Fludarabine and Rituximab With or Without Pixantrone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma

Sponsor

CTI BioPharma (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT00551239

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as fludarabine and pixantrone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving fludarabine together with rituximab is more effective with or without pixantrone in treating indolent non-Hodgkin lymphoma.

PURPOSE: This randomized phase III trial is studying fludarabine and rituximab to compare how well they work with or without pixantrone in treating patients with relapsed or refractory indolent non-Hodgkin lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma	Biological: rituximab Drug: fludarabine phosphate Drug: pixantrone dimaleate	Phase 3

Detailed Description

OBJECTIVES:

Primary

To compare the progression-free survival (PFS) of patients with relapsed or refractory indolent non-Hodgkin lymphoma treated with fludarabine phosphate and rituximab with vs without pixantrone.

Secondary

To compare the overall objective response rate (complete response [CR], unconfirmed complete response [CRu], and partial response [PR]) in these patients.
To compare the CR and CRu rate in these patients.
To compare the duration of response and time to progression in these patients.
To compare the overall survival and disease-specific survival of these patients.
To compare the safety (including cardiac safety) and tolerability of these regimens in these patients.

OUTLINE: This is a multicenter study. Patients are stratified by Follicular Lymphoma International Prognostic Index (FLIPI) score (0 or 1 vs ≥ 2), number of prior treatments (1 or 2 vs > 2), and prior anti-CD20 regimen (yes vs no). Patients are randomized to 1 of 2 treatment arms.

Arm I (control): Patients receive rituximab IV on day 1 and fludarabine phosphate IV on days 2-4. Treatment repeats every 28 days for up to 6 courses* in the absence of unacceptable toxicity or disease progression.
Arm II: Patients receive rituximab and fludarabine phosphate as in arm I. Patients also receive pixantrone IV on day 2. Treatment repeats every 28 days for up to 6 courses* in the absence of unacceptable toxicity or disease progression.

NOTE: *Only patients achieving complete response, unconfirmed complete response, or partial response after 4 courses receive courses 5 and 6.

After completion of study therapy, patients are followed periodically for up to 5 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Primary Purpose:

Treatment

Official Title:

A Randomized Phase III Trial Comparing the Combination of Fludarabine, BBR 2778 (Pixantrone) and Rituximab (FP-R) With the Combination of Fludarabine and Rituximab (F-R) in the Treatment of Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

Study Start Date :

Aug 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I (control) Patients receive rituximab IV on day 1 and fludarabine phosphate IV on days 2-4. Treatment repeats every 28 days for up to 6 courses.	Biological: rituximab Given IV Drug: fludarabine phosphate Given IV
Experimental: Arm II Patients receive rituximab and fludarabine phosphate as in arm I. Patients also receive pixantrone IV on day 2. Treatment repeats every 28 days for up to 6 courses.	Biological: rituximab Given IV Drug: fludarabine phosphate Given IV Drug: pixantrone dimaleate Given IV

Arm

Intervention/Treatment

Active Comparator: Arm I (control)

Patients receive rituximab IV on day 1 and fludarabine phosphate IV on days 2-4. Treatment repeats every 28 days for up to 6 courses.

Biological: rituximab

Given IV

Drug: fludarabine phosphate

Given IV

Experimental: Arm II

Patients receive rituximab and fludarabine phosphate as in arm I. Patients also receive pixantrone IV on day 2. Treatment repeats every 28 days for up to 6 courses.

Biological: rituximab

Given IV

Drug: fludarabine phosphate

Given IV

Drug: pixantrone dimaleate

Given IV

Outcome Measures

Primary Outcome Measures

Progression-free survival []

Secondary Outcome Measures

Complete response and unconfirmed complete response rate at the end of course 4 and at end of treatment []
Overall objective response rate at the end of course 4 and at the end of treatment []
Duration of response []
Time to progression []
Overall survival []
Disease-specific survival []
Safety []

