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Bortezomib, Vorinostat and Dexamethasone for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

3 december 2017 bijgewerkt door: Masonic Cancer Center, University of Minnesota

A Therapeutic Trial of Bortezomib (Velcade), Vorinostat (SAHA) and Dexamethasone for Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL)

Both of bortezomib and vorinostat have identified Phase II doses for pediatric and adult patients of which no grade 4 dose limiting toxicities have been observed in prior studies. The pre-clinical synergy of these 2 agents when used in combination along with the lack of over-riding toxicities and different mechanisms of action provide strong rationale for a clinical trial investigating bortezomib and vorinostat in combination. This trial will use the identified Phase II dose which is at or below the maximum tolerated dose for both agents which have very acceptable toxicity profiles and such should prove feasible and tolerable in this relapsed/refractory ALL population.

Studie Overzicht

Gedetailleerde beschrijving

This is a phase II study of bortezomib 1.3 mg/m^2 by intravenous pyelogram (IVP) on days 1, 4, 8, and 11, vorinostat 180 mg/m^2 by mouth (PO) per day (not to exceed 400 mg per day) days 1-14, and dexamethasone 6 mg/m^2 PO days 4-15 for the treatment of relapsed/refractory acute lymphoblastic leukemia (ALL). No more than 3 treatment courses may be given.

Studietype

Ingrijpend

Inschrijving (Werkelijk)

2

Fase

  • Fase 2

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studie Locaties

    • Minnesota
      • Minneapolis, Minnesota, Verenigde Staten, 55455
        • Masonic Cancer Center, University if Minnesota

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

2 jaar tot 30 jaar (Kind, Volwassen)

Accepteert gezonde vrijwilligers

Nee

Geslachten die in aanmerking komen voor studie

Allemaal

Beschrijving

Inclusion Criteria:

  • Diagnosis of lymphoblastic lymphoma or acute lymphoblastic leukemia (ALL) with ≥ 5% blasts in the bone marrow (M2/M3) with or without extramedullary disease that meets one of the following criteria:

    • Refractory Disease/Induction Failure: Failure to achieve initial remission after 2 attempts of standard induction therapy
    • Relapsed Disease: Patients in relapse #1 or higher for whom standard curative therapies or therapies to prolong survival do not exist.

Patients who are Philadelphia chromosome-positive (Ph + ALL) are eligible provided they are not imatinib resistant or intolerant.

Patients with CNS positive disease will be eligible.

  • Age 2 to 30 years
  • Karnofsky ≥ 50% for patients 16 years and older and Lansky status ≥ 50 for patients under 16 years of age.
  • Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator.
  • Have acceptable organ function as defined within 7 days of starting treatment:

    • Renal: creatinine clearance ≥ 70ml/min/1.73m^2 or serum creatinine based on age/gender as follows: Maximum serum creatinine (mg/dl) 0.8 for 2 years to <6 years; 1.0 for 6 years to <10 years; 1.2 for 10 years to <13 years; 1.5 male and 1.4 female for 13 years to <16 years; 1.7 male and 1.4 female for ≥ 16 years
    • Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5x upper limit of normal (ULN) for age.
    • Cardiac: left ventricular ejection fraction ≥ 40% by echocardiogram/multi gated acquisition scan (ECHO/MUGA). Normal QTc on electrocardiogram (EKG) (not to exceed upper limit of normal - men: 430 milliseconds (ms); women: 450 ms; children up to 15 years: 440 ms).
  • Prior Therapy:

    • Patients must have recovered from the non-hematologic toxic effects of all prior therapy before entry onto this trial. Recovery is defined as a Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 toxicity grade <2, unless otherwise specified in the Inclusion and Exclusion Criteria.

Cytotoxic therapy: Patients must have had their last dose of chemotherapy at least two weeks prior to study entry.

  • Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor and at least 14 days since pegfilgrastim (Neulasta®) administration.
  • Biologic (anti-neoplastic) therapy: At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Monoclonal antibodies: At least 3 half-lives of the antibody after the last administration of a monoclonal antibody.
  • Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of Graft-versus-Host Disease (GVHD).

    • Women of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of treatment and for 2 months after the last dose of chemotherapy. Sexually active men must agree to use barrier contraceptive for the duration of treatment and for 2 months after the last dose of chemotherapy.
    • Voluntary written consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject/guardian at any time without prejudice to future medical care.

