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Venetoclax

Aldesleukin

Interleukin-2

polysaccharide-K

Analgesics, Non-Narcotic

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Anti-Retroviral Agents

Antiviral Agents

A maximum tolerated dose (MTD) will be established, and dosage will start at dose level 0. 5-10 participants at dose level 0 will complete:

* Baseline visit.
* Bone marrow biopsies: at screening visit #2, end of treatment, and at discretion of PI.
* Days -6 through -2: predetermined doses of standard-of-care lymphodepleting chemotherapy.
* Day 0: Predetermined dose of CIML NK cells 1x daily. Hospitalization for up to 3 to 4 weeks for CIML NK infusion.
* Days 0 through 12: Predetermined dose of IL-2 1x daily every other day for up to 7 doses.
* Day 7 through Day 21: Predetermined dose of Venetoclax 1 x daily.
* If ≤1 dose-limiting toxicities (DLTs) are observed, this dose will be the MTD, and 5 additional participants will be enrolled.
* Follow-up visits: Days 42, 60, 100 and months 6, 9, and 12.

De-escalation to dose level -1 will be conducted per protocol if DLTs occur in Cohort 1 dose Level 0. Participants will complete:

* Baseline visit.
* Bone marrow biopsies: at screening visit #2, end of treatment, and at discretion of PI.
* Days -6 through -2: predetermined doses of standard-of-care lymphodepleting chemotherapy.
* Day 0: Predetermined dose of CIML NK cells 1x daily. Hospitalization for up to 3 to 4 weeks for CIML NK infusion.
* Days 0 through 12: Predetermined dose of IL-2 1x daily every other day for up to 7 doses.
* Day 7 through Day 21: Predetermined dose of Venetoclax 1 x daily.
* Follow-up visits: Days 42, 60, 100 and months 6, 9, and 12.

Allogeneic, cytokine induced memory-like natural killer cells, via intravenous infusion per protocol.

Cytokine-Induced Memory-like Natural Killer Cells

Recombinant, human glycoprotein, single-use 22 MIU vials, via subcutaneous (under the skin) injection per protocol.

Selective inhibitor of BCL-2 protein, 10, 50, or 100 mg tablets, via orally per standard-of-care.

Maximilian Stahl, MD

The purpose of this research study is to test the safety and to explore the effectiveness of infusing cytokine- induced memory-like (CIML) natural killer (NK) cells in combination with Interleukin-2 (IL-2) and standard-of-care venetoclax as a treatment for Acute Myeloid Leukemia (AML).

Names of the study therapies involved in this study are:

* Lymphodepleting therapy with Fludarabine and Cyclophosphamide prior to CIML NK cell infusion
* CIML NK (a cellular therapy)
* IL-2 (a recombinant, human glycoprotein)
* Venetoclax (a selective inhibitor of BCL-2 protein)

This is an open-label, single center phase I trial combining Cytokine-induced memory-like natural killer (CIML NK) cell therapy with low-dose IL-2 and with venetoclax as consolidation therapy in acute myeloid leukemia (AML).

This is the first time that CIML NK cells in combination with venetoclax will be given to humans.

The U.S. Food and Drug Administration (FDA) has not approved CIML NK cells as a treatment for AML.

The U.S. FDA has not approved IL-2 for AML but it has been approved for other uses.

The U.S. FDA has approved venetoclax as a treatment option for AML.

The research study procedures include screening for eligibility, study treatment visits, electrocardiograms (ECGs), bone marrow biopsies, blood tests, and echocardiograms.

Participants will be followed for up to 1 year after the start of therapy.

It is expected that about 10 people will take part in this research study.

This research is funded by the Leukemia and Lymphoma Society.

One group of patients, two dose levels (arms)

CIML NK Cells With Venetoclax for AML

A Phase 1 Study of Cytokine-induced Memory-like (CIML) NK Cells With Venetoclax as Consolidation Therapy in AML

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

A DLT is defined as an adverse event (AE) that is related to the CIML NK cell infusion with venetoclax as consolidation therapy. Toxicities are to be assessed according to the CTCAEv5.

