Non-Hodgkin's Lymphoma
Conditions
Keywords
NHL, Follicular NHL, Rituxan, Apo2L/TRAIL
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.
Interventions
DRUGDulanermin
Dulanermin was administered by intravenous (IV) infusion over 1 hour on days 1-5 of each 21-day cycle.
DRUGRituximab
Rituximab was administered by intravenous (IV) infusion at 375 mg/m\^2 weekly for up to eight doses.
Sponsors
Amgen
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Serum Concentration of Dulanermin | 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. | The dulanermin serum concentration was measured using enzyme linked immunosorbent assay (ELISA). |
| Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 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 | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 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 | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms) | 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 | Baseline and Treatment Termination visit (8 weeks for Rituximab arm and 12 weeks for combination and Dulanermin arms). | 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. |
| Phase Ib: Number of Participants With a Dose-limiting Toxicity | 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). | 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 | 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) | 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) | From Baseline through Study Termination (up to approximately 33 months) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Overall Survival | From Baseline through Study Termination (up to approximately 33 months) | 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 | From Baseline through Study Termination (up to approximately 33 months) | 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 | From Baseline through Study Termination (up to approximately 33 months) | 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. |
| Phase II: Progression Free Survival | From Baseline through Study Termination (up to approximately 33 months) | 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. |
Participant flow
Recruitment details
The Phase Ib part of this study was completed prior to the start of Phase II. Phase Ib participants were not eligible for participation in Phase II.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| 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. | 6 |
| Phase II - Rituximab Participants received rituximab administered by intravenous (IV) infusion at 375 mg/m\^2 weekly for up to eight doses. | 22 |
| 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. | 26 |
| 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. | 11 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase Ib | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Phase Ib | Death | 1 | 0 | 0 | 0 | 0 |
| Phase Ib | Disease Progression | 4 | 4 | 0 | 0 | 0 |
| Phase II | Death | 0 | 0 | 1 | 2 | 0 |
| Phase II | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Phase II | Patient began new, non-protocol, therapy | 0 | 0 | 1 | 0 | 0 |
| Phase II | Physician Decision | 0 | 0 | 1 | 1 | 0 |
| Phase II | Sponsor's decision to terminate | 0 | 0 | 18 | 22 | 11 |
| Phase II | Withdrawal by Subject | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Phase Ib - Dulanermin 4 mg/kg | Phase Ib - Dulanermin 8 mg/kg | Phase II - Rituximab | Phase II - Combination Therapy | Phase II - Dulanermin | Total |
|---|---|---|---|---|---|---|
| Age Continuous | 56.3 years STANDARD_DEVIATION 15.9 | 63.7 years STANDARD_DEVIATION 9 | NA years | NA years | NA years | 60.0 years STANDARD_DEVIATION 12.9 |
| Age, Customized | NA years | NA years | 58.0 years STANDARD_DEVIATION 8.5 | 58.4 years STANDARD_DEVIATION 9.8 | 61.4 years STANDARD_DEVIATION 13.3 | 58.8 years STANDARD_DEVIATION 10 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 9 Participants | 7 Participants | 2 Participants | 20 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 13 Participants | 19 Participants | 9 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 16 / 22 | 22 / 26 | 8 / 11 |
| serious Total, serious adverse events | 1 / 6 | 1 / 6 | 1 / 22 | 4 / 26 | 0 / 11 |
Outcome results
Primary
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.