Exclusion Criteria:

  • Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus and there is no information on the excretion of agents into breast milk. Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for surgically sterilized women.
  • Known hypersensitivity to bortezomib, boron or mannitol or any of the agents or their ingredients used in this study.
  • Inability to swallow capsules.
  • Grade 2 or greater peripheral neuropathy within 14 days before study registration.
  • Patients with untreated positive blood cultures or progressive infections as assessed by radiographic studies.
  • Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (appendix VI), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
  • Serious concomitant medical or psychiatric disorders (e.g., active infection, uncontrolled diabetes) that, in the opinion of the investigator, would compromise the safety of the patient or likely to interfere with participation in this clinical study.
  • Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.
  • Patient has received investigational drugs within the 14 days before study registration.
  • Radiation therapy within 3 weeks before registration. Enrollment of patients who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

  • Primair doel: Behandeling
  • Toewijzing: NVT
  • Interventioneel model: Opdracht voor een enkele groep
  • Masker: Geen (open label)

Wapens en interventies

Deelnemersgroep / Arm
Interventie / Behandeling
Experimenteel: Chemotherapy
Bortezomib IV Vorinostat PO Dexamethasone PO Intrathecal Methotrexate Imatinib Mesylate PO (for Ph+ ALL patients only)
1.3 mg/m^2 by intravenous pyelogram (IVP) over 3-5 seconds on days 1, 4, 8 and 11.
Andere namen:
  • Velcade(R)
180 mg/m^2 (max dose 400mg) by mouth (PO) divided twice a day (BID) on days 1-14
Andere namen:
  • Zolinza
  • suberoylanilide hydroxamzuur (SAHA)
6 mg/m^2 by mouth (PO) divided twice a day (BID) on days 4-15.
Andere namen:
  • Decadron
Intrathecal Methotrexate at age based dose on day 1 (repeat on day 15 or 16 for CNS positive patients only)
Andere namen:
  • amethopterine
  • Trexall

For Ph+ acute lymphoblastic leukemia (ALL) patients only:

Imatinib Mesylate is allowable at 340 mg/m2 PO once a day (rounded to the nearest 100 mg) for age ≤18 years and 400 mg for >18 years on Days 1-16.

Andere namen:
  • Gleevec(R)

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of Subjects Who Achieved Complete Remission of Their Disease
Tijdsspanne: Day 30
Complete Remission (CR): A CR requires that the following be recorded concurrently: an absolute neutrophil count (segs and bands) > 1000/μL, no circulating blasts, platelets > 100,000/μL; adequate bone marrow cellularity with trilineage hematopoiesis, and < 5% marrow leukemia blast cells. All previous extramedullary manifestations of disease must be absent. If patients continue on with treatment, there can be no evidence of recurrence of ALL for at least 4 weeks.
Day 30

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Number of Subjects Experiencing Drug Related Adverse Events
Tijdsspanne: Day 1 of Treatment to 30 Days Post Treatment
To characterize the toxicities of bortezomib, vorinostat and dexamethasone when used in combination. Toxicity will be graded using the NCI's Common Terminology Criteria for Adverse Events (CTCAE 4.0).
Day 1 of Treatment to 30 Days Post Treatment
Number of Subjects With Activated Caspases and Other Regulators of Apoptosis
Tijdsspanne: From Day 1 to 30 Days After Last Dose
Activation of caspases and other regulators of apoptosis in treated blast cells will be determined by Western analysis (correlative lab analysis).
From Day 1 to 30 Days After Last Dose

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Onderzoekers

  • Hoofdonderzoeker: Michael Burke, MD, Masonic Cancer Center, University of Minnesota

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start

1 juni 2011

Primaire voltooiing (Werkelijk)

1 januari 2013

Studie voltooiing (Werkelijk)

1 januari 2013

Studieregistratiedata

Eerst ingediend

9 maart 2011

Eerst ingediend dat voldeed aan de QC-criteria

10 maart 2011

Eerst geplaatst (Schatting)

11 maart 2011

Updates van studierecords

Laatste update geplaatst (Werkelijk)

28 december 2017

Laatste update ingediend die voldeed aan QC-criteria

3 december 2017

Laatst geverifieerd

1 december 2017

Meer informatie

Deze informatie is zonder wijzigingen rechtstreeks van de website clinicaltrials.gov gehaald. Als u verzoeken heeft om uw onderzoeksgegevens te wijzigen, te verwijderen of bij te werken, neem dan contact op met register@clinicaltrials.gov. Zodra er een wijziging wordt doorgevoerd op clinicaltrials.gov, wordt deze ook automatisch bijgewerkt op onze website .

Klinische onderzoeken op Bortezomib

3
Abonneren