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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00723658
• Other study ID #: S0629
• Secondary ID: S0629U10CA032102
• Status: Withdrawn
• Phase: Phase 2
• First received: July 26, 2008
• Last updated: March 5, 2015
• Start date: September 2008

Study information

• Verified date: March 2015
• Source: Southwest Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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 0.

• 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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. primary completion date: May 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Waldenstrom Macroglobulinemia

Intervention

Biological:
• rituximab

Drug:
• bortezomib

• carmustine

• cisplatin

• cyclophosphamide

• cytarabine

• dexamethasone

• doxorubicin hydrochloride

• etoposide

• melphalan

• thalidomide

Procedure:
• autologous-autologous tandem hematopoietic stem cell transplantation

• peripheral blood stem cell transplantation

Locations

Country	Name	City	State
United States	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan
United States	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan
United States	St. Francis Hospital and Health Centers - Beech Grove Campus	Beech Grove	Indiana
United States	CCOP - Dayton	Dayton	Ohio
United States	David L. Rike Cancer Center at Miami Valley Hospital	Dayton	Ohio
United States	Good Samaritan Hospital	Dayton	Ohio
United States	Grandview Hospital	Dayton	Ohio
United States	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Blanchard Valley Medical Associates	Findlay	Ohio
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	Hurley Medical Center	Flint	Michigan
United States	Middletown Regional Hospital	Franklin	Ohio
United States	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center	Hartford	Connecticut
United States	Foote Memorial Hospital	Jackson	Michigan
United States	Charles F. Kettering Memorial Hospital	Kettering	Ohio
United States	Sparrow Regional Cancer Center	Lansing	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	St. Mary Mercy Hospital	Livonia	Michigan
United States	St. Joseph Mercy Oakland	Pontiac	Michigan
United States	Mercy Regional Cancer Center at Mercy Hospital	Port Huron	Michigan
United States	Reid Hospital & Health Care Services	Richmond	Indiana
United States	Seton Cancer Institute at Saint Mary's - Saginaw	Saginaw	Michigan
United States	UVMC Cancer Care Center at Upper Valley Medical Center	Troy	Ohio
United States	St. John Macomb Hospital	Warren	Michigan
United States	Wesley Medical Center	Wichita	Kansas
United States	Clinton Memorial Hospital	Wilmington	Ohio
United States	Ruth G. McMillan Cancer Center at Greene Memorial Hospital	Xenia	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Southwest Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival at 3 years		3 years	No
Secondary	Overall survival		3 years	No
Secondary	Response rate (complete response, very good partial response, and partial response)		3 years	No
Secondary	Standard prognostic factors and other potential correlates that may relate to progression, symptomatic disease, and/or survival		3 years	No
Secondary	Toxicity		3 years	Yes