Trial Outcomes & Findings for Regorafenib and Nivolumab Simultaneous Combination Therapy (NCT NCT03406871)

Last Updated: 2025-01-24

Results Overview

The procedure for DLT assessment was as follows: 1. When DLT is observed in 1 out of 3 cases, 3 additional cases are added to the administration level. 2. When DLT is observed in more than 2 of 3 cases, it is judged that the administration level exceeds Maximum Tolerated Dose (MTD). 3. If the number of DLT is 1 case or less in 6 cases, shift to the next level. 4. If MTD is exceeded, shift to the next lower level. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases. When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD. If it is judged that Level 1 exceeds the MTD, review the dose or consider stopping the trial. 5. MTD should be the highest dose level of DLT expression less than 1 in 6 cases. - After the RD was determined and the patient moved to the expansion cohort, G3 skin toxicity occurred, so based on the recommendation of the Data and Safety Monitoring Committee, the RD was reduced by one level and the trial was resumed.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

50 participants

Primary outcome timeframe

4 weeks

Results posted on

2025-01-24

Participant Flow

* 25January2018: First subject enrollment * 23October2018: Last subject enrollment * This study was conducted at second site in Japan. * The number of 'completers' and 'non-completers' in dose escalation cohorts will be determined by whether DLT criteria are met or not. * The number of cases in Expansion cohort and Dose escalation cohort who received the same dose were combined for analysis of this study.

\*The dose escalation cohort will focus on whether the criteria for DLT evaluation were met in the first cycle, i.e., safety in the first cycle, while the final analysis of the expansion cohort will focus on clinical efficacy and safety in all cycles. \*\*The planned number of cases in this clinical trial was 9 to 18 in the dose escalation cohort and approximately 30 in the expansion cohort, but the actual number was 14 in the dose escalation cohort and 36 in the expansion cohort.

Participant milestones

Participant milestones
Measure	Regorafenib 80mg/Day Regorafenib: Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 1 is confirmed, confirm the tolerability at level 2. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed. For the dose-escalation method, see Section "Outcome Measure Description" in " 1. Primary Outcome".	Regorafenib 120mg/Day Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 2 is confirmed, confirm the tolerability at level 3. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed. For the dose-escalation method, see Section "Outcome Measure Description" in " 1. Primary Outcome".	Regorafenib 160mg/Day Regorafenib was administered once daily at a dose of 160 mg/day for 21 consecutive days, followed by a 1-week rest period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 3 is confirmed, set the doses at level 3 as Recommended Dose (RD). For the dose-escalation method, see Section "Outcome Measure Description" in" 1. Primary Outcome".
Dose Escalation Cohort STARTED	4	7	3
Dose Escalation Cohort COMPLETED	3	6	3
Dose Escalation Cohort NOT COMPLETED	1	1	0
Expansion Cohort(Final Analysis) STARTED	22	25	3
Expansion Cohort(Final Analysis) COMPLETED	0	0	0
Expansion Cohort(Final Analysis) NOT COMPLETED	22	25	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Regorafenib 80mg/Day Regorafenib: Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 1 is confirmed, confirm the tolerability at level 2. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed. For the dose-escalation method, see Section "Outcome Measure Description" in " 1. Primary Outcome".	Regorafenib 120mg/Day Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 2 is confirmed, confirm the tolerability at level 3. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed. For the dose-escalation method, see Section "Outcome Measure Description" in " 1. Primary Outcome".	Regorafenib 160mg/Day Regorafenib was administered once daily at a dose of 160 mg/day for 21 consecutive days, followed by a 1-week rest period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. After starting the trial, three cases are enrolled for each dose level, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If tolerability at level 3 is confirmed, set the doses at level 3 as Recommended Dose (RD). For the dose-escalation method, see Section "Outcome Measure Description" in" 1. Primary Outcome".
Dose Escalation Cohort DLT assesment cancellation**	1	1	0
Expansion Cohort(Final Analysis) Completion of 54 doses of Nivolumab	4	2	1
Expansion Cohort(Final Analysis) Progression of primary disease	17	22	1
Expansion Cohort(Final Analysis) Physician Decision	1	0	0
Expansion Cohort(Final Analysis) Death	0	1	0
Expansion Cohort(Final Analysis) Adverse Event	0	0	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Final Analysis: Regorafenib 80mg/Day n=22 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of Regorafenib 80mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Follow the instructions in this clinical protocol to suspend and resume administration.	Final Analysis: Regorafenib 120mg/Day n=25 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 120mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Follow the instructions in this clinical protocol to suspend and resume administration.	Final Analysis: Regorafenib 160mg/Day n=3 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 160mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Follow the instructions in this clinical protocol to suspend and resume administration.	Total n=50 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=22 Participants	0 Participants n=25 Participants	0 Participants n=3 Participants	0 Participants n=50 Participants
Age, Categorical Between 18 and 65 years	12 Participants n=22 Participants	17 Participants n=25 Participants	2 Participants n=3 Participants	31 Participants n=50 Participants
Age, Categorical >=65 years	10 Participants n=22 Participants	8 Participants n=25 Participants	1 Participants n=3 Participants	19 Participants n=50 Participants
Sex: Female, Male Female	5 Participants n=22 Participants	4 Participants n=25 Participants	1 Participants n=3 Participants	10 Participants n=50 Participants
Sex: Female, Male Male	17 Participants n=22 Participants	21 Participants n=25 Participants	2 Participants n=3 Participants	40 Participants n=50 Participants
Race and Ethnicity Not Collected	—	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Japan	22 Participants n=22 Participants	25 Participants n=25 Participants	3 Participants n=3 Participants	50 Participants n=50 Participants

