Low Dose Melphalan and Bortezomib for AML and High-Risk MDS

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00789256
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 26
• Locations: 2
• Arm: 1
• Duration (Months): 51
• Patients Per Site: 13
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Acute Myelogenous Leukemia; Myelodysplastic Syndromes	Drug: Melphalan; Drug: Bortezomib; Drug: Melphalan and bortezomib	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Low Dose Melphalan and Bortezomib for Treatment of Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndromes
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study treatment All patients will receive the following regimen: 1) Melphalan 2 mg orally, once daily. 2) Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.	Drug: Melphalan; Melphalan: 2mg orally, once daily; Other Names: Velcade ; Drug: Bortezomib; Bortezomib: 1.0mg/M2 IV on days 1, 4, 8, 11; Drug: Melphalan and bortezomib

Outcome Measures

Primary Outcome Measures

1. Response Rate of the Combination of Bortezomib and Melphalan in Patients With AML and High-risk MDS. [Post Cycle 1 through 28 days post-treatment]

   Determine disease response to treatment using Cheson 2000 report of an international working group to standardize response criteria for myelodysplastic syndromes.

Secondary Outcome Measures

1. Determine Safety Profile of the Combination of Bortezomib and Melphalan. [Start of treatment through 28 days post-treatment]

   The safety profile is based on the number of adverse events experienced by participants as reported in the Adverse Events results section for this protocol.

2. Number of Participants With Correlation Between in Vitro and in Vivo Activity of the Combination of Bortezomib and Melphalan. [Pre-treatment and at complete response]

   Leukemic cells will be collected to test the presence of the study drugs using a cell viability assay in vitro and in vivo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

4. High intensity cytotoxic treatment (7&3 induction, High Dose Ara-C): 4 weeks

5. Hematopoeitic growth factors: no delay required

6. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Integrated Community Oncology Network	Jacksonville	Florida	United States	32256
2	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Marc Gautier, MD, Dartmouth-Hitchcock Medical Center
• Principal Investigator: Jeffrey Bubis, DO, Integrated Community Oncology Network

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

• 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. Epub 2001 Jun 28.
• Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, Löwenberg 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.
• Common Terminology Criteria for Adverse Events. 2003, National Cancer Institute Cancer Therapy Evaluation Program.
• David P. Schenkein, M., Proteosome Inhibition, D. Jeffrey A. Bubis, Editor. 2003:Lebanon, New Hampshire.
• 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.
• 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.
• Felix CA. Secondary leukemias induced by topoisomerase-targeted drugs. Biochim Biophys Acta. 1998 Oct 1;1400(1-3):233-55. Review.
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• King RW, Deshaies RJ, Peters JM, Kirschner MW. How proteolysis drives the cell cycle. Science. 1996 Dec 6;274(5293):1652-9. Review.
• 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.
• 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.
• Mitchell BS. The proteasome--an emerging therapeutic target in cancer. N Engl J Med. 2003 Jun 26;348(26):2597-8.
• Olsson I, Bergh G, Ehinger M, Gullberg U. Cell differentiation in acute myeloid leukemia. Eur J Haematol. 1996 Jul;57(1):1-16. Review.
• 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.
• 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.
• 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. Review. Erratum in: Leuk Res 1997 Nov-Dec;21(11-12):1145.
• 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.
• 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.
• 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. Review.
• Slingerland JM, Minden MD, Benchimol S. Mutation of the p53 gene in human acute myelogenous leukemia. Blood. 1991 Apr 1;77(7):1500-7.
• 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.

• Responsible Party: Marc Gautier, Associate Director, Regional Affairs at Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT00789256
• Other Study ID Numbers: D0337
• First Posted: Nov 11, 2008
• Last Update Posted: Oct 24, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Marc Gautier, Associate Director, Regional Affairs at Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center: Acute Myelogenous Leukemia; AML; Myelodysplastic Syndromes; MDS; Melphalan; Bortezomib; Velcade
• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Bortezomib; Melphalan

Study Results

Participant Flow

Recruitment Details	Recruitment for this study was open at Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center - Manchester (NH), White River Junction Veteran's Administration Medical Center, and Integrated Community Oncology Network - Florida.
Pre-assignment Detail	The intention was to accrue 13 evaluable patients for the initial stages of this study. For each strata, if there were no responders within the first 13 patients, the study would statistically rule-out a response rate of 20% or more with p = 0.05. If there were any responders, the study would accrue an additional 11 evaluable patients.