The MTD in the CIML NK cell infusion with venetoclax as consolidation therapy is determined by the number of participants who experience a DLT. See previous primary outcome measure for the DLT definition. If ≤1 DLTs are observed at dose-level 0, this dose will be the MTD. If ≥2 DLTs are observed in a cohort of 5 evaluable participants, then the MTD is considered exceeded. If this is dose level 0, dose de-escalation will take place, and 5 evaluable participants will be enrolled at dose level -1. If ≥2 DLTs are observed at dose level -1, accrual will stop.

MRD- rate is defined as the proportion pf participants achieving MRD. MRD clearance is evaluated by both highly sensitive flow cytometry and duplex sequencing on paired bone marrow samples.

Leukemia free survival based on the Kaplan-Meier method is defined as the the duration of time from study entry to documented disease progression (leukemic relapse or death from any cause) or death. 100-day LFS is calculated from the KM curve with standard error.

Leukemia free survival based on the Kaplan-Meier method is defined as the the duration of time from study entry to documented disease progression (leukemic relapse or death from any cause) or death. 1-year LFS is calculated from the KM curve with standard error.

100-day OS is a probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at date last known alive.

1-year OS is a probability estimated using the Kaplan-Meier method; OS is defined as the time from study entry to death, or censored at date last known alive.

Acute GVHD Rate is defined as the proportion of participants that has achieved acute GVHD. The criteria of acute GVHD grading is attached in protocol appendix c.

Chronic GVHD Rate is defined as the proportion of participants that has achieved chronic GVHD by NCI common toxicity criteria (appendix d).

The Leukemia and Lymphoma Society

Dana-Farber Cancer Institute

Principal Investigator

Cytarabine

Lenograstim

Cladribine

Gemtuzumab

Antimetabolites

Immunosuppressive Agents

Immunologic Factors

Adjuvants, Immunologic

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Cladribine, Cytarabine, and Granulocyte-Colony Stimulating Factor with Fractionated Gemtuzumab Ozogamicin (CLAG-GO)

Induction:

G-CSF 300 mcg subcutaneously daily on days 0-5.

Cladribine 5 mg/m2 in normal saline given intravenously over 2 hours daily on days 1-5.

Cytarabine 2000 mg/m2 in normal saline given intravenously over 4 hours daily on days 1-5.

Gemtuzumab ozogamicin 3 mg/m2 intravenously over 2 hours on days 1 and 4, prior to cladribine and cytarabine.

Consolidation:

If CRMRD-, CR or CRi is confirmed by bone marrow biopsy and aspirate after induction chemotherapy, patients may receive one cycle of consolidation chemotherapy (at the discretion of the investigator) with the same CLAG-GO regimen at the same doses given for induction. In addition, the investigator has the option of giving CLAG alone without GO if there is concern for increased risk of sinusoidal obstruction syndrome.

Patients who remain in CRMRD-, CR or CRi after consolidation chemotherapy may receive up to eight infusions of GO 2 mg/m2 approximately every 28 days.

Larissa Sanglard

Veronica Kflu

Vu H Duong, MD

Vu H. Duong, MD, MS

This study involves evaluating a combination of chemotherapy drugs known as "CLAG-GO" \[cladribine, cytarabine, granulocyte-colony stimulating factor (G-CSF) and gemtuzumab ozogamicin (GO)\] in the treatment of acute myeloid leukemia (AML) that has not responded well to standard therapy or has returned after an initial remission (relapsed). The trial will be conducted at the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC). Potential participants will go through a screening period to see if they are eligible to join the study. If eligible, participants will be hospitalized for 4-5 weeks to receive study treatment with CLAG-GO, called induction chemotherapy. If tests show that the cancer is in remission after induction chemotherapy, participants may undergo further chemotherapy (known as consolidation) or may proceed with bone marrow/stem cell transplantation. Patients who receive consolidation chemotherapy and remain in remission may have up to 8 cycles of outpatient maintenance therapy. A cycle lasts about 28 days. All participants will be monitored carefully for both side effects and to see if the study treatment is working. Lab tests and exams will be conducted throughout the entire study. In addition, special studies will be done at various time points to try to understand better how the drugs work and which patients are likely to respond best.

