APOLLON: A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With Colorectal Cancer

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02613221
• Collaborator: (none)
• Enrollment: 56
• Locations: 32
• Arm: 1
• Actual Duration (Months): 27.7
• Patients Per Site: 1.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the combination of panitumumab and Triflridine/Tipiracil (FTD/TPI; TAS-102) in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: Panitumumab + TAS-102	Phase 1/Phase 2

Detailed Description

The purpose of this study is to evaluate the combination of panitumumab and TAS-102 in patients with RAS wild-type metastatic colorectal cancer (CRC) refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines, irinotecan and angiogenesis inhibitors).

Patients who are judged eligible for the study based on the inclusion and exclusion criteria will be received panitumumab (6 mg/kg) every 2 weeks and TAS-102 (35 mg/m² given orally twice a day in a 28-day) in 2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period.

A maximum of 58 participants will be enrolled.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study for the Safety and Efficacy of Panitumumab in Combination With TAS-102 for Patients With RAS (KRAS, NRAS) Wild-type, Unresectable, Advanced/Recurrent Colorectal Cancer
• Actual Study Start Date: Dec 7, 2015
• Actual Primary Completion Date: Oct 6, 2017
• Actual Study Completion Date: Mar 30, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: panitumumab + TAS-102 combination therapy Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).	Drug: Panitumumab + TAS-102; panitumumab + TAS-102 combination therapy; Other Names: Panitumumab + Triflridine/Tipiracil (FTD/TPI)

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicity (DLT) With Panitumumab Plus TAS-102 Combination Therapy [Up to approximately 1 month]

   DLT was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and was defined as any of the following events: 1. Grade 4 neutropenia for more than 7 days under maximum supportive therapy; 2. Febrile neutropenia; 3. Platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; 4. If Course 2 was not initiated within 14 days due to AE related to the protocol treatment; 5. Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (eg, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.

2. Progression Free Survival (PFS) Rate at 6 Months [Up to 6 months]

   PFS rate at 6 months was defined as the crude rate of surviving participants who survived or were not determined as progressive at 6 months from the day of enrollment. Although the subjects who had no imaging data on progression at 6 months after enrollment or the subjects who had lost to follow-up were included in the denominator, these subjects were not handled as progression-free. Progression included both progression disease (PD) based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

Secondary Outcome Measures

1. Overall Survival (OS) [From date of enrollment until the death, assessed up to approximately 29 months]

   OS was defined as the period from the day of enrollment until death by all causes.

2. Progression Free Survival (PFS) [From date of enrollment until the date of progression or death, assessed up to approximately 29 months]

   PFS was defined as the period from the day of enrollment until the day of documented progression or the day of death due to all causes whichever comes earlier. Progression included both PD based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

3. Response Rate (RR) [From date of enrollment until the end of follow-up period, assessed up to approximately 29 months]

   RR was defined as the percentage of participants who had shown complete response (CR) or partial response (PR) as the best overall response in accordance with the RECIST 1.1 criteria. The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

4. Duration of Response (DOR) [From date of CR or PR until the date of PD or death, assessed up to approximately 29 months]

   DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier.

5. Disease Control Rate (DCR) [From date of enrollment until the end of follow-up period, assessed up to approximately 29 months]

   DCR was defined as the percentage of participants who had shown CR, PR, or SD as the best overall response in accordance with the RECIST version 1.1 criteria.

6. Time to Treatment Failure (TTF) [From date of enrollment until the date of the protocol treatment discontinuation, progression or death, assessed up to approximately 29 months]

   TTF was defined as the time from the date of enrollment to the date of the decision to discontinue the protocol treatment, the date of documented progression during the protocol treatment, or the date of death from any cause, whichever had come earlier.

7. Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs) [From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy, assessed up to approximately 29 months]

   Adverse events (AEs) were any unfavorable medical events encountered in a participant treated with a drug. They were not limited to the events with clear causal relationship with treatment with the concerned drug. Treatment-emergent adverse events (TEAEs) were defined as AEs that had occurred after the initiation of protocol treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Investigator and subinvestigator judge a candidate is understand clinical trial and comply this protocol.

2. Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment

3. Aged ≥20 to <75 years at the time of informed consent

4. Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)

5. Participants with lesion(s) that can be evaluated. It is essential to be evaluated the tumor according to the Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1.

6. Participants who have received chemotherapies for metastatic colorectal cancer and are refractory to or failing those chemotherapies* including; fluoropyrimidines, irinotecan, oxaliplatin, and an angiogenesis inhibitors.

*: Refractory to or failing those chemotherapies are defied as following;

• If recurrence is observed by imaging during neoadjuvant/adjuvant therapy, or within 6 months of the completion of adjuvant therapy.

• If imaging or clinical progression is observed during or within 3 months of the last dose of chemotherapy for advanced cancer.

• When it is determined that the drugs (ie, fluropyrimidines, oxaliplatin, irinotecan, and angiogenesis inhibitors) are not allowed to be resume due to intolerable AE toxicities (eg, serious allergic reaction and accumulative neuropathy).

1. Participants classified as KRAS/NRAS wild-type** by KRAS/NRAS testing*.

*: KRAS/NRAS test will be performed using the in vitro diagnostic listed in the National Health Insurance.

**: Participants with no mutation in any of the codons shown below are considered wild type.

KRAS: EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) NRAS：EXON2 (codon 12, 13), EXON3 (codon 59, 61),EXON4 (codon 117, 146)

1. Participants are able to take medications orally.

2. Participants who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment

• Neutrophil count ≥1.5×10^3/µL

• Platelet count ≥1.0×10^4/µL

• Hemoglobin ≥8.0 g/dL

• Total bilirubin ≤1.5 mg/dL

• Aspartate aminotransferase (AST) ≤ 100 IU/L ( ≤200 IU/L if liver metastases are present)

• Alanine aminotransferase (ALT) ≤ 100 IU/L ( ≤200 IU/L if liver metastases are present)

• Serum creatinine ≤ 1.5 mg/dL

1. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1

2. Life expectancy of ≥ 3 months (90 days) after enrollment

Exclusion Criteria:

1. Has received anti-EGFR antibodies (cetuximab or panitumumab), regorafenib, or TAS-102.

2. Has had treatment with radiotherapy and/or chemotherapy within 2 weeks (14 days) prior to study drug administration (except for limited field radiation in order to rescue of pain).

3. Known brain metastasis or strongly suspected of brain metastasis

4. Synchronous cancers or metachronous cancers with a disease-free period of ≥ 5 years (excluding colorectal cancer) excluding mucosal cancers cured or be possibly cured by regional resection (esophageal, stomach, and cervical cancer, non-melanoma skin cancer, bladder cancer, etc.).

5. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)

6. Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy

7. Any investigational agent received within prior 4 weeks (28 days).

8. Disease requiring systemic steroids for treatment (excluding topical steroids)

9. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)

10. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment.

11. Serious drug hypersensitivity (without allergy to oxaliplatin)

12. Local or systemic active infection requiring treatment, or fever indicating infection

13. NYHA class II or higher heart failure or serious heart disease

14. Active hepatitis B

15. Known HIV infection

16. Adverse event due to previous treatment that has not recovered to Grade 1 (Grade 2 for peripheral sensory neuropathy) by CTCAE (Japanese edition JCOG version 4.03) (excluding hemoglobin content)

17. Known BRAF mutation

18. Other participants judged by the investigator or subinvestigator to be ineligible for enrollment in the study (such as patients who were coerced to give consent)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya	Aichi	Japan
2		Kashiwa	Chiba	Japan
3		Matsuyama	Ehime	Japan
4		Kitakyushu	Fukuoka	Japan
5		Kurume	Fukuoka	Japan
6		Hakodate	Hokkaido	Japan
7		Kushiro	Hokkaido	Japan
8		Sapporo	Hokkaido	Japan
9		Amagasaki	Hyogo	Japan
10		Kobe	Hyogo	Japan
11		Tsukuba	Ibaragi	Japan
12		Kasama	Ibaraki	Japan
13		Miki	Kagawa	Japan
14		Sagamihara	Kanagawa	Japan
15		Osaki	Miyagi	Japan
16		Matsumoto	Nagano	Japan
17		Sasebo	Nagasaki	Japan
18		Yamatotakada	Nara	Japan
19		Takatsuki	Osaka	Japan
20		Ina	Saitama	Japan
21		Shizuoka	Shizioka	Japan
22		Nagaizumi	Shizuoka	Japan
23		Koto-ku	Tokyo	Japan
24		Minato-ku	Tokyo	Japan
25		Chiba		Japan
26		Fukui		Japan
27		Fukuoka		Japan
28		Kumamoto		Japan
29		Okayama		Japan
30		Okinawa		Japan
31		Osaka		Japan
32		Toyama		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

