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 ongoing, but not recruiting participants.
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: April 23, 2015
Last verified: April 2015
  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: September 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01748240

Locations
France
CHU d'Angers
Angers, France, 49033
CH Annecy
Annecy, France, 74374
Hôpital Avignon
Avignon, France, 84000
Centre hospitalier de la côte Basque
Bayonne, France, 64100
Hôpital Avicenne
Bobigny, France, 93009
CHU de Haut-Lévèque
Bordeaux Pessac, France, 33604
CHU de Grenoble
Grenoble, France, 38043
CH Le mans
Le mans, France, 72037
CH Lyon Sud
Lyon, France, 69495
IPC-Unité d'Hématologie 3
Marseille, France, 13273
CHU Nantes
Nantes, France, 44093
Hôpital Archet1
Nice, France, 06202
GHU Caremeau
Nimes, France, 30029
Hopital Cochin-Hematology
Paris, France, 75679
Hopital Saint Louis - AP-HP, Hematology Dpt
Paris, France, 75475
Hôpital Saint Louis
Paris, France, 75010
Hôpital Saint-Louis
Paris, France, 75475
Centre Hospitalier Joffre
Perpignan, France, 66046
Centre Henri Becquerel
Rouen, France, 76038
Hopital Purpan-Medecine interne
Toulouse, France, 31059
Hôpital PURPAN, Service d'Hématologie Clinique
Toulouse, France, 31059
CHU Bretonneau
Tours, France, 37044
CH de Valence
Valence, France, 26953
CHU Brabois
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: April 23, 2015
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
Neoplasms
Precancerous Conditions
Azacitidine
Vorinostat
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on July 01, 2015