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Vorinostat to Prevent Graft Versus Host Disease Following Reduced Intensity, Related Donor Stem Cell Transplant

5 mars 2014 mis à jour par: Pavan Reddy, MD

Phase II Trial of Vorinostat Plus Tacrolimus & Mycophenolate to Prevent Graft Versus Host Disease Following Reduced Intensity Conditioning Related Donor Allogeneic Transplant

The proposed research study is to test the drug vorinostat, in a new use as an additional medication, with other standard treatments for the prevention of severe acute graft versus host disease (GVHD).

If this treatment is safe and effective, when combined with a reduced intensity transplant, the research may achieve a more effective therapy for patients with high-risk, blood cell related cancers.

All subjects will receive an identical, known treatment to test if the treatment is safe and effective (a phase II trial). For patients to take part they must have a high-risk, blood cell cancer, be suitable candidates to receive a reduced intensity transplant and have a matched, related donor.

Adult subjects (age 18 years and older) will be considered as subjects provided, as detailed in the protocol, they meet additional criteria and are not excluded from participating. About fifty (50) subjects will be enrolled in this study at the University of Michigan.

Patients who receive blood stem cell transplants (HSCT), also called bone marrow transplants, to treat their cancer are at risk for serious complications, which may sometimes be fatal. The more common, serious ones are relapse (return of their disease), body organ injury from the intensity of the chemotherapy given prior to their transplant, and a serious complication called graft versus host disease (GVHD). GVHD is a form of rejection, where the transplanted cells of the donor attack the recipient's body as foreign, and do damage to organs and tissues.

To decrease the side effects of the chemotherapy given before a transplant, reduced intensity treatment plans(regimens)have recently been developed at a number of transplant centers. A decrease in the side effects of chemotherapy (called toxicities) has been achieved; however, this success with "less intensive" treatments has been partially offset by less successful results in controlling the patient's cancer.

As mentioned above, GVHD is a form of transplant rejection. GVHD can affect the digestive system, skin, liver and other body systems. GVHD can increase the risk of infection. After a matched, related donor stem cell transplant, GVHD when severe, is a major cause of discomfort, organ damage, and even death. When a graft vs host reaction develops, but is kept under control, studies show there may be a beneficial graft versus tumor effect, helping to destroy tumor cells in the patient, and thus providing a more effective control of their cancer.

The goal of this study is to try to maximize the potential benefits, of giving patients less intense chemotherapy to reduce the toxic effects, letting the graft vs host effect help in destroying tumor cells, but preventing acute severe GVHD by using the drug vorinostat, combined with standard medicines, to reduce the chance of serious GVHD-related complications.

Aperçu de l'étude

Statut

Complété

Les conditions

Intervention / Traitement

Type d'étude

Interventionnel

Inscription (Réel)

61

Phase

  • Phase 2
  • La phase 1

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

  • États-Unis
    • Michigan
      • Ann Arbor, Michigan, États-Unis, 48109
        • University of Michigan Cancer Center
    • Missouri
      • St. Louis, Missouri, États-Unis, 63110
        • Washington University School of Medicine

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans et plus (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

La description

Inclusion Criteria:

  • Have a 7/8 or 8/8 HLA A, B, C and DR, HLA-matched related donor willing and able to donate allogeneic stem cells.
  • For patients with multiple myeloma, CLL, and lymphoma: must be in CR, PR, or stable disease.
  • For MDS, acute leukemia or CML: must have <20% blasts on marrow exam.
  • For all other diseases: must have non-refractory disease.

and meet at least ONE of the next three criteria:

  • Any patient ≥ 18 years of age with a hematological malignancy and not considered a candidate for allogeneic myeloablative transplant due to illness and/or age (≥55 years).
  • Any patient ≥ 18 years of age who has relapsed following prior autologous or allogeneic transplant for a hematologic malignancy.
  • Any patient ≥ 18 years of age diagnosed with a hematological malignancy for which reduced intensity transplant is institutionally preferred over myeloablative transplant (eg, chronic lymphocytic leukemia).

Exclusion Criteria:

  • Less than 18 years of age.
  • Currently taking any HDAC inhibitors, or have taken an HDAC inhibitor within 30 days of the trial.
  • Positive serum tests for HIV, HTLV1 / HTLV2.
  • Detectable hepatitis B virus (HBV), hepatitis C (HCV) or Epstein-Barr (EBV).
  • Pregnancy.

