Clinical Trial Results:
Phase II study of Bortezomib, Adriamycin and Dexamethasone (PAD) therapy for previously untreated patients with multiple myeloma: Impact of minimal residual disease (MRD) in patients with deferred ASCT (PADIMAC)
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Summary
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EudraCT number |
2010-021598-35 |
Trial protocol |
GB |
Global end of trial date |
13 Nov 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
03 May 2021
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First version publication date |
03 May 2021
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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 |
UCL/08/0255
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Additional study identifiers
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ISRCTN number |
ISRCTN03381785 | ||
US NCT number |
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WHO universal trial number (UTN) |
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Other trial identifiers |
Funder reference: LRF/10018, REC reference : 10/H0502/58 | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
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Public contact |
PADIMAC Trial Coordinator, Cancer Research UK & UCL Cancer Trials
Centre, ctc.sponsor@ucl.ac.uk
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Scientific contact |
PADIMAC Trial Coordinator, Cancer Research UK & UCL Cancer Trials
Centre, ctc.sponsor@ucl.ac.uk
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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 |
26 May 2020
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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 |
13 Nov 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
PADIMAC is a phase II study designed as a single arm study to evaluate the safety of a no treatment option for patients achieving CR/VGPR post induction therapy on the PAD regimen and not proceeding to ACST.
The main objective of the study is to provide a reliable estimate of the 2-year progression-free survival (PFS) for patients who, having achieved CR/VGPR following PAD therapy (measured following peripheral blood stem cell harvest, PBSCH), do not receive any further treatment until clinical indication of relapse. This is addressed separately for patients who are minimal residual disease positive (MRD+), and those who are MRD negative (MRD-), at end of induction therapy.
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Protection of trial subjects |
Pregnancy testing prior to each treatment cycle was mandated for all women of child bearing potential, due to the unknown risk from bortezomib exposure to human embryo /foetus, crossing of dexamethasone through the placenta causing possible foetal development abnormalities and possible teratogenicity of doxorubicin. All patients had to consent to trial acceptable methods of contraception during the study and for six months post trial treatment. Due to the possible effect of doxorubicin on male fertility, for safety reasons, men wanting babies were advised on sperm cryopreservation prior to trial treatment.
Patients who did not achieve at least a PR following trial treatment, immediately went on to receive salvage treatment. Patients who were assigned to no further treatment, following trial treatment and a negative MRD result, were offered off-trial ASCT on relapse. Cardiac function assessment was done at the end of trial treatment, due to possible cardiotoxicity from doxorubicin.
Local supportive care protocols including antiemetic schedules, mesna, thromboprophylaxis (to prevent tumour lysis), transfusion support, mouthcare and prophylactic antimicrobial therapy were followed as required.
Prior to each trial treatment dose, patients were evaluated for possible toxicities that might have occurred from the previous dose. For each of the trial drugs, dose modifications were put in place for specific haematological and non-haematological toxicities. Treatment delays were also allowed for toxicities that were not related to any of the trial drugs.
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Background therapy |
Patients who achieved at least a partial response (PR) following the trial treatment received PBSC Mobilisation before peripheral blood stem cell harvest (PBSCH): Cyclophosphamide, iv infusion in 500 ml NaCl 0.9%, 1.5-3 g/m^2 G-CSF, subcutaneous, 5-10 mcg/kg/day or 150 mcg/m^2/day Patients who achieved a partial response (PR) with adequate PBSCH, received high dose melphalan with autologous stem cell rescue (ASCT): NaCl 0.9% + 20 mmol KCl, 1 litre/hour Furosemide, 20 to 40 mg, IV stat Dexamethasone, 8 mg, IV stat Granisetron, 3 mg, IV stat Melphalan, 200 mg/m^2, short infusion (as per local protocol) in 100 ml NaCl 0.9% NaCl 0.9%, 1 litre over 2 hours + KCl 20 mmol to maintain urine output of at least 500 ml/hr NaCl 0.9% + KCl 1 litre four hourly x 1 NaCl 0.9% + KCl 1 litre six hourly x 3 | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Apr 2011
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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 |
United Kingdom: 153
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Worldwide total number of subjects |
153
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EEA total number of subjects |
0
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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) |
129
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From 65 to 84 years |
24
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85 years and over |
0
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Recruitment
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Recruitment details |
14 UK sites were opened to participate in the trial over a period of 2 years (09/03/2011 to 13/03/2013). Of these, only 13 recruited patients into the trial. A total of 153 patients were recruited over 2 years and 9 months (01/04/2011 - 14/01/2014), a planned increase from the initial 120 target. | ||||||||||||||||
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Pre-assignment
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Screening details |
Patients aged ≥18 years with previously untreated symptomatic myeloma were screened. They had to have measurable disease, suitable for high dose therapy and ASCT, adequate full blood count, renal, cardiac, pulmonary and hepatobiliary functions. Patients with ≥Gr2 peripheral neuropathy/neuropathic pain were excluded. Screening logs were maintained. | ||||||||||||||||
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Period 1
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Period 1 title |
Main trial (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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PAD Regimen | ||||||||||||||||
Arm description |
Bortezomib (Velcade), Doxorubicin and Dexamethasone | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
Bortezomib
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Investigational medicinal product code |
L01XX32
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Other name |
Velcade
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
At the start of the trial, bortezomib was given twice weekly in combination with Doxorubicin and Dexamethasone (PAD) at a dose of 1.3mg/m^2 as a bolus IV injection on days 1, 4, 8 and 11 of each 21-day cycle for a minimum of 4 cycles to a maximum of 6 cycles. It was given with doxorubicin on days 1 & 4 and with dexamethasone on days 1 & 4 for every cycle and days 8 & 11 for the first cycle only. Dose was calculated on D1 of each cycle and same dose was administered through out the days of that cycle. If a notable change in weight occurred within a cycle, as determined by an unscheduled weight assessment, dose was to be recalculated at that time.
