Phase I/II Trial of Redox Regulation in Patients With Relapsed or Refractory CD20+ NHL

Phase 2TerminatedNCT00089284

Northwestern University30 enrolled

Overview

Monoclonal antibodies such as rituximab and yttrium Y 90 ibritumomab tiuxetan can locate cancer cells and either kill them or deliver radioactive cancer-killing substances to them without harming normal cells. Motexafin gadolinium may increase the effectiveness of yttrium Y 90 ibritumomab tiuxetan by making the cancer cells more sensitive to the drug. This phase I/II trial is studying the side effects and best dose of motexafin gadolinium when administered with rituximab and yttrium Y 90 ibritumomab tiuxetan and to see how well they work in treating patients with stage II, stage III, or stage IV relapsed or refractory non-Hodgkin's lymphoma.

This is a phase I, dose-escalation study of motexafin gadolinium followed by a phase II study. Patients are stratified according to extent of lymphomatous involvement (≤ 5% vs \> 5 but ≤ 24% of cellular elements). Cohorts of 3-6 patients in each stratum receive escalating doses of motexafin gadolinium until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 2 of 6 patients experience dose-limiting toxicity (DLT) OR the dose preceding that at which 2 of 3 or 3 of 6 patients experience DLT. * Once the MTD is determined, additional patients are treated at that dose level as in phase I. Patients are followed weekly for 3 months and then monthly for 5 years.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Hodgkin's Lymphoma (NHL)

Interventions

RituxanDRUG

Patients receive motexafin gadolinium IV over 30-60 minutes on days 1-4 and 8-11. At least 1 hour after motexafin gadolinium administration, patients receive rituximab IV over 3-4 hours on days 1 and 8. After rituximab administration, patients receive indium In 111 ibritumomab tiuxetan IV over 10 minutes on day 1. Patients undergo gamma camera scanning on days 1, 2\*, 4\*, and 7 and dosimetry on days 2, 4, and 7. If safe biodistribution is demonstrated, patients receive yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes (after rituximab administration) on day 8.

motexafin gadoliniumDRUG

111Indium-Zevalin and 90Yttrium-ZevalinDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

DISEASE CHARACTERISTICS: * Histologically confirmed diagnosis of one of the following: * Low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL) * The following histologies are eligible: * Small lymphocytic lymphoma * Lymphoplasmacytoid lymphoma * Follicular center grades 1, 2, or 3 lymphoma * Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type * Nodal marginal zone B-cell lymphoma * Relapsed or refractory after 2 prior treatment regimens or 1 anthracycline regimen * Diffuse large B-cell NHL or mantle cell lymphoma in first or second relapse * Transformed NHL, defined as low-grade NHL transformed to diffuse large B-cell lymphoma, with no more than 1 relapse since transformation Age 18 and over Recovered from prior immunotherapy Life expectancy At least 3 months Recovered from prior chemotherapy * More than 4 weeks since prior major surgery and recovered * More than 4 weeks since prior anticancer therapy recovered from prior radiotherapy Exclusion criteria: No major bleeding within the past 4 weeks No uncontrolled hypertension No stroke within the past 4 weeks * No active infection * No other active nonmalignant disease * No known G6PD deficiency * No history of porphyria * No other condition that would preclude study participation * No human anti-mouse antibodies * No known history of HIV * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No prior radioimmunoconjugate therapy * No prior exposure to murine antibodies other than rituximab * More than 4 weeks since prior rituximab * No history of failed stem cell collection

Outcomes

Primary Outcomes

Dose Limiting Toxicities (DLT)

The number of Dose Limiting Toxicities (DLT) observed in patients treated with Motexafin Gadolinium at different dose levels in combination with Rituxan, Indium-Zevalin, and 90Yttrium-Zevalin was used to determine the Maximum Tolerated Dose (MTD) to be used for phase II of the study. The number of dose-limiting toxicities observed in each cohort of patients determined whether to continue dose escalation. Each cohort = at least 3 patients. All toxicities will be graded according to the NCI Common Toxicity Criteria, version 2.0, with a DLT defined as any of the following: Grade 3 or 4 non-hematologic toxicity (other than grade 3 nausea or vomiting). Grade 4 vomiting despite maximal antiemetic support. Grade 4 neutropenia and thrombocytopenia either lasting longer than 14 days-Grade 4 duration will be measured (in days) from the first date in grade 4 to last date in grade 4 after nadir (growth factor and transfusion independent, respectively).

Time frame: Weekly during treatment and continuing up through Day 90

Maximum Tolerated Dose (MTD)

The maximum tolerated dose (MTD) of Motexafin Gadolinium in combination with Rituxan, Indium-Zevalin, and 90Yttrium-Zevalin was determined using a modified Fibonacci phase I study design (with patient allocation based on amount of lymphoma bone marrow involvement) and will be used in phase II of the study. The MTD will be that dose at which 0/3 or 1/6 patients or 2/9 experience a Dose Limiting Toxicity (DLT), with the next higher dose level provoking DLT in 2/3 or 3/6 or 4/9 patients.

Time frame: Weekly during treatment and continuing up through Day 90

Secondary Outcomes

Anti-lymphoma Efficacy

To assess the anti-lymphoma efficacy of the combination of MGd and 90Yttrium-Zevalin therapy. Disease response to treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or complete response/unconfirmed (CRu). The overall response rate (ORR) was then calculated. The time to treatment failure (TTF), overall survival (OS), and duration of response were determined.

Time frame: At 1, 3 and 6 months

Study and Describe the Bio-locationization of Motexafin Gadolinium (MGd) in Tumors Using MRIs

To study the tumor-specific bio-localization of MGd in lymphoma through magnetic resonance imaging (MRI) in a subset of patients. The first 2 patients of each cohort will have MRI imaging to measure if signal intensity, a correlate for MGd uptake, is increased in known areas of lymphomatous involvement.

Time frame: At baseline (pre-treatment) and on Day 4 of treatment

Correlative Laboratory Studies

To explore correlative laboratory studies of MGd (ie, uptake of MGd by peripheral mononuclear cells, effect of MGd upon peripheral lymphocyte subset populations).

Time frame: On Day 1 and 4