, BS

Naveen Pemmaraju, MD

Daniel Egan, MD

This study will find the maximum tolerated dose or the maximum planned dose of CYNK-001 which contains natural killer (NK) cells derived from human placental CD34+ cells and culture-expanded. CYNK-001 cells will be given after lymphodepleting chemotherapy. The safety of this treatment will be evaluated, and researchers want to learn if NK cells will help in treating acute myeloid leukemia.

Experimental: Minimal Residual Disease (MRD) positive AML patients; Cyclophosphamide + Fludarabine + CYNK-001. On Days 0, 7, and 14, (and 21 in certain arms) CYNK-001 at 3 varying dose levels.

Experimental: Relapsed/Refractory AML patients; Cyclophosphamide + Fludarabine + CYNK-001. On Days 0, 7, and 14, (and 21 at certain dose levels) CYNK-001 at 3 varying dose levels.

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

A Phase I Multi-dose Study of Human Placental Hematopoietic Stem Cell Derived Natural Killer Cells (CYNK-001) With or Without Recombinant Human Interleukin-2 (rhIL-2) in Adults With Primary or Secondary Acute Myeloid Leukemia (AML) in Morphologic Complete Remission With Minimal Residual Disease (MRD) or Relapsed/Refractory (R/R) AML

The number of participants who experience a DLT will be measured.

The maximum dose safely administered for the treatment of patients with AML.

Frequency and severity of Adverse Events will be evaluated.

The number of participants who convert from MRD positive to MRD negative in the MRD positive arm.

The time it takes to convert from MRD positive to MRD negative in the MRD positive arm.

The measure of how long participants remain MRD negative in the MRD positive arm.

Date of first CYNK-001 infusion to date of disease progression in the MRD positive arm.

Duration from first Morphologic CR observation to time of disease progression in the MRD positive arm.

Date of first CYNK-001 infusion to date of death.

Defined as achievement of Complete Remission (CR), Complete Remission with incomplete (CRi) hematologic recovery, or Morphologic leukemic-free state (MLFS) in the Relapsed/Refractory AML arm.

Duration of best response in the Relapsed/Refractory AML arm.

Celularity Incorporated

Syndrome

Preleukemia

Myelodysplastic Syndromes

Bone Marrow Diseases

Precancerous Conditions

Anti-Bacterial Agents

Azacitidine

Antibiotics, Antitubercular

Antimetabolites

Enzyme Inhibitors

Azacitidine 75 mg/m\^2/day Subcutaneous for 7 days Day every 28 days for up to 6 cycles

Subjects will receive azacitidine 75 mg/m2/day SC for 7 days every 28 days for up to 6 cycles, unless they are discontinued from the treatment. In addition, subjects may receive best supportive care as needed, including antibiotics and transfusions, per Investigator discretion.

C L Beach, PharmD

The primary purpose of this study is to determine the effectiveness and safety of azacitidine in the treatment of Taiwanese subjects with higher-risk Myelodysplastic Syndrome (MDS).

The study has 3 phases which include the Screening Phase, the Treatment Phase, and the Post-Treatment Phase and outlined as follows:

Screening Phase:

Subjects will provide informed consent prior to undergoing any study-related procedures. Screening procedures are to take place within 28 days prior to the initiation of azacitidine treatment (Day 1, Cycle 1). Subject eligibility will be based on central pathology review. Bone marrow aspirate and bone marrow biopsy will be collected at screening and sent for morphological assessment by a central pathology reviewer prior to the subject receiving IP. The central pathology reviewer will document the MDS classification according to the FAB and WHO criteria (Appendix A and B, respectively).

A standard cytogenetic metaphase preparation will be prepared from the bone marrow aspirate and sent to the local or central laboratory (for sites without local analysis capability) for the cytogenetic analysis prior to receiving IP.

The IPSS score will be calculated using the central reviewer's pathology report for bone marrow blast percentage, local cytogenetic assessment for karyotype, and central laboratory report for number of cytopenias (Appendix D).

