Description:
This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical
activity, and predictive biomarkers of durvalumab in combination with R-CHOP or R2-CHOP,
followed by durvalumab consolidation therapy in previously untreated subjects with high-risk
diffuse large B-cell lymphoma (DLBCL). Induction treatment with R-CHOP (± lenalidomide) will
last for a total of up to 6 to 8 treatment cycles (21 day cycles), and the total time on
study treatment, including durvalumab consolidation, will last up to 12 months.
On 05-Sep-2017, the US FDA has issued a Partial Clinical Hold on this study resulting in the
discontinuation of enrollment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US
FDA Partial Clinical Hold, new eligible participants have been enrolled in Arm A (Durvalumab
+ R-CHOP).
Title
- Brief Title: A Study of Durvalumab in Combination With R-CHOP or Lenalidomide Plus R-CHOP in Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma
- Official Title: A Phase 2, Open-label, Multicenter Study to Evaluate the Safety and Clinical Activity of Durvalumab in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (R-CHOP) or With Lenalidomide Plus R-CHOP (R2-CHOP) in Subjects With Previously Untreated, High-Risk Diffuse Large B-Cell Lymphoma
Clinical Trial IDs
- ORG STUDY ID:
MEDI4736-DLBCL-001
- SECONDARY ID:
2015-005173-20
- NCT ID:
NCT03003520
Conditions
- Lymphoma, Large B-Cell, Diffuse
Interventions
| Drug | Synonyms | Arms |
|---|
| Durvalumab | MEDI4736, IMFINZI™, DUR | DUR + R-CHOP |
| Rituximab | RITUXAN® | DUR + R-CHOP |
| Doxorubicin | Adriamycin | DUR + R-CHOP |
| Vincristine | leurocristine, Oncovin | DUR + R-CHOP |
| Cyclophosphamide | cytophosphane, Cytoxan | DUR + R-CHOP |
| Prednisone | corticosteroid, prednisolone | DUR + R-CHOP |
| Lenalidomide | Revlimid® | DUR + R2-CHOP |
Purpose
This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical
activity, and predictive biomarkers of durvalumab in combination with R-CHOP or R2-CHOP,
followed by durvalumab consolidation therapy in previously untreated subjects with high-risk
diffuse large B-cell lymphoma (DLBCL). Induction treatment with R-CHOP (± lenalidomide) will
last for a total of up to 6 to 8 treatment cycles (21 day cycles), and the total time on
study treatment, including durvalumab consolidation, will last up to 12 months.
On 05-Sep-2017, the US FDA has issued a Partial Clinical Hold on this study resulting in the
discontinuation of enrollment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US
FDA Partial Clinical Hold, new eligible participants have been enrolled in Arm A (Durvalumab
+ R-CHOP).
Detailed Description
This research study is conducted in participants with previously untreated, high-risk diffuse
large B-cell lymphoma (DLBCL). Patients with high-risk DLBCL typically have insufficient
therapeutic outcomes. Therefore, the addition of novel agents to the currently used induction
therapy (R-CHOP) is a rational approach to improve therapeutic outcomes in this disease
setting.
Based on pre-clinical and clinical observations, it is hypothesized that durvalumab will have
activity in DLBCL because the PD 1/PD L1 pathway is involved in the pathophysiology of DLBCL.
In particular, the addition of durvalumab may augment the anti-tumor activity of R-CHOP
against high-risk DLBCL sub-types.
The safety of durvalumab has already been explored. However, as there is limited clinical
experience with durvalumab in DLBCL, the study is divided into two stages:
- A Safety Run-in Stage to evaluate the safety of the treatment combinations until at
least 10 subjects are included in each of the two treatment arms
- An Expansion Stage to analyze the clinical activity of the treatment combinations
Results posted following Primary Outcome Completion date are based on a database cut-off of
August 2, 2018.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| DUR + R-CHOP | Experimental | On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP (IV rituximab 375 mg/m^2, doxorubicin 50 mg/m^2, vincristine 1.4 mg/m^2 (maximum dose of 2.0 mg total), and cyclophosphamide 750 mg/m^2); Participants also were administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. Induction treatment continued for a total of 6-8 cycles.
Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months. | - Durvalumab
- Rituximab
- Doxorubicin
- Vincristine
- Cyclophosphamide
- Prednisone
|
| DUR + R2-CHOP | Experimental | Participants start the study on durvalumab in combination with R-CHOP (as described in Arm DUR + R-CHOP). Based on their DLBCL Cell-of-Origin subtype (test typically done between cycles 1 and 2), participants with ABC subtype continue the study taking durvalumab in combination with R2-CHOP. On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP. Participants were also administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. In addition, a daily oral lenalidomide 15 mg was administered from Day 1 to 14 of each 21-day cycle. Induction treatment continued for a total of 6-8 cycles.
Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months.