Following protocol amendments, bortezomib administration was changed to subcutaneous (2011) and then to either subcutaneous or intravenous routes (2014) using the same schedule. The preferred route of administration was subcutaneous, but IV injection was allowed only if a patient experienced ≥Gr2 SC injection site reactions.
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Investigational medicinal product name |
Doxorubicin
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Investigational medicinal product code |
L01DB01
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
9mg/m^2 /day as continuous IV infusion or by IV bolus injection, on days 1 - 4 of each 21 day cycle (minimum 4, maximum 6).
Doxorubicin was given with bortezomib on days 1 & 4, and with dexamethasone on days 1 - 4. Dose was calculated on D1 of each cycle and same dose was administered through out the days of that cycle.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
A01AC02, C05AA09
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
40 mg/day on days 1 - 4 of each 21 day cycle (minimum of 4 and a maximum of 6). For the first cycle only, it was also administered on days 8 - 11 and days 15 - 18.
It was given, in every cycle, with doxorubicin on days 1 - 4 and with bortezomib on days 1 & 4 (and days 8 & 11 for the first cycle only).
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Baseline characteristics reporting groups
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Reporting group title |
Main trial (overall period)
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Reporting group description |
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End points reporting groups
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Reporting group title |
PAD Regimen
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Reporting group description |
Bortezomib (Velcade), Doxorubicin and Dexamethasone | ||
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End point title |
2-year PFS by MRD status within the VGPR-W&W group [1] | ||||||||||||
End point description |
2-year progression free survival (PFS) for patients post PBSCH, who receive no further treatment after achieving a major response to induction therapy with PAD.
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End point type |
Primary
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End point timeframe |
Time from date of PBSCH to date of the first progression/relapse or date of death from all causes whichever occurs first estimated at 2 years post-PBSCH.
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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: Primary analyses are descriptive, with simple estimates and 95% confidence intervals. Exploratory comparison by MRD status at day 100: Cox regression HR=0.74 (95% CI: 0.40-1.37, p=0.33) |
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| Notes [2] - Number here is the 2-year rate |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Overall Response (OR) to PAD induction therapy | ||||||||||||||||
End point description |
Disease response was measured by serum and urinary paraprotein, with Complete Response (CR), Very Good partial Response (VGPR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) defined as per the International response criteria (Durie et al, 2006). Patients achieving CR and VGPR were categorised as the ≥VGPR group.
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End point type |
Secondary
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End point timeframe |
Time from start of PAD therapy until post PBSCH
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| Notes [3] - 36/44 PR post-PBSCH had ASCT OR rate post induction = 82.4%(126/153) with 63(41.2%) achieving ≥VGPR |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
MRD status post PBSCH | ||||||||||||
End point description |
MRD was assessed by Multiparameter Flow Cytometry (MPF) of bone marrow samples from patients after PBSCH
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End point type |
Secondary
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End point timeframe |
MRD status was assessed post stem cell harvesting (PBSCH)
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| Notes [4] - MRD -ve (25.3%) MRD +ve (74.7%) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
MRD status at D100 post-ASCT for PR-ASCT group | ||||||||||||
End point description |
MRD was assessed by MPF of bone marrow samples from patients after stem cell harvesting, at 100 days post ASCT for PR patients
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End point type |
Secondary
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End point timeframe |
MRD assessed at 100 days post ASCT
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| Notes [5] - 20 (74.1%) and 7 (25.9%) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
MRD status at D100 post-PBSCH for VGPR-W&W group | ||||||||||||
End point description |
MRD was assessed by MPF of bone marrow samples from patients at 100 days post-PBSCH for ≥VGPR patients. These are the patients that received no further treatment until relapse (VGPR-W&W)
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End point type |
Secondary
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End point timeframe |
MRD assessment at 100 days post-PBSCH
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| Notes [6] - 32 (64.0%) and 18 (36.0%) |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
PFS post-PBSCH for PR-ASCT group | ||||||||||||
End point description |
Progression free survival (PFS) of patients proceeding to ASCT (PR-ASCT), following PBSCH
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End point type |
Secondary
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End point timeframe |
Time from date of Peripheral Blood Stem Cell Harvest (PBSCH), following PAD therapy, to date of the first progression/relapse or date of death from all causes whichever occurs first
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| No statistical analyses for this end point | |||||||||||||
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End point title |
2-year PFS2 rate post-PBSCH | ||||||||||||
End point description |
Patients were followed up from PBSCH until second disease relapse or death.
