Vorinostat Combined With Gemtuzumab Ozogamicin, Idarubicin and Cytarabine in Acute Myeloid Leukemia

NCT01039363 | Unknown Phase 2

• 1 other identifier: 2009-08-029
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

The prognosis of elderly patients with relapsed or refractory acute myeloid leukemia (AML) is grave. Because of their chronological age and/or the presence of multiple co-morbidities, treatment-related mortality in elderly patients with AML is quite high although higher intensive treatment is mandatory to overcome chemoresistant characteristic of their disease. Several regimens have been evaluated as salvage chemotherapy for relapsed or refractory AML such as Mitoxantrone/High dose Cytarabine or Amsacrine/High dose Cytarabine. These regimens could achieve complete remission (CR) in a part of patients, but resulted in higher treatment related mortality (TRM). Accordingly, less intensive salvage regimen is needed for elderly patients with relapsed or refractory AML. The activity of histone deacetylase (HDAC) inhibitor, Vorinostat or Suberoylanilide hydroxamic acid (SAHA), against AML has been suggested in cell line models and in animal model as well as in a phase 1 trial. The phase 1 study determined the MTD of oral Vorinostat as 200mg twice daily or 250mg thrice daily. In addition, the phase 1 trial showed the antitumor activity of Vorinostat with 17% of response rate in patients with advanced leukemia or myelodysplastic syndrome (MDS). Accordingly, further study is recommended to demonstrate the clinical activity of Vorinostat in AML. In terms of the combining drug with Vorinostat, anthracycline is one of the best candidate. A in vitro study demonstrated that the combination of anthracycline (esp. idarubicin) with HDAC inhibitor have significant clinical activity against leukemia. Another candidate is Gemtuzumab ozogamicin, which is a calicheamicin-conjugated antibody directed against CD33 antigen on AML blasts. The U.S. FDA also approved the use of GO in relapsed AML as a monotherapy. A study also showed that the combinational therapy of GO with attenuated doses of standard induction chemotherapy could successfully induce CR without increasing treatment-related mortality in AML patients aged 55 or older. A in vitro study reported that HDAC inhibitor valproic acid augmented the clinical activity of GO toward CD33+ AML cells. The study demonstrated that the strategy using HDAC inhibitor together with GO could potentially induce synergistic proapoptotic activity against AML blasts without increasing toxicity. In our center, so far we treated relapsed or refractory AML patients using the salvage regimen including GO (3mg/m2/dayx1day) plus attenuated Idarubicin/Cytarabine (Idarubicin 12mg/m2/day for 2 days and intermediate dose Cytarabine). So far, the CR rate from the regimen is around 50% without increasing TRM. Accordingly, we will determine the efficacy and toxicity of Vorinostat-incorporating salvage regimen based on the GO+IA chemotherapy in patients 50 years old or older with relapsed or refractory AML.

Conditions

Acute Myeloid Leukemia

Keywords

Relapse or refractory acute myeloid leukemia

Outcome Measures

Primary Outcomes (1)

• Progression-free survival

Secondary Outcomes (1)

• response rate

Study Arms (1)

Vorinostat

EXPERIMENTAL

Vorinostat combined with salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat maintenance

Drug: Salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat

Interventions

Salvage reinduction chemotherapy including Gemtuzumab ozogamicin, Idarubicin and Cytarabine and Vorinostat DRUG

Salvage reinduction therapy: Vorinostat 200mg BID po (D1-14) Gemtuzumab ozogamicin 3 mg/m2 once (D1) Idarubicin 12mg/m2 for 2 days (D2-3) Cytarabine 500mg/m2 bid IV for 5 days (D2-6) Maintenance: Once achieved CR, then Vorinostat 200mg BID po for 2 weeks, then 1 week's rest (1 cycle) for 11 cycles * Vorinostat should be stopped at least 2 weeks ahead of starting of consolidation therapy. * Gemtuzumab will be omitted in a consolidation schedule. * Allogeneic hematopoietic stem cell transplantation (HSCT) can be performed if HLA-matched sibling or unrelated donor is available. Vorinostat will be stopped 2 weeks prior to starting of conditioning regimen for allogeneic HSCT.

Vorinostat

Eligibility Criteria

• Age: 50 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \> 50 years.
• ECOG Performance Status of 0, 1 or 2
• Life expectancy of at least 12 weeks.
• Subjects in relapse or refractory after any kinds of chemotherapy for acute myeloid leukemia expressing CD33 antigen on ≥ 50% of myeloblasts.
• Adequate liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days and adequate bone marrow within 14 days prior to screening:
• Total bilirubin \< 1.5 times the upper limit of normal
• ALT and AST \< 2.5 x upper limit of normal
• Alkaline phosphatase \< 4 x ULN
• PT-INR/PTT \< 1.5 x upper limit of normal \[Patients who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists.\]
• Serum creatinine \< 1.5 x upper limit of normal.
• Signed and dated informed consent before the start of specific protocol procedures.