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed relapsed or refractory indolent non-Hodgkin lymphoma (NHL)
Histological assessment must be confirmed by an independent laboratory prior to study randomization
Slides from a biopsy or tissue blocks suitable for review must be available
Tissue samples may be from the original diagnostic specimen if samples were obtained within the past 24 months, or may be from a biopsy at the time of study entry
Re-biopsy must be done prior to study randomization for patients with signs of rapid progression (i.e., lactate dehydrogenase [LDH] level ≥ 2 times upper limit of normal [ULN])
Any stage disease (with or without B symptoms), including the following:
Grade I or II follicular lymphoma, defined as follows:
Grade I follicular center cell lymphoma (formerly known as follicular small cleaved)
Grade II follicular center cell lymphoma (formerly known as follicular mixed)
Small lymphocytic lymphoma or chronic lymphocytic leukemia (CLL)
Patients with CLL must have lymph node involvement that is measurable by radiographic techniques
Extranodal marginal zone B-cell lymphoma (excluding gastric MALT)
Nodal marginal zone B-cell lymphoma (monocytoid B-cell lymphoma)
Splenic marginal zone lymphoma (splenic lymphoma with various lymphocytes)
CD20+ lymphoma (confirmed by immunochemistry)
Measurable disease
At least one objectively bidimensionally measurable lesion as demonstrated by CT scan, spiral CT scan, PET/CT scan, or MRI, that can be followed for response as a target lesion
Patients with only skin lesions or only palpable lymph nodes are not eligible
Patients with spleen or bone marrow as only site of disease are not eligible
Patients must have received at least 1 prior therapy
Prior treatment with fludarabine phosphate, doxorubicin, and/or mitoxantrone is allowed provided there was a response to treatment (complete response [CR], unconfirmed complete response [CRu], or partial response [PR]) that lasted ≥ 8 months from the start of that therapy
Patients refractory to treatments other than anthracycline/anthracenedione, fludarabine phosphate, or rituximab-containing regimens may be eligible for this study
No HIV-related lymphoma
No active CNS involvement based on clinical evaluation
If the patient requires a diagnostic lumbar puncture due to high risk criteria (i.e., sinus involvement, high LDH, high International Prognostic Index score, or bone marrow involvement), intrathecal chemotherapy (which may include methotrexate, cytarabine, and corticosteroids) may be administered according to institutional standards

PATIENT CHARACTERISTICS:

Life expectancy ≥ 3 months
ECOG performance status 0-1
LVEF ≥ 50% by MUGA scan
Creatinine ≤ 1.5 times ULN
Total bilirubin ≤ 1.5 times ULN (CTC grade 1) (patients with Gilbert's syndrome or other hereditary bilirubin defects may be eligible regardless of bilirubin levels)
AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN if there is hepatic involvement with lymphoma)
ANC ≥ 1,500/mm³ (≥ 500/mm³ if bone marrow is involved)
Platelet count ≥ 75,000/mm³ (with no bleeding)
No known hypersensitivity to the study drugs or to their excipients
No known type I hypersensitivity or anaphylactic reactions to murine proteins or to any component of rituximab
No clinically significant cardiovascular abnormalities (i.e., NYHA class III-IV heart disease), including myocardial infarction within the past 6 months, severe arrhythmia, uncontrolled hypertension, or congestive heart failure requiring current active therapy
No concurrent serious (NCI CTCAE grade 3-4) infection, including infection requiring oral antibiotics or deep-seated or systemic mycotic infections
No clinical symptoms suggesting unresolved HIV, hepatitis B, or hepatitis C virus infection
Patients with seropositivity presumed to be due to prior vaccination against hepatitis B virus or resolved infection are eligible
No history of another malignancy except curatively treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in remission, or any other cancer from which the patient has been disease-free for 5 years
No other condition that, in the judgment of the investigator, would place the patient at undue risk, interfere with the results of the study, or make the patient otherwise unsuitable for the study
Not pregnant or nursing
Fertile patients must use effective contraception during and for 6 months after the completion of study treatment

PRIOR CONCURRENT THERAPY:

Recovered from all acute toxicities from prior therapies (except alopecia or grade 1 peripheral neuropathy)
No prior treatment with a cumulative dose of doxorubicin equivalent exceeding 450 mg/m²
More than 4 weeks since prior radiotherapy, chemotherapy, or other therapies for NHL
More than 5 days since prior systemic corticosteroids for treatment of NHL
More than 3 months since prior radioimmunotherapy
More than 4 weeks since prior major thoracic and/or abdominal surgery and recovered
More than 1 week since prior minor surgery and recovered
More than 30 days since prior and no other concurrent investigational drugs
Concurrent corticosteroids (equivalent of 10 mg of prednisone or less per day) allowed provided they are only used to treat concurrent disease (other than NHL)
No other concurrent systemic anticancer therapy
No concurrent radiotherapy to target lesions
Concurrent palliative radiotherapy to preexisting stable sites of nonmeasurable disease allowed