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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

Antirheumatic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Anti-HIV Agents

Anti-Retroviral Agents

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. NK cells administration will not be followed by sc IL-2. N=3.

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 3.0 x 10\^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=3

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 6.0 x 10\^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=6

Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood

UCB-NK cells

IL-2

P.M.M. van Hauten, MSc

H. Dolstra, Ass. Prof.

N.P.M. Schaap

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia (AML) exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This is a prospective phase I/IIa study. The first phase is a IL-2 dose-escalating safety study in twelve patients. The second phase of the study is designed as a Simon's optimal two-stage single-arm phase IIa study, comprising seventeen patients. Prior to NK cell infusion, all patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. On day 0, all patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic umbilical cord blood-derived NK cells (UCB-NK cells). These cells are generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit.

In phase I of the study patients will receive UCB-NK cells without subcutaneous (SC) IL-2, with lower dose SC IL-2 or with higher dose SC IL-2 (n=3 per treatment group, n=6 in the highest tolerable dose). After establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase IIa of the study, with ten patients in the first stage (including the six patients from phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional seven patients in the second stage.

The study is divided in two phases. In phase I, we will determine the safety of our UCB-NK cell product with or without sc IL-2, following a non-myeloablative immunosuppressive conditioning regimen in patients with AML. Three patients will receive NK cells without IL-2. If no dose limiting toxicities occur another three patients will receiving NK cells with a low dose IL-2, and if safe, another six patients will receive NK cells with a higher dose IL-2.

The primary objective of phase IIa of the study is to evaluate the effect of UCB-NK cell adoptive immunotherapy in combination with SC IL-2 following a non-myeloablative immunosuppressive conditioning regime on disease activity in patients with AML. Therefore 17 patients will be evaluated using a Simon's optimal two-stage single-arm study design, with 10 patients in the first stage and an additional 7 patients in the second stage. These patients will receive NK cells with the highest tolerable dose IL-2, established after phase I.

Natural Killer-cell Therapy for Acute Myeloid Leukemia

Infusion of ex Vivo-generated Allogeneic Natural Killer Cells in Combination With Subcutaneous IL-2 in Patients With Acute Myeloid Leukemia: a Phase I/IIa Study

Patients will be evaluated intensively using the CTCAE toxicity criteria and graft versus host disease (GvHD) classification criteria, defining dose limiting toxicities (DLTs): 1. Any treatment-emergent non-hematologic grade 3 toxicity lasting \>72 hours, except for transient constitutional symptoms, diarrhea, fatigue or skin rash not requiring systemic steroid therapy. 2. Acute GvHD \>grade 2 within 6 weeks of the first IL-2 dose. If in any of the three patients of each individual cohort of the phase I study a DLT occurs, the cohort will be extended to 6 patients. If 2 patients experience DLT within a cohort of 3 or 6 patients the study will be stopped in case the patients were only receiving NK cells or the study will be continued without IL-2 or the lower dose of IL-2 in case the patients were receiving NK cells in combination with IL-2. Serious, life threatening adverse events or grade 4 toxicity will be a reason to terminate the study or continue without IL-2 cytokine support.

The primary objective of phase IIa of the study is to evaluate the effect of UCB-NK cell adoptive immunotherapy in combination with SC IL-2 following a non-myeloablative immunosuppressive conditioning regime on disease activity in patients with AML. At day 28 a bone marrow biopsy will be performed to evaluate % blasts or % minimal residual disease (MRD) in the bone marrow. A complete remission is defined as BM blasts \<5%; marrow should not be merely 'aplastic': at least 200 cells should be enumerated or cellularity should be at least 10%. MRD will be evaluated by flow cytometry (leukemia associated phenotypes (LAPs)) and/or molecular quantification of patient specific mutations (PCR).

For phase IIa of the study the clinical evaluation data (% blasts and % MRD positivity) will be translated in a clinical response (stable disease, partial remission, complete remission) and quantitative presented.

We will determine the percentage and absolute number of donor-derived NK cells in peripheral blood and bone marrow after infusion using flow cytometry and DNA chimerism analysis. A positive expansion rate of the infused NK cells requires an absolute number of ≥100 donor-derived NK cells per μl blood at day +7 and/or +14.

NK cells from peripheral blood and bone marrow will be obtained. These cells will be stimulated in vitro for 4 hours and subsequently the degranulation marker CD107a and immunoregulatory marker IFNy will be measured by flow cytometry. These results can be compared between patients that did receive IL-2 or did not.

This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.

Dutch Cancer Society

Radboud University Medical Center

Decitabine

Idarubicin

Relapsed or refractroy acute myeloid leukemia patients reveive chidamide, decitabine combined with priming IAG regimen treatment.

