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

5. marts 2014 opdateret af: 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.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

61

Fase

  • Fase 2
  • Fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Forenede Stater
    • Michigan
      • Ann Arbor, Michigan, Forenede Stater, 48109
        • University of Michigan Cancer Center
    • Missouri
      • St. Louis, Missouri, Forenede Stater, 63110
        • Washington University School of Medicine

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

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.

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: Vorinostat prophylaxis
Vorinostat,combined with standard GVHD prevention medications(tacrolimus, mycophenolate) for adults who received a reduced intensity, related donor stem cell transplant
Medicin: mycophenolat (standard GVHD profylakse)
Mycophenolat begynder på dag 0 med 10 mg/kg/dosis (op til 1 gram pr. dosis) hver 8. time oralt eller intravenøst ​​og vil fortsætte indtil dag 28.
Procedure: 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.

Medicin: 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
Medicin: 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.

Andre navne:
  • ZOLINZA

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
100-day Cumulative Incidence of Grade 2-4 Acute Graft Versus Host Disease (GVHD)
Tidsramme: 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

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Number of Serious Adverse Events
Tidsramme: 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.
Tidsramme: two years
Determine the cumulative incidence of relapse at 2 years.
two years
Percent Survival at 2-years
Tidsramme: two years
To determine 2-year overall survival rate
two years

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Pavan Reddy, MD

Efterforskere

  • Ledende efterforsker: Pavan Reddy, MD, University of Michigan Rogel Cancer Center

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Generelle publikationer

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart

1. januar 2009

Primær færdiggørelse (Faktiske)

1. april 2013

Studieafslutning (Faktiske)

1. juli 2013

Datoer for studieregistrering

Først indsendt

17. december 2008

Først indsendt, der opfyldte QC-kriterier

17. december 2008

Først opslået (Skøn)

18. december 2008

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Skøn)

11. april 2014

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

5. marts 2014

Sidst verificeret

1. marts 2014

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • UMCC 2008.095

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

Kliniske forsøg med Graft vs værtssygdom

Kliniske forsøg med mycophenolat (standard GVHD profylakse)

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