Clinical Trial Results:
An open-label, randomized, multicenter, phase II trial designed to estimate the activity of CAPTEM combination versus FOLFIRI as second line treatment in patients who have progressed on or after first-line oxaliplatin - containing chemotherapy for advanced, MGMT methylated, RAS mutated colorectal cancer

Trial information Top of page
Trial identification
Sponsor protocol code	CAPTEM
Additional study identifiers
ISRCTN number	-
US NCT number	NCT02414009
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Fondazione IRCCS Istituto Nazionale Tumori
Sponsor organisation address	via Venezian, 1, Milan, Italy, 20133
Public contact	trialcenter, trialcenter, trialcenter@istitutotumori.mi.it
Scientific contact	trialcenter, trialcenter, trialcenter@istitutotumori.mi.it
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	30 Jul 2019
Is this the analysis of the primary completion data?	Yes
Primary completion date	16 Jul 2019
Global end of trial reached?	Yes
Global end of trial date	16 Jul 2019
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	Progression free survival
Protection of trial subjects	laboratory test and clinical visit before every drugs subministrations Each patient had a direct contact to inform physicians about possible symptoms due to site effects of the experimental drugs and he received consultation about the optimal management.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	31 Jul 2014
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Italy: 86
Worldwide total number of subjects	86
EEA total number of subjects	86
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	31
From 65 to 84 years	55
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	18 Italian centers. Between November 6, 2014 and May 10, 2019, a total of 155 patients were pre-screened for MGMT methylation status and 86 molecularly eligible patients were randomized
Pre-assignment
Screening details	Inclusion criteria: age of 18 years or more; ECOG PS 0–1; RAS-mutated status and MGMT methylation; PD after previous oxaliplatin based regimen (no more than 1 prior treatment line); misurable lesion; adequate bone marrow, liver, and renal function. Exclusion: deficiency DPD; Gilbert S.; relevant cardiovascular disease; active malignancies; pregnanc
Pre-assignment period milestones
Number of subjects started	86
Number of subjects completed	86
Period 1
Period 1 title	overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Not blinded
Arms
Are arms mutually exclusive	Yes
Arm title	CAPTEM
Arm description	The schedule of CAPTEM regimen consisted of oral capecitabine 750 mg/sqm twice daily from days 1 to 14 every 28 days plus temozolomide 75 mg/sqm twice daily from days 10 to 14 every 28 days.
Arm type	Experimental
Investigational medicinal product name	CAPECITABINE
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	750 mg/sqm twice daily from days 1 to 14 every 28 days
Investigational medicinal product name	TEMOZOLOMIDE
Investigational medicinal product code
Other name
Pharmaceutical forms	Tablet
Routes of administration	Oral use
Dosage and administration details	75mg/sqm twice daily from days 10 to 14 every 28 days
Arm title	FOLFIRI
Arm description	The schedule of FOLFIRI regimen consisted of irinotecan 180 mg/sqm i.v. over 60 minutes on day 1, leucovorin 200 mg/sqm i.v. over 120 minutes on days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/sqm i.v. bolus and then 5-FU 600 mg/sqm administered as a continuous intravenous infusion over 22 +/- 2 hours, both on days 1 and 2, every two weeks.
Arm type	Active comparator
Investigational medicinal product name	IRINOTECAN
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection/infusion
Routes of administration	Intravenous use
Dosage and administration details	180 mg/sqm i.v. over 60 minutes on day 1
Investigational medicinal product name	LEUCOVORIN
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	200 mg/sqm i.v. over 120 minutes on days 1 and 2
Investigational medicinal product name	5-FLUORURACIL (5-FU)
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	5-fluorouracil (5-FU) 400 mg/sqm i.v. bolus on day 1 and 2
Investigational medicinal product name	5-FLUORURACIL (5-FU)
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for infusion
Routes of administration	Intravenous use
Dosage and administration details	600 mg/sqm administered as a continuous intravenous infusion over 22  2 hours, both on days 1 and 2, every two weeks
Number of subjects in period 1 CAPTEM FOLFIRI Started 43 43 Completed 43 43

