Clinical Trial Results:
MEDI4736-MM-005 (FUSION MM-005): A Multicenter, Single-arm, Phase 2 Study to Determine the Efficacy of the Combination of Daratumumab (DARA) Plus Durvalumab (DURVA) (D2) in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM) who have Progressed on DARA While on a DARA-containing Regimen as the Most Recent MM Therapy.
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Summary
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EudraCT number |
2016-003801-32 |
Trial protocol |
DE SE ES GR NL AT IT |
Global end of trial date |
04 Dec 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Nov 2018
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First version publication date |
23 Nov 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
MEDI4736-MM-005
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03000452 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Celgene Corporation
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Sponsor organisation address |
86 Morris Avenue, Summit, United States, 07901
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Public contact |
Clinical Trial Disclosure, Celgene Corporation, 01 8882601599, ClinicalTrialDisclosure@Celgene.com
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Scientific contact |
Steven Novick, MD, Celgene Corporation, 01 (908) 6084596, snovick@celgene.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Dec 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
04 Dec 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To determine the efficacy of daratumumab plus durvalumab (DURVA) in subjects with relapsed and refractory multiple myeloma who have progressed on daratumumab while on a daratumumab-containing regimen as the most multiple myeloma recent treatment.
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Protection of trial subjects |
The study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents and informed consent.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Mar 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Greece: 5
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Sweden: 2
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Country: Number of subjects enrolled |
United States: 6
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Worldwide total number of subjects |
18
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EEA total number of subjects |
12
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
9
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From 65 to 84 years |
9
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85 years and over |
0
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Recruitment
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Recruitment details |
The study was conducted at 8 sites in 4 countries including Greece, Spain, Sweden and the United States, from 03 March 2017 to 04 December 2017 | ||||||||||||||||
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Pre-assignment
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Screening details |
Eligible participants included those with relapsed and refractory multiple myeloma (RRMM) who progressed on daratumumab (DARA) while on a DARA-containing regimen as the most recent multiple myeloma (MM) therapy. Participants had to have received at least 3 prior anti-myeloma therapies. | ||||||||||||||||
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Period 1
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Period 1 title |
Treatment Period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||
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Arms
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Arm title
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Daratumumab and Durvalumab | ||||||||||||||||
Arm description |
Participants received intravenous daratumumab at 16 mg/kg on the same dosing schedule (weekly, every 2 weeks, or every 4 weeks of each 28-day treatment cycle) on their last prior therapy containing daratumumab regimen. The dosing schedule for daratumumab could be adjusted during the course of the study, provided the participant had a response of stable disease or better. Participants also received IV durvalumab at 1500 mg on Day 2 of Cycle 1 and then on Day 1 of Cycles ≥ 2 of each 28-day treatment cycle. Participants could continue on study treatment until progressive disease or unacceptable toxicity. | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Daratumumab
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Investigational medicinal product code |
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Other name |
Darzalex
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Pharmaceutical forms |
Dental gel, Blood fraction modifier, Concentrate for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Daratumumab by intravenous (IV) administration at 16 mg/kg on the same dosing schedule (weekly, every 2 weeks, or every 4 weeks of each 28-day treatment cycle) on their last prior therapy containing daratumumab regimen.
