Addition of Vorinostat to Azacitidine in Higher Risk MDS a Phase II add-on Study in Patients With Azacitidine Failure

NCT01748240 | Terminated Phase 2 Results DMC

• 1 other identifier: GFM-Aza-Vor 2012-001401-25
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 24

Brief Summary

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

Conditions

Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Response Rate

  All eligible patients will be treated with Azacitidine and oral vorinostat for 6 cycles of 28 days. The response rate (CR, PR, HI or marrow CR) 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. Complete Response (CR): Bone marrow: less than 5% myeloblasts with Peripheral blood: HI responses). Partial remission (RP): Bone marrow blasts decreased by at least 50% but still more than 5% with Peripheral blood: HI responses). Marrow CR:Bone marrow: maximum of 5% myeloblasts and decrease by at least 50% over pretreatment HI (hematologic improvement) * Erythroid response: Hgb increase at least by 1.5 g/dL * Platelet response: Increase from less than 20x109/L to more than 20x109/L and by at least 100% * Neutrophil response: At least 100% increase and an absolute increase of at least 0.5x109/L

  6 month

Study Arms (1)

Azacitidine and oral vorinostat

EXPERIMENTAL

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

Interventions

Azacitidine and oral vorinostat DRUG

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.

Also known as: Suberoylanilide Hydroxamic acid (Vorinostat), Azacitidine (Vidaza)

Azacitidine and oral vorinostat

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (24)

CHU d'Angers

Angers, 49033, France

Location

CH Annecy

Annecy, 74374, France

Location

Hôpital Avignon

Avignon, 84000, France

Location

Centre hospitalier de la côte Basque

Bayonne, 64100, France

Location

Hôpital Avicenne

Bobigny, 93009, France

Location

CHU de Grenoble

Grenoble, 38043, France

Location

CH Le mans

Le Mans, 72037, France

Location

CH Lyon Sud

Lyon, 69495, France

Location

IPC-Unité d'Hématologie 3

Marseille, 13273, France

Location

CHU Nantes

Nantes, 44093, France

Location

Hôpital Archet1

Nice, 06202, France

Location

GHU Caremeau

Nîmes, 30029, France

Location

Hôpital Saint Louis

Paris, 75010, France

Location

Hopital Saint Louis - AP-HP, Hematology Dpt

Paris, 75475, France

Location

Hôpital Saint-Louis

Paris, 75475, France

Location

Hopital Cochin-Hematology

Paris, 75679, France

Location

Centre Hospitalier Joffre

Perpignan, 66046, France

Location

CHU de Haut-Lévèque

Pessac, 33604, France

Location

Centre Henri Becquerel

Rouen, 76038, France

Location

Hopital Purpan-Medecine interne

Toulouse, 31059, France

Location

Hôpital PURPAN, Service d'Hématologie Clinique

Toulouse, 31059, France

Location

CHU Bretonneau

Tours, 37044, France

Location

CH de Valence

Valence, 26953, France

Location

CHU Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Azacitidine; Vorinostat

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Results Point of Contact

• Title: Groupe Francophone des Myelodysplasies
• Organization: academic group

fatiha.chermat@aphp.fr

+ 33 (0)1 71 20 70 59

Study Officials

• Thomas Prebet, MD

  Unité d'Hématologie-Institut Paoli Calmettes,Marseille

  PRINCIPAL INVESTIGATOR

• Pierre Fenaux, MD

  Hôpital Saint Louis, hematology

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2012
• First Posted: December 12, 2012
• Study Start: March 1, 2013
• Primary Completion: October 1, 2013
• Study Completion: July 1, 2015
• Last Updated: June 4, 2019
• Results First Posted: August 10, 2018

Record last verified: 2019-05

Data Sharing

• IPD Sharing: Will not share

Locations

FR (24)