  • One or more of the following organ system function criteria

    • Cardiac: Ejection fraction ≤ 40%
    • Renal: Estimated or actual GFR ≤ 40 ml/min (corrected for BSA)
    • Pulmonary: FEV1, FVC, or DLCO ≤ 40% predicted
    • Hepatic: Total bilirubin ≥3 mg% and AST/ALT >5 x institutional normal for age
    • Karnofsky score ≤50 (Requires considerable assistance and frequent medical care).
  • Persistent invasive infections not controlled by antimicrobial medication.
  • Any physical or psychological condition that, in the opinion of the investigator, would pose unacceptable risk to the patient.

Plan d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

  • Objectif principal: Traitement
  • Répartition: N / A
  • Modèle interventionnel: Affectation à un seul groupe
  • Masquage: Aucun (étiquette ouverte)

Armes et Interventions

Groupe de participants / Bras
Intervention / Traitement
Expérimental: Vorinostat prophylaxis
Vorinostat,combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a reduced intensity, related donor stem cell transplant
Médicament: mycophénolate (prophylaxie standard de la GVHD)
Le mycophénolate commencera le jour 0 à 10 mg/kg/dose (jusqu'à 1 gramme par dose) toutes les 8 heures par voie orale ou intraveineuse et se poursuivra jusqu'au jour 28.
Procédure: reduced intensity, related donor stem cell transplant

Fludarabine /Busulfan(FluBu2)regimen

Fludarabine: 40 mg/m2/day in 0.9 NS, administered IV on days -5 to day -2 pre-transplant for a total of 4 doses. Busulfan: 3.2 mg/kg in 0.9 NS administered IV on days -5 and -4 for a total of 2 doses. Total body irradiation 200 cGy delivered in a single fraction will be given on day 0 for patients receiving an HLA-mismatched transplant.

Médicament: tacrolimus (standard GVHD prophylaxis)
Tacrolimus will begin on day -3, IV or oral. Target trough level for tacrolimus is 8-12 ng/ml. In the absence of GVHD, tacrolimus tapering will begin on day +56 post transplant
Médicament: vorinostat

Vorinostat given at a dose 100 mg PO BID starting day -10. If tolerated, vorinostat will be continued until day 100 post-transplant,whether or not acute GVHD develops.

Dose escalation/ de-escalation

Ten subjects treated at a dose of 100 mg PO BID. If dosing modifications are not required, during the pre-engraftment period in more than 4 patients, AND no more than two observed drug related toxicities CTC grade 4 or higher [probably or definitely related to the drug] then vorinostat dose will be escalated to 200 mg PO BID.

If dose escalation does not occur due to failure to meet the above criteria,then the study will enroll at the 100 mg PO BID dosing, subject to the protocol stopping rules.

If dose escalation occurs, subjects will be treated at 200 mg PO BID dosing level. If the probability of unacceptable toxicity exceeds the rules in protocol, then the dose of vorinostat will be de-escalated to 100 mg PO BID for the remainder of study.

Autres noms:
  • ZOLINZA

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats
Description de la mesure
Délai
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Délai: 100 days
Assess if the addition of Vorinostat to standard GVHD prophylaxis regimen can reduce the rate of grades 2-4 acute GVHD when compared to 48% in a cohort of identically treated RIC HSCT patients without vorinostat. A reduction of incidence to less than 25% will be considered successful.
100 days

Mesures de résultats secondaires

Mesure des résultats
Description de la mesure
Délai
Number of Serious Adverse Events
Délai: 100 days
The safety and feasibility will be partially measured by the number of serious adverse events (SAE) recorded by participants receiving at least one dose of Vorinostat.
100 days
Percent Cumulative Incidence of Relapse at 2 Years.
Délai: two years
Determine the cumulative incidence of relapse at 2 years.
two years
Percent Survival at 2-years
Délai: two years
To determine 2-year overall survival rate
two years

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Pavan Reddy, MD

Les enquêteurs

  • Chercheur principal: Pavan Reddy, MD, University of Michigan Rogel Cancer Center

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 janvier 2009

Achèvement primaire (Réel)

1 avril 2013

Achèvement de l'étude (Réel)

1 juillet 2013

Dates d'inscription aux études

Première soumission

17 décembre 2008

Première soumission répondant aux critères de contrôle qualité

17 décembre 2008

Première publication (Estimation)

18 décembre 2008

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

11 avril 2014

Dernière mise à jour soumise répondant aux critères de contrôle qualité

5 mars 2014

Dernière vérification

1 mars 2014

Plus d'information

Termes liés à cette étude

Termes MeSH pertinents supplémentaires

Autres numéros d'identification d'étude

  • UMCC 2008.095

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