Treatment Phase:

The first dose of azacitidine for each subject begins on Day 1 of Cycle 1. All subjects will receive azacitidine 75 mg/m2/day SC for 7 days every 28 days for up to 6 cycles, unless they are discontinued from treatment. Visits during the treatment phase are to be scheduled weekly for the first 2 cycles, then every other week for all subsequent cycles throughout the rest of the study. Safety and efficacy measures are to be performed weekly, every other week, every 4 weeks, or at 24 weeks, depending on the procedure.

Post-Treatment Phase:

All discontinued subjects, regardless of reason for discontinuation, should undergo end-of-study procedures at the time of study discontinuation. Subjects will have a follow-up visit for the collection of adverse events up to 28 days after last IP dose.

Study of Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes (MDS)

A Phase 4, Open-Label, Single-Arm Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Subcutaneous Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes.

A participant was considered transfusion dependent at baseline if the participant had one or more Red Blood Cell transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no transfusions during any 56 consecutive days or more (e.g., Day 1 through 56, Day 2 through 57, etc). Otherwise, they were considered transfusion dependent.

The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12)

A participant was considered RBC transfusion-independent at baseline if the participant had no RBC transfusions during the 56 days prior to first dose. During the study, a participant was considered transfusion independent during the on-treatment period if the participant had no RBC transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered transfusion dependent.

The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: RBC dependent at BL=32, RBC independent at BL=12)

A participant was considered platelet transfusion dependent at baseline if the participant had one or more platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent.

The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26)

A participant was considered platelet transfusion independent at baseline if the participant had no platelet transfusions during the 56 days prior to first dose. During the study, a participant was considered platelet transfusion independent during the on-treatment period if the participant had no platelet transfusions during any 56 consecutive days or more (eg, Days 1 through 56, Days 2 through 57, etc.). Otherwise, they were considered platelet transfusion dependent.

The total N=44, but 1 participant can only be dependent or independent at baseline for each type of transfusion (ie, total = 44: platelet dependent at BL=18, platelet independent at BL=26)

Hematologic Response according to the 2000 International Working Group (IWG) response criteria for MDS was based on the Investigators determination and defined as:

* Complete Response (CR): repeat bone marrow (BM) shows \<5% myeloblasts, and peripheral blood values lasting ≥ 2 months of hemoglobin (hgb) (\>110 g/L), neutrophils (≥1.5x10\^9/L), platelets (≥100x10\^9/L), blasts (0%) and no dysplasia
* Partial Response (PR): same as CR for peripheral blood: BM shows blasts decrease by ≥ 50% or a less advanced FAB classification from pretreatment
* Stable disease (SD): failure to achieve a PR, no evidence of progression for at least 2 months.
* Failure: death during treatment or disease progression
* Relapse After CR or PR: return to pretreatment BM blast percent or decrement of ≥ 50% from remission/response levels in granulocytes or platelets; or reduction in hgb by ≥20 g/L or transfusion dependence
* Disease Progression: change in blast levels
* Disease Transformation to AML

Hematologic improvements (HI) have 4 categories:

1. Erythroid response (HI-E): Major \>20g/L increase or transfusion independent. Minor- 10-20g/L increase or ≥50% decrease in transfusion requirements.
2. Platelet response (HI-P): Major absolute increase of ≥30x10\^9/L or platelet transfusion independence. Minor-≥50% increase.
3. Neutrophil response (HI-N): Major 100% increase or an absolute increase of \>0.5x10\^9/L. Minor-≥100% increase and absolute increase of \<0.5x10\^9/L
4. Progression or relapse after HI

Overall hematological improvement (HI) was defined as any type (major or minor) of improvement of HI-E, HI-P, or HI-N. Criteria: Pretreatment=hemoglobin \<100g/L or RBC transfusion-dependent, platelet count \<100x10\^9/L or platelet transfusion dependent, absolute neutrophil count \<1.5x10\^9/L. Sponsor's determination was derived using clinically relevant data.

Denominator for progression/relapse after HI included participants who had achieved HI.

The number of transfusions received 56 days prior to treatment and during study were standardized per 28 days and summarized by cycle for RBCs. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of RBC transfusions per cycle.

The number of transfusions received 56 days prior to treatment and during study was standardized per 28 days and summarized by cycle for platelets. The formula for standardizing per 28 days was: \[(# of transfusions in the measurement period / length of the measurement period (days)) x 28\], where the measurement period was either baseline or the relevant cycle length. For each participant the overall post-baseline average was calculated as the average of # of platelet transfusions per cycle.