PRIMARY outcome

Timeframe: 4 weeks

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=3 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg n=6 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg n=3 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg n=18 Participants Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
The Number of Dose Limiting Toxicity (DLT) for RD Determination	0 Participants	0 Participants	3 Participants	5 Participants

SECONDARY outcome

Timeframe: 2year

Population: The primary objective of this study was to evaluate the RD on the basis of the safety of the combination of nivolumab and regorafenib, and the clinical trial was intended to evaluate the efficacy of this therapy secondarily. Therefore, dose-specific efficacy analyses were not preplanned or considered to evaluate this outcome measure. Ultimately, the trial was intended to provide an overall efficacy in this study.

\*Objective Response Rate is defined as the proportion of patients whose best overall response, as per the Response Evaluation Criteria in Solid Tumors (RECIST) guideline version 1.1 and immune-related RECIST (irRECIST), is either Complete Response (CR) or Partial Response (PR).

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=50 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
Objective Response Rate (ORR)	42.0 percentage of participants Interval 28.2 to 56.8	—	—	—

SECONDARY outcome

Timeframe: 6 months

\*PFS is defined as the time from the enrollment date to either the date when disease progression is determined or the date of death from any cause, whichever came earlier. The data were compiled according to the analysis plan outlined in the protocol. No analysis was conducted to determine efficacy by cancer type or dose level.

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=50 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
Progression-Free Survival(PFS)	6.3 months Interval 3.9 to 10.4	—	—	—

SECONDARY outcome

Timeframe: 2year

\*OS is defined as the period from the date of enrollment to the date of death from any cause. Surviving patients are censored on the last confirmation date of survival (confirmation of survival by telephone is permitted; the fact that survival is confirmed is to be recorded in the medical record, etc.). Patients lost to follow-up are censored on the last date on which their survival is confirmed before being lost to follow-up. The data were compiled according to the analysis plan outlined in the protocol. No analysis was conducted to determine efficacy by cancer type or dose level.

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=50 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
Overall Survival(OS)	14.4 median of months Interval 9.8 to 21.7	—	—	—

SECONDARY outcome

Timeframe: 2year

\*DCR is defined as the proportion of patients whose best overall response assessed based on the RECIST guideline version 1.1 and irRECIST is any of CR, PR, or Stable Disease (SD). The data were compiled according to the analysis plan outlined in the protocol. No analysis was conducted to determine efficacy by cancer type or dose level.

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=50 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
Disease Control Rate(DCR)	86.0 percentage of participants Interval 73.3 to 94.2	—	—	—

SECONDARY outcome

Timeframe: 2 year

Population: This protocol specifies that secondary endpoint were not analysed separately for colorectal cancer and gastric cancer, and cases both the dose escalation cohort and the expansion cohort were included.

* The occurrences rate of each AE of the worst grade occurring in this study was evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 throughout the entire cycles will be calculated. Additionally, this study included a special note regarding abnormal laboratory values. If clinical signs and symptoms observed in this study were induced, the diagnosis and associated data were collected based on whether or not they were due to abnormal laboratory values. Therefore, for example, results of grading regarding liver dysfunction may differ between non-hematologic toxicity and laboratory values. * Adverse-Events occurrences means "prevalence proportion" of any undesirable occurrence based on investigator's medical decision in this study.

