Addition of Vorinostat to Azacitidine in Higher Risk MDS a Phase II add-on Study in Patients With Azacitidine Failure (GFM-AZA-VOR)

This study is currently recruiting participants.
Verified December 2012 by Groupe Francophone des Myelodysplasies
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier:
NCT01748240
First received: December 7, 2012
Last updated: March 14, 2014
Last verified: December 2012
  Purpose

Azacytidine (AZA) is the current standard of care for frontline patient treated with high-risk MDS and is clinically active in all type of MDS, however, 50% of the patients will never respond. Vorinostat is an orally available HDAC inhibitor with clinical activity in MDS and proven in vitro synergy with AZA. Patient treated upfront with a combination of this agents have shown more responses based on phase I/II data. In the present study, we will use the combination of these two drugs to try to create a synergetic effect and generate a response for patients who experienced treatment failure after AZA.

All eligible patients will be treated with Azacitidine and oral vorinostat for 6 cycles of 28 days. Study Design


Condition Intervention Phase
Myelodysplastic Syndrome
Drug: Azacitidine and oral vorinostat
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Addition of Suberoylanilide Hydroxamic Acid (Vorinostat) to Azacitidine in Patients With Higher Risk Myelodysplastic Syndromes (MDS): a Phase II add-on Study in Patients With Azacitidine Failure.

Resource links provided by NLM:


Further study details as provided by Groupe Francophone des Myelodysplasies:

Primary Outcome Measures:
  • Response rate [ Time Frame: 6 month ] [ Designated as safety issue: No ]

    All eligible patients will be treated with Azacitidine and oral vorinostat for 6 cycles of 28 days.

    The response rate will be evaluated after six cycles, according to IWG 2006. In patients still responding after six cycles, the drugs will continue to be supplied, and follow up until death or unacceptable tolerance will be continued in all patients.



Estimated Enrollment: 48
Study Start Date: March 2013
Estimated Study Completion Date: March 2016
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azacitidine and oral vorinostat

Patients who meet eligibility criteria will be administered vorinostat orally at 300mg two times daily for 7 days. AZA will be administered SC at 75 mg/m2/day x 7 consecutive days or at maximum tolerated dose if a dose reduction of AZA was needed before entering the trial with a minimum dose of 50mg/m2/d for 7 consecutive days.

Each cycle will last 28 days with AZA starting on day 1 of each cycle and vorinostat starting on day 3.

Drug: Azacitidine and oral vorinostat
In patients still responding after six cycles, the drugs will continue to be supplied, and follow up until death or unacceptable tolerance will be continued in all patients.
Other Names:
  • Suberoylanilide Hydroxamic acid (Vorinostat)
  • Azacitidine (Vidaza)

Detailed Description:

Patients who meet eligibility criteria will be administered vorinostat orally at 300mg two times daily for 7 days as outlined in table 1.1. AZA will be administered SC at 75 mg/m2/day x 7 consecutive days or at maximum tolerated dose if a dose reduction of AZA was needed before entering the trial with a minimum dose of 50mg/m2/d for 7 consecutive days.

Each cycle will last 28 days with AZA starting on day 1 of each cycle and vorinostat starting on day 3.

Patients will receive 6 cycles unless progression is documented. Patients with a complete remission (CR), partial remission (PR), or hematological improvement (HI), will be treated until progression.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Myelodysplastic syndrome (WHO and FAB classified) including: RA, RARS, RCMD, RCMD-RS RAEB , RAEB-t and CMML with WBC < 13000/mm3)
  • IPSS score 1.5 or higher (IPSS intermediate-2 and high risk categories) at the beginning of azacitidine,
  • Absence of response (CR, PR, marrow CR or HI according to IWG 2006) after a minimum of 6 cycles of azacitidine single agent at 75 mg/m²/d for 7 days per cycle. Patients with a previous dose reduction of AZA may be eligible if the maximum tolerated dose was equal to or above 350mg/m2/cycle (i.e. 50 mg/m²/d for 7 days or 75mg/m2/d for 5 days).
  • Age more or egal to 18 years
  • ECOG performance status ≤ 2 (cf. appendix 2);
  • Patient must have adequate organ function as indicated by the following laboratory values

Renal Serum creatinine or calculated creatinine clearancea < 2 mg/dl OR ≥ 60 mL/min for patients with creatinine levels > 1.5 X institutional ULN Hepatic

Serum total bilirubin ≤ 2.5 X ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels ≥ 2 mg/dL.

AST (SGOT) and ALT (SGPT) ≤ 2.5 times ULN Alkaline Phosphatase ≤ 5 X ULN If > 2.5 X ULN, then liver fraction should be ≤ 2.5 X ULN a Creatinine clearance should be calculated per institutional standard.

  • Patient is known to not be refractory to platelet transfusions.
  • Patient ineligible for allogeneic hematopoietic stem cell transplantation at the time of inclusion in the study
  • Adherence to the study visit schedule;
  • 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.

Agree to learn about the procedures for preservation of sperm.

