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

Phase 2TerminatedNCT00400764

Genentech, Inc.72 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Non-Hodgkin's Lymphoma

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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).

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).

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).

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)

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).

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 Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: From Baseline through Study Termination (up to approximately 33 months)