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Myelodysplastic/myeloproliferative Disease

Chromosome 5q Deletion

Escalating doses of pacritinib (cohort 1)

Low-risk cohort (cohort 2): Initiated on pacritinib 100 mg BID. After three cycles, pacritinib dose escalated to 200 mg BID, the adult phase II recommended dose, if not in complete remission.High-risk cohort (cohort 3): Initiated on pacritnib 200 mg BID, the adult phase II recommended dose.

Pacritinib will be administered orally on a continuous basis for 28 day cycles without a rest period between cycles. Dose assigned by dose level/phase.

pacritinib

Rosandra N Kaplan, M.D.

National Cancer Institute Referral Office

Background:

Myelodysplastic syndrome (MDS) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are blood disorders that can cause serious complications in children and adults. MDS and MDS/MPN can also progress to acute myeloid leukemia. Treatments for these disorders are risky and not always effective. Better treatments are needed.

Objective:

To test a study drug (pacritinib) in adults and children with MDS or MDS/MPN.

Eligibility:

Children (aged 12 to 17 years) and adults (aged 18 years and older) with MDS or MDS/MPN.

Design:

Participants will be screened. They will have a physical exam with blood tests. They will have tests of their heart function. They may have a bone marrow biopsy: An area over the hip will be numbed; a needle will be inserted to remove a sample of soft tissue from inside the hipbone.

Pacritinib is a capsule taken by mouth. All participants will take the study drug 2 times a day, every day, in 28-day cycles. They will write down the date and time they take each capsule. Doctors will assign varying dosages of the drug to different participants.

Participants will have clinic visits each week during cycle 1; every 2 weeks during cycle 2; and gradually increasing to every 3 months after cycle 13. Treatment will continue for up to 8 years.

Bone marrow biopsies, heart tests, and other tests will be repeated at intervals throughout the study. Participants will also fill out questionnaires about their quality of life, the symptoms of their disease, and other topics.

Background:

-Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by peripheral cytopenia, ineffective and dysplastic hematopoiesis, and increased risk of progression to acute myeloid leukemia (AML).

-The significant genetic heterogeneity of MDS contributes to the challenges in treatment.

* Targeting the bone marrow microenvironment (BMME) may allow for treatments that bypass the genetic complexity of MDS.
* MDS studies support a role for changes within the BMME and support the emerging concept that interdependency between the MDS clone and diverse cell populations in the BMME contributes to disease pathophysiology.
* CSF1R is a receptor tyrosine kinase involved in myeloid-lineage cell survival, proliferation, and differentiation.
* The presence of CSF1R-expressing cells in the AML BMME has been shown with evidence that these cells support leukemic cells through cytokine secretion, and the ligand for CSF1R, CSF1, has been shown to be increased in peripheral blood and bone marrow of some patients with MDS, together supporting CSF1R inhibition as a plausible therapeutic target in myeloid malignancies.
* IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in patients with MDS, supporting IRAK1 inhibition as a plausible therapeutic target in MDS.
* A small percentage of patients with MDS have activating mutations in JAK2 or FLT3, and in these patients, JAK2 or FLT3 inhibition may allow for direct anti-tumor effect.
* Pacritinib is a multi-kinase inhibitor of CSF1R, IRAK1, JAK2, and FLT3, all of which are of therapeutic interest in MDS as discussed above and has been overall well tolerated in clinical trials and has shown efficacy in the treatment of myelofibrosis.

Objectives:

-Phase I:

* To determine the safety and confirm the recommended phase II dose of pacritinib in participants who are 12-17 years of age with MDS or MDS/MPN (myelodysplastic/myeloproliferative neoplasms).

  -Phase II:
* To determine the efficacy of pacritinib in participants who are \>= 18 years of age with MDS or MDS/MPN, as measured by overall response rate, separately by risk-based cohort.