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Investigational medicinal product name |
Durvalumab
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Investigational medicinal product code |
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Other name |
Imfinzi
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Durvalumab 1500 mg by intravenous administration on Day 2 of Cycle 1 and then on Day 1 of Cycles ≥ 2 of each 28-day treatment cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Daratumumab and Durvalumab
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Reporting group description |
Participants received intravenous daratumumab at 16 mg/kg on the same dosing schedule (weekly, every 2 weeks, or every 4 weeks of each 28-day treatment cycle) on their last prior therapy containing daratumumab regimen. The dosing schedule for daratumumab could be adjusted during the course of the study, provided the participant had a response of stable disease or better. Participants also received IV durvalumab at 1500 mg on Day 2 of Cycle 1 and then on Day 1 of Cycles ≥ 2 of each 28-day treatment cycle. Participants could continue on study treatment until progressive disease or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Daratumumab and Durvalumab
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Reporting group description |
Participants received intravenous daratumumab at 16 mg/kg on the same dosing schedule (weekly, every 2 weeks, or every 4 weeks of each 28-day treatment cycle) on their last prior therapy containing daratumumab regimen. The dosing schedule for daratumumab could be adjusted during the course of the study, provided the participant had a response of stable disease or better. Participants also received IV durvalumab at 1500 mg on Day 2 of Cycle 1 and then on Day 1 of Cycles ≥ 2 of each 28-day treatment cycle. Participants could continue on study treatment until progressive disease or unacceptable toxicity. | ||
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End point title |
Numberof Participants With an Objective Response According to International Myeloma Working Group (IMWG) Uniform Response Criteria [1] | ||||||
End point description |
Objective response is defined as a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) based on the investigator assessment: sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow; CR: Negative serum and urine on immunofixation, disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥ 90% reduction in serum M-protein and urine M-protein level < 100 mg/24 hours; PR: ≥ 50% reduction of serum M-Protein and reduction in urinary M-protein by ≥ 90% or to < 200 mg/24 hours. In addition to the above, if present at baseline a ≥ 50% reduction in the size of soft tissue plasmacytomas is also required. The population analyzed included the full analysis set (FAS), meaning all participants who enrolled in the study.
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End point type |
Primary
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End point timeframe |
From randomization until the data cut-off date of 17 April 2018. The median duration of treatment for durvalumab and daratumumab was 7.9 weeks and 8.0 weeks respectively.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed as no subject achieved a best response better than stable disease of the study. Following the DMC review of the data from Part 1 Stage 1 and prior to the first formal interim analysis, the sponsor decided based on DMC recommendation, to close the study as the number of responses was not reached. |
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| No statistical analyses for this end point | |||||||
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End point title |
Time-to-Response (TTR) | ||||||||
End point description |
TTR was defined as the time from treatment initiation to the first documentation of response (PR or greater) based on IMWG criteria. sCR: CR and normal free light chain (FLC) ratio and no clonal cells in bone marrow (BM); CR: Negative serum and urine on immunofixation (IFX), disappearance of any soft tissue plasmacytomas and ≤5% plasma cells in BM; VGPR: Serum and urine M-protein detectable by IFX but not on electrophoresis or ≥90% reduction in serum and urine M-protein levels <100 mg/24 hours; PR: ≥50% reduction of serum M-Protein and reduction in urinary M-protein by ≥90% or to <200 mg/24 hours. A ≥50% decrease in the difference between involved and uninvolved FLC levels in place of the M-protein basis or a ≥50% reduction in plasma cells in place of M-protein if baseline was ≥30%. If present at baseline a ≥50% reduction in size of soft tissue plasmacytomas. Analyses was not conducted for TTR due to no subject achieving a response better than stable disease in Stage 1 of the study.
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End point type |
Secondary
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End point timeframe |
From randomization until the data cut-off date of 17 April 2018. The median duration of treatment for durvalumab and daratumumab was 7.9 weeks and 8.0 weeks respectively.
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| Notes [2] - No subject achievied a response better than SD |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Response (DOR) | ||||||||
End point description |
Duration of response was defined as time from the first documentation of response (PR or greater) to the first documentation of PD or death, whichever is earlier, based on the investigator assessments according to the IMWG Uniform Response Criteria. Analyses was not conducted for duration of response due to no subject achieving a response better than stable disease in Stage 1 of the study.
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End point type |
Secondary
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End point timeframe |
From randomization until the data cut-off date of 17 April 2018. The median duration of treatment for durvalumab and daratumumab was 7.9 weeks and 8.0 weeks respectively.
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| Notes [3] - No subject achieving a response better than stable disease |
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival | ||||||||
End point description |
Progression free survival was defined as the time from treatment initiation to the first documentation of PD or death from any cause during study, whichever occurred earlier. Time to event analysis for PFS and was not analyzed due to insufficient follow up time because of early termination of the trial.