Enrollment into Arm B was discontinued. | - Durvalumab
- Rituximab
- Doxorubicin
- Vincristine
- Cyclophosphamide
- Prednisone
- Lenalidomide
|
Eligibility Criteria
Inclusion Criteria:
1. CD20+Diffuse Large B-Cell Lymphoma.
2. Ann Arbor stage 3 or 4 or stage 2 with bulky disease
3. High or high-intermediate disease risk.
4. No prior anti-lymphoma treatment.
5. Subject is willing and able to undergo biopsy.
6. Investigator considers R-CHOP immunochemotherapy appropriate.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
8. Adequate hematology laboratory results (absolute neutrophil count ≥ 1.5 * 10^9/L,
platelet count ≥ 75 * 10^9/L, hemoglobin ≥ 10.0 g/dL).
9. Adequate biochemistry laboratory results (aspartate aminotransferase (AST/SGOT) and
alanine aminotransferase (ALT/SGPT) ≤ 3.0 * upper limit of normal; bilirubin ≤ 2.0
mg/dL; creatinine clearance of ≥ 40 mL/min).
10. Bi-dimensionally measurable disease (> 2.0 cm).
11. Subject is using effective contraception.
Exclusion Criteria:
1. Diagnosis of lymphoma other than Diffuse Large B-Cell Lymphoma.
2. Composite lymphoma or transformed lymphoma.
3. Primary or secondary Central Nervous System involvement by lymphoma.
4. Seropositive or active viral infection with hepatitis B virus, human immunodeficiency
virus or hepatitis C virus.
5. History of other malignancies, unless disease-free for ≥ 5 years.
6. Left ventricular ejection fraction < 50%.
7. Peripheral neuropathy ≥ Grade 2.
8. Prior use of lenalidomide, or monoclonal antibodies against CTLA-4, PD-1, or PD-L1.
9. High risk of developing thromboembolic events, who are unwilling to take venous
thromboembolism prophylaxis.
10. Active or prior documented autoimmune or inflammatory disorders within the past 3
years.
11. Current or prior use of immunosuppressive medication within 28 days before start of
treatment.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Percentage of Participants Who Achieved a Complete Response (CR) at the End of Induction Therapy |
| Time Frame: | From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period). |
| Safety Issue: | |
| Description: | The primary efficacy analysis evaluated the complete response rate (CRR) at the end of the induction therapy in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin's Lymphoma (NHL) (Cheson, 2014). CR was defined as a complete metabolic response and radiographic evidence showing target nodes/nodal masses regressed to ≤ 1.5 cm in longest diameter, no new lesions, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis for the primary endpoint was rejected if the lower limit of the confidence interval for the complete response rate at the completion of the induction therapy in the efficacy evaluable population is above 55%. |
Secondary Outcome Measures
| Measure: | Percentage of Participants Who Responded During Induction and Continued Into Consolidation Therapy (Database Cutoff Date: 02-Aug-2018) |
| Time Frame: | From first dose of study drug to completion of at least one cycle in the Consolidation Period (Day 1 up to Week 52) |
| Safety Issue: | |
| Description: | The percentage of participants who achieved a partial response (PR) or complete response (CR) at the end of Induction and continued into consolidation period in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin's Lymphoma (NHL) (Cheson, 2014). CR was defined in outcome #1. PR was defined as a partial metabolic response and radiographic evidence showing ≥ 50% decrease in sum of perpendicular diameters (SPD) of up to 6 target measurable nodes and extranodal sites, no new lesions, spleen must have regressed > 50% in length beyond normal, and residual bone marrow involvement improved from baseline. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis was rejected if the lower limit of the confidence interval for the rate of subjects who continue consolidation therapy out of all subjects. |
| Measure: | Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density |
| Time Frame: | Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period). |
| Safety Issue: | |
| Description: | Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. |
| Measure: | Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Total Percentage |
| Time Frame: | Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period). |
| Safety Issue: | |
| Description: | Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. |
| Measure: | Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Percentage of Tumor Cells |
| Time Frame: | Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period). |
| Safety Issue: | |
| Description: | Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. |
| Measure: | Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for the Interferon Gamma Score (IFNG-Score) From Ribonucleic Acid (RNA)-Sequencing Data |
| Time Frame: | Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period). |
| Safety Issue: | |
| Description: | Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. |
| Measure: | Participants With Treatment Emergent Adverse Events (TEAE) (Database Cutoff Date: 02-Aug-2018) |
| Time Frame: | From the date of the first dose of study drug to within 90 days after the last dose of durvalumab or 28 days after the last dose of any investigational product (IP) whichever is greater. Day 1 up to Week 54 at time of database cutoff date. |
| Safety Issue: | |
| Description: | An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during a study. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild (no limitation in activity or intervention); - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); - Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); - Grade 4 = Life-threatening; - Grade 5 = Death. Relation to IP is determined by the investigator. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Celgene |
Trial Keywords
- Lymphoma
- Diffuse-large B-Cell Lymphoma
- Durvalumab
- Anti-PD-L1 Antibody
- MEDI4736
- Immune Checkpoint
- Rituximab
- Cyclophosphamide
- Doxorubicin
- Vincristine
- Prednisone/Prednisolone
- Lenalidomide
Last Updated
April 21, 2020
