A Study of LDE255 in Combination With Azacitidine for High Risk Myelodysplastic Syndrome Patients

NCT02323139 | Completed Phase 1 DMC

• 2 other identifiers: GFM-AZA-LDE2013-003108-38
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 24

Brief Summary

This study is a phase Ib add-on study of the combination of LDE255 to azacitidine in patients without marrow response after at least 6 cycles of azacitidine.

Conditions

MDS

Keywords

High risk MDS; Azacitidine; LDE255

Outcome Measures

Primary Outcomes (1)

• Safety of the combination assessed by evaluation of hematological and non-hematological toxicities at day 28 of cycle 1

  1 month

Secondary Outcomes (1)

• Clinical efficacy assessed by total percentage of responses, including all patients achieving CR, PR, marrow CR or hematologic improvement, evaluated according to IWG 2006 criteria after 6 treatment cycles

  6 months

Other Outcomes (1)

• Overall survival

  3 years

Study Arms (1)

Combination of azacitidine and LDE255

EXPERIMENTAL

Combination of azacitidine at maximum tolerated dose and LDE255 at dose escalation, the starting dose will be 400 mg

Drug: Azacitidine and LDE255

Interventions

Azacitidine and LDE255 DRUG

Azacitidine at maximum tolerated dose. LDE255 at dose escalation (200, 400 or 800 mg)

Also known as: Vidaza

Combination of azacitidine and LDE255

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• High risk myelodysplastic syndrome (MDS) according to International Prognosis Scoring System (IPSS) or acute myeloid leukemia (AML) with low blast count (Bone marrow blast count between 20 and 30%) or non proliferative chronic myelomonocytic leukemia (CMML) (White blood cell (WBC) below 13 G/L)
• Age over 18 years
• Performance Status 0 to 2
• Patient must have recovered from toxicities of any prior treatment regimen (no common toxicity criteria for adverse events (CTCAE)) grading over 1 for non-hematological toxicities, return to baseline for hematological values)
• Patient must have been treated with azacitidine single agent for at least 6 cycles
• According to International working group (IWG) 2006 criteria, patient may have a/ stable disease, OR b/ disease progression limited to patients with loss of hematological improvement without bone marrow progression. Patients with bone marrow progression (i.e. increased bone marrow blast count of 50% or more) should not be included.
• Bone marrow blast count should be 10% to 30%
• Adequate liver and renal function:
• Serum creatinine less than 1.5 x the institutional upper limit of normal (ULN)
• Total bilirubin less than 1.5 x the ULN unless considered due to Gilbert's syndrome
• Alanine aminotransferase (ALT, SGPT), or aspartate aminotransferase (AST, SGOT) less than 2.5 x the ULN unless considered due to organ leukemic involvement
• Creatine Kinase less than 1.5 x the ULN
• Able to understand and sign the written informed consent
• Women of childbearing potential must agree to use effective contraception without interruption throughout the study and for a further 3 months after the end of treatment
• Men must agree to not conceive during the treatment and to use effective contraception during the treatment period (including periods of dose reduction or temporary suspension) and for a further 3 months after the end of treatment if their partner is of childbearing potential.

You may not qualify if:

• Allogeneic stem cell transplantation (SCT) within the last 4 months and/or active graft versus host disease (GVHD), or autologous SCT within the last 4 weeks. Patient suitable for allogeneic transplantation and with an identified allogeneic donor (Extension phase only).
• Active central nervous system (CNS) leukemic involvement.
• Major surgery within 2 weeks of initiation of study medication.
• Concurrent uncontrolled medical conditions that may interfere or potentially affect the interpretation of the study.
• Unable to take oral drugs, or lack of physical integrity of the upper gastrointestinal tract, or known malabsorption syndromes.
• Patients with unresolved diarrhea \> CTCAE grade 2.
• Patients who have previously been treated with systemic LDE225 or with other Hh pathway inhibitors.
• Patients who have neuromuscular disorders (i.e. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if necessary, with extra caution.
• Patients who are planning on embarking on new physical activities, such as strenuous exercise, that can result in significant increases in plasma creatine kinase levels while on study treatment. Strenuous muscular activity MUST be avoided within 1 week of blood tests during the study.
• Patient has history of cardiac dysfunction including any of the following:
• Myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of life ventricular ejection fraction (LVEF) function within the last six months.
• History of documented congestive heart failure (New York Association functional classification III-IV).
• Documented cardiomyopathy.
• Familial history of long QT syndrome.
• Patient has active cardiac disease including any of the following:

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• Novartis: collaborator

Study Sites (24)

CHU d'Amiens

Amiens, 80054, France

Location

CHU d'Angers

Angers, 49033, France

Location

CH Henri Duffaut

Avignon, 84000, France

Location

CH de la Côte Basque

Bayonne, 64 100, France

Location

Hôpital Avicenne

Bobigny, 93009, France

Location

Hôpital Henri Mondor

Créteil, 94010, France

Location

CHU de Grenoble

Grenoble, 38043, France

Location

CH Le Mans

Le Mans, 72037, France

Location

IPC-Unité d'Hématologie 3

Marseille, 13273, France

Location

Centre Hospitalier de Meaux

Meaux, 77100, France

Location

CHU de Montpellier

Montpellier, 34295, France

Location

Hôpital Hôtel Dieu

Nantes, 44093, France

Location

Centre Antoine Lacassagne

Nice, 06189, France

Location

Hôpital Archet 1

Nice, 06202, France

Location

CHU de Nîmes

Nîmes, 30029, France

Location

Hôpital Saint Louis - Service Hématologie Sénior

Paris, 75010, France

Location

Hôpital Saint-Louis - Service d'hématologie AJA

Paris, 75010, France

Location

Hôpital Cochin

Paris, 75014, France

Location

CHU de Haut-Lévèque

Pessac, 33604, France

Location

CH Lyon Sud

Pierre-Bénite, 69495, France

Location

CH Annecy Genevois

Pringy, 74374, France

Location

Hôpital Henri Becquerel

Rouen, 76038, France

Location

IUC Oncopole - Médecine interne

Toulouse, 31059, France

Location

CHU Nancy-Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

MeSH Terms

Interventions

Azacitidine

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Thomas PREBET, MD

  Paoli Calmettes institute

  PRINCIPAL INVESTIGATOR

• Pierre FENAUX, MD, PHD

  Saint-Louis Hospital, Paris, France

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 26, 2014
• First Posted: December 23, 2014
• Study Start: February 10, 2015
• Primary Completion: January 1, 2018
• Study Completion: August 1, 2018
• Last Updated: December 6, 2018

Record last verified: 2018-12

Locations

FR (24)