• Statistical Analysis Plan - Jul 10, 2018
• Study Protocol - Sep 29, 2017

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02613221
• Other Study ID Numbers: Panitumumab-1501; U1111-1176-3692; JapicCTI-153076
• First Posted: Nov 24, 2015
• Last Update Posted: Jul 31, 2019
• Last Verified: Jul 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Metastatic colorectal cancer, Panitumumab, TAS-102
• Additional relevant MeSH terms: Colorectal Neoplasms; Panitumumab

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 25 investigative sites in Japan, from 08 December 2015 to 30 March 2018.
Pre-assignment Detail	Participants with a historical diagnosis of RAS wild-type, unresectable, advanced/recurrent colorectal cancer were enrolled in this study.

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Period Title: Overall Study
STARTED	56
Safety Population: Received Study Drug	55
COMPLETED	1
NOT COMPLETED	55

Baseline Characteristics

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Overall Participants	55
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.5 (9.9)
Sex: Female, Male (Count of Participants)
Female	26 47.3%
Male	29 52.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Number) [Number]
Japan	55 100%
Height (Centimeters (cm)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Centimeters (cm)]	162.5 (9.2)
Weight (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	62.66 (14.67)
Body Mass Index (BMI) (kilogram per square meter (kg/m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram per square meter (kg/m^2)]	23.57 (4.39)
Duration of First-line Treatment (Days) [Median (Full Range) ]
Median (Full Range) [Days]	595.5
Primary Tumor Location (Single/Multiple) (Count of Participants)
Single	54 98.2%
Multiple	1 1.8%
Primary Tumor Location (Colon/Rectal) (Count of Participants)
Colon	34 61.8%
Rectal	21 38.2%
Primary Tumor Location (Right side/Left side) (Count of Participants)
Right side	7 12.7%
Left side	48 87.3%
Number of metastatic organ (Count of Participants)
1	23 41.8%
=>2	32 58.2%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (Count of Participants)
0	38 69.1%
1	17 30.9%
Resection of Primary Tumor (Count of Participants)
Yes	43 78.2%
No	12 21.8%
Adjuvant Chemotherapy (Count of Participants)
Yes	16 29.1%
No	39 70.9%
Number of prior lines of chemotherapy (Count of Participants)
1	6 10.9%
2	37 67.3%
3	12 21.8%
Complication (Count of Participants)
Had No Presence of Complications	10 18.2%
Had Presence of Complications	45 81.8%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicity (DLT) With Panitumumab Plus TAS-102 Combination Therapy
Description	DLT was evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and was defined as any of the following events: 1. Grade 4 neutropenia for more than 7 days under maximum supportive therapy; 2. Febrile neutropenia; 3. Platelet counts decreased of Grade 3 requiring platelet transfusion or blood platelet decreased of Grade 4; 4. If Course 2 was not initiated within 14 days due to AE related to the protocol treatment; 5. Grade 3 or higher non-hematologic toxicity that was considered clinically significant, except the following cases, Grade 3 gastrointestinal symptoms that could be controlled with supportive therapy (eg, appropriate use of antiemetics, antidiarrheals), and Grade 3 or higher electrolyte abnormalities that were not deemed clinically significant.
Time Frame	Up to approximately 1 month

Outcome Measure Data

Analysis Population Description

DLT Evaluation Set; DLT Evaluation Set was defined as participants who were enrolled and received at least one dose of the study drug in order to assess recommended dose of panitumumab in combination with TAS-102 (Total number of DLT Evaluation Set was 6).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	6
Count of Participants [Participants]	0 0%

