Clinical trial NCT00789256: Low Dose Melphalan and Bortezomib for AML and High-Risk MDS
Official title: A Pilot Study of Low Dose Melphalan and Bortezomib for Treatment of Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Acute Myelogenous Leukemia
Myelodysplastic Syndromes
Keywords: Acute Myelogenous Leukemia
AML
Myelodysplastic Syndromes
MDS
Melphalan
Bortezomib
Velcade
Lead sponsor: Dartmouth-Hitchcock Medical Center
Sponsor class: OTHER
Collaborators: name: Millennium Pharmaceuticals, Inc.
First posted: 2008-11-11
Enrollment: 26
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the response rate of the combination of bortezomib and melphalan in patients with Acute Myelogenous Leukemia (AML) or high-risk Myelodysplastic Syndromes (MDS).

Detailed description: In patients who develop acute myelogenous leukemia (AML) or a high-risk myelodysplastic syndrome (MDS), the current standard treatment involves multidrug induction chemotherapy utilizing an anthracycline or anthraquinone with cytarabine. While chemotherapy has proven effective at inducing remission in up to 90% of patients, elderly patients fair far worse. In patients over the age of sixty, the disease is not only less responsive to therapy, but an increased number of comorbid conditions makes induction therapy a more dangerous endeavor. Because of this, many patients are not offered standard induction chemotherapy and there is a dearth of viable alternatives for treatment of these otherwise fatal diseases.

Low dose melphalan has previously been shown to be an effective palliative treatment for patients diagnosed with AML and high-risk MDS. It was found to have an overall response rate of 40% in AML patients (30% complete remission and 10% partial remission) and a 57% overall response in high-risk MDS patients (33% complete remission, 5% partial remission, and 19% minor responses). This therapy, while not curative, is one of the few options for patients unable to tolerate more intensive treatment regimens, but desiring a potentially effective palliative regimen.

Bortezomib (VELCADE®) is an intravenously administered reversible, selective inhibitor of the 26S proteosome. Although all of the mechanisms by which this novel drug acts as an antineoplastic agent are not fully understood, in vivo and in vitro studies indicate they ultimately result in the inhibition of the gene expression necessary for cell growth and survival pathways, apoptotic pathways, and cellular adhesion, migration, and angiogenesis mechanisms.

Preclinical and clinical evaluation of the combination of melphalan and bortezomib has demonstrated impressive synergy in refractory multiple myeloma cell lines and patients with myeloma. This study aims to determine if these findings hold true in AML and MDS patients.

Eligibility criteria: Inclusion Criteria:

* Pathologic diagnosis of AML or high-risk MDS Patients with chronic myelomonocytic leukemia or a refractory cytopenia with multilineage dysplasia are eligible if that have one of the following criteria:

  * \>4 units of red blood cells transfused during the previous 3 months
  * platelet count \<50,000/uL
  * absolute neutrophil count \<1000/uL and a recent infection requiring antibiotics
* Patients may either be considered to be poor candidates for standard induction chemotherapy based on reasonable medical evidence or have declined such therapy, but still desire palliative treatment beyond that of best supportive care
* Primary refractory disease or have disease that has relapsed after prior cytoxic therapy
* Karnofsky performance status of \>50%
* Patients may receive prior growth factor therapy
* Patients who received prior therapies (ex. melphalan, 5-azacitidine, low-dose cytarabine) to control their MDS or AML prior to registration (Stratum 2), but are clearly nonresponders are eligible for enrollment if expected toxicity of the prior therapy has resolved
* Voluntary written informed consent
* If female, the subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (ie, a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
* If male, the subject agrees to use an acceptable method for contraception for the duration of the study
* Patients that have been previously treated will be eligible for study if:

  1. the previous therapy was ineffective and
  2. all expected toxicity of the previous treatment has resolved
  3. In general the following guidelines regarding the elapsed time from previous treatment to eligibility should be followed

     1. High intensity cytotoxic treatment (7\&3 induction, High Dose Ara-C): 4 weeks
     2. Hematopoeitic growth factors: no delay required
     3. Low intensity treatment (such as oral melphalan or hydrea, low dose cytarabine or 5-azacitidine) No delay required if expected toxicity has resolved and regimen ineffective

Exclusion Criteria:

