1.3 Elementos de la autoría mediata en virtud de aparatos organizados de
1.3.4 La desvinculación del ordenamiento jurídico del aparato de poder
There is strong evidence to suggest that FCM-miniR is not non-inferior to FCR in terms of CR at 3 months post treatment.
TABLE 60 Incidence and type of secondary cancer
Incidence and type of secondary
cancer FCR,N(%) FCM-miniR,N(%) FCM-miniR/FCR,N(%) Total,N(%)
Has the participant reported a secondary cancer?
Yes 11 (11.0) 10 (12.7) 1 (5.3) 22 (11.1)
No 89 (89.0) 69 (87.3) 18 (94.7) 176 (88.9)
Total 100 (100) 79 (100) 19 (100) 198 (100)
Secondary cancer type
Haematological (lymphoma) 2 (16.7) 2 (18.2) 0 (0.0) 4 (16.7)
Haematological (AML/MDS) 3 (25.0) 2 (18.2) 0 (0.0) 5 (20.8)
Skin (non-melanoma) 2 (16.7) 7 (63.6) 1 (100) 10 (41.7)
Skin (melanoma) 1 (8.3) 0 (0.0) 0 (0.0) 1 (4.2)
Non-haematological (solid tumours) 4 (33.3) 0 (0.0) 0 (0.0) 4 (16.7)
Total 12 (100) 11 (100) 1 (100) 24 (100)
AML, acute myeloid leukaemia; MDS, myelodysplastic syndrome.
TABLE 61 Further detail on type of secondary cancer
Secondary cancer type FCR,N(%)
FCM-miniR, N(%) FCM-miniR/FCR, N(%) Total,N(%) Lymphoma (other) 2 (16.7) 2 (18.2) 0 (0.0) 4 (16.7) Myelodysplastic syndrome 2 (16.7) 2 (18.2) 0 (0.0) 4 (16.7)
Acute myeloid leukaemia 1 (8.3) 0 (0.0) 0 (0.0) 1 (4.2)
Basal cell carcinoma 0 (0.0) 3 (27.3) 0 (0.0) 3 (12.5)
Squamous cell carcinoma 2 (16.7) 4 (36.4) 1 (100) 7 (29.2)
Melanoma 1 (8.3) 0 (0.0) 0 (0.0) 1 (4.2)
Lung 1 (8.3) 0 (0.0) 0 (0.0) 1 (4.2)
Hepatobiliary 1 (8.3) 0 (0.0) 0 (0.0) 1 (4.2)
Urological (prostate) 2 (16.7) 0 (0.0) 0 (0.0) 2 (8.3)
From December 2009 to September 2012, 200 of a planned 206 patients were recruited from 34 centres across the UK. A good proportion of participants (n=141, 70.5%) completed the recommended six cycles of treatment, with a slightly higher proportion in the FCR arm than in the FCM-miniR arm (70% vs. 64.6%), and the majority of participants who discontinued treatment early doing so for reasons of toxicity. A similar proportion of participants in each of the treatment arms experienced at least one dose
modification to their protocol-defined dose of treatment, and just under half (47.0%) received treatment with GCSF at some stage during their treatment period.
At the interim analysis, carried out on the first half of patients randomised to the trial (n=103), of those with available data, 82.9% of participants achieved a CR in the FCR arm compared with 61.4% in the FCM-miniR arm. The difference in proportions (FCM-miniR–FCR) was–21.6% (99.5% CI–48.0% to 4.8%), which was not statistically significant at the 0.5% (p=0.005) level, although the experimental treatment had the worst performance. This was confirmed by the adjusted analysis (OR 0.32, 99.5% CI 0.07 to 1.48; p=0.037). The primary aim of the interim analysis was to be able to release information of any potential large differences in efficacy between the treatment arms and inform the continued treatment of trial participants earlier than would have been the case with the final analysis. As the results were approaching significance in favour of the control group, and there was evidence of additional toxicity in the FCM-miniR arm, the trial was closed early at the recommendation of the DMEC and participants still receiving FCM-miniR were recommended to transfer to treatment with FCR for the remainder of their treatment cycles.
At the final analysis of the primary end point (at 3 months post treatment), 76.1% of participants in the FCR arm achieved a CR compared with 54.7% in the FCM-miniR arm. The difference in proportions (FCM-miniR–FCR) was–21.4% (95% CI–35.8% to–7.0%) and the adjusted analysis gave an OR of 0.37 for the treatment effect (95% CI 0.19 to 0.73), indicating that participants in the FCM-miniR were
significantly less likely to achieve a CR. As the lower limit of the 95% CI and the mean OR were<0.61 (equivalent to a difference in proportions of 10% based on the observed control rate) and the upper limit of the 95% CI was also below 1, there was very strong evidence that FCM-miniR is not non-inferior to FCR in terms of CR rates at 3 months post treatment, and that it is in fact inferior. The analysis of the PP population and the sensitivity analyses agreed with this conclusion. The exploratory subgroup analyses indicated that there was a significant trend towards participants who received more than three cycles of treatment, and those who did not have a 17p deletion, performing better in terms of response.