This is a single-arm, two-stage phase II trial of cladribine, cytarabine, granulocyte colony stimulating factor and gemtuzumab ozogamicin (CLAG-GO) in adult patients with acute myeloid leukemia (AML) who are either have persistent disease after initial induction chemotherapy or are in first relapse, with early stopping for unacceptable toxicity. The trial will be conducted at the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC), with a target enrollment of 39 patients if the trial proceeds to the second stage. Eligible patients will receive induction chemotherapy with CLAG-GO at the doses detailed below. In the first stage of the trial, a sequential boundary is used to monitor induction mortality and halt accrual if this mortality is significantly above 10%. If more than 6 responses are seen in the initial 19 patients, 20 additional patients will be enrolled in the 2nd stage. Responders may proceed to allogeneic hematopoietic stem cell transplantation (alloHSCT) at any time after induction, and these patients will be monitored for at least 30 days post-transplantation for veno-occlusive disease. Responding patients will also have the option of having a single cycle of consolidation therapy using the same CLAG-GO regimen, followed by maintenance with GO monotherapy for up to 8 additional cycles. Responses will be categorized according to the European LeukemiaNet (ELN) response criteria for AML. Assessment of measureable residual disease (MRD) will be conducted with bone marrow aspirate samples and changes in immunophenotype will be evaluated. In addition, single nucleotide polymorphism (SNP) analysis and sialylation status of CD33, along with sialidase activity of myeloblasts will be evaluated and correlated with responses and survival times. Safety and toxicity will be evaluated continuously, and event-free survival, and overall survival as well as the proportion of patients proceeding to receive alloHSCT will be estimated.

CLAG-GO for Patients With Persistent, Relapsed or Refractory AML

A Phase II Study of Cladribine, Cytarabine, and Granulocyte-Colony Stimulating Factor With Fractionated Gemtuzumab Ozogamicin (CLAG-GO) for the Treatment of Patients With Persistent, Relapsed or Refractory Acute Myeloid Leukemia

Individual results will not be shared with participants nor their primary care physician. IPD (Individual Patient Data) would only be shared with the applicable regulatory parties in the event of an audit or for monitoring purposes. All HIPAA laws will be followed. We will not be sharing IPD in publications nor with other researchers not specified in the protocol. Aggregate findings will be reported in scholarly journals.

Responses will be judged according to modified European LeukemiaNet recommendations published in 2017. Patients who achieve either 1) complete remission without minimal residual disease, 2) complete remission, or 3) complete remission with incomplete hematologic recovery will be considered responders

All adverse events will be graded according to CTCAE version 5.

This is determined by flow cytometry completed through Hematologics, Inc.

Time to relapse is measured from the date of confirmed remission until the date of confirmed relapse. Time to death (survival) is measured from the date of enrollment until the date of death, assessed up to 2 years.

Hematologics, Inc

University of Maryland, Baltimore

Assistant Professor of Medicine

Anti-Inflammatory Agents

Antirheumatic Agents

Dermatologic Agents

Reproductive Control Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Amino Acids

Etoposide

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Fludarabine

Fludarabine phosphate

Methotrexate

Prednisolone

Etoposide phosphate

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

Quizartinib

Enzyme Inhibitors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Tyrosine

All participants will receive re-induction therapy that includes fludarabine and cytarabine in combination with experimental drug quizartinib. For prophylaxis, IT chemotherapy with cytarabine, methotrexate and prednisolone/hydrocortisone will be given prior to or between re-induction cycles. After completing re-induction therapy, eligible participants may also receive optional consolidation chemotherapy which includes cytarabine, etoposide and quizartinib, if HSCT is not available immediately. After completing re-induction or HSCT successfully, eligible participants can go on to receive continuation therapy with quizartinib.

Administered orally once daily starting on Day 6 and continuing through Day 28;

Optional low intensity consolidation with chemotherapy:

Administered orally once daily starting on Day 1 and continuing through Day 28

30 mg/m\^2/day IV infusion given over 30 minutes on Days 1 through 5 (administered based on body weight)

2000 mg/m\^2/day IV infusion given over 3 hours on Days 1 through 5 (begin 4 hours after the start of fludarabine) (administered in accordance with standard of care);

Optional high intensity consolidation with chemotherapy and quizartinib:

500 mg/m\^2/day as a continuous 96-hour IV infusion on Days 1 through 4;

Optional low intensity consolidation with chemotherapy:

