Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Preleukemia

Myelodysplastic Syndromes

Cytopenia

Anemia

Syndrome

Neoplasms by Histologic Type

Hematologic Diseases

Precancerous Conditions

Bone Marrow Diseases

Hypoglycemic Agents

All Drugs and Chemicals

Metformin

2000 mg/day metformin for 12 months (1000 mg b.i.d.) with a slow up-titration six weeks prior to full dose treatment.

Kirsten Grønbæk, Professor, MD

Stine Ulrik Mikkelsen, MD

This is a single-arm pilot study of the feasibility and safety of metformin in patients with clonal cytopenia of undetermined significance (CCUS) or lower-risk myelodysplastic neoplasms (LR-MDS).

The research plan is divided into three work packages (WP):

WP0: Bone Marrow Adipose Tissue, Gut Microbiota, and Intestinal Permeability in CCUS and LR-MDS Patients.

The aim of WP0 is to investigate biological features which the investigators hypothesize to be of pathogenetic relevance for MDS progression and may be possible targets of metformin treatment. For this purpose, 20 elderly (≥60 years) healthy controls will be included for comparison to patients with CCUS or LR-MDS from WP1.

The primary objectives are to investigate 1) the abundance and properties of bone marrow adipose tissue (BMAT) and bone marrow (BM) adipocytes, and 2) the gut microbiota and intestinal permeability of patients with CCUS or LR-MDS compared to age-, sex- and body mass index (BMI)-matched healthy controls. Secondary objectives are to characterize DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns, and hormone and cytokine levels in BM plasma from healthy controls and patients with CCUS or LR-MDS.

WP1: Safety, feasibility, and mechanisms of action of metformin in patients with CCUS or LR-MDS.

In this WP up to 40 patients with CCUS or LR-MDS will receive metformin 2000 mg daily or their maximum tolerated dose (MTD) for 12 months. The aim of WP1 is to investigate safety of metformin and feasibility of the protocol in patients with CCUS or LR-MDS. Potential mechanisms of anti-leukemic action of metformin will also be explored in order to identify a suitable outcome measure and estimate standard deviation of the outcome measure. All in order to inform the design of a future phase 3 RCT of the efficacy of metformin in CCUS and LR-MDS patients. Endpoints of WP1 are specified in the corresponding section.

WP2: Safety and efficacy of metformin compared to placebo. The primary objective of WP2 is to compare safety and preliminary efficacy of metformin in patients with CCUS or LR-MDS to a cohort of patients with CCUS or LR-MDS receiving placebo in context of our EVI-2 randomized, controlled pilot study (NCT03999723).

Data and samples from approximately 50 historical controls will be included from the EVI-2 study in which participants were randomized to receive placebo or oral vitamin C supplement for 12 months.

Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS

STOP-LEUKEMIA: Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS

To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients.

To assess safety of metformin treatment in this off-label indication by median maximum tolerated dose and a description of any changes in individual medication doses.

To assess feasibility of the study protocol in terms of recruitment and refusal rates.

To assess feasibility of the study protocol in terms of rate of study completion.

To assess safety of metformin treatment in this off-label indication by the type, grade, and number of adverse events and serious adverse events including any suspected unexpected serious adverse reactions in the patients; drop-out rates; and a description of any changes in individual medication doses including median maximum tolerated dose.

To assess feasibility of the study protocol in terms of rate of adherence to protocol procedures (study medication and study procedures).

Change in variant allele frequency (ΔVAF) by next generation sequencing (NGS)

Change in patient-reported outcome measures (PROM), based on the validated European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).

Change in patient-reported outcome measures (PROM), based on the validated Short Form 36 Health Survey Questionnaire (SF-36).

Change in patient-reported outcome measures (PROM), based on the validated European Quality of Life Five Dimension questionnaire (EQ-5D).

Change in bone marrow adipose tissue (BMAT) content in bone marrow (BM) measured by MR spectroscopy

Change in bone mineral density (BMD) measured by DEXA scan measured in grams per cubic centimeter with resulting Z score.