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	CAPTEM
Reporting group description	The schedule of CAPTEM regimen consisted of oral capecitabine 750 mg/sqm twice daily from days 1 to 14 every 28 days plus temozolomide 75 mg/sqm twice daily from days 10 to 14 every 28 days.
Reporting group title	FOLFIRI
Reporting group description	The schedule of FOLFIRI regimen consisted of irinotecan 180 mg/sqm i.v. over 60 minutes on day 1, leucovorin 200 mg/sqm i.v. over 120 minutes on days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/sqm i.v. bolus and then 5-FU 600 mg/sqm administered as a continuous intravenous infusion over 22 +/- 2 hours, both on days 1 and 2, every two weeks.
Reporting group values CAPTEM FOLFIRI Total Number of subjects 43 43 86 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 11 20 31     From 65-84 years 32 23 55     85 years and over 0 0 0 Age continuous Units: years     median (full range (min-max)) 70.0 (63.0 to 74.5) 67.0 (61.0 to 73.0) - Gender categorical Units: Subjects     Female 25 19 44     Male 18 24 42 ECOG performance status Units: Subjects     ECOG PS 0 24 22 46     ECOG PS1 19 21 40 Primary tumor location Units: Subjects     Right 15 17 32     Left 28 26 54 Primary tumor resected Units: Subjects     YES 30 31 61     NO 13 12 25 Prior adjuvant treatment Units: Subjects     YES 10 11 21     NO 33 32 65 Number of metastatic sites Units: Subjects     ONE 18 15 33     MORE THAN ONE 25 28 53 Liver-limited disease Units: Subjects     YES 11 7 18     NO 32 36 68 Synchronous metastases Units: Subjects     YES 31 29 60     NO 12 14 26 First-line PFS Units: Subjects     LESS THAN NINE MONTHS 20 19 39     NINE MONTHS OR MORE 23 24 47 Prior bevacizumab Units: Subjects     YES 30 29 59     NO 13 14 27

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	CAPTEM
Reporting group description	The schedule of CAPTEM regimen consisted of oral capecitabine 750 mg/sqm twice daily from days 1 to 14 every 28 days plus temozolomide 75 mg/sqm twice daily from days 10 to 14 every 28 days.
Reporting group title	FOLFIRI
Reporting group description	The schedule of FOLFIRI regimen consisted of irinotecan 180 mg/sqm i.v. over 60 minutes on day 1, leucovorin 200 mg/sqm i.v. over 120 minutes on days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/sqm i.v. bolus and then 5-FU 600 mg/sqm administered as a continuous intravenous infusion over 22 +/- 2 hours, both on days 1 and 2, every two weeks.

End points Top of page

Primary: Progression-free survival Top of page
End point title	Progression-free survival
End point description
End point type	Primary
End point timeframe	Between November 2014 and May 2019,
End point values CAPTEM FOLFIRI Number of subjects analysed 43 43 Units: month     median (full range (min-max)) 3.5 (2.0 to 5.0) 3.5 (2.3 to 6.1)
Statistical analysis title	PFS
Comparison groups	CAPTEM v FOLFIRI
Number of subjects included in analysis	86
Analysis specification	Pre-specified
Analysis type	superiority
P-value	= 0.05
Method	Logrank
Parameter type	Hazard ratio (HR)
Point estimate	95
Confidence interval
level	95%
sides	1-sided
lower limit	-
upper limit	95

Primary: Progression-free survival Top of page

Secondary: overall survival Top of page
End point title	overall survival
End point description
End point type	Secondary
End point timeframe	Between November 2014 and May 2019.
End point values CAPTEM FOLFIRI Number of subjects analysed 43 43 Units: month     median (full range (min-max)) 9.5 (8.2 to 25.8) 10.6 (8.5 to 20.8)
Statistical analysis title	OS
Comparison groups	CAPTEM v FOLFIRI
Number of subjects included in analysis	86
Analysis specification	Pre-specified
Analysis type	other
P-value	= 0.05
Method	Logrank
Parameter type	Cox proportional hazard
Point estimate	95
Confidence interval
level	95%
sides	2-sided
lower limit	0
upper limit	100