Exclusion Criteria:

  • Patient had prior treatment with an HDAC inhibitor (e.g., depsipeptide or NSC-630176, MS 275, LAQ-824, PXD-101, LBH589, MGCD0103, CRA024781, etc). Patients who have received compounds with HDAC inhibitor-like activity, such as valproic acid, as anti-tumor therapy should not enroll in this study. Patients who have received such compounds for other indications, e.g. valproic acid for epilepsy, may enroll after a 30-day washout period.
  • Severe infection or any other uncontrolled severe condition.
  • Last dose of AZA was given more than 3 months before entering the trial.
  • Patient already enrolled in another therapeutic trial of an investigational drug
  • HIV infection or active hepatitis B or C.
  • Patient has a known allergy or hypersensitivity to any component of vorinostat or azacitidine.
  • Active cancer, or cancer during the year prior to trial entry other than basal cell carcinoma or carcinoma in situ of the cervix or breast.
  • Less than 30 days since prior treatment with growth factors (EPO, G-CSF) or non-cytotoxic agents (including low-dose oral chemotherapy); in the event of prior treatment with cytotoxic or demethylating agents, an interval of 3 months is required;
  • Patient is on any systemic steroids that have not been stabilized to the equivalent of ≤ 10 mg/day prednisone during the 4 weeks prior to the start of the study drugs.
  • Patients with clinical evidence of CNS leukemia.
  • Patient has a history of GI surgery or other procedures that might interfere with the absorption or swallowing of the study drugs.
  • Women who are or could become pregnant, or who are currently breastfeeding
  • Patient eligible for allotransplantation at the time of inclusion.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01748240

Contacts
Contact: Chermat Fatiha +331 48 95 58 90 fatiha.chermat@avc.aphp.fr
Contact: Pr Fenaux Pierre, MD +331 70 20 70 22 pierre.fenaux@sls.aphp.fr

Locations
France
CHU d'Angers Active, not recruiting
Angers, France, 49033
CH Annecy Recruiting
Annecy, France, 74374
Contact: Pascale Cony-Makhoul    0450636608    pconymakhoul@ch-annecy.fr   
Principal Investigator: Pascale Cony-Makhoul, MD         
Hôpital Avignon Active, not recruiting
Avignon, France, 84000
Centre hospitalier de la côte Basque Active, not recruiting
Bayonne, France, 64100
Hôpital Avicenne Recruiting
Bobigny, France, 93009
Contact: Thorsten Braun, MD    (0) 33 1 48 95 70 51    thorsten.braun@avc.aphp.fr   
Principal Investigator: Thorsten Braun, MD         
CHU de Haut-Lévèque Active, not recruiting
Bordeaux Pessac, France, 33604
CHU de Grenoble Active, not recruiting
Grenoble, France, 38043
CH Le mans Active, not recruiting
Le mans, France, 72037
CH Lyon Sud Recruiting
Lyon, France, 69495
Contact: Eric Wattel    033472117401    wattel@lyon.fnclcc.fr   
Principal Investigator: Eric Wattel, MD         
IPC-Unité d'Hématologie 3 Recruiting
Marseille, France, 13273
Contact: Thomas Prebet    0334 91 22 36 67    PREBETT@ipc.unicancer.fr   
Principal Investigator: Thomas Prebet, MD         
CHU Nantes Recruiting
Nantes, France, 44093
Contact: Jacques Delaunay    033240083333    jacques.delaunay@chu-nantes.fr   
Principal Investigator: Jacques Delaunay, MD         
Hôpital Archet1 Active, not recruiting
Nice, France, 06202
GHU Caremeau Active, not recruiting
Nimes, France, 30029
Hôpital Saint Louis Active, not recruiting
Paris, France, 75010
Hopital Cochin-Hematology Active, not recruiting
Paris, France, 75679
Hôpital Saint-Louis Not yet recruiting
Paris, France, 75475
Contact: Emmanuel Raffoux    0142499643    ammanuel.raffoux@sls.aphp.fr   
Principal Investigator: Emmanuel Raffoux, MD         
Hopital Saint Louis - AP-HP, Hematology Dpt Active, not recruiting
Paris, France, 75475
Centre Hospitalier Joffre Active, not recruiting
Perpignan, France, 66046
Centre Henri Becquerel Active, not recruiting
Rouen, France, 76038
Hopital Purpan-Medecine interne Active, not recruiting
Toulouse, France, 31059
Hôpital PURPAN, Service d'Hématologie Clinique Active, not recruiting
Toulouse, France, 31059
CHU Bretonneau Active, not recruiting
Tours, France, 37044
CH de Valence Active, not recruiting
Valence, France, 26953
CHU Brabois Active, not recruiting
Vandoeuvre, France, 54511
Sponsors and Collaborators
Groupe Francophone des Myelodysplasies
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Thomas Prebet, MD Unité d'Hématologie-Institut Paoli Calmettes,Marseille
Study Director: Pierre Fenaux, MD Hôpital Saint Louis, hematology
  More Information

No publications provided

Responsible Party: Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier: NCT01748240     History of Changes
Other Study ID Numbers: GFM-Aza-Vor 2012-001401-25
Study First Received: December 7, 2012
Last Updated: March 14, 2014
Health Authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Vorinostat
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Histone Deacetylase Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014