Back to resultsA Study of Dulanermin in Combination With Rituximab in Subjects With Follicular and Other Low Grade, CD20+, Non-Hodgkin's Lymphomas
Primary Purpose
Non-Hodgkin's Lymphoma
Status
Terminated
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Dulanermin
Rituximab
Sponsored by
About this trial
This is an interventional treatment trial for Non-Hodgkin's Lymphoma focused on measuring NHL, Follicular NHL, Rituxan, Apo2L/TRAIL
Eligibility Criteria
Inclusion Criteria:
- Signed Informed Consent Form
- Age ≥ 18 years
- History of histologically confirmed CD20+ follicular NHL Grade 1, 2, or 3a
- Progression of disease following the most recent treatment with rituximab-containing therapy that resulted in stable disease or a partial or complete response lasting ≥ 6 months
- Measurable disease
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., contraceptive pill, intrauterine device [IUD], physical barrier throughout the trial and for 1 year following their final exposure to study treatment).
- Life expectancy of > 3 months
Exclusion Criteria:
- Prior radiotherapy to a measurable, metastatic lesion(s) to be used to measure response unless that lesion shows unequivocal progression at baseline
- Radiation therapy to a peripheral lesion within 14 days prior to Day 1; Radiation therapy to a thoracic, abdominal, or pelvic field within 28 days prior to Day 1
- Chemotherapy, hormonal therapy, radiotherapy, or immunotherapy within 4 weeks prior to Day 1
- Patients who have received radioimmunotherapy for relapsed or refractory, follicular NHL are eligible for the study if they received this therapy at least 1 year prior to Day 1, they have adequate bone marrow function, and they have no evidence of myelodysplastic syndrome on bone marrow aspirate/biopsy
- Prior treatment with dulanermin or an agonist antibody to DR4 or DR5
- Concurrent systemic corticosteroid therapy
- Evidence of clinically detectable ascites on Day 1
- Other invasive malignancies within 5 years prior to Day 1
- History or evidence upon physical examination of central nervous system (CNS) disease within 1 year prior to study entry
- Active infection requiring parenteral antibiotics on Day 1
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study and fine needle aspirations within 7 days prior to Day 1
- Pregnancy or lactation
- Serious nonhealing wound, ulcer, or bone fracture
- Current or recent participation in another experimental drug study
- Clinically significant cardiovascular disease
- Known positive test result for HIV, hepatitis B surface antigen (sAg), hepatitis B IgG or IgM core antibody, or hepatitis C antibody
- Known sensitivity to murine or human antibodies
- History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Active Comparator
Experimental
Experimental
Arm Label
Phase Ib: Dulanermin 4 mg/kg
Phase Ib: Dulanermin 8 mg/kg
Phase II: Rituximab
Phase II: Combination Therapy
Phase II: Dulanermin
Arm Description
Participants received 4.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles.
Outcomes
Primary Outcome Measures
Phase Ib: Number of Participants With a Dose-limiting Toxicity
A dose-limiting toxicity (DLT) was defined as a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 Grade ≥ 3 hematologic or major organ toxicity that was related to study drug (i.e., dulanermin). Although a patient may have experienced a DLT at any time during the study, only events that occurred within the DLT assessment window were considered for dose-escalation decisions and determination of the maximum tolerated dose (MTD).
Number of Participants With Treatment-Emergent Adverse Events by Severity Grade
Safety was assessed through summaries of treatment-emergent adverse events (AEs); AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, according to the following guidelines: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (Life-threatening or disabling) and Grade 5 (Death related to AE).
Phase II: Objective Response as Assessed by the Independent Review Facility (IRF)
Objective response was defined as a confirmed or unconfirmed complete response (CR, CRu) or partial response (PR) assessed on the basis of clinical, radiographic (computed tomography (CT) scans of the neck, chest, abdomen, pelvis and inguinal region), and pathologic (i.e., bone marrow) criteria and according to the modified International Working Group (IWG) criteria. All radiographic and clinical data for the evaluation of objective response were submitted to an IRF for blinded and impartial assessment.
Patients without a post-baseline tumor assessment were considered non-responders.
Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit
Blood pressure was measured at baseline and throughout the study. Change from baseline was calculated using the patient's last recorded measurement at the completion of treatment visit - baseline measurement.
Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit
Heart rate was measured at baseline and throughout the study. Change from baseline was calculated using the patient's last recorded measurement at the completion of treatment visit - baseline measurement.
Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit
Body temperature was measured at baseline and throughout the study. Change from baseline was calculated using the patients last recorded measurement at the completion of treatment visit - baseline measurement.
Number of Participants With a Clinically Significant Laboratory Abnormality
Laboratory Parameters were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). A clinically significant abnormality was defined as a Grade 3 (severe) or Grade 4 (very severe, life threatening, or disabling) laboratory toxicity according to the NCI CTCAE v3.0.
Mean Serum Concentration of Dulanermin
The dulanermin serum concentration was measured using enzyme linked immunosorbent assay (ELISA).
Secondary Outcome Measures
Phase II: Progression Free Survival
Progression free survival (PFS) was defined as the time from randomization to documented disease progression or death, whichever occurred first and was based on the investigator's assessment using the modified IWG criteria. Kaplan-Meier methods were used to estimate median time to PFS. Data for patients without disease progression or death on study were censored at the time of the last tumor assessment.
Phase II: Overall Survival
Median overall survival could not be estimated because of the low number of deaths at the time of study termination.
Phase II: Objective Response as Assessed by the Investigator
Objective response was defined as a confirmed or unconfirmed complete response(CR, CRu) or partial response (PR) assessed on the basis of clinical, radiographic (computed tomography (CT) scans of the neck, chest, abdomen, pelvis and inguinal region), and pathologic (i.e., bone marrow) criteria and according to the modified International Working Group (IWG) criteria. Patients without a post-baseline tumor assessment were considered non-responders.
Phase II: Duration of Response as Assessed by the Investigator
An event was defined as documented disease progression or death on study, whichever occurred first. Duration of objective response was defined only for patients with an objective response as determined by the investigator and was the time from the initial response to disease progression or death on study.
Kaplan-Meier methods were used to estimate median, percentiles, and range of duration of response.
Full Information
NCT ID
NCT00400764
First Posted
November 15, 2006
Last Updated
November 15, 2011
Sponsor
Genentech, Inc.
Collaborators
Amgen
1. Study Identification
Unique Protocol Identification Number
NCT00400764
Brief Title
A Study of Dulanermin in Combination With Rituximab in Subjects With Follicular and Other Low Grade, CD20+, Non-Hodgkin's Lymphomas
Official Title
A Phase Ib/II, Open-Label, Multicenter Study of the Safety, Pharmacokinetics, and Efficacy of Dulanermin Administered Intravenously in Combination With Rituximab to Subjects With Follicular and Other Low-Grade, CD20+, B-Cell Non-Hodgkin's Lymphomas That Have Progressed Following Previous Rituximab Therapy
Study Type
Interventional
2. Study Status
Record Verification Date
November 2011
Overall Recruitment Status
Terminated
Study Start Date
June 2006 (undefined)
Primary Completion Date
May 2010 (Actual)
Study Completion Date
undefined (undefined)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Genentech, Inc.
Collaborators
Amgen
4. Oversight
5. Study Description
Brief Summary
This Phase Ib/II, open-label, multicenter trial is designed to evaluate the safety, pharmacokinetics, and efficacy of dulanermin when combined with rituximab in subjects with follicular, CD20+, B-cell Non-Hodgkin's Lymphoma (NHL) that has progressed following a response of ≥ 6 months duration to a prior rituximab-containing therapy. The multicenter, international, randomized Phase II part of this study will commence only after the safety and available pharmacokinetic data from the Phase Ib part of the study have been evaluated by the Sponsor and have been provided to participating investigators and the FDA.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-Hodgkin's Lymphoma
Keywords
NHL, Follicular NHL, Rituxan, Apo2L/TRAIL
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
72 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase Ib: Dulanermin 4 mg/kg
Arm Type
Experimental
Arm Description
Participants received 4.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Arm Title
Phase Ib: Dulanermin 8 mg/kg
Arm Type
Experimental
Arm Description
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Arm Title
Phase II: Rituximab
Arm Type
Active Comparator
Arm Description
Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Arm Title
Phase II: Combination Therapy
Arm Type
Experimental
Arm Description
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles. Participants also received rituximab administered by IV infusion at 375 mg/m^2 weekly for up to eight doses.