The on-treatment adverse event of infection requiring IV antibiotics, antifungals, or antivirals per 28 days/cycle. The overall post-baseline average is the average of number of infections requiring IV antibiotics or IV antiviral per 28 days/cycle. For each participant the overall post-baseline average was calculated as the average of # of infections requiring IV antibiotics or IV antiviral per 28 days per cycle.

An AE that resulted in any of the following outcomes was defined as a serious adverse event (SAE):

* Death;
* Life-threatening event;
* Any inpatient hospitalization or prolongation of existing hospitalization;
* Persistent or significant disability or incapacity;
* Congenital anomaly or birth defect;
* Any other important medical event.

The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Treatment Emergent AEs (TEAE) were defined as AEs with an onset date on or after the first dose of study drug and within 28 days after the date of the last dose. In addition, any AE that occurred beyond this timeframe and that was assessed by the investigator as possibly related to study drug was considered a TEAE.

Area under the plasma concentration-time curve from time zero to infinity (AUC∞) following multiple doses of Azacitidine on Day 7; if possible, the area under the concentration-time curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity was calculated according to the following equation: AUC∞ = AUCt + (Ct/ λz ), where Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If % AUC extrapolated is ≥ 25%, AUC∞ was not reported.

Area under the plasma concentration-time curve from time zero to the last quantifiable time point, calculated by the linear trapezoidal rule when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.

The observed maximum plasma concentration obtained directly from the observed concentration versus time data.

Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data.

The apparent terminal half-life was calculated according to the following equation t½ = 0.693/λz.

Apparent total plasma clearance (CL/F) of Azacitidine was calculated as Dose/AUC∞

Apparent volume of distribution, was calculated according to the equation: Vd/F = (CL/F)/λz

Celgene

Azacitidine 75 mg/m\^2/day subcutaneously (SC) for 7 days every 28 days for up to 6 cycles

Age, Continuous

Sex: Female, Male

Race/Ethnicity, Customized

FAB is a classification system for five (5) subtypes of myelodysplastic syndrome that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts or a monocytosis. Classification was made by the Local Reviewer.

Myelodysplastic Syndrome (MDS) French-American-British (FAB) Classification

The World Health Organization (WHO) classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.

World Health Organization (WHO) Classification

The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis. The assessment was performed by the local investigator

International Prognostic Scoring System (IPSS)

The intention-to-treat (ITT) population was defined as all enrolled participants.

Anne McClain

Overall (CR+PR)

Overall (CR+PR+SD)

Complete Remission (CR)

Partial Remission (PR)

Stable Disease (SD)

Disease Progression (DP)

Transformation to AML

Failure

No Response Assessed

The intention-to-treat (ITT) population was defined as all enrolled participants

Percentage of Participants With a Hematologic Response Using International Working Group (IWG) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Investigator

Any improvement

Hematologic Improvement-E (major)

Hematologic Improvement-E (minor)

Hematologic Improvement-P (major)

Hematologic Improvement-P (minor)

Hematologic Improvement-N (major)

Hematologic Improvement-N (minor)

Progression/relapse after HI

Percentage of Participants Showing Hematologic Improvement Using International Working Group (IWG Criteria for Hematologic Improvement Cheson 2000) Criteria for Myelodysplastic Syndrome (MDS) and Assessed by Sponsor

Baseline Dependent: On-Treatment Independent

Baseline Dependent; On-Treatment Dependent

The intent-to-treat (ITT) participants who were transfusion dependent

Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Dependent at Baseline

Baseline Independent; On-Treatment Independent

Baseline Independent; On-Treatment Dependent

The Intent to Treat (ITT) participants who were transfusion independent

Participants' Red Blood Cell (RBC) Transfusion Status for Participants Who Were Transfusion Independent at Baseline

Baseline (N = 44)

Overall Post-Baseline Average (N = 44)

overall Change from Baseline ( N = 44)

Cycle 1 ( N = 44)

Cycle 2

Cycle 3

Cycle 4

Cycle 5

Cycle 6

ITT Population- The intent-to-treat (ITT) population was defined as all enrolled participants.