You may not qualify if:

• History of cardiac disease: congestive heart failure \>NYHA class 3 or 4; active CAD (MI more than 6 mo prior to study entry is allowed); cardiac arrythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension.
• History of HIV infection or chronic hepatitis B or C (except the case receiving Lamivudine or entecavir and in control of HBV infection)
• Active clinically serious infections (\> grade 2 NCI-CTC version 3.0)
• Patients with seizure disorder requiring medication (such as anti-epileptics)
• Patients with evidence or history of bleeding diasthesis before diagnosis of acute myeloid leukemia
• Patients undergoing renal dialysis
• Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry.
• Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed). Major surgery within 4 weeks of start of study
• Investigational drug therapy outside of this trial during or within 4 weeks of study entry
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
• Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study, such as Alzheimer's disease or dementia
• Patients unable to swallow oral medications.

Sponsors & Collaborators

• Samsung Medical Center: lead

Study Sites (1)

Samsung Medical Center

Seoul, 135-710, South Korea

Location

Related Publications (7)

• Garcia-Manero G, Yang H, Bueso-Ramos C, Ferrajoli A, Cortes J, Wierda WG, Faderl S, Koller C, Morris G, Rosner G, Loboda A, Fantin VR, Randolph SS, Hardwick JS, Reilly JF, Chen C, Ricker JL, Secrist JP, Richon VM, Frankel SR, Kantarjian HM. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008 Feb 1;111(3):1060-6. doi: 10.1182/blood-2007-06-098061. Epub 2007 Oct 25.

  PMID: 17962510 BACKGROUND

• Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001 Jun;7(6):1490-6.

  PMID: 11410481 BACKGROUND

• Eom KS, Kim HJ, Min WS, Lee S, Min CK, Cho BS, Kim SY, Kim YJ, Lee DG, Choi SM, Cho SG, Kim DW, Lee JW, Shin WS, Kim CC. Gemtuzumab ozogamicin in combination with attenuated doses of standard induction chemotherapy can successfully induce complete remission without increasing toxicity in patients with acute myeloid leukemia aged 55 or older. Eur J Haematol. 2007 Nov;79(5):398-404. doi: 10.1111/j.1600-0609.2007.00946.x. Epub 2007 Oct 4.

  PMID: 17916082 BACKGROUND

• Johnstone RW. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov. 2002 Apr;1(4):287-99. doi: 10.1038/nrd772.

  PMID: 12120280 BACKGROUND

• Nimmanapalli R, Fuino L, Stobaugh C, Richon V, Bhalla K. Cotreatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) enhances imatinib-induced apoptosis of Bcr-Abl-positive human acute leukemia cells. Blood. 2003 Apr 15;101(8):3236-9. doi: 10.1182/blood-2002-08-2675. Epub 2002 Nov 21.

  PMID: 12446442 BACKGROUND

• Sanchez-Gonzalez B, Yang H, Bueso-Ramos C, Hoshino K, Quintas-Cardama A, Richon VM, Garcia-Manero G. Antileukemia activity of the combination of an anthracycline with a histone deacetylase inhibitor. Blood. 2006 Aug 15;108(4):1174-82. doi: 10.1182/blood-2005-09-008086. Epub 2006 May 4.

  PMID: 16675713 BACKGROUND

• ten Cate B, Samplonius DF, Bijma T, de Leij LF, Helfrich W, Bremer E. The histone deacetylase inhibitor valproic acid potently augments gemtuzumab ozogamicin-induced apoptosis in acute myeloid leukemic cells. Leukemia. 2007 Feb;21(2):248-52. doi: 10.1038/sj.leu.2404477. Epub 2006 Nov 23.

  PMID: 17122863 BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Recurrence

Interventions

Idarubicin; Cytarabine; Vorinostat

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids

Study Officials

• Dong Hwan Kim, M.D.,Ph.D.

  Division of Hematology and Oncology/Samsung Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Dong Hwan Kim, M.D.,Ph.D.

CONTACT

+82-2-3410-1768; dr.dennis.kim@samsung.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: December 23, 2009
• First Posted: December 25, 2009
• Last Updated: December 25, 2009

Record last verified: 2009-10

Locations

KR (1)