Arm Title
Phase II: Dulanermin
Arm Type
Experimental
Arm Description
Participants received 8.0 mg/kg/day dose of dulanermin, administered by intravenous (IV) infusion for 5 consecutive days at the start of each 21-day treatment cycle for up to four cycles.
Intervention Type
Drug
Intervention Name(s)
Dulanermin
Intervention Description
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Description
Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Primary Outcome Measure Information:
Title
Phase Ib: Number of Participants With a Dose-limiting Toxicity
Description
A dose-limiting toxicity (DLT) was defined as a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0 Grade ≥ 3 hematologic or major organ toxicity that was related to study drug (i.e., dulanermin). Although a patient may have experienced a DLT at any time during the study, only events that occurred within the DLT assessment window were considered for dose-escalation decisions and determination of the maximum tolerated dose (MTD).
Time Frame
The DLT assessment window was defined as the duration required to complete two full cycles of treatment with dulanermin (2 * 21 days) and four doses of rituximab (usually through Day 28).
Title
Number of Participants With Treatment-Emergent Adverse Events by Severity Grade
Description
Safety was assessed through summaries of treatment-emergent adverse events (AEs); AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, according to the following guidelines: Grade 1 (Mild); Grade 2 (Moderate); Grade 3 (Severe); Grade 4 (Life-threatening or disabling) and Grade 5 (Death related to AE).
Time Frame
From Baseline through Study Termination (up to a maximum of approximately 13 months for phase Ib and up to approximately 33 months for phase II)
Title
Phase II: Objective Response as Assessed by the Independent Review Facility (IRF)
Description
Objective response was defined as a confirmed or unconfirmed complete response (CR, CRu) or partial response (PR) assessed on the basis of clinical, radiographic (computed tomography (CT) scans of the neck, chest, abdomen, pelvis and inguinal region), and pathologic (i.e., bone marrow) criteria and according to the modified International Working Group (IWG) criteria. All radiographic and clinical data for the evaluation of objective response were submitted to an IRF for blinded and impartial assessment.
Patients without a post-baseline tumor assessment were considered non-responders.
Time Frame
From Baseline through Study Termination (up to approximately 33 months)
Title
Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit
Description
Blood pressure was measured at baseline and throughout the study. Change from baseline was calculated using the patient's last recorded measurement at the completion of treatment visit - baseline measurement.
Time Frame
Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms)
Title
Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit
Description
Heart rate was measured at baseline and throughout the study. Change from baseline was calculated using the patient's last recorded measurement at the completion of treatment visit - baseline measurement.
Time Frame
Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms)
Title
Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit
Description
Body temperature was measured at baseline and throughout the study. Change from baseline was calculated using the patients last recorded measurement at the completion of treatment visit - baseline measurement.
Time Frame
Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms)
Title
Number of Participants With a Clinically Significant Laboratory Abnormality
Description
Laboratory Parameters were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). A clinically significant abnormality was defined as a Grade 3 (severe) or Grade 4 (very severe, life threatening, or disabling) laboratory toxicity according to the NCI CTCAE v3.0.
Time Frame
Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms).
Title
Mean Serum Concentration of Dulanermin
Description
The dulanermin serum concentration was measured using enzyme linked immunosorbent assay (ELISA).
Time Frame
Blood samples were taken 0.5, 1.5, 2, 3, 5, 7 and 24 hours after the start of the infusion on Day 1 of Cycle 1.
Secondary Outcome Measure Information:
Title
Phase II: Progression Free Survival
Description
Progression free survival (PFS) was defined as the time from randomization to documented disease progression or death, whichever occurred first and was based on the investigator's assessment using the modified IWG criteria. Kaplan-Meier methods were used to estimate median time to PFS. Data for patients without disease progression or death on study were censored at the time of the last tumor assessment.