Eligibility:

-Participants with MDS or MDS/MPN, including therapy-related MDS or MDS/MPN, and MDS or MDS/MPN with germline predisposition, as defined according to the 2016 WHO criteria, 2022 WHO criteria, or 2022 International Consensus Classification

* Age 12-17 years for phase I and age \>= 18 years for phase II
* Participants \>= 18 years of age with higher-risk MDS (HR-MDS) must have resistance to hypomethylating agents as defined as failure to show improvement after at least 4 cycles of treatment (primary resistance) or relapse in participants with initial response to long-term treatment (secondary resistance) OR have intolerance to hypomethylating agents OR have a contraindication to hypomethylating agents
* Participants \>= 18 years of age with LR-MDS must be refractory to OR ineligible to receive standard of care therapies (i.e., erythropoietin-stimulating agents, lenalidomide, luspatercept), and present with one of the following characteristics:

  * Severe neutropenia defined by absolute neutrophils count \<=0.5x10\^9/L without the use of granulocyte colony-stimulating factors
  * Symptomatic anemia defined by hemoglobin 16-week average \<10 g/dL and symptoms that may include fatigue, weakness, reduced exercise tolerance, dyspnea on exertion, palpitations, (orthostatic) hypotension, near syncope and restless legs
  * Thrombocytopenia defined as platelets \<20x10\^9/L or platelets \<50x10\^9/L and a history of clinically relevant non-major or major bleeding according to the ISTH classification
* Participants 12-17 years of age with MDS: must be relapsed/refractory OR ineligible to receive immunosuppressive therapy and hematopoietic stem cell transplantation

  * Ineligibility to receive hematopoietic stem cell transplantation will include participants who are not anticipated to be candidates to receive transplantation within the next 3 months due to medical comorbidities, lack of appropriate donor, or logistical barriers

to transplant

* Participants 12-17 years of age must weigh \>= 35 kg
* Participants with MDS/MPN must be relapsed/refractory (failed a minimum of 1 standard of care therapy) OR ineligible to receive standard of care OR without known life-prolonging therapy options OR have a diagnosis for which no known standard of care exists

Design:

-This study consists of two phases, which will enroll concurrently:

--Phase I: 3 plus 3 dose-escalation of pacritinib in participants 12-17 years of age with two planned dose levels per group: Group 1 = weight 35 kg to \< 50 kg \[DL1 = 100 mg BID, DL2 = 200 mg BID\], Group 2 = weight \>= 50 kg \[DL1 = alternating days of 100 mg

BID and 200 mg BID, DL2 = 200 mg BID\]

--Phase II: activity evaluation of pacritinib in participants \>= 18 years of age, separated into two cohorts:

* Low risk cohort: Initiate on pacritinib 100 mg BID, after completion of 3 cycles, participants will undergo dose escalation to 200 mg BID, the adult phase II recommended dose, unless they meet criteria for complete remission, in which case lower dose pacritinib will be continued without escalation
* High risk cohort: Initiate on pacritinib 200 mg BID, the adult phase II recommended dose

  * In all participants, pacritinib will be administered orally on a continuous basis for cycles of 28 days.

Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

Phase I/II Trial of Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms

.All IPD recorded in the medical record will be shared with intramural investigators upon request. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Determined by the number of participants with dose-limiting toxicities (DLTs) reported at each dose level studied

Clinical responses evaluated by CBC and bone marrow biopsy/aspirate reported separately by cohort, with a separate 95% confidence interval for each cohort

AUC, half-life, and steady state concentration of pactritinib evaluated separately by dose level using descriptive statistics

Grades and types of toxicity noted for the agent at each dose level, separately by cohort

National Cancer Institute (NCI)

Antineoplastic Agents

All Drugs and Chemicals

Lenalidomide

Immunologic Factors

Angiogenesis Inhibitors

Growth Inhibitors

Patients who were prescribed Revlimid from 31October 2008 to present.

lenalidomide

Sante Cundari, PhD, MSc

The purpose of this study is to collect clinical and laboratory data for patients affected by intermediate 1 and low risk Myelodysplastic Syndrome (MDS) associated by deletion 5q who were prescribed Revlimid from 31October 2008 to present. Revlimid is available in Italy for these patients since October 2008 based on a local disposition of the Italian Drug Agency (AIFA) issued according to a National law named 648/96.

There will be retrospective collection and integration of clinical laboratory data as well as prospective data collection on the same patients.