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End point type |
Secondary
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End point timeframe |
2 years from date of PBSCH to the second relapse or death
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| Notes [7] - This includes the PR-ASCT and VGPR-W&W groups. Number refers to the 2-year rate |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
2-year OS rate | ||||||||||||
End point description |
Overall survival (OS) rate was measured from date of PBSCH to death. The VGPR-W&W and PR-ASCT groups were combined and OS was calculated by MRD status at
D100 post PBSCH
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End point type |
Secondary
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End point timeframe |
2 years from date of PBSCH to death event
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| Notes [8] - Number refers to the 2-year rate |
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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 |
All adverse events (including serious) that occur between first administration of trial treatment (PAD) and 30 days post last trial treatment (PAD) administration (or after this date if thought to be related to the trial treatment)
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Adverse event reporting additional description |
Trial subjects were assessed for adverse events (AEs) prior the start of each PAD cycle. All AEs were recorded in the patient notes and the trial CRFs. Those meeting the definition of Serious, excluding exempted events, were to be reported using the trial specific SAE Reporting template within 24 hours of observing or learning of the event.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
NCI - CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4.0
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Reporting groups
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Reporting group title |
PAD therapy
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Reporting group description |
Bortezomib, doxorubicin and dexamethasone | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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01 Jul 2011 |
Protocol was amended to allow the following:
- IV administration of bortezomib was replaced with subcutaneous administration
- IV bolus injection administration of doxorubicin, administration of doxorubicin over 4 days (total dose 36/mg/m2)
- inclusion criterion for Creatinine Clearance was changed from ≥ 30mL/min to ≥ 20mL/min
- Serum free light chain essay was made mandatory post PBSCH and 100 days post PBSCH/ASCT
Patient Information Sheet (PIS) was updated to include:
- information on changed routes of administration for bortezomib and doxorubicin
- additional details on effective contraception
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29 Nov 2011 |
Urgent Safety Measure - There was an precautionary recall of the supplied bortezomib, Velcade, following a 'Dear Investigator' letter from the supplier. Due to GMP compliance issues identified at Ben Venue Laboratories, BVL, Ohio, USA, one of the manufacturing facilities for Velcade, there was a recall of batches manufactured at this site. Some of the clinical trial subcutaneous (SC) Velcade stock for the trial were affected and immediate action had to be taken as it was detrimental for patients not to receive treatment.
The urgent measure taken was to allow patients to be treated subcutaneously using IV labelled trial supply, once it was confirmed by the manufacturer (Janssen) that the IV and SC formulations were the same. A site, where IV labelled supply was not available, was given the go ahead following confirmation from Janssen to administer the SC labelled supply from the affected batch to their patients. All sites were to revert to using new batches of unaffected sc labelled trial supply once received. Increased monitoring of adverse events at sites was advised. The plan of actions to be taken were discussed with the REC and MHRA before implementation. |
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30 Nov 2012 |
Protocol amendment: changes were made to protocol v2
- IV administration of bortezomib was allowed as an alternative route
- Inclusion criteria states inclusion of patients with ECOG PS of 0-3. Patients with an ECOG performance score of >3 when this score is due to disease processes such as spinal cord compression, and who would otherwise have a score of ≤3, were included in the trial
- exclusion of patients with active HIV, hepatitis B or C infection
Detailed information on toxicity assessment, sample collection and other relevant information, were also included.
The PIS was updated to include detailed explanation on side effects of bortezomib for both SC and IV routes, and other relevant updates made to the protocol. |
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29 Aug 2014 |
Target accrual number was increased from 120 to 153
Protocol was amended as follows:
- Additional assessments and samples at relapse
- RSI for subcutaneous bortezomib was changed from the Investigator's Brochure to the SPC |
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04 Dec 2014 |
Protocol was amended as follows:
- Update to the trial endpoints and outcome measures: PFS2 (time from start of salvage treatment to 2nd relapse) and OS (overall survival) were added as secondary endpoints
- Update to the outcome measures and assessment of the measures for the trial
- Update to the long term follow-up schedule for the trial due to the addition of OS as a secondary endpoint
- Update to the End of Trial definition
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| Non-serious AEs: 'occurrences all number' can't be provided as only highest grade experienced by patients are collected on CRFs; number of subjects affected has been entered. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/33715154 |
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