Number of Red Blood Cell (RBC) Transfusions by Cycle

Baseline Dependent; On-Treatment Independent

The intent-to-treat (ITT) population who were transfusion dependent

Participants' Platelet Transfusion Status for Participants Who Were Transfusion Dependent at Baseline

Baseline Independent: On-Treatment Independent

The intent-to-treat (ITT) participants who were transfusion independent

Participants' Platelet Transfusion Status for Participants Who Were Transfusion Independent at Baseline

Baseline ( N = 44)

Overall Post-Baseline Average ( N= 44)

OverallChange from Baseline ( N = 44)

The intent-to-treat (ITT) population was defined as all enrolled participants.

Number of Platelet Transfusions by Cycle

Baseline

Overall Post Baseline

Overall Change from Baseline

Cycle 1

Number of Infections (Post-baseline Average) Requiring Intravenous Antibiotics, Anti-fungals, or Antivirals Per 28 Days

≥ 1 TEAE

≥ 1 NCI Grade 3 or 4 TEAE

≥ TEAE related to study drug

≥ 1 NCI Grade 3 or 4 TEAE related to study drug

≥ 1 serious TEAE

≥ 1 NCI CTC Grade 3 or 4 serious TEAE

≥ 1 serious TEAE related to study drug

TEAE leading to discontinuation of study drug

TEAE leading to study drug dose reduction

TEAE leading to study drug dose interruption

TEAE leading to dose reduction or interruption

TEAE leading to death

Safety Population included enrolled participants who received at least one dose of investigational product and had at least one postdose assessment

Number of Participants With Adverse Events (AE)

The PK population includes all participants with evaluable azacitidine plasma PK profile.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Natural Killer Cell (CYNK-001) Infusions in Adults With AML	NCT04310592	Leukemia Leukemia, Myelo... Leukemia, Myelo... Neoplasms by Hi... Neoplasms Immunosuppressi... Immunologic Fac... Physiological E... Alkylating Agen... Antimetabolites... Antiviral Agent... Analgesics, Non... Anti-infective ... Analgesics Peripheral Nerv... Hematologic Dis... Hematologic Neo... Leukemia in Rem... Relapsed Adult ... Refractory AML	CYNK-001	18 Years - 80 Years	Celularity Incorporated
Study of Azacitidine in Adult Taiwanese Subjects With Higher-Risk Myelodysplastic Syndromes (MDS)	NCT01201811	Myelodysplastic...	Azacitidine	18 Years -	Celgene
An Extended Feasibility Phase I/II Study of Methylenetetrahydrofolate (Arfolitixorin) and Pemetrexed Single Agent, Given as Neoadjuvant Treatment in Patients With Resectable Rectal Cancer	NCT01397305	Rectal Cancer	[6R] 5,10-methy... Pemetrexed	18 Years -	Isofol Medical AB
Phase I/II Study of KRN330 Plus Irinotecan in Patients With Metastatic Colorectal Cancer	NCT00838578	Colorectal Canc...	KRN330 Irinotecan	18 Years -	Kyowa Kirin Co., Ltd.
Natural Killer Cell (CYNK-001) Infusions in Adults With AML	NCT04310592	Leukemia Leukemia, Myelo... Leukemia, Myelo... Neoplasms by Hi... Neoplasms Immunosuppressi... Immunologic Fac... Physiological E... Alkylating Agen... Antimetabolites... Antiviral Agent... Analgesics, Non... Anti-infective ... Analgesics Peripheral Nerv... Hematologic Dis... Hematologic Neo... Leukemia in Rem... Relapsed Adult ... Refractory AML	CYNK-001	18 Years - 80 Years	Celularity Incorporated
Nab-paclitaxel and Gemcitabine vs Gemcitabine Alone as Adjuvant Therapy for Patients With Resected Pancreatic Cancer (the "Apact" Study)	NCT01964430	Pancreatic Neop... Digestive Syste... Neoplasms by Si... Neoplasms Endocrine Gland... Pancreatic Dise... Digestive Syste... Endocrine Syste... Gemcitabine Antimetabolites...	nab-Paclitaxel Gemcitabine	18 Years -	Celgene

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