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

NCT00400764 | Terminated Phase 1 Results

• 1 other identifier: APO3585g
• Study Type: interventional
• Target: 72
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Non-Hodgkin's Lymphoma

Keywords

NHL; Follicular NHL; Rituxan; Apo2L/TRAIL

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• Phase II: Progression Free Survival

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

• Phase II: Overall Survival

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

• Phase II: Objective Response as Assessed by the Investigator

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

• Phase II: Duration of Response as Assessed by the Investigator

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

Study Arms (5)

Phase Ib: Dulanermin 4 mg/kg

EXPERIMENTAL

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; Drug: Rituximab

Phase Ib: Dulanermin 8 mg/kg

EXPERIMENTAL

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; Drug: Rituximab

Phase II: Rituximab

ACTIVE COMPARATOR

Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m\^2 weekly for up to eight doses.

Drug: Rituximab

Phase II: Combination Therapy

EXPERIMENTAL

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; Drug: Rituximab

Phase II: Dulanermin

EXPERIMENTAL

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

Interventions

Dulanermin DRUG

Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.

Phase II: Combination Therapy; Phase II: Dulanermin; Phase Ib: Dulanermin 4 mg/kg; Phase Ib: Dulanermin 8 mg/kg

Rituximab DRUG

Rituximab was administered by intravenous (IV) infusion at 375 mg/m\^2 weekly for up to eight doses.

Phase II: Combination Therapy; Phase II: Rituximab; Phase Ib: Dulanermin 4 mg/kg; Phase Ib: Dulanermin 8 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genentech, Inc.: lead
• Amgen: collaborator

Related Publications (1)

• 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.

  PMID: 26687959 DERIVED

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

TNFSF10 protein, human; Rituximab

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The Sponsor terminated the study on 5 May 2010, prior to the completion of the 36-month follow-up (FU) period, based on the primary analysis results. All patients were off-study or in survival FU (the treatment period was completed).

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffman-LaRoche

800-821-8590

Study Officials

• Chia Portera, PhD., M.D

  Genentech, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 15, 2006
• First Posted: November 17, 2006
• Study Start: June 1, 2006
• Primary Completion: May 1, 2010
• Last Updated: November 23, 2011
• Results First Posted: October 7, 2011

Record last verified: 2011-11