S0629, Observation or Combination Chemotherapy, Bortezomib, Thalidomide, and Rituximab Followed By Two Autologous Peripheral Blood Stem Cell Transplants in Treating Patients With Waldenstrom Macroglobulinemia

Sponsor

Southwest Oncology Group (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00723658

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arms

Patients Per Site

Study Details

Study Description

Brief Summary

RATIONALE: Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. Giving combination chemotherapy together with bortezomib, thalidomide, and rituximab before an autologous peripheral stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as G-CSF, helps stem cells move from the bone marrow to the blood so they can be collected and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

PURPOSE: This observational and phase II trial is studying how well giving combination chemotherapy together with bortezomib, thalidomide, and rituximab followed by two autologous peripheral blood stem cell transplants works in treating patients with Waldenstrom macroglobulinemia.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: rituximab Drug: bortezomib Drug: carmustine Drug: cisplatin Drug: cyclophosphamide Drug: cytarabine Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: etoposide Drug: melphalan Drug: thalidomide Procedure: autologous-autologous tandem hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation	Phase 2

Detailed Description

OBJECTIVES:

Primary

To assess the progression-free and overall survival of patients with symptomatic Waldenstrom macroglobulinemia treated with bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin hydrochloride, cyclophosphamide, and etoposide (VDT-PACE) in combination with rituximab, followed by single or tandem autologous peripheral blood stem cell transplantation and maintenance therapy.
To assess the confirmed and unconfirmed response in patients treated with this regimen.

Secondary

To evaluate the feasibility and toxicity of this regimen in these patients.
To correlate the time to symptom development and overall survival with standard prognostic factors and cytopenias.
To examine the natural history of Waldenstrom macroglobulinemia.
To identify, in a preliminary fashion, biological correlates that may relate to progression or to symptomatic disease.

OUTLINE: This is a multicenter study. Patients with asymptomatic disease at study entry proceed directly to observation. Patients with symptomatic disease at study entry proceed directly to induction therapy.

Observation: Patients with asymptomatic disease undergo observation monthly for 3 months and then every 3 months for up to 3 years. Patients who develop symptomatic disease proceed to induction therapy within 28 days of onset of disease symptoms. Patients who continue to have asymptomatic disease after 3 years of observation are removed from the study.
Induction therapy: Patients receive oral dexamethasone and oral thalidomide on days 1-4; cisplatin IV, doxorubicin hydrochloride IV, cyclophosphamide IV, and etoposide IV continuously on days 1-4; bortezomib IV on days 1, 4, 8, and 11; and rituximab IV on days 1, 8, and 15. Treatment repeats every 6-8 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.
Peripheral blood stem cell (PBSC) collection: Patients receive filgrastim (G-CSF) IV beginning on day 9 of course 1 of induction therapy and continuing until WBC counts are adequate for apheresis. Patients also receive G-CSF IV beginning on day 6 of course 2 of induction therapy and continuing until apheresis is complete.
First autologous PBSC transplantation*: Beginning approximately 4-6 weeks after the completion of induction therapy, patients receive conditioning therapy comprising high-dose melphalan IV and bortezomib IV on days -4 and -1. Patients undergo autologous PBSC transplantation on day 0 NOTE: *Patients who will receive a single transplant (for medical, insurance, or other reasons) will not receive melphalan and bortezomib, but will receive conditioning with carmustine, etoposide, cytarabine, and melphalan (BEAM) and will proceed to Maintenance Therapy.
Second autologous PBSC transplantation: Beginning approximately 56-90 days after the first transplant, patients receive conditioning therapy comprising carmustine IV over 2 hours on day -5; etoposide IV over 1 hour and cytarabine IV over 1 hour on days -5 to -2; and melphalan IV on day -1. Patients undergo autologous PBSC transplantation on day

Maintenance therapy: Beginning after platelet counts recover, patients receive bortezomib IV on days 1, 4, 8, and 11 and rituximab IV over 2 hours on day 11. Treatment repeats every 3 months for 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 6 months for up to 5 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

S0629, Observational Study of Asymptomatic Waldenstrom's Macroglobulinemia and Phase II Study of Tandem Autologous Transplant and Maintenance Treatment for Patients With Symptomatic Disease

Study Start Date :

Sep 1, 2008

Actual Primary Completion Date :