Chidamide 30mg orally twice every week for 2 weeks on days 1, 4, 8, 11, decitabine 20mg/m2 intravenously daily for 5 days (d1-d5) and IAG regimen (cytarabine, 10 mg/m2 subcutaneously every 12 h on days 4-17; idarubicin, 5mg intravenously every other day on days 4, 6, 8, 10, 12, 14; and concurrent granulocyte colony-stimulating factor, 200mg/m2/day subcutaneously daily on days 3-17.

CDIAG regimen

This study is to investigate the therapeutic efficacy and side effect of chidamide, decitabine combined with priming IAG regimen for relapsed or refractroy acute myeloid leukemia

CDIAG Regimen in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Chidamide, Decitabine Combined With Priming IAG Regimen in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Remission rate achieved after one-two couses induction therapy by CDIAG regimen

It is measured from the date of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive.

Record of adverse events in hematological system during and after CDIAG regimen induction

Record of adverse events in other organs or systmes during and after CDIAG regimen induction

Jining Medical University

The First Affiliated Hospital of Soochow University

accociate professor

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Patients will be enrolled sequentially in cohorts and treated at different dose levels of F16IL2 and a fixed dose of cytarabine.

All patients first receive an initial run-in dose of 30 Mio IU of F16IL2 on day 1 and escalating doses of F16IL2 on day 1, 8, 15 and 22.

Treatment will be repeated every 28 days for up to three cycles.

F16IL2

Patients will be treated with cytarabine (5 mg twice daily s.c. for 10 days). Treatment will be repeated every 28 days for up to three cycles.

cytarabine

Phase I, open label, non-randomized, multicenter, prospective dose escalation study of F16IL2 in combination with very low-dose cytarabine in subjects with acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT).

Phase I, open label, non-randomized, multicenter, prospective dose escalation study of F16IL2 in combination with very low-dose cytarabine in subjects with acute myeloid leukemia relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT).

The aim of the study is to determine a recommended dose for F16IL2 in AML relapse after alloHSCT and investigating the toxicity of the combination regimen.

Patients will be enrolled sequentially in cohorts and treated at different dose levels of F16IL2 and a fixed dose of cytarabine. All patients first receive an initial run-in dose of 30 Mio IU of F16IL2 on day 1 and escalating doses of F16IL2 on day 1, 8, 15 and 22. Patients will be treated with cytarabine (5 mg twice daily s.c. for 10 days). The following F16IL2 administration will be at the dose of the respective cohort (days 8, 15 and 22).

The RD will be defined following a traditional 3+3 design. The dose escalation will continue until the MTD is found, that is until at least two patients among a cohort of three to six patients experience a dose limiting toxicity (DLT) (i.e., \>33 % of patients with a DLT). The RD is defined as the dose level just below the MTD level. If the MTD is not found at cohort 5 the RD for this study will be considered equal to the cohort 5 dosage.

A Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Very Low-dose Cytarabine in Patients With AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

A Dose-finding Phase I Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Very Low-dose Cytarabine in Patients With AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation

To assess the safety, including maximum tolerated dose (MTD), recommended dose (RD) and dose limiting toxicity (DLT) of F16IL2 combined with very low dose cytarabine, Adverse Events (AEs) assessment based on CTCAE v.4.03 will be considered.

The rate of patients with chronic GvHD will be summarized according to the following Chronic GVHD Staging:

* mild: involvement of 1 to 2 organs/sites (except for lung) with a maximum score of 1;
* moderate: involvement of at least 1 organ/site with a score of 2 or ≥ 3 organs/sites with a score of 1 or lung involvement with a score of 1;
* severe: any organ/site with a score of 3 or lung involvement with a score of 2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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
Natural Killer-cell Therapy for Acute Myeloid Leukemia	NCT04347616	Acute Myeloid L... Acute Myeloid L...	UCB-NK cells IL-2	18 Years -	Radboud University Medical Center
CDIAG Regimen in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia	NCT03985007	Acute Myeloid L...	CDIAG regimen	18 Years - 70 Years	The First Affiliated Hospital of Soochow University
Natural Killer-cell Therapy for Acute Myeloid Leukemia	NCT04347616	Acute Myeloid L... Acute Myeloid L...	UCB-NK cells IL-2	18 Years -	Radboud University Medical Center
A Study of the Tumor-targeting Human F16IL2 Monoclonal Antibody-cytokine Fusion Protein in Combination With Very Low-dose Cytarabine in Patients With AML Relapse After Allogeneic Hematopoietic Stem Cell Transplantation	NCT02957032	Acute Myeloid L...	F16IL2 cytarabine	18 Years -	Philogen S.p.A.

Spots Global Cancer Trial Database for acute myeloid leukemia, relapsed, adult