Population: Safety-evaluable population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 2 hours after the start of infusion | 49.9 µg/ml | Standard Deviation 32.04 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 5 hours after the start of infusion | 2.21 µg/ml | Standard Deviation 1.87 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 1.5 hours after the start of infusion | 40.4 µg/ml | Standard Deviation 19.03 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 7 hours after the start of infusion | 4.89 µg/ml | Standard Deviation 15.69 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 3 hours after the start of infusion | 29.5 µg/ml | Standard Deviation 20.75 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 24 hours after the start of infusion | 0.324 µg/ml | Standard Deviation 0.66 |
| Phase Ib - Dulanermin 4 mg/kg | Mean Serum Concentration of Dulanermin | 30 minutes after the start of infusion | 0.109 µg/ml | Standard Deviation 0.37 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 24 hours after the start of infusion | 0.002 µg/ml | Standard Deviation 0 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 30 minutes after the start of infusion | 0.001 µg/ml | Standard Deviation 0 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 1.5 hours after the start of infusion | 51.5 µg/ml | Standard Deviation 14 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 2 hours after the start of infusion | 79.8 µg/ml | Standard Deviation 22.54 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 3 hours after the start of infusion | 28.7 µg/ml | Standard Deviation 10.13 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 5 hours after the start of infusion | 9.89 µg/ml | Standard Deviation 21.86 |
| Phase Ib - Dulanermin 8 mg/kg | Mean Serum Concentration of Dulanermin | 7 hours after the start of infusion | 0.445 µg/ml | Standard Deviation 0.26 |
Primary
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).
Population: Safety Evaluable population consisting of all randomized patients who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With a Clinically Significant Laboratory Abnormality | 3 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With a Clinically Significant Laboratory Abnormality | 4 participants |
| Phase II - Rituximab | Number of Participants With a Clinically Significant Laboratory Abnormality | 5 participants |
| Phase II - Combination Therapy | Number of Participants With a Clinically Significant Laboratory Abnormality | 11 participants |
| Phase II - Dulanermin | Number of Participants With a Clinically Significant Laboratory Abnormality | 5 participants |
Primary
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)
Population: Safety Evaluable population, consisting of all randomized patients who received at least one dose of treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 3 AE | 1 participants |
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 5 AE | 0 participants |
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 2 AE | 4 participants |
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Any Grade AEs | 6 participants |
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 4 AE | 1 participants |
| Phase Ib - Dulanermin 4 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 1 AE | 0 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 5 AE | 0 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 4 AE | 0 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 2 AE | 1 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 1 AE | 2 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Any Grade AEs | 6 participants |
| Phase Ib - Dulanermin 8 mg/kg | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 3 AE | 3 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 1 AE | 6 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Any Grade AEs | 16 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 4 AE | 0 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 3 AE | 1 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 5 AE | 1 participants |
| Phase II - Rituximab | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 2 AE | 8 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 1 AE | 7 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 2 AE | 10 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 5 AE | 0 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 4 AE | 0 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Any Grade AEs | 23 participants |
| Phase II - Combination Therapy | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 3 AE | 6 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Any Grade AEs | 8 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 5 AE | 0 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 4 AE | 0 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 3 AE | 0 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 2 AE | 4 participants |
| Phase II - Dulanermin | Number of Participants With Treatment-Emergent Adverse Events by Severity Grade | Grade 1 AE | 4 participants |
Primary
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).
Population: The DLT-evaluable population consisted of all patients enrolled in the Phase Ib who received at least two complete cycles of dulanermin and four doses of rituximab and complete study assessments through the DLT Assessment Window without a DLT (usually through Day 28) or experienced a DLT and withdrew from the study within the DLT Assessment Window.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Phase Ib: Number of Participants With a Dose-limiting Toxicity | 0 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase Ib: Number of Participants With a Dose-limiting Toxicity | 0 participants |
Primary
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)
