ICORG07-01

Cancer Trials Ireland

RCSI House, 121 St. Stephen's Green, Dublin, Ireland, D02 H903

Chief Operations Officer, Cancer Trials Ireland, +353 16677211, regulatory@cancertrials.ie

Chief Operations Officer, Cancer Trials Ireland, +353 16677211, regulatory@cancertrials.ie

No

No

No

Final

30 Jan 2020

Yes

21 Nov 2019

Yes

21 Nov 2019

No

•Complete remission rate by NCI Criteria (Appendix 3) and using MRD analysis.

This clinical study was designed, implemented, and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations SI 190 of 2004 as amend and European Directive 2001/20/EC. The study was approved by the HPRA and SJH/AMNCH Research Ethics Committee.

19 Sep 2008

No

No

Ireland: 52

52

52

0

0

0

0

0

0

42

10

0

Overall Study (overall period)

Non-randomised - controlled

Patients non blinded

Fludarabine

Powder for solution for injection/infusion, Tablet

Oral use, Intravascular use

Tablet: BSA calculations were used to calculate number of tablets patients should take per day (total daily dose) Fludarabine tablets can be taken either on an empty stomach or together with food. 40mg/m2/day PO. The tablets have to be swallowed whole with water; they should not be chewed or broken. IV: Fludarabine iv should be reconstituted and diluted according to local practice. Dilution in 100ml NaCl 0.9% and administration over 30 minutes is suggested. 25mg/m2/day IV. Can be taken via IV or PO on Days 1,2 & 3 of a 28 day cycle. Taken for 4 or 6 cycles depending on MRD analysis.

Cyclophosphamide

Endoxana

Tablet, Powder for solution for injection

Oral use, Intravenous use

Cyclophosphamide IV is usually given directly into the tubing of a fast running intravenous infusion. Cyclophosphamide tablets should be swallowed whole with sufficient fluid. The tablets are coated and should not be divided. 250mg/m2/day iv or Po. Taken on days 1,2 &3

Rituxumab

Mabthera

Concentrate for solution for infusion

Intravenous use

Omit Rituximab in cycle 1. Dose is 375 mg/m2 IV on Day 1 of the cycle. When infused for the first time, the infusion should be started at 50mg/hr. The rate can be increased by 50mg/hour increments every 30 minutes to a maximum of 400mg/hr. On second and subsequent infusions, the rate may be set to 100mg/hr, if the infusion was well tolerated previously, and increased in 100mg/hr increments every 30 minutes to a maximum of 400mg/hr.

Pegfilgrastim

Solution for injection

Subcutaneous use

Should be given no sooner than 24 hours post last dose of chemotherapy. Dose is 6mg subcut on day 4 of a cycle

Overall Study (overall period)

Single Arm

Single Arm

Arm created so that the study can include statistical analysis even though it is just a one armed study (Error appears unless 2 arms selected for this analysis)

The primary response variable (endpoint) is the CR rate achieved using NCI Criteria and MRD analysis. Twenty-nine out of 52, 55.8%, were MRD-ve CR at EOT (95% CI using Wilson’s method 42.3% to 68.4%). The lower bound of the CI is above 30% indicating that there is evidence that population percentage of patients achieving MRD-ve CR at the end of treatment is > 30% (as hypothesised in the sample size calculations). This result should be interpreted with caution however, since this is an open-label non-randomised study and there exists a risk of potential sources of bias, particularly selection bias. In addition to this, 18 out of 52 patients, 34.6%, were MRD-ve CR at the end of cycle 4 (95% CI using Wilson’s method 23.2% to 48.2%).

Primary

Measured at end of trial and end of cycle 4

Single Arm v Single Arm

104

Pre-specified

55.8

2-sided

No Confidence Intervals for median TTF are presented. All that is presented is the medians and the p-value of 0.0008 for a superiority test. MRD status at EoT was the most significant prognostic factor for TTF in univariate analysis. Patients MRD-negative at EoT experienced prolonged TTF.

Secondary

Median TTF for both sets of patients (MRD negative and positive) was taken at EoT.

The median overall survival was not reached as there were only 6 deaths, so no further analysis is presented for overall survival. (the 6 deaths occured after median follow up of 62.3 months, 5 from progressive disease and one of t-cell lymphoma)

Secondary

OS was to be calculated from date of enrolment until death or clinical progression

Creation of a predictive model for TTF and OS using hypermutation analysis .Originally immunophenotype and FISH analyses were also to be used in determining TTF and OS but it was decided that there was no further information to be gleaned from the study for the secondary objectives apart from the analyses using hypermutation analysis. Patients with mutations in SF3B1 and NOTCH1 experienced significantly shorted TTF than their wild types. There was too little data on overall survival in order to be able to calculate the median OS, so there are no results on OS . As well, the median TTF for u-IGHV was 67.9 months but wasn’t sufficient data to estimate the medianfor m-IGHV, but because the median TTF for all patients was 71.1 months, TTF for m-IGHV must be shorter, though the difference is not statistically significance (p=0.310).

Secondary

TTF was calculated from date of enrollment until death or clinical progression, respectively

Modified Combination of Fludarabine, cyclophosphamide and rituximab. FCR was modified at cycle 4 or 6 depending on MDR analysis. Patients who were MRD negative and in CR on CT scan stopped therapy after 4 courses of FCR. Patients with evidence of ongoing disease proceeded to a total of 6 courses of chemotherapy and patients with progressive disease came off trial. No difference was noted in TTF in MRD-negative patients following FCR4 or FCR6. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.

Secondary

Time to Treatment Failure is from time of patient enrollment to time of treatment failure

Monitored from Baseline through the study until completion of therapy

Occurrences causally related to treatment number for individual SAEs was not recorded, therefore in the tables below it is recorded as 0.

23

Single Arm