MORE - Monitoring Revlimid - Collecting of Patient Information From Myelodysplastic Syndrome (MDS) Italian National Registry

Observational, Non-interventional, Multicenter Study Aimed at Collecting Retrospective/Prospective 648/96 Italian Registry Data Related to Lenalidomide (Revlimid®) Prescription to Patients With Myelodysplastic Syndromes

Celgene

Diseases and Abnormalities at or Before Birth

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Congenital Abnormalities

Chromosome Aberrations

Chromosome Disorders

Genetic Diseases, Inborn

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

AML With Myelodysplasia-related Features

description of MDS pzatient cohort

Nathalie Douet-Guilbert, MD, PhD

Marie-Bérengère Troadec, PhD

Nathalie DOUET-GUILBERT

Nathalie Douet-Guilbert, MD,PhD

Myelodysplastic syndromes (MDS) are chronic myeloid hemopathies characterized by ineffective hematopoiesis (with peripheral cytopenias) and which contrast with a marrow of normal richness. MDS is considered one of the four most common blood diseases. The incidence is estimated at 4,059 cases / year in 2012 with an average age of 78 years in men and 81 years in women (INCA report, Cancers in France in 2015). The incidence increases with lengthening of the lifespan. The main risk of MDS is transformation to acute leukemia in 30 to 40% of cases. Treatment options depend on clinical, hematologic and chromosomal abnormalities. The prognosis is considered to be at low or high risk of developing acute leukemia. This distinction will therefore have an impact on the therapeutic solution (s). MDS exhibit clinical, morphological and genetic heterogeneity. It is therefore necessary to form subgroups of patients to better understand the physiopathogenesis of this pathology. The constitution of a biocollection will make it possible to search for clinical and biological prognostic markers in order to identify patients progressing to acute myeloid leukemia.

The objective of the biocollection is to respond to 3 scientific projects in MDS :

Project 1: splicing anomalies in MDS with SF3B1 mutations : About 95% of the coding genes in humans are subjected to alternative splicing, a complex, highly regulated mechanism that diversifies the proteome by defining multiple proteins from a single gene. Deregulation of splicing is observed in many cancers and hemopathies (review Yoshida et al., 2014), especially in myelodysplastic syndromes More than half of MDS patients present an acquired mutation in a gene involved in the splicing of pre -RNA messengers. The SF3B1 gene (splice factor 3B subunit 1), which encodes a protein involved in the recognition of 3 'splice sites is the most frequently mutated gene in SMDs, at a frequency of 20-28% MDS, and up to 85% of myelodysplastic syndromes with crowned sideroblasts (Yoshida et al., 2011, Papaemmanuil et al., 2011). The functional consequences of the splicing abnormalities thus generated on the pathophysiology of MDS are far from clear. The transcriptome analyzes (by RNA-seq) carried out recently in various acquired pathologies that the most frequent variants of the SF3B1 gene lead to the formation of aberrant transcripts by the use of a 3 ' cryptic splicing site. The investigators seek to study the functional implications of SF3B1 mutations found in MDS patients in particular on the formation of sideroblasts in the crown. The investigators want to identify, by RNAseq, the aberrant junctions specifically expressed in the cells of MDS patients with mutated SF3B1, and which would affect transcripts of genes involved in iron metabolism or its regulation. For this, the investigators will use the cells obtained from the marrow of SMD SF3B1WT patients versus SF3B1K700E and collected in the Chromosomal Genetics laboratory, site of the CRB of the CHRU of Brest. The investigators will then analyze the functional repercussions associated with the presence of these aberrant junctions on the cells in culture of these same patients (detection of certain proteins, enzymatic analyzes, etc.). The collection of biological and clinical data from these patients of interest is essential for the interpretation of the results. This project is part of a more global approach to the study of the various splicing anomalies in this pathology.

Project 2: splicing abnormalities in MDS with chromosomal abnormalities as 5q deletion : Chromosome 5 deletions are the most frequent structural abnormalities in MDS and constitute a good prognostic entity if isolated or associated with an anomaly and poor prognosis if associated with more than 3 chromosomal abnormalities. Two genes located on chromosomes 5 encode proteins of a complex involved in the splicing of pre-messenger RNAs: the RBM22 gene (RNA Binding Motif Protein 22) and the SLU7 gene (SLU7 Homolog Splicing Factor).

The investigators want to identify subgroups of patients with loss of these 2 genes or loss of RBM22 and conservation of SLU7. Does the loss of one or both genes play a role in the pathophysiogenesis of MDS with chromosome deletions and is it associated with worsening of the disease? Understanding these mechanisms could also have an impact on the therapeutic management of this pathology.

The study of these chromosomal abnormalities associated with splicing abnormalities in MDS for the chromosomal genetics laboratory both from a diagnostic and research perspective. Several works carried out have given rise to numerous scientific publications with an international reading committee for several years.

Project 3: Evolution of MDS in acute myeloid leukemia (AML) More than one third of patients with MDS progress to AML. The investigators want to focus on this group of patients and understand the clonal architecture of their malignant cells to detect new predictive markers of indolent or rapid disease progression.