Population: The phase II Efficacy-Evaluable population consisted of all randomized patients who received at least one dose of study treatment and had measurable disease at baseline, as assessed by the IRF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Total Objective Response | 14 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response | 5 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response unconfirmed | 0 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Partial Response | 9 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Partial Response | 11 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Total Objective Response | 16 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response unconfirmed | 2 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response | 3 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Partial Response | 1 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response | 0 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Complete Response unconfirmed | 0 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Independent Review Facility (IRF) | Total Objective Response | 1 participants |
Primary
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)
Population: Safety Evaluable population, consisting of all randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit | -0.0 degrees Celsius | Standard Deviation 0.6 |
| Phase Ib - Dulanermin 8 mg/kg | Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit | -0.3 degrees Celsius | Standard Deviation 0.7 |
| Phase II - Rituximab | Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit | 2.8 degrees Celsius | Standard Deviation 13.1 |
| Phase II - Combination Therapy | Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit | -0.1 degrees Celsius | Standard Deviation 0.4 |
| Phase II - Dulanermin | Vital Signs: Change From Baseline in Body Temperature at Treatment Termination Visit | 0.0 degrees Celsius | Standard Deviation 0.4 |
Primary
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)
Population: Safety Evaluable population, consisting of all randomized patients who received at least one dose of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Diastolic Blood Pressure | -8.7 mmHg | Standard Deviation 10.9 |
| Phase Ib - Dulanermin 4 mg/kg | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Systolic Blood Pressure | -3.2 mmHg | Standard Deviation 16.8 |
| Phase Ib - Dulanermin 8 mg/kg | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Diastolic Blood Pressure | -5.2 mmHg | Standard Deviation 7.9 |
| Phase Ib - Dulanermin 8 mg/kg | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Systolic Blood Pressure | -4.7 mmHg | Standard Deviation 10.9 |
| Phase II - Rituximab | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Diastolic Blood Pressure | 2.3 mmHg | Standard Deviation 9.9 |
| Phase II - Rituximab | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Systolic Blood Pressure | -3.4 mmHg | Standard Deviation 14.8 |
| Phase II - Combination Therapy | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Systolic Blood Pressure | -2.2 mmHg | Standard Deviation 19.6 |
| Phase II - Combination Therapy | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Diastolic Blood Pressure | 1.6 mmHg | Standard Deviation 9.2 |
| Phase II - Dulanermin | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Diastolic Blood Pressure | -0.8 mmHg | Standard Deviation 5.6 |
| Phase II - Dulanermin | Vital Signs: Change From Baseline in Diastolic and Systolic Blood Pressure at Treatment Termination Visit | Systolic Blood Pressure | -4.2 mmHg | Standard Deviation 9.5 |
Primary
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)
Population: Safety Evaluable population, consisting of all randomized patients who received at least one dose of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit | 7.0 beats/minute | Standard Deviation 21.4 |
| Phase Ib - Dulanermin 8 mg/kg | Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit | -1.5 beats/minute | Standard Deviation 6.7 |
| Phase II - Rituximab | Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit | 0.5 beats/minute | Standard Deviation 9.6 |
| Phase II - Combination Therapy | Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit | 3.3 beats/minute | Standard Deviation 10.6 |
| Phase II - Dulanermin | Vital Signs: Change From Baseline in Heart Rate at Treatment Termination Visit | 5.0 beats/minute | Standard Deviation 13.2 |
Secondary
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)
Population: Safety-evaluable patients with an objective response determined by the Investigator.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Duration of Response as Assessed by the Investigator | 21.4 months |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Duration of Response as Assessed by the Investigator | 11.3 months |
| Phase II - Rituximab | Phase II: Duration of Response as Assessed by the Investigator | NA months |
Secondary
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)
Population: Safety Evaluable population, consisting of all randomized patients who received at least one dose of treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Partial Response | 8 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Complete Response | 7 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Complete Response unconfirmed | 0 participants |
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Total Objective Response | 15 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Complete Response | 7 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Total Objective Response | 17 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Partial Response | 9 participants |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Objective Response as Assessed by the Investigator | Complete Response unconfirmed | 1 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Investigator | Partial Response | 0 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Investigator | Complete Response | 1 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Investigator | Complete Response unconfirmed | 0 participants |
| Phase II - Rituximab | Phase II: Objective Response as Assessed by the Investigator | Total Objective Response | 1 participants |
Secondary
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)
Secondary
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)
Population: Safety-Evaluable population consisting of all randomized patients who received at least one dose of study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase Ib - Dulanermin 4 mg/kg | Phase II: Progression Free Survival | 29.9 months |
| Phase Ib - Dulanermin 8 mg/kg | Phase II: Progression Free Survival | 17.9 months |
| Phase II - Rituximab | Phase II: Progression Free Survival | 6.9 months |