75 mg/m\^2/day as once daily subcutaneous or IV on Days 1 through 4 and Days 15 through 18

IT cytarabine, methotrexate, and either prednisolone or hydrocortisone; doses are based on the participant's age and standard practice at each site

Intrathecal (IT) triple chemotherapy prophylaxis

Optional high intensity consolidation with chemotherapy and quizartinib:

100 mg/m\^2/dose once daily as an IV infusion over 3 hours on Days 1 through 5

Daiichi Sankyo Contact for Clinical Information

Study Coordinator

Site Coordinator

Global Clinical Leader

Quizartinib is an experimental drug. It is not approved for regular use. It can only be used in medical research.

Children or young adults with a certain kind of blood cancer (FLT3-ITD AML) might be able to join this study if it has come back after remission or is not responding to treatment.

The medical condition being investigated is relapsed or refractory AML in participants aged ≥1 month to ≤21 years with Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) mutations (FLT3-ITD AML), following failure of front-line intensive chemotherapy.

The trial will be conducted in multiple phases. An independent data monitoring committee (DMC) will protect the rights, safety, and well-being of participants by monitoring the progress and results. The DMC will comprise qualified physicians and scientists who are not Investigators in the study and not otherwise directly associated with the Sponsor and will be convened at the end of Phase 1.

A. Dose Escalation/De-escalation Phase:

Number of participants is determined by age group. Participants will be enrolled by dose-level to determine the recommended Phase 2 dose (RP2D) of quizartinib for pediatric participants that provides similar exposure to adult patients treated at the target adult dose of 60 mg orally once daily.

B. Dose-Expansion Phase:

Participants will receive the RP2D of quizartinib for their respective age group.

During both dose escalation and dose expansion phases, participants will receive:

Re-Induction Therapy

* Intrathecal (IT) triple chemotherapy prophylaxis prior to and between cycles
* In re-induction Cycles 1 and 2, fludarabine/cytarabine (FLA) followed by quizartinib as a single agent

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Period:

After re-induction therapy, participants will be evaluated for eligibility to undergo allogeneic hematopoietic stem cell transplant (HSCT). Eligible participants may receive a single 28-day cycle of consolidation therapy (standard of care chemotherapy with or without quizartinib) if an allogeneic HSCT is not available immediately. The options for consolidation therapy are as follows:

* High intensity chemotherapy with quizartinib, or
* Low intensity chemotherapy alone, or
* Low intensity therapy with quizartinib as a single agent

Continuation Therapy:

Participants in remission after HSCT, or who are not eligible for HSCT but achieve at least a partial remission (PR) after re-induction, will receive up to 12 continuous 28-day cycles of quizartinib continuation therapy at the same dose received during re-induction in the dose expansion phase.

Long-term Follow-up:

The long-term follow-up phase begins upon completion of 12 cycles of quizartinib Continuation Therapy or permanent discontinuation of quizartinib at any time. After completion of the 30-day safety follow-up visit, subsequent visits will occur at the following frequencies to assess survival and anti-leukemic treatments:

* every 3 months for the first 2 years, and then
* once a year thereafter until the last participant enrolled has been followed for three years from the date of enrollment

A single group will progress through a multiple phase study design as described in the detailed description.

Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood

A Phase 1/2, Multicenter, Dose-Escalating Study To Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy Of Quizartinib Administered in Combination With Re-Induction Chemotherapy, and as a Single-Agent Continuation Therapy, in Pediatric Relapsed/Refractory AML Subjects Aged 1 Month to <18 Years (and Young Adults Aged up to 21 Years) With FLT3-ITD Mutations

De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

CRc rate is defined as percentage of participants with best response of complete remission (CR) or CR with incomplete hematological recovery (CRi) after completion of up to 2 re-induction cycles

CR rate is defined as the percentage of participants achieving CR after completion of up to 2 re-induction cycles

CRi rate is defined as the percentage of participants achieving CRi after completion of up to 2 re-induction cycles

Duration of CR is defined as the time from the first documented CR until documented relapse

Duration of CRi is defined as the time from the first documented CRi until documented relapse

Duration of CRc is defined as the time from the first documented CR or CRi until documented relapse

CR rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CR after completion of re-induction Cycle 1

CRi rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving a CRi after completion of re-induction Cycle 1