Change in body composition measured by DEXA scan presented as whole body bone mass and soft tissue composition with ratios of lean mass, body fat, and bone mass.

Change in gut microbiota by 16S rRNA sequencing or whole genome sequencing of intestinal bacteria.

Change in small intestinal permeability by functional assessment by urine-lactulose/mannitol measurement and ion chromatography or by indirect assessment by qPCR and 16S rRNA sequencing of whole blood.

Change in DNA methylation and hydroxymethylation (5-mC and 5-hmC) patterns in hematopoietic cells by global 5-hmC/5-mC assessment and EPIC arrays.

Change in RNA expression in hematopoietic cells and BM adipocytes.

Change in protein profiles in hematopoietic cells and BM adipocytes by proteomics.

Rates of response and disease progression as according to the International Working Group (IWG) response criteria in myelodysplastic neoplasms.

Change in niche factors in bone marrow by ELISA.

Change in cytokine levels in peripheral blood and bone marrow plasma by ELISA.

Steno Diabetes Center Copenhagen

Zealand University Hospital

Van Andel Research Institute

Herlev Hospital

Technical University of Denmark

Region Hovedstadens Apotek

University of Copenhagen

Kirsten Grønbæk

Professor, MD, DMSc

Myeloproliferative Disorders

Myelodysplastic-Myeloproliferative Diseases

Chronic Myeloproliferative Disorders

Myelodysplastic/myeloproliferative Disease

Antineoplastic Agents

Decitabine

Decitabine and cedazuridine drug combination

Antimetabolites

Participants will take ASTX029 daily on days 1-21 of each 28-day cycle. ASTX029 should be taken with water on an empty stomach, no food 2 hours before and 2 hours after dose.

Participants will take ASTX029 daily on days 1-21 of each 28-day cycle. ASTX727 daily on days 1-5 of each 28-day cycle. Both ASTX029 and ASTX727 should be taken with water on an empty stomach, no food 2 hours before and 2 hours after dose.

ASTX029

ASTX727

Guillermo Montalban Bravo, MD

Guillermo Montalban Bravo

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of ASTX029 that can be given in combination with ASTX727 to participants who have RAS-mutant MDS or MDS/MPN. The goal of Part 2 of this clinical research study is to learn if the dose of ASTX029 found in Part 1 can help to control the disease when used in combination with ASTX727.

Primary Objectives:

* Phase 1 dose escalation: to determine safety, tolerability and MTD of ASTX029 in RAS mutant MDS, CMML and other MDS/MPN
* Phase 2 dose expansion: to determine the safety, tolerability and overall response rate (ORR) of ASTX727 in combination with ASTX029 in RAS mutant MDS, CMML and other MDS/MPN
* Incidence of AEs, MTD and changes in clinical laboratory values.
* Measures of efficacy: overall response rate (ORR) defined as sum of CR + complete cytogenetic remission + partial remission + marrow response + clinical benefit for MDS/MPN and defined as CR + mCR + PR + HI in MDS

Secondary Objectives:

* To determine other efficacy outcomes such as duration of response, leukemia-free survival (LFS), progression-free survival (PFS) and overall survival (OS).
* To evaluate differences in response and efficacy outcomes by MDS/MPN IWG response criteria based on disease subtypes and genomic features.
* Correlative studies
* To evaluate changes in clonal composition and VAF of identified mutations with therapy.
* To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of ASTX029 and the combination of ASTX727 with ASTX029 in patients with RAS mutant MDS, CMML and other MDS/MPN

Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms

Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0

M.D. Anderson Cancer Center

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Influenza, Human

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Sarcoma

Leukemia, Myelomonocytic, Chronic

Leukemia, Myelomonocytic, Juvenile

Sarcoma, Myeloid

Neoplasms, Connective and Soft Tissue

Chronic Disease

Disease Attributes

Myeloid Leukemia

Acute Myeloid Leukemia

Chronic Graft Versus Host Disease

Acute Non Lymphoblastic Leukemia

Soft Tissue Sarcoma

Acute Graft Versus Host Disease

Chronic Myelomonocytic Leukemia

Juvenile Myelomonocytic Leukemia

Myeloid Sarcoma

Anti-Infective Agents

Cytarabine

Fludarabine

Fludarabine phosphate

Busulfan

Thiotepa

Xianmin Song, MD

This study is a multicenter, single-arm, prospective phase II clinical trial that evaluates the efficacy and safety of an intensive conditioning regimen with thiotepa combined with busulfan, fludarabine, and cytarabine for allogeneic hematopoietic stem cell transplantation in the treatment of myeloid malignancies with extramedullary involvement. The conditioning regimen includes thiotepa at a dose of 5mg/kg/d from d -9 to d -8 (2 days), fludarabine at 30mg/m2/d from d -7 to d -3 (5 days), cytarabine at 1-1.5g/m2/d from d -7 to d -3 (5 days), and busulfan at 3.2mg/kg/d from d -5 to d -3 (3 days). Conditioning begins on day -9, and donor hematopoietic stem cell infusion is performed on day 0. All patients will undergo bone marrow examination on day 14 and day 28 post-transplant, followed by bone marrow examinations every 30 days within the first year after transplantation, and every 60 days within the second year after transplantation. If disease relapse is suspected during the follow-up period, bone marrow or extramedullary relapse site examinations will be conducted at any time. The primary study endpoints are the 1-year and 2-year progression-free survival (PFS) rates post-transplant. Secondary study endpoints include the incidence of acute graft-versus-host disease (GVHD) within 180 days post-transplant, cumulative relapse rates at 1 year and 2 years post-transplant, 1-year and 2-year overall survival (OS), graft-versus-host disease-free, relapse-free survival (GRFS), non-relapse mortality (NRM), cumulative incidence of chronic GVHD, and the incidence of Cytomegalovirus （CMV）and Epstein-Barr virus（EBV）reactivation within 1 year.

Intensive Conditioning With Thiotepa Combined With Bu/Flu/Ara-C in Allo-HSCT for Myeloid Malignancies With Extramedullary Involvement

Intensive Conditioning Regimen With Thiotepa Combined With Busulfan, Fludarabine and Cytarabine for Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Myeloid Malignancies With Extramedullary Involvement

1-year and 2-year progression-free survival (PFS) rates post-transplant

acute graft-versus-host disease (GVHD) within 180 days post-transplant

cumulative relapse rates (CIR) at 1 year and 2 years post-transplant

overall survival (OS) at 1 year and 2 years post-transplant

graft-versus-host disease-free, relapse-free survival (GRFS) at 2 years post-transplant

non-relapse mortality (NRM) at 2 years post-transplant

cumulative incidence of chronic GVHD at 2 years post-transplant

the incidence of CMV and EBV reactivation within 1 year

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Repurposing Metformin as a Leukemia-preventive Drug in CCUS and LR-MDS	NCT04741945	Preleukemia Myelodysplastic... Cytopenia Preleukemic Ane...	Metformin	18 Years -	Rigshospitalet, Denmark
Phase I/II Study of a Combination of Decitabine and Cedazuridine (ASTX727) and ASTX029, an ERK Inhibitor, for Patients With RAS Pathway Mutant Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms	NCT06284460	Pathway Mutant ... Myelodysplastic... Myeloproliferat...	ASTX029 ASTX727	18 Years -	M.D. Anderson Cancer Center
Intensive Conditioning With Thiotepa Combined With Bu/Flu/Ara-C in Allo-HSCT for Myeloid Malignancies With Extramedullary Involvement	NCT06111612	Acute Myeloid L... Myelodysplastic... Chronic Myelomo... Myeloid Sarcoma Extramedullary ...		18 Years - 55 Years	Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

Spots Global Cancer Trial Database for myelodysplastic neoplasm