A Study of Dulanermin in Combination With Rituximab in Subjects With Follicular and Other Low Grade, CD20+, Non-Hodgkin's Lymphomas

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Dulanermin
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: Dulanermin 4 mg/kg<br>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. | Drug: Dulanermin<br>* Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.<br>Drug: Rituximab<br>* Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.<br>|
| Experimental: Phase Ib: Dulanermin 8 mg/kg<br>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. | Drug: Dulanermin<br>* Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.<br>Drug: Rituximab<br>* Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.<br>|
| Active Comparator: Phase II: Rituximab<br>Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses. | Drug: Rituximab<br>* Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.<br>|
| Experimental: Phase II: Combination Therapy<br>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. | Drug: Dulanermin<br>* Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.<br>Drug: Rituximab<br>* Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.<br>|
| Experimental: Phase II: Dulanermin<br>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. | Drug: Dulanermin<br>* Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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). | 
| 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). | 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) | 
| 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. | From Baseline through Study Termination (up to approximately 33 months) | 
| 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. | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 
| 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. | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 
| 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. | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 
| 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. | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms). | 
| Mean Serum Concentration of Dulanermin | The dulanermin serum concentration was measured using enzyme linked immunosorbent assay (ELISA). | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From Baseline through Study Termination (up to approximately 33 months) | 
| Phase II: Overall Survival | Median overall survival could not be estimated because of the low number of deaths at the time of study termination. | From Baseline through Study Termination (up to approximately 33 months) | 
| 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. | From Baseline through Study Termination (up to approximately 33 months) | 
| 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. | From Baseline through Study Termination (up to approximately 33 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, Follicular NHL, Rituxan, Apo2L/TRAIL