Trial Outcomes & Findings for A Study of Nimotuzumab Combinated With Gemcitabine in K-RAS Wild-type Locally Advanced and Metastatic Pancreatic Cancer (NCT NCT02395016)

Last Updated: 2024-04-04

Results Overview

The primary endpoint was overall survival (OS, defined as from randomization to death due to any cause). We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. The primary end point was evaluated in the full analysis set (FAS; all eligible patients who received at least one dose of nimotuzumab/placebo and had one evaluation of efficacy).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

90 participants

Primary outcome timeframe

up to 3 years

Results posted on

2024-04-04

Participant Flow

We screened 480 patients between April 10, 2015, and September 2020, at 25 study sites in China. Finally, 90 patients with K-Ras gene wild-type were enrolled.

Participant milestones

Participant milestones
Measure	Nimotuzumab and Gemcitabine nimotuzumab,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. nimotuzumab: nimotuzumab,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine: Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test.	Placebo and Gemcitabine placebo,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine: Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. Placebo: Placebo，400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test.
Overall Study STARTED	45	45
Overall Study COMPLETED	30	33
Overall Study NOT COMPLETED	15	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Nimotuzumab and Gemcitabine nimotuzumab,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. nimotuzumab: nimotuzumab,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine: Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test.	Placebo and Gemcitabine placebo,400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. Gemcitabine: Gemcitabine，1000mg/m2，Intravenous infusion over 30 minutes,Once every three weeks, rest one week (d1,8,15; q28d), Every 4 weeks for a period,Until disease progression or intolerable toxicity or subjects ask to leave the test. Placebo: Placebo，400mg/w，Intravenous infusion over 60 minutes,Until disease progression or intolerable toxicity or subjects ask to leave the test.
Overall Study Adverse Event	4	3
Overall Study Withdrawal by Subject	9	6
Overall Study Protocol Violation	2	3

Baseline Characteristics

A Study of Nimotuzumab Combinated With Gemcitabine in K-RAS Wild-type Locally Advanced and Metastatic Pancreatic Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks) until disease progression or unacceptable toxicity.	Placebo-Gemcitabine Group n=41 Participants receive Placebo plus gemcitabine (1000 mg/m2 on days 1, 8, and 15, every four weeks) until disease progression or unacceptable toxicity.	Total n=82 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	33 Participants n=5 Participants	30 Participants n=7 Participants	63 Participants n=5 Participants
Age, Categorical >=65 years	8 Participants n=5 Participants	11 Participants n=7 Participants	19 Participants n=5 Participants
Age, Continuous	53 years n=5 Participants	57 years n=7 Participants	55 years n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	17 Participants n=7 Participants	31 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	24 Participants n=7 Participants	51 Participants n=5 Participants
Race/Ethnicity, Customized Han	41 Participants n=5 Participants	39 Participants n=7 Participants	80 Participants n=5 Participants
Race/Ethnicity, Customized Others	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Karnofsky performance-status score 90-100 score	20 Participants n=5 Participants	22 Participants n=7 Participants	42 Participants n=5 Participants
Karnofsky performance-status score 60-80 score	21 Participants n=5 Participants	19 Participants n=7 Participants	40 Participants n=5 Participants
Diagnosis Locally advanced	9 Participants n=5 Participants	8 Participants n=7 Participants	17 Participants n=5 Participants
Diagnosis Metastatic	32 Participants n=5 Participants	33 Participants n=7 Participants	65 Participants n=5 Participants
Pancreatic tumor location Head	17 Participants n=5 Participants	17 Participants n=7 Participants	34 Participants n=5 Participants
Pancreatic tumor location Body	6 Participants n=5 Participants	7 Participants n=7 Participants	13 Participants n=5 Participants
Pancreatic tumor location Tail	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants

PRIMARY outcome

Timeframe: up to 3 years

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=41 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Overall Survival（OS）	10.9 months Interval 5.6 to 16.3	8.5 months Interval 5.7 to 10.0

SECONDARY outcome

Timeframe: up to 3 years

Population: We screened 90 pts (90 patients were allocated for treatment) from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 82 pts were included in FAS. Secondary end points were analyzed only in the FAS.