Arm/Group Title	Strata 1	Strata 2
Arm/Group Description	Includes patients who have not seen prior medical intervention for their disease. Patients assigned to Strata 1 will receive Melphalan 2mg orally, once daily and Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.	Includes patients who have received prior medical intervention for their disease. Patients assigned to Strata 2 will receive Melphalan 2mg orally, once daily and Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.
Period Title: Overall Study
STARTED	14	12
COMPLETED	14	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Strata 1	Strata 2	Total
Arm/Group Description	Group 1 will include patients who have not seen prior medical intervention for their disease.	will include patients who have received prior medical intervention for their disease.	Total of all reporting groups
Overall Participants	14	12	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	5 41.7%	5 19.2%
>=65 years	14 100%	7 58.3%	21 80.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73 (4.53)	68 (9.07)	71 (7.69)
Sex: Female, Male (Count of Participants)
Female	6 42.9%	3 25%	9 34.6%
Male	8 57.1%	9 75%	17 65.4%
Region of Enrollment (participants) [Number]
United States	14 100%	12 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate of the Combination of Bortezomib and Melphalan in Patients With AML and High-risk MDS.
Description	Determine disease response to treatment using Cheson 2000 report of an international working group to standardize response criteria for myelodysplastic syndromes.
Time Frame	Post Cycle 1 through 28 days post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Strata 1	Strata 2
Arm/Group Description	Group 1 will include patients who have not seen prior medical intervention for their disease.	will include patients who have received prior medical intervention for their disease.
Measure Participants	14	12
Number [participants]	5 35.7%	2 16.7%

2. Secondary Outcome

Title	Determine Safety Profile of the Combination of Bortezomib and Melphalan.
Description	The safety profile is based on the number of adverse events experienced by participants as reported in the Adverse Events results section for this protocol.
Time Frame	Start of treatment through 28 days post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Treatment
Arm/Group Description	All patients will receive the following regimen: 1) Melphalan 2 mg orally, once daily. 2) Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11. Melphalan: Melphalan: 2mg orally, once daily Bortezomib: Bortezomib: 1.0mg/M2 IV on days 1, 4, 8, 11 Melphalan and bortezomib
Measure Participants	26
Reported adverse events	24 171.4%
Without reportable adverse event	2 14.3%

3. Secondary Outcome

Title	Number of Participants With Correlation Between in Vitro and in Vivo Activity of the Combination of Bortezomib and Melphalan.
Description	Leukemic cells will be collected to test the presence of the study drugs using a cell viability assay in vitro and in vivo.
Time Frame	Pre-treatment and at complete response

Outcome Measure Data

Analysis Population Description

No data was collected and these results were not obtained. The collaborating laboratory with the capability to perform the assay with leukemic cells was not available to analyze the samples.

Arm/Group Title	Strata 1	Strata 2
Arm/Group Description	Includes patients who have not seen prior medical intervention for their disease. Patients assigned to Strata 1 will receive Melphalan 2mg orally, once daily and Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.	Includes patients who have received prior medical intervention for their disease. Patients assigned to Strata 2 will receive Melphalan 2mg orally, once daily and Bortezomib 1.0 mg/M2 IV on days 1, 4, 8, 11.
Measure Participants	0	0

Adverse Events

Arm/Group Title	Strata 1		Strata 2
Arm/Group Description	Group 1 will include patients who have not seen prior medical intervention for their disease.		will include patients who have received prior medical intervention for their disease.
All Cause Mortality
	Strata 1		Strata 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Strata 1		Strata 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		3/12 (25%)
Cardiac disorders
Myocardial Infarction	0/14 (0%)	0	1/12 (8.3%)	1
Infections and infestations
Febrile neutropenia	1/14 (7.1%)	1	0/12 (0%)	0
Legionella Pneumonia	0/14 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
CNS Hemorrhage	0/14 (0%)	0	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Strata 1		Strata 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/14 (100%)		10/12 (83.3%)
Blood and lymphatic system disorders
Neutropenia	10/14 (71.4%)	10	6/12 (50%)	6
Thrombocytopenia	10/14 (71.4%)	10	7/12 (58.3%)	7
Anemia	5/14 (35.7%)	5	3/12 (25%)	3
Pancytopenia	1/14 (7.1%)	1	0/12 (0%)	0
Cardiac disorders
Atrial fibrillation	2/14 (14.3%)	2	0/12 (0%)	0
General disorders
Fatigue	1/14 (7.1%)	1	0/12 (0%)	0
Generalized weakness	1/14 (7.1%)	1	0/12 (0%)	0
Infections and infestations
Pneumonia	2/14 (14.3%)	2	3/12 (25%)	3
Urinary Tract Infection	1/14 (7.1%)	1	0/12 (0%)	0
Zoster reactivation	1/14 (7.1%)	1	0/12 (0%)	0
Infection NOS	1/14 (7.1%)	1	0/12 (0%)	0
Cellulitis	0/14 (0%)	0	1/12 (8.3%)	1
Febrile neutropenia	3/14 (21.4%)	3	1/12 (8.3%)	1
Metabolism and nutrition disorders
Hypokalemia	0/14 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Neuropathy	1/14 (7.1%)	1	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/14 (14.3%)	2	0/12 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/14 (0%)	0	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.