Time Frame
From Baseline through Study Termination (up to approximately 33 months)
Title
Phase II: Overall Survival
Description
Median overall survival could not be estimated because of the low number of deaths at the time of study termination.
Time Frame
From Baseline through Study Termination (up to approximately 33 months)
Title
Phase II: Objective Response as Assessed by the Investigator
Description
Objective response was defined as a confirmed or unconfirmed complete response(CR, CRu) or partial response (PR) assessed on the basis of clinical, radiographic (computed tomography (CT) scans of the neck, chest, abdomen, pelvis and inguinal region), and pathologic (i.e., bone marrow) criteria and according to the modified International Working Group (IWG) criteria. Patients without a post-baseline tumor assessment were considered non-responders.
Time Frame
From Baseline through Study Termination (up to approximately 33 months)
Title
Phase II: Duration of Response as Assessed by the Investigator
Description
An event was defined as documented disease progression or death on study, whichever occurred first. Duration of objective response was defined only for patients with an objective response as determined by the investigator and was the time from the initial response to disease progression or death on study.
Kaplan-Meier methods were used to estimate median, percentiles, and range of duration of response.
Time Frame
From Baseline through Study Termination (up to approximately 33 months)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Signed Informed Consent Form
Age ≥ 18 years
History of histologically confirmed CD20+ follicular NHL Grade 1, 2, or 3a
Progression of disease following the most recent treatment with rituximab-containing therapy that resulted in stable disease or a partial or complete response lasting ≥ 6 months
Measurable disease
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
For subjects of reproductive potential (males and females), use of a reliable means of contraception (e.g., contraceptive pill, intrauterine device [IUD], physical barrier throughout the trial and for 1 year following their final exposure to study treatment).
Life expectancy of > 3 months
Exclusion Criteria:
Prior radiotherapy to a measurable, metastatic lesion(s) to be used to measure response unless that lesion shows unequivocal progression at baseline
Radiation therapy to a peripheral lesion within 14 days prior to Day 1; Radiation therapy to a thoracic, abdominal, or pelvic field within 28 days prior to Day 1
Chemotherapy, hormonal therapy, radiotherapy, or immunotherapy within 4 weeks prior to Day 1
Patients who have received radioimmunotherapy for relapsed or refractory, follicular NHL are eligible for the study if they received this therapy at least 1 year prior to Day 1, they have adequate bone marrow function, and they have no evidence of myelodysplastic syndrome on bone marrow aspirate/biopsy
Prior treatment with dulanermin or an agonist antibody to DR4 or DR5
Concurrent systemic corticosteroid therapy
Evidence of clinically detectable ascites on Day 1
Other invasive malignancies within 5 years prior to Day 1
History or evidence upon physical examination of central nervous system (CNS) disease within 1 year prior to study entry
Active infection requiring parenteral antibiotics on Day 1
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study and fine needle aspirations within 7 days prior to Day 1
Pregnancy or lactation
Serious nonhealing wound, ulcer, or bone fracture
Current or recent participation in another experimental drug study
Clinically significant cardiovascular disease
Known positive test result for HIV, hepatitis B surface antigen (sAg), hepatitis B IgG or IgM core antibody, or hepatitis C antibody
Known sensitivity to murine or human antibodies
History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the subject at high risk from treatment complications
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chia Portera, PhD., M.D
Organizational Affiliation
Genentech, Inc.
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
26687959
Citation
Cheah CY, Belada D, Fanale MA, Janikova A, Czucman MS, Flinn IW, Kapp AV, Ashkenazi A, Kelley S, Bray GL, Holden S, Seymour JF. Dulanermin with rituximab in patients with relapsed indolent B-cell lymphoma: an open-label phase 1b/2 randomised study. Lancet Haematol. 2015 Apr;2(4):e166-74. doi: 10.1016/S2352-3026(15)00026-5. Epub 2015 Mar 25.
Results Reference
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A Study of Dulanermin in Combination With Rituximab in Subjects With Follicular and Other Low Grade, CD20+, Non-Hodgkin's Lymphomas
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