TTP, defined as from randomization to the first observation of disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=41 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Time to Progression（TTP）	4.7 months Interval 2.7 to 9.0	3.7 months Interval 2.0 to 5.4

SECONDARY outcome

Timeframe: up to 3 years

PFS, defined as from randomization to disease progression or all-cause death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=41 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Progression Free Survival（PFS）	4.2 months Interval 2.7 to 7.3	3.6 months Interval 2.0 to 5.0

SECONDARY outcome

Timeframe: Once every eight weeks，up to 5.4 months

Objective response rate (ORR), including complete response (CR) and partial response (PR). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), at least a 30% decrease in the sum of the longest diameter of target lesions.

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=41 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Objective Response Rate（ORR）	3 Participants	4 Participants

SECONDARY outcome

Timeframe: Once every eight weeks，up to 5.4 months

Disease control rate (DCR), including complete response (CR) and partial response (PR) and stable disease(SD). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: CR, disappearance of all target lesions; PR, at least a 30% decrease in the sum of the longest diameter of target lesions. SD, neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD (PD, defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions).

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=41 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=41 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Disease Control Rate（DCR）	28 Participants	26 Participants

SECONDARY outcome

Timeframe: every 8 weeks, up to 5.4 months

The clinical benefit response(CBR)was evaluated every 8 weeks on the basis of the Burris criteria. CBR included pain (intensity of pain and consumption of analgesics), PS (performance status, evaluated according to KPS) and weight changes. Effective is defined as at least one positive improvement in the CBR index (pain, physical status or weight change) and no negative indicator is found, which can be rated as a clinical benefit case.

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=28 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=31 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Clinical Benefit Response（CBR）	11 Participants	10 Participants

SECONDARY outcome

Timeframe: up to 75.2 months

Population: We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS (n=90).

Adverse Events as any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.

Outcome measures

Outcome measures
Measure	Nimotuzumab- Gemcitabine Group n=45 Participants receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=45 Participants receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Number of Participants With Adverse Events Treatment-related Adverse Events	31 participants	29 participants
Number of Participants With Adverse Events Serious Adverse Events	1 participants	2 participants
Number of Participants With Adverse Events Drug reduction or discontinued for AE	4 participants	6 participants
Number of Participants With Adverse Events Withdrawal for AE	2 participants	1 participants
Number of Participants With Adverse Events All-Cause Mortality	36 participants	40 participants

Adverse Events

Nimotuzumab- Gemcitabine Group

Serious events: 15 serious events

Other events: 44 other events

Deaths: 36 deaths

Placebo-Gemcitabine Group

Serious events: 5 serious events

Other events: 44 other events

Deaths: 40 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Nimotuzumab- Gemcitabine Group n=45 participants at risk receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=45 participants at risk receive placebo plus gemcitabine until disease progression or unacceptable toxicity
Investigations white blood cell count decreased	75.6% 34/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	57.8% 26/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Investigations utrophil count decreased	68.9% 31/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	60.0% 27/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.

Additional Information

Director of Clinical Trials

Biotech Pharmaceutical Co., Ltd.

Phone: 010-51571020

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Nimotuzumab- Gemcitabine Group n=45 participants at risk receive nimotuzumab (400 mg, weekly) plus gemcitabine until disease progression or unacceptable toxicity	Placebo-Gemcitabine Group n=45 participants at risk receive placebo plus gemcitabine until disease progression or unacceptable toxicity
General disorders Fever	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Gastrointestinal disorders ileus	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Gastrointestinal disorders enteritis	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Gastrointestinal disorders stomachache	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Gastrointestinal disorders vomiting	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Respiratory, thoracic and mediastinal disorders pneumonitis	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Respiratory, thoracic and mediastinal disorders interstitial lung disease	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Respiratory, thoracic and mediastinal disorders pleurisy	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Investigations bilirubin increased	4.4% 2/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Investigations weight decreased	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Investigations Hemoglobin decreased	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Investigations platelet count decreased	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Vascular disorders Embolic cerebral infarction	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Nervous system disorders diabetic neuropathy	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Blood and lymphatic system disorders coagulopathy	4.4% 2/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Blood and lymphatic system disorders anemia	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Metabolism and nutrition disorders hypoproteinemia	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Hepatobiliary disorders cholecystitis	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.
Musculoskeletal and connective tissue disorders tenosynovitis	2.2% 1/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.	0.00% 0/45 • up to 75.2 months We screened 90 pts from 480 pts, of whom 8 pts were excluded due to serious violation of the inclusion criteria: 7 pts with K-Ras mutants, 1 pt with gallbladder cancer. Finally, 90 pts were included in SS (safety set). Adverse Events were analyzed in the SS.