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

This study has been terminated.
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Genentech
ClinicalTrials.gov Identifier:
NCT00400764
First received: November 15, 2006
Last updated: November 15, 2011
Last verified: November 2011
  Purpose

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.


Condition Intervention Phase
Non-Hodgkin's Lymphoma
Drug: Dulanermin
Drug: Rituximab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Genentech:

Primary Outcome Measures:
  • Phase Ib: Number of Participants With a Dose-limiting Toxicity [ 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). ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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) [ Time Frame: From Baseline through Study Termination (up to approximately 33 months) ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms). ] [ Designated as safety issue: No ]
    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 [ 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. ] [ Designated as safety issue: No ]
    The dulanermin serum concentration was measured using enzyme linked immunosorbent assay (ELISA).


Secondary Outcome Measures:
  • Phase II: Progression Free Survival [ Time Frame: From Baseline through Study Termination (up to approximately 33 months) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From Baseline through Study Termination (up to approximately 33 months) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From Baseline through Study Termination (up to approximately 33 months) ] [ Designated as safety issue: No ]
    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 [ Time Frame: From Baseline through Study Termination (up to approximately 33 months) ] [ Designated as safety issue: No ]

    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.



Enrollment: 72
Study Start Date: June 2006
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase Ib: Dulanermin 4 mg/kg
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
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.
Drug: Rituximab
Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Experimental: Phase Ib: Dulanermin 8 mg/kg
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
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.
Drug: Rituximab
Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Active Comparator: Phase II: Rituximab
Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Drug: Rituximab
Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Experimental: Phase II: Combination Therapy
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
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.
Drug: Rituximab
Rituximab was administered by intravenous (IV) infusion at 375 mg/m^2 weekly for up to eight doses.
Experimental: Phase II: Dulanermin
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
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00400764

Sponsors and Collaborators
Genentech
Amgen
Investigators
Study Director: Chia Portera, PhD., M.D Genentech
  More Information

No publications provided

Responsible Party: Genentech
ClinicalTrials.gov Identifier: NCT00400764     History of Changes
Other Study ID Numbers: APO3585g
Study First Received: November 15, 2006
Results First Received: September 1, 2011
Last Updated: November 15, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech:
NHL
Follicular NHL
Rituxan
Apo2L/TRAIL
APO2L/TRAIL

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 22, 2014