Outcome measures

Outcome measures
Measure	Dose Escalation Cohort Regorafenib 80mg n=22 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. Register 3 cases first at each dose level, and temporarily suspend case registration until the safety assessment of the first course of all cases is completed. If no DLT is observed in 3 cases, proceed to the next dose level. If DLT is not observed in 3 cases of level 3, add 3 more cases to this level (total 6 cases). In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 120mg n=25 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period. When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level. In addition, if there are patients who are not eligible for level transition, additional patients will be enrolled so that DLT evaluation can be performed.	Dose Escalation Cohort Regorafenib 160mg n=3 Participants Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab at a dose of 3.0 mg/kg was administered once every 2 weeks. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met. If it is judged that MTD is exceeded, 6 cases of DLT evaluation are already carried out at the level one level below and if the DLT is 1 case or less of 6 cases, the dose is taken as MTD and RD. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases (total 6 cases). When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD.	Expansion Cohort : Regorafenib 120mg Regorafenib: One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. After moving to the expansion cohort, G3 skin-related toxicity occurred, and RD was reduced by one level based on the recommendation of the Data and Safety Monitoring Committee as specified in this clinical protocol.
Adverse-Events	22 Participants	25 Participants	3 Participants	—

Adverse Events

Final Analysis: Regorafenib 80mg/Day

Serious events: 4 serious events

Other events: 22 other events

Deaths: 0 deaths

Final Analysis: Regorafenib 120mg/Day

Serious events: 5 serious events

Other events: 25 other events

Deaths: 1 deaths

Final Analysis: Regorafenib 160mg

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Final Analysis: Regorafenib 80mg/Day n=22 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.	Final Analysis: Regorafenib 120mg/Day n=25 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 120mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.	Final Analysis: Regorafenib 160mg n=3 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.
Skin and subcutaneous tissue disorders rash maculo-papular	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders large intestine perforation	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders death	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Skin and subcutaneous tissue disorders erythema multiforme	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders diarrhea	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders fever	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders abdominal pain	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Endocrine disorders hypopituitarism	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Nervous system disorders Guillain-Barre syndrome	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Respiratory, thoracic and mediastinal disorders interstitial lung disease	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders malaise	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Metabolism and nutrition disorders hyperglycemia	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Respiratory, thoracic and mediastinal disorders pleural effusion	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.

Other adverse events

Additional Information

Dr.Kohei Shitara

NationalCCHE,JAPAN

Phone: +81-4-7133-1111

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Final Analysis: Regorafenib 80mg/Day n=22 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 80 mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.	Final Analysis: Regorafenib 120mg/Day n=25 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 120mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.	Final Analysis: Regorafenib 160mg n=3 participants at risk Regorafenib: One course will last 28 days. Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week rest period. Nivolumab: One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg. With 1 cycle being 28 days, the treatment was repeated until any of the discontinuation criteria was met.
Metabolism and nutrition disorders decreased appetite	27.3% 6/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	28.0% 7/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Skin and subcutaneous tissue disorders palmar-plantar erythrodysesthesia syndrome	59.1% 13/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	80.0% 20/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	66.7% 2/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Vascular disorders hypertension	50.0% 11/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	56.0% 14/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders malaise	50.0% 11/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	40.0% 10/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	66.7% 2/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders fever	45.5% 10/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	40.0% 10/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Renal and urinary disorders proteinuria	27.3% 6/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	36.0% 9/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	66.7% 2/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Skin and subcutaneous tissue disorders maculo-papular rash	13.6% 3/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	32.0% 8/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders stomatitis	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	24.0% 6/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	66.7% 2/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders diarrhea	27.3% 6/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	16.0% 4/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	66.7% 2/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Hepatobiliary disorders Liver disorders	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	24.0% 6/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Endocrine disorders hypothyroidism	22.7% 5/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations platelet count decreased	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	20.0% 5/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations asparate aminotaransferase increased	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Respiratory, thoracic and mediastinal disorders dysphonia	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Endocrine disorders hyperthyroidism	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations weight decreased	22.7% 5/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Infections and infestations pneumonia	9.1% 2/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations neutrophil count decreased	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Infections and infestations nasopharygititis	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	12.0% 3/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Skin and subcutaneous tissue disorders rash	31.8% 7/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	16.0% 4/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Musculoskeletal and connective tissue disorders back pain	13.6% 3/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor pain	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Musculoskeletal and connective tissue disorders arthralgia	13.6% 3/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	12.0% 3/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Blood and lymphatic system disorders anemia	18.2% 4/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Gastrointestinal disorders constipation	13.6% 3/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	4.0% 1/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
General disorders fatigue	9.1% 2/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations alanine aminotransferase increased	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations blood bilirubin increased	0.00% 0/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	33.3% 1/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.
Investigations blood creatinine phosphokinase increased	4.5% 1/22 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	8.0% 2/25 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.	0.00% 0/3 • 2 year, 2months \*Adverse events were not analyzed separately for colorectal cancer and gastric cancer.