Health services research and follow up DMS

Biocollection in MyeloDysplastic Syndrome (P-MDS)

Biocollection in Patients With Myelodysplastic Syndrome (P-MDS)

All collected data that underlie results in a publication

University Hospital, Brest

Experimental treatment branch with Lenalidomide 5 mg/day (oral use)

Treatment with Revlimid (lenalidomide), oral use, 5 mg daily during study treatment (104 weeks).

Placebo, oral use, daily during study treatment (104 weeks)

Placebo

Consuelo del Cañizo, MD

María Díez Campelo, MD

Trial Design:

This clinical trial is a phase III multicenter, randomized, double blind and controlled with placebo trial and with two arms designed to assess the efficiency and toxicity of the scheme Lenalidomide versus observation in a series of 60 patients with low risk myelodysplastic syndrome associated to 5q deletion with anemia (Hb≤12g/dL) but without the need of transfusion. Patients are randomized in the study in a 2:1 ratio. They will receive treatment for 104 weeks until progression of the disease, which implies that the patient suffering from anemia due to myelodysplastic syndrome requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months), or unacceptable toxicity.

Disease:

Low risk myelodysplastic syndrome associated to the loss of 5q without transfusion requirements.

Total number of patients:

In total 60 patients will be included, 40 assigned to the treatment branch and 20 to the placebo branch.

Calendar:

First patient first visit: February 2010, and Last patient last visit expected in February 2016. (Recruitment was initially expected to take place over a period of 24 months and was expected to be finished in February 2012, but due to low rate of recruitment it was extended until the population sample is included in the trial).

General summary of myelodysplastic syndrome with alteration in 5q. Myelodysplastic syndromes (MDS) are a very heterogenic group of diseases characterized by the presence of morphologic features of dyshemopoiesis in bone marrow (BM) and in peripheral blood (PB), which is translated into an inefficient hematopoiesis. This will lead to the concomitant development of peripheral cytopenias which will be the cause of complications in these patients and, in most cases, the cause of death. In addition, these patients have an increased risk of developing acute leukemia, and this risk increases with the progression of the disease.MDS represents an incurable disease with standard treatments with a quite variable survival mean ranging from 3 months to 15 years depending on the number of blasts, the number of cytopenias and the type of cytogenetic disorders2. The sole curative treatment of the MDS is the allogenic transplant of hematopoietic progenitors but this option is only available for a 5% of the patients with MDS.

Lenalidomide, initially known as CC-5013, is an analogue of the immunomodulator Drug Thalidomide (Thalidomid®; Pharmion Corp., Boulder, CO, USA), which was the first drug with anti-angiogenic and immunomodulator properties investigated in MDS. Lenalidomide has, as well as thalidomide, a broad array of potential activities against dysplastic cells, not fully known, among which we find immunomodulator and non-immunomodulator properties (anti-angiogenic effect, anti-proliferative and pro-apoptotic). The greater advantage of Lenalidomide in comparison with thalidomide is that the former is between 50 and 2000 times stronger tan thalidomide in what respects to its immunomodulator effects. And moreover, the toxic profile of Lenalidomide seems lower than that of its analogue; Thalidomide.

There is no treatment indication on the present times for patients with low risk MDS associated to the loss of 5q without transfusion dependent anemia. The results with Lenalidomide are highly promising for patients with low risk MDS associated to the loss of 5q when (it has so been tested) there is red blood cells transfusion dependent anemia. In this sense, the proposal consists on being able to state that treatment with Lenalidomide can be efficient from diagnose preventing CH transfusions with an acceptable toxicity.

In this sense, the present study has the intention to treat early patients with low-risk MDS associated to the loss of 5q with a view to prevent CH transfusion. Therefore, we could extend in these patients the time until CH transfusion and even assess the possibility of eradicating the disease at a cytogenetic/morphologic level. In the present trial and given the characteristics of the patients, we have chosen the option of supplying Lenalidomide at a dose of 5mg/day. The option of considering a lower dose to the one currently considered as "standard" (10mg/day) is to reduce toxicity, mainly hematologic, in patients who do not receive treatment normally. A dose with lower toxicity has been chosen which has revealed itself efficient.

Main efficiency objective:

•To assess if treatment with Revlimid (Lenalidomide) extends the period until the progression to myelodysplastic syndrome del(5q) considered as transfusion independent, documented verification that the patient suffering from anemia due to MDS requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months). Revlimid will be compared to the current standard treatment for patients with low risk myelodysplastic syndrome associated with the loss of 5qwithout transfusion dependent anemia, which is the therapeutic abstention and monitoring until its progression.