CRc rate after completion of re-induction Cycle 1 is defined as the percentage of participants achieving CRc after completion of re-induction Cycle 1

Time to relapse is defined as the time from the first documented response (CR, CRi) until documented relapse

Rate of relapse is defined as the percentage of participants who achieved CRc at the end of re-induction and had relapsed at 3 categorical time points Categories: 1 year, 2 years, 3 years

Cumulative incidence of relapse at the end of the study is defined as the percentage of participants who achieved CRc at the end of re-induction and relapsed by the end of the study

Overall survival is defined as the time from the start of re-induction therapy until death from any cause

Event-free survival is defined as the time from the start of re-induction therapy until the earliest date of the following:

* Refractory disease at the end of re-induction
* Relapse after CR or CRi
* Death from any cause at any time during the study

MRD is defined as the presence of leukemic cells in the bone marrow detected above a predefined cut-off level by a validated assay in participants who achieved a CR or CRi

Categories: at screening, at re-induction cycle 1, at re-induction cycle 2, at time of relapse

Acceptability is assessed by palatability using a 5-point hedonic scale (from "Super bad" to "Super good") for participants who are developmentally able to answer. If unable, the caregiver provides information in a free text field stating whether the participant spit it out, may not have liked the flavor, etc.

Innovative Therapies For Children with Cancer Consortium

Children's Oncology Group

Daiichi Sankyo

The relapsed/refractory AML patients will receive allogenic CD123-Targeted CAR-NK cells infusion (1x10\^9, 1-2x10\^7/kg) after precondition chemotherapy.

CD123-CAR-NK is an allogenic CD123-Targeted chimeric antigen receptor NK-cell (CAR-NK) therapy.

CD123-CAR-NK cells

Liangding Hu, Doctor

Yao Sun, Doctor

Liangding Hu, Ph.D

Yao Sun, Ph.D

Liangding Hu, Docotr

The CD123-Targeted CAR-NK cell therapy is a new treatment that is being investigated for treatment of acute myeloid leukemia (AML). The purpose of this study is to evaluate the safety of CD123-CAR NK cells given to these patients.

This is a study of allogenic CD123-CAR NK cells. The relapsed/refractory AML patients will receive FC (F, Fludarabine, C, Cyclophosphamide) chemotherapy followed by infusion of CD123-CAR-NK cells. No graft-versus-host disease (GVHD) prevention will be conducted before or after infusion. Dose-limiting toxicity, incidence of adverse events, disease response and PK/PD will be detected post-infusion.

Allogenic CD123-CAR-NK Cells in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia

Early Clinical Study of Allogenic CD123-CAR-NK Cells (JD023 Injection) in the Treatment of Refractory or Relapsed CD123-positive Acute Myeloid Leukemia

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CIML NK Cells With Venetoclax for AML	NCT06152809	Acute Myeloid L... Acute Myeloid L... Leukemia Leukemia, Myelo...	Cytokine-Induce... Interleukin-2 Venetoclax	18 Years -	Dana-Farber Cancer Institute
CLAG-GO for Patients With Persistent, Relapsed or Refractory AML	NCT04050280	Acute Myeloid L... Acute Myeloid L... Acute Myeloid L...	Cladribine, Cyt...	18 Years -	University of Maryland, Baltimore
Safety and Efficacy of Quizartinib in Children and Young Adults With Acute Myeloid Leukemia (AML), a Cancer of the Blood	NCT03793478	Acute Myeloid L...	Quizartinib Fludarabine Cytarabine Intrathecal (IT... Etoposide	1 Month - 21 Years	Daiichi Sankyo
Allogenic CD123-CAR-NK Cells in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia	NCT05574608	Acute Myeloid L... Acute Myeloid L...	CD123-CAR-NK ce...	18 Years -	Affiliated Hospital to Academy of Military Medical Sciences
Allogenic CD123-CAR-NK Cells in the Treatment of Refractory/Relapsed Acute Myeloid Leukemia	NCT05574608	Acute Myeloid L... Acute Myeloid L...	CD123-CAR-NK ce...	18 Years -	Affiliated Hospital to Academy of Military Medical Sciences

Spots Global Cancer Trial Database for acute myeloid leukemia recurrent