* AML FAB M3
* No concomitant malignancy other than a curatively treated carcinoma in situ of cervix or basal or squamous cell carcinoma of the skin
* Active, uncontrolled infections
* Chronic liver disease not due to AML, or bilirubin \>2.0mg/dL
* End stage kidney disease on dialysis
* Active CNS disease. A lumbar puncture prior to treatment is not required and should not be performed in the absence of significant CNS symptoms or signs
* Patient has sensory peripheral neuropathy \> grade 2 or painful peripheral neuropathy \> grade 1 (see appendix A for NCI sensory neuropathy toxicity criteria) within 14 days before enrollment
* Hypersensitivity to bortezomib, boron or mannitol
* Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Primary outcomes:
measure: Response Rate of the Combination of Bortezomib and Melphalan in Patients With AML and High-risk MDS.
timeFrame: Post Cycle 1 through 28 days post-treatment
Secondary outcomes:
measure: Determine Safety Profile of the Combination of Bortezomib and Melphalan.
timeFrame: Start of treatment through 28 days post-treatment
measure: Number of Participants With Correlation Between in Vitro and in Vivo Activity of the Combination of Bortezomib and Melphalan.
timeFrame: Pre-treatment and at complete response
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: Integrated Community Oncology Network
state: Florida
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
Study officials:
affiliation: Dartmouth-Hitchcock Medical Center
name: Marc Gautier, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Integrated Community Oncology Network
name: Jeffrey Bubis, DO
role: PRINCIPAL_INVESTIGATOR
References:
citation: Phillips GL, Reece DE, Shepherd JD, Barnett MJ, Brown RA, Frei-Lahr DA, Klingemann HG, Bolwell BJ, Spinelli JJ, Herzig RH, et al. High-dose cytarabine and daunorubicin induction and postremission chemotherapy for the treatment of acute myelogenous leukemia in adults. Blood. 1991 Apr 1;77(7):1429-35.
citation: Johnson PR, Yin JA. Prognostic factors in elderly patients with acute myeloid leukaemia. Leuk Lymphoma. 1994 Dec;16(1-2):51-6. doi: 10.3109/10428199409114139.
citation: Maslak PG, Weiss MA, Berman E, Yao TJ, Tyson D, Golde DW, Scheinberg DA. Granulocyte colony-stimulating factor following chemotherapy in elderly patients with newly diagnosed acute myelogenous leukemia. Leukemia. 1996 Jan;10(1):32-9.
citation: Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM, Head DR, Appelbaum FR, Willman CL. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. 1997 May 1;89(9):3323-9.
citation: Denzlinger C, Bowen D, Benz D, Gelly K, Brugger W, Kanz L. Low-dose melphalan induces favourable responses in elderly patients with high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia. Br J Haematol. 2000 Jan;108(1):93-5. doi: 10.1046/j.1365-2141.2000.01825.x.
citation: Omoto E, Deguchi S, Takaba S, Kojima K, Yano T, Katayama Y, Sunami K, Takeuchi M, Kimura F, Harada M, Kimura I. Low-dose melphalan for treatment of high-risk myelodysplastic syndromes. Leukemia. 1996 Apr;10(4):609-14.
citation: Mitchell BS. The proteasome--an emerging therapeutic target in cancer. N Engl J Med. 2003 Jun 26;348(26):2597-8. doi: 10.1056/NEJMp030092. No abstract available.
citation: King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science. 1996 Dec 6;274(5293):1652-9. doi: 10.1126/science.274.5293.1652.
citation: Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002 Apr;2(4):301-10. doi: 10.1038/nrc780.
citation: Haefner B. NF-kappa B: arresting a major culprit in cancer. Drug Discov Today. 2002 Jun 15;7(12):653-63. doi: 10.1016/s1359-6446(02)02309-7.
citation: Dokter WH, Tuyt L, Sierdsema SJ, Esselink MT, Vellenga E. The spontaneous expression of interleukin-1 beta and interleukin-6 is associated with spontaneous expression of AP-1 and NF-kappa B transcription factor in acute myeloblastic leukemia cells. Leukemia. 1995 Mar;9(3):425-32.
citation: Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta. 1998 Oct 1;1400(1-3):233-55. doi: 10.1016/s0167-4781(98)00139-0.
citation: Chernov MV, Bean LJ, Lerner N, Stark GR. Regulation of ubiquitination and degradation of p53 in unstressed cells through C-terminal phosphorylation. J Biol Chem. 2001 Aug 24;276(34):31819-24. doi: 10.1074/jbc.M103170200. Epub 2001 Jun 28.
citation: Olsson I, Bergh G, Ehinger M, Gullberg U. Cell differentiation in acute myeloid leukemia. Eur J Haematol. 1996 Jul;57(1):1-16. doi: 10.1111/j.1600-0609.1996.tb00483.x.
citation: Padua RA, Guinn BA, Al-Sabah AI, Smith M, Taylor C, Pettersson T, Ridge S, Carter G, White D, Oscier D, Chevret S, West R. RAS, FMS and p53 mutations and poor clinical outcome in myelodysplasias: a 10-year follow-up. Leukemia. 1998 Jun;12(6):887-92. doi: 10.1038/sj.leu.2401044.
citation: Parry TE. The non-random distribution of point mutations in leukaemia and myelodysplasia--a possible pointer to their aetiology. Leuk Res. 1997 Jun;21(6):559-74. doi: 10.1016/s0145-2126(97)83221-3.
citation: Rosenfeld C, Kantarjian H. Is myelodysplastic related acute myelogenous leukemia a distinct entity from de novo acute myelogenous leukemia? Potential for targeted therapies. Leuk Lymphoma. 2001 May;41(5-6):493-500. doi: 10.3109/10428190109060340.
citation: Slingerland JM, Minden MD, Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991 Apr 1;77(7):1500-7.
citation: Yang, H.H., et al., A phase I/II study of combination treatment with bortezomib and melphalan (Vc+M) in patients with relapsed or refractory multiple myeloma (MM). Proceedings of ASCO, 2003. Abstract 2340.
citation: Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003 Jun 26;348(26):2609-17. doi: 10.1056/NEJMoa030288.
citation: David P. Schenkein, M., Proteosome Inhibition, D. Jeffrey A. Bubis, Editor. 2003:Lebanon, New Hampshire.
citation: Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Lowenberg B, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Wijermans PW, Gore S, Greenberg PL; World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000 Dec 1;96(12):3671-4.
citation: Common Terminology Criteria for Adverse Events. 2003, National Cancer Institute Cancer Therapy Evaluation Program.