Non-Hodgkin's Lymphoma (NHL)
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGRituxan
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.
DRUGmotexafin gadolinium
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.
DRUG111Indium-Zevalin and 90Yttrium-Zevalin
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.
Sponsors
Robert H. Lurie Cancer Center
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicities (DLT) | Weekly during treatment and continuing up through Day 90 | 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). |
| Maximum Tolerated Dose (MTD) | Weekly during treatment and continuing up through Day 90 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Anti-lymphoma Efficacy | At 1, 3 and 6 months | 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. |
| Study and Describe the Bio-locationization of Motexafin Gadolinium (MGd) in Tumors Using MRIs | At baseline (pre-treatment) and on Day 4 of treatment | 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. |
| Correlative Laboratory Studies | On Day 1 and 4 | To explore correlative laboratory studies of MGd (ie, uptake of MGd by peripheral mononuclear cells, effect of MGd upon peripheral lymphocyte subset populations). |
Countries
United States
Participant flow
Recruitment details
The study was open to accrual between the dates of September 10, 2003 and October 31, 2007 with the first patient enrolled on study October 28, 2003. Patients were recruited from the outpatient Hematology-Oncology clinic at Northwestern Medical Faculty Foundation, and the in-patient Hematology-Oncology service of Northwestern Memorial Hospital.
Pre-assignment details
For phase I, patients were allocated according to the amount of bone marrow involvement they expressed (either ≤ 5% or ≤ 6-24% involvement). Initially, patients were accrued to the first cohort of the ≤ 5% involvement group. After that group moved to the second cohort, patients in the ≤ 6-24% involvement group were enrolled to the first cohort.
Participants by arm
| Arm | Count |
|---|---|
| Phase I: 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement For the phase I dose-escalation portion, patients were allocated based on the amount of lymphoma bone marrow involvement. Initially, enrollment to the first cohort (2.5 mg/kg MGd) was open only to those with ≤ 5% of bone marrow involvement. | 7 |
| Phase I: 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement In the phase I portion of the study, following completion of enrollment of patients with ≤ 5% bone marrow involvement to their first cohort (2.5 mg/kg MGd), patients with 6-24% bone marrow involvement could be enrolled to their first cohort (2.5 mg/kg MGd). | 3 |
| Phase I: 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement After completion of the first cohort (2.5 mg/kg MGd) in the ≤ 5% Bone Marrow Involvement group, patients with ≤ 5% Bone Marrow Involvement were enrolled to the second cohort (3.5 mg/kg MGd). | 6 |
| Phase I: 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement After completion of the second cohort (3.5 mg/kg MGd) in the ≤ 5% Bone Marrow Involvement group, patients with ≤ 5% Bone Marrow Involvement were enrolled to the third cohort (5.0 mg/kg MGd). | 6 |
| Phase II: 5.0 mg/kg MGd & </= 5% Bone Marrow Involvement After completion of the Phase I portion, patients were enrolled to the maximum tolerated dose (MTD) group of 5.0 mg/kg MGd for \</+ 5% Bone Marrow Involvement. | 8 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse event before starting treatment | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Phase I: 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Phase I: 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Phase I: 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Phase I: 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Phase II: 5.0 mg/kg MGd & </= 5% Bone Marrow Involvement | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 4 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 2 Participants | 3 Participants | 4 Participants | 4 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 3 Participants | 5 Participants | 6 Participants | 8 Participants | 28 Participants |
| Region of Enrollment United States | 7 participants | 3 participants | 6 participants | 6 participants | 8 participants | 30 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 5 Participants | 15 Participants |
| Sex: Female, Male Male | 4 Participants | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 3 / 3 | 6 / 6 | 13 / 13 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 7 | 1 / 3 | 2 / 6 | 4 / 13 | 0 / 0 | 0 / 0 |
Outcome results
Primary
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
Population: Only patients enrolled during the phase I portion of this trial were analyzed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Dose Limiting Toxicities (DLT) | 0 Dose-Limiting Toxicities |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Dose Limiting Toxicities (DLT) | 0 Dose-Limiting Toxicities |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Dose Limiting Toxicities (DLT) | 0 Dose-Limiting Toxicities |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Dose Limiting Toxicities (DLT) | 0 Dose-Limiting Toxicities |
Primary
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
Population: Phase I arms were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Maximum Tolerated Dose (MTD) | 5.0 mg/kg |
Secondary
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
Population: All phase I and phase II patients were evaluated for response to treatment (anti-lymphoma efficacy). For the cohort with ≤ 5% bone marrow involvement treated at the 5.0 mg/kg MGd dose, results are based on 6 phase I patients and 8 phase II patients. 2 patients were determined not to be evaluable as they did not reach response time points.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Progressive Disease (PD) | 1 Participants |
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Partial Response (PR) | 0 Participants |
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response/Uncofirmed (CRu) | 0 Participants |
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Stable Disease (SD) | 0 Participants |
| 2.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response (CR) | 6 Participants |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Anti-lymphoma Efficacy | Stable Disease (SD) | 1 Participants |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Anti-lymphoma Efficacy | Progressive Disease (PD) | 0 Participants |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response/Uncofirmed (CRu) | 1 Participants |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Anti-lymphoma Efficacy | Partial Response (PR) | 1 Participants |
| 2.5 mg/kg MGd & 6-24% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response (CR) | 0 Participants |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Stable Disease (SD) | 2 Participants |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response (CR) | 2 Participants |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Partial Response (PR) | 1 Participants |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Progressive Disease (PD) | 0 Participants |
| 3.5 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response/Uncofirmed (CRu) | 0 Participants |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Progressive Disease (PD) | 3 Participants |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Partial Response (PR) | 1 Participants |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response (CR) | 3 Participants |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Stable Disease (SD) | 5 Participants |
| 5.0 mg/kg MGd & ≤ 5% Bone Marrow Involvement | Anti-lymphoma Efficacy | Complete Response/Uncofirmed (CRu) | 1 Participants |
Secondary
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
Population: Data not collected for analysis of this outcome measure.
Secondary
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
Population: Data was not collected for analysis of this outcome measure due to lack of funding.