May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Observation Non-symptomatic patients are monitored monthly for 3 months, then every 3 months thereafter.
Experimental: Treatment Symptomatic pts: 2 cycles VTDPACE+R: dex 40 mg PO D1-4 thalid 200 mg PO D1-4 cisplatin 10 mg/m2 IV D1-4 dox 10 mg/m2 IV D1-4 cyclophos 400 mg/m2 IV D1-4 etoposide 40 mg/m2 IV D1-4 bortezomib 1.0 mg/m2 IV D1,4,8,11 ritux 375 mg/m2 IV D1,8,15 lovenox 40 mg/d SQ D1-platelets >50,000/mcl GCSF 10 mcg/kg/d IV D9-WBC <2,000/mcl apheresis >/= 20x10^6 when WBC and CD34 within normal range, up to 4 cycles st Trans: mel 200 mg/m2 IV D-1 bortezomib 1.3 mg/m2 IV D-4, -1 PBSC >/=3.0x10^6/kg CD34 cells IV D0 GCSF 5 mcg/kg/d SQ D6-WBC recovery D5NS 500 ml IV D-1 dex 40 mg/d PO D-4 to -1 ondansetron 24 mg OR granisetron 2 mg PO D-1 nd Trans: BCNU 300 mg/m2 IV D-5 etoposide 200 mg/m2 IV D-5 to -2 AraC 400 mg/m2 IV D-5 to -2 mel 140 mg/m2 IV D-1 PBSC infusion >/=3.0x10^6/kg CD34 cells IV D0 GCSF 5 mcg/kg/d SQ D6-WBC recovery D5NS 150 ml/hr IV D-5 to -1 dex 40 mg/d PO D-4 to -1 ondansetron 24 mg OR granisetron 2 mg PO D-1	Biological: rituximab Drug: bortezomib Drug: carmustine Drug: cisplatin Drug: cyclophosphamide Drug: cytarabine Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: etoposide Drug: melphalan Drug: thalidomide Procedure: autologous-autologous tandem hematopoietic stem cell transplantation Procedure: peripheral blood stem cell transplantation

Arm

Intervention/Treatment

No Intervention: Observation

Non-symptomatic patients are monitored monthly for 3 months, then every 3 months thereafter.

Experimental: Treatment

Symptomatic pts: 2 cycles VTDPACE+R: dex 40 mg PO D1-4 thalid 200 mg PO D1-4 cisplatin 10 mg/m2 IV D1-4 dox 10 mg/m2 IV D1-4 cyclophos 400 mg/m2 IV D1-4 etoposide 40 mg/m2 IV D1-4 bortezomib 1.0 mg/m2 IV D1,4,8,11 ritux 375 mg/m2 IV D1,8,15 lovenox 40 mg/d SQ D1-platelets >50,000/mcl GCSF 10 mcg/kg/d IV D9-WBC <2,000/mcl apheresis >/= 20x10^6 when WBC and CD34 within normal range, up to 4 cycles st Trans: mel 200 mg/m2 IV D-1 bortezomib 1.3 mg/m2 IV D-4, -1 PBSC >/=3.0x10^6/kg CD34 cells IV D0 GCSF 5 mcg/kg/d SQ D6-WBC recovery D5NS 500 ml IV D-1 dex 40 mg/d PO D-4 to -1 ondansetron 24 mg OR granisetron 2 mg PO D-1 nd Trans: BCNU 300 mg/m2 IV D-5 etoposide 200 mg/m2 IV D-5 to -2 AraC 400 mg/m2 IV D-5 to -2 mel 140 mg/m2 IV D-1 PBSC infusion >/=3.0x10^6/kg CD34 cells IV D0 GCSF 5 mcg/kg/d SQ D6-WBC recovery D5NS 150 ml/hr IV D-5 to -1 dex 40 mg/d PO D-4 to -1 ondansetron 24 mg OR granisetron 2 mg PO D-1

Biological: rituximab

Drug: bortezomib

Drug: carmustine

Drug: cisplatin

Drug: cyclophosphamide

Drug: cytarabine

Drug: dexamethasone

Drug: doxorubicin hydrochloride

Drug: etoposide

Drug: melphalan

Drug: thalidomide

Procedure: autologous-autologous tandem hematopoietic stem cell transplantation

Procedure: peripheral blood stem cell transplantation

Outcome Measures

Primary Outcome Measures

Progression-free survival at 3 years [3 years]