The ORR was high at 92.6% with 7.5% fewer participants achieving at least a PR in the FCM-miniR arm compared with the FCR arm (95% CI–15.6% to 0.6%). The difference in the ORR proportions was not statistically significant, although it is approaching significance.
TABLE 62 Timing of secondary cancer
Timing of secondary cancer FCR FCM-miniR FCM-miniR/FCR Total
Months from randomisation to diagnosis
Mean (SD) 23.9 (14.9) 18.7 (9.4) 24.3 21.5 (12.3)
Median (range) 25.4 (1.6–46.5) 20.0 (6.4–31.6) 24.3 (24.3–24.3) 22.3 (1.6–46.5)
n 12 11 1 24
Months from end of treatment to diagnosis
Mean (SD) 19.9 (14.3) 13.2 (8.7) 19.2 16.8 (11.9)
Median (range) 21.7 (0.3–41.5) 14.6 (1.7–25.7) 19.2 (19.2–19.2) 16.1 (0.3–41.5)
n 12 11 1 24
STATISTICAL TRIAL RESULTS
NIHR Journals Library www.journalslibrary.nihr.ac.uk
At 3 months post treatment, 53.0% of participants were MRD negative, a higher percentage of participants in the FCR arm (57.0%) than in the FCM-miniR arm (46.4%). The difference in proportions (FCM-miniR–FCR) was–10.6% (95% CI–26.1% to 4.9%) and the adjusted analysis gave an OR of 0.63 for the treatment effect (95% CI 0.34 to 1.20) which was not statistically significant (χ2=1.97;p=0.160), although it was approaching significance.
There was no conclusion of a significant difference between the treatment arms with respect to time to progression (log-rank test,p=0.2790; Wilcoxon rank-sum test,p=0.1081), confirmed by the adjusted Cox regression analysis (HR 1.39, 95% CI 0.77 to 2.49;p=0.2771). There was also no conclusion of a significant difference between the treatment arms with respect to OS (log-rank test,p=0.2779; Wilcoxon rank-sum test,p=0.1013), confirmed by the adjusted Cox regression analysis (HR 1.57, 95% CI 0.68 to 3.58;p=0.2876). However, there was a non-significant trend towards the FCM-miniR participants performing worse. At 24 months from randomisation, 89.4% of the FCR participants remained progression-free compared with 79.1% of the FCM-miniR participants. In terms of OS at 24 months, 95.8% of the FCR participants remained alive compared with 88.5% of the FCM-miniR participants. In the exploratory subgroup analyses, PFS and OS were significantly improved for participants who were MRD negative or had achieved a CR at 3 months post treatment, or who received more than three cycles of treatment. In addition, of those participants who were MRD positive, OS was worse in participants who received FCM-miniR than in those who received FCR, suggesting that after progression the participants initially treated with FCM-miniR responded worse to salvage therapies or died before further treatment was possible. Longer follow-up data are required to be able to assess reliably the time-to-event outcomes, and these will be updated in future.
More participants experienced an SAE in the FCM-miniR arm than the FCR arm (58.2% vs. 49.0%), as well as an SAR (49.4% vs. 41.0%). One SUSAR (‘squamous cell carcinoma’) was reported during the trial in the FCR arm. More participants in the FCM-miniR arm were hospitalised for an SAE during the trial (51.9% vs. 46.0%) and six SAEs were deemed to be life-threatening or resulted in death compared with three in the FCR arm. A similar proportion of participants experienced an AE in each treatment arm, but a higher proportion of CTCAE grade 3 and 4 AEs were reported in the FCM-miniR arm (22.4% vs. 15.0%). There were no treatment-related mortalities within 3 months of completing protocol treatment.
Throughout the duration of the trial there were nine withdrawals (4.5%), with a similar number of participants coming from each treatment arm.
Chapter 4
Economic evaluation
S
ections of this chapter have been reproduced from Howardet al.1with permission.The health economics analysis was designed to provide an economic evaluation of previously untreated patients with CLL to compare FCR and FCM-miniR. The aim was to assess the cost-effectiveness of FCR compared with FCM-miniR from a UK NHS and PSS perspective.