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End point type |
Secondary
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End point timeframe |
From randomization until the data cut-off date of 17 April 2018. The median duration of treatment for durvalumab and daratumumab was 7.9 weeks and 8.0 weeks respectively.
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| Notes [4] - Time to event analysis for PFS and was not analyzed due to early termination |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival | ||||||||
End point description |
Overall Survival was defined as the time from treatment initiation to death due to any cause. Time to event analysis for overall survival was not analyzed due to insufficient follow up time because of early termination of the trial.
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End point type |
Secondary
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End point timeframe |
From randomization until the data cut-off date of 17 April 2018. The median duration of treatment for durvalumab and daratumumab was 7.9 weeks and 8.0 weeks respectively.
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| Notes [5] - Time to event analysis for overall survival was not analyzed due to early termination. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-time Curve from Time 0 to the Time of the Last Quantifiable Concentration Of Durvalumab | ||||||||
End point description |
Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-time Curve from Time 0 to Extrapolated to Infinity (AUC-inf) of Durvalumab | ||||||||
End point description |
Area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC %Extrap was ≥25%, AUC inf was not reported. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Observed Concentration (Cmax) Of Durvalumab | ||||||||
End point description |
Maximum observed plasma concentration, obtained directly from the observed concentration versus time data. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Reach Maximum Concentration (Tmax) of Durvalumab | ||||||||
End point description |
Time to Cmax, obtained directly from the observed concentration versus time data. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Terminal Half-Life (T1/2) of of Durvalumab | ||||||||
End point description |
Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. t1/2 was only calculated when a reliable estimate for λz could be obtained. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK Durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Total Clearance (CL/F) of of Durvalumab | ||||||||
End point description |
Apparent total clearance, calculated as [Dose/AUCinf]. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK Durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Volume of Distribution (Vz/F) of Durvalumab | ||||||||
End point description |
Apparent volume of distribution, calculated as [(CL/F)/λz]. The pharmacokinetic population included participants who received at least 1 dose of study medication and had evaluable plasma PK Durvalumab profiles.
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End point type |
Secondary
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End point timeframe |
Pharmacokinetic samples were drawn on Cycle 1 on Day 2 (C1D2) pre-dose, at the end of the infusion, on Day 8 at 144 hour post dose, on Day 15 at 312 hours post dose and on Day 22 at 480 hours post C1D2 infusion.
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| No statistical analyses for this end point | |||||||||
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End point title |
Participants with Treatment-Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
TEAEs include AEs between the earliest of the first dose date of either study drug and 90 days after the last dose of either study drug. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.03, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above. The safety population consisted of all participants who received at least one dose of Durvalumab (Durva) or Daratumumab (Dara
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End point type |
Secondary
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End point timeframe |
From the date of the first dose of study drug until 90 days after the last dose of durvalumab or daratumumab , whichever is later. Maximum overall time on treatment was 16 weeks for daratumumab and durvalumab
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the date of the first dose of study drug until 90 days after the last dose of durvalumab or daratumumab , whichever is later. Maximum overall time on treatment was 16 weeks for daratumumab and durvalumab
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
V20.0
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Reporting groups
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Reporting group title |
Daratumab and Durvalumab
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Reporting group description |
Participants received intravenous daratumumab at 16 mg/kg on the same dosing schedule (weekly, every 2 weeks, or every 4 weeks of each 28-day treatment cycle) on their last prior therapy containing daratumumab regimen. The dosing schedule for daratumumab could be adjusted during the course of the study, provided the participant had a response of stable disease or better. Participants also received IV durvalumab at 1500 mg on Day 2 of Cycle 1 and then on Day 1 of Cycles ≥ 2 of each 28-day treatment cycle. Participants could continue on study treatment until progressive disease or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||||||
Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| An independent DMC reviewed data from Part 1 Stage 1 of the study on 26 Oct 2017; based on their recommendations, Celgene decided to close the study due to unfavorable efficacy results (number of responses to move to Stage 2 was not reached). | |||||||