Secondary Outcome Measures

Overall survival [3 years]
Response rate (complete response, very good partial response, and partial response) [3 years]
Standard prognostic factors and other potential correlates that may relate to progression, symptomatic disease, and/or survival [3 years]
Toxicity [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of Waldenstrom macroglobulinemia (WM)
Measurable disease as determined by IgM protein quantification
Must be registered to the treatment portion of the study within 28 days of experiencing disease-related symptoms* AND must present with ≥ 1 of the following disease-related symptoms:
Hemoglobin ≤ 11 g/dL
Platelet count ≤ 100,000/mm³
Marked tumor mass, defined as lymphadenopathy > 2 cm, palpable hepatomegaly, splenomegaly, or significant marrow involvement (> 50%)
Serum albumin < 2.5 g/dL
Persistently elevated beta-2-microglobulin > 3.0 mg/L in the absence of renal impairment or active infections
Presence of B symptoms (i.e., fever, night sweats, or weight loss of > 10% from baseline)
Appearance of new or worsening neuropathy manifested by numbness and tingling or pain
Symptomatic cryoglobulinemia (i.e., Raynaud phenomenon, skin ulcers, cold urticaria, or skin necrosis)
Symptoms of hyperviscosity, if measured viscosity > 4 cp (i.e., new headaches, vertigo, ataxia, dizziness with or without evident causes of changes in funduscopic exam, including retinal vein engorgement, hemorrhages, or exudates)
NOTE: *Appearance of any of the above symptoms caused by WM with no other obvious cause is a trigger for treatment initiation. Symptoms need not persist for any specified time frame.

PATIENT CHARACTERISTICS:

Zubrod performance status 0-2 (Zubrod performance status 3 allowed provided it is based solely on morbidity due to WM)
ANC > 1,500/mm³ (unless more marked cytopenias can be explained by marked marrow involvement or autoimmune myelosuppression)
Serum creatinine < 3 mg/dL
Creatinine clearance > 30 mL/min
SGOT/SGPT < 2 times upper limit of normal
Direct bilirubin < 2.0 mg/dL
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception according to the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®) program
Ejection fraction ≥ 50% by ECHO or MUGA scan
Patients with evidence of amyloidosis (i.e., periorbital perforation, proteinuria not attributable to Bence-Jones protein, unexplained arrhythmias, increased liver function tests, peripheral neuropathy, carpal tunnel syndrome, and/or macroglossia) must have an ECHO, rather than MUGA, performed to evaluate for cardiac amyloidosis (septal thickness, diastolic dysfunction, granular sparkling, or low-voltage QRS complexes)
No myocardial infarction within the past 6 months
No unstable angina
No difficult-to-control congestive heart failure or cardiac arrhythmias
No uncontrolled hypertension
No peripheral neuropathy ≥ grade 2
No history of multi-infarced dementia or multiple strokes
No known hypersensitivity to boron or mannitol
No hepatitis B or C positivity
No HIV positivity
No other prior malignancy within the past 5 years except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

At least 28 days since prior chemotherapy and/or radiotherapy and recovered
No prior bortezomib
No concurrent glucocorticoids unless used to control autoimmune disease associated with WM
Concurrent participation in the Myeloma Specimen Repository study allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center	Hartford	Connecticut	United States	06105
2	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana	United States	46107
3	Reid Hospital & Health Care Services	Richmond	Indiana	United States	47374
4	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
5	Wesley Medical Center	Wichita	Kansas	United States	67214
6	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
7	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
8	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
9	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
10	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
11	Hurley Medical Center	Flint	Michigan	United States	48503
12	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
13	Foote Memorial Hospital	Jackson	Michigan	United States	49201
14	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
15	St. Mary Mercy Hospital	Livonia	Michigan	United States	48154
16	St. Joseph Mercy Oakland	Pontiac	Michigan	United States	48341-2985
17	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan	United States	48060
18	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan	United States	48601
19	St. John Macomb Hospital	Warren	Michigan	United States	48093
20	Grandview Hospital	Dayton	Ohio	United States	45405
21	Good Samaritan Hospital	Dayton	Ohio	United States	45406
22	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio	United States	45409
23	CCOP - Dayton	Dayton	Ohio	United States	45420
24	Blanchard Valley Medical Associates	Findlay	Ohio	United States	45840
25	Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
26	Charles F. Kettering Memorial Hospital	Kettering	Ohio	United States	45429
27	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio	United States	45373-1300
28	Clinton Memorial Hospital	Wilmington	Ohio	United States	45177
29	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio	United States	45385