Secondary: overall survival Top of page

Secondary: disease control rate (DCR) Top of page
End point title	disease control rate (DCR)
End point description
End point type	Secondary
End point timeframe	Between November 2014 and May 2019
End point values CAPTEM FOLFIRI Number of subjects analysed 43 43 Units: percentage protection     number (not applicable) 53.5 53.5
Statistical analysis title	DCR
Comparison groups	FOLFIRI v CAPTEM
Number of subjects included in analysis	86
Analysis specification	Pre-specified
Analysis type	other
P-value	= 0.05
Method	Logrank
Parameter type	Cox proportional hazard
Point estimate	95
Confidence interval
level	95%
sides	2-sided
lower limit	0
upper limit	100

Secondary: disease control rate (DCR) Top of page

Secondary: ORR Top of page
End point title	ORR
End point description
End point type	Secondary
End point timeframe	Between November 2014 and May 2019
End point values CAPTEM FOLFIRI Number of subjects analysed 43 43 Units: NUMBER     median (confidence interval 95%) 11.6 (3.9 to 25.1) 11.6 (3.9 to 25.1)
Statistical analysis title	ORR
Comparison groups	CAPTEM v FOLFIRI
Number of subjects included in analysis	86
Analysis specification	Pre-specified
Analysis type	other
P-value	= 0.05
Method	t-test, 2-sided
Confidence interval
level	95%
sides	2-sided
lower limit	-
upper limit	-

Secondary: ORR Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	The data cut-off date for the analyses was July 30, 2019.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	NCI CTCAE
Dictionary version	4.0
Reporting groups
Reporting group title	CAPTEM
Reporting group description	-
Reporting group title	FOLFIRI
Reporting group description	-
Serious adverse events CAPTEM FOLFIRI Total subjects affected by serious adverse events      subjects affected / exposed 0 / 43 (0.00%) 0 / 43 (0.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0
Frequency threshold for reporting non-serious adverse events: 1%
Non-serious adverse events CAPTEM FOLFIRI Total subjects affected by non serious adverse events      subjects affected / exposed 14 / 43 (32.56%) 23 / 43 (53.49%) Blood and lymphatic system disorders Anemia      subjects affected / exposed 7 / 43 (16.28%) 23 / 43 (53.49%)      occurrences all number 1 1 Neutropenia      subjects affected / exposed 2 / 43 (4.65%) 19 / 43 (44.19%)      occurrences all number 1 1 Thrombocytopenia      subjects affected / exposed [1] 10 / 14 (71.43%) 3 / 23 (13.04%)      occurrences all number 1 1 AST increased      subjects affected / exposed [2] 1 / 14 (7.14%) 5 / 23 (21.74%)      occurrences all number 1 1 ALT increased      subjects affected / exposed [3] 3 / 14 (21.43%) 4 / 23 (17.39%)      occurrences all number 1 1 Blood bilirubin increased      subjects affected / exposed [4] 4 / 14 (28.57%) 0 / 23 (0.00%)      occurrences all number 1 1 General disorders and administration site conditions Hand–foot syndrome      subjects affected / exposed [5] 4 / 14 (28.57%) 1 / 23 (4.35%)      occurrences all number 1 1 Fatigue      subjects affected / exposed [6] 14 / 14 (100.00%) 18 / 23 (78.26%)      occurrences all number 1 1 Gastrointestinal disorders Diarrhea      subjects affected / exposed [7] 6 / 14 (42.86%) 19 / 23 (82.61%)      occurrences all number 1 1 Nausea      subjects affected / exposed [8] 11 / 14 (78.57%) 14 / 23 (60.87%)      occurrences all number 1 1 Vomiting      subjects affected / exposed [9] 12 / 14 (85.71%) 8 / 23 (34.78%)      occurrences all number 1 1 Stomatitis      subjects affected / exposed [10] 1 / 14 (7.14%) 6 / 23 (26.09%)      occurrences all number 1 1
Notes [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal. Justification: not equal because not all the patients showed the same AEs

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? No
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported
Online references
http://www.ncbi.nlm.nih.gov/pubmed/31740551

More information Top of page