Secondary efficiency objectives:

* Erythroid response according to the Criteria of the myelodysplastic syndrome International Work Team 2006).
* Duration of the red blood cells transfusion independency (defined as the number of days elapsed between the randomization and the first transfusion after this period free of transfusions).
* Change of hemoglobin concentration (Hb) in relation to baseline levels of patients who show erythroid response.
* Variation in platelets absolute count in relation to baseline levels.
* Variation in neutrophils absolute count in relation to baseline levels.
* Cytogenetic response according to the Criteria of the myelodysplastic syndrome International Work Team.
* Bone marrow response according to the Criteria of the myelodysplastic syndrome International Work Team.
* To assess the safety and tolerance of the Lenalidomide scheme, measured according to the incidence of clinical and laboratory toxicity.
* Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia.
* Time from diagnose to transfusion independence.

Main safety objective:

Safety (type, frequency and severity \[Criteria of normal terminology of adverse reactions of the National Cancer Institute (NCI CTCAE) version 3.0\] of adverse reactions (AR)and list of the AR with Lenalidomide.

Four of the sites of this Clinical Trial are member of the European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) which is partially co-funded by the European Union within the framework of the Third Health Programme. "ERN-2016 - Framework Partnership Agreement 2017-2021." FPA 739541".

Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome

Multicenter, Randomized, Double-blind, Phase III Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome (Low and Intermediate-1 IPSS) With Alteration in 5q- and Anemia Without the Need of Transfusion.

To assess if treatment with Revlimid (Lenalidomide) extends the period until the progression to MDS of(5q) considered as transfusion independent, documented verification that the patient suffering from anemia due to MDS requires transfusion of at least 2 UCH/56 days (2 months) with a minimum follow up of 112 days (4 months). Revlimid will be compared to the current standard treatment for patients with low risk MDS associated with the loss of 5q without transfusion dependent anemia, which is the therapeutic abstention and monitoring until its progression.

Erythroid response according to the Criteria of the MDS International Work Team.

Red blood cells transfusion independency,defined as the number of days elapsed between the randomization and the first transfusion after this period free of transfusions.

Change of the hemoglobin concentration (Hb) in relation to baseline levels of patients who show erythroid response.

Variation in platelets and neutrophils absolute count in relation to baseline levels

Cytogenetic response according to the Criteria of the MDS International Work Team.

Bone marrow response according to the Criteria of the MDS International Work Team.

Global survival, Event Free Survival and Rate of Transformation to Acute Leukemia

Time from diagnose to transfusion independence

Safety (type, frequency and severity \[Criteria of normal terminology of adverse reactions of the National Cancer Institute (NCI CTCAE) version 3.0\] of adverse reactions (AR)and list of the AR with Lenalidomide.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pacritinib, a Kinase Inhibitor of CSF1R, IRAK1, JAK2, and FLT3, in Adults and Pediatric Participants 12 Years of Age or Older With Myelodysplastic Syndromes or Myelodysplastic/Myeloproliferative Neoplasms	NCT06303193	Myelodysplastic...	pacritinib	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)
MORE - Monitoring Revlimid - Collecting of Patient Information From Myelodysplastic Syndrome (MDS) Italian National Registry	NCT01347944	Myelodysplastic...	lenalidomide	18 Years -	Celgene
Biocollection in MyeloDysplastic Syndrome (P-MDS)	NCT04869683	Myelodysplastic... Myelodysplastic... Myelodysplastic... Myelodysplastic... Acute Myeloid L... Chromosome Abno...	description of ...	18 Years -	University Hospital, Brest
Study of REVLIMID (Lenalidomide) Versus Placebo in Patients With Low Risk Myelodysplastic Syndrome	NCT01243476	Myelodysplastic...	Lenalidomide Placebo	18 Years -	Fundación General de la Universidad de Salamanca
MORE - Monitoring Revlimid - Collecting of Patient Information From Myelodysplastic Syndrome (MDS) Italian National Registry	NCT01347944	Myelodysplastic...	lenalidomide	18 Years -	Celgene

Spots Global Cancer Trial Database for 5q deletion

Every month we try and update this database with for 5q deletion cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for 5q deletion

Every month we try and update this database with for 5q deletion cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for 5q deletion cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.