2. Primary Outcome

Title	Progression Free Survival (PFS) Rate at 6 Months
Description	PFS rate at 6 months was defined as the crude rate of surviving participants who survived or were not determined as progressive at 6 months from the day of enrollment. Although the subjects who had no imaging data on progression at 6 months after enrollment or the subjects who had lost to follow-up were included in the denominator, these subjects were not handled as progression-free. Progression included both progression disease (PD) based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Number (90% Confidence Interval) [Percentage of Participants]	33.3 60.5%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the period from the day of enrollment until death by all causes.
Time Frame	From date of enrollment until the death, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Median (95% Confidence Interval) [Months]	14.1

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the period from the day of enrollment until the day of documented progression or the day of death due to all causes whichever comes earlier. Progression included both PD based on diagnostic imaging assessed according to response evaluation criteria in solid tumors (RECIST) ver 1.1 and primary disease progression that cannot be confirmed by diagnostic imaging (clinical progression). PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time Frame	From date of enrollment until the date of progression or death, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Median (95% Confidence Interval) [Months]	5.8

5. Secondary Outcome

Title	Response Rate (RR)
Description	RR was defined as the percentage of participants who had shown complete response (CR) or partial response (PR) as the best overall response in accordance with the RECIST 1.1 criteria. The best overall response was CR, followed by PR, stable disease (SD), progressive disease (PD), and not evaluable (NE). CR: disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters as the best overall response after randomization., SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time Frame	From date of enrollment until the end of follow-up period, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Number (95% Confidence Interval) [Percentage of Participants]	37.0 67.3%

6. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier.
Time Frame	From date of CR or PR until the date of PD or death, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Median (95% Confidence Interval) [Months]	4.1

7. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of participants who had shown CR, PR, or SD as the best overall response in accordance with the RECIST version 1.1 criteria.
Time Frame	From date of enrollment until the end of follow-up period, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Number (95% Confidence Interval) [Percentage of Participants]	81.5 148.2%

8. Secondary Outcome

Title	Time to Treatment Failure (TTF)
Description	TTF was defined as the time from the date of enrollment to the date of the decision to discontinue the protocol treatment, the date of documented progression during the protocol treatment, or the date of death from any cause, whichever had come earlier.
Time Frame	From date of enrollment until the date of the protocol treatment discontinuation, progression or death, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS); FAS was defined as participants who were enrolled and received at least one dose of protocol treatment (the recommended dose confirmed in the phase I part).

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	54
Median (95% Confidence Interval) [Months]	5.8

9. Secondary Outcome

Title	Number of Participants Reporting One or More Treatment-Emergent Adverse Events (TEAEs)
Description	Adverse events (AEs) were any unfavorable medical events encountered in a participant treated with a drug. They were not limited to the events with clear causal relationship with treatment with the concerned drug. Treatment-emergent adverse events (TEAEs) were defined as AEs that had occurred after the initiation of protocol treatment.
Time Frame	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy, assessed up to approximately 29 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Set, The safety analysis set was defined as all participants who received at least one dose of the study drug during the study.

Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
Measure Participants	55
Count of Participants [Participants]	55 100%

Adverse Events

Time Frame	From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy, assessed up to approximately 29 months
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Panitumumab + TAS-102
Arm/Group Description	Panitumumab 6 mg/kg every 2 weeks, plus TAS-102 35 mg/m² given orally twice a day in 5 days followed by a 2-day rest period for 2-week cycle, and then a 14-day rest period (28 days per 1 course).
All Cause Mortality
	Panitumumab + TAS-102
	Affected / at Risk (%)	# Events
Total	6/55 (10.9%)
Serious Adverse Events
	Panitumumab + TAS-102
	Affected / at Risk (%)	# Events
Total	13/55 (23.6%)
Blood and lymphatic system disorders
Anaemia	1/55 (1.8%)
Febrile neutropenia	5/55 (9.1%)
Gastrointestinal disorders
Vomiting	1/55 (1.8%)
General disorders
General physical health deterioration	1/55 (1.8%)
Infections and infestations
Pyelonephritis	1/55 (1.8%)
Injury, poisoning and procedural complications
Infusion related reaction	1/55 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer	3/55 (5.5%)
Metastases to spine	1/55 (1.8%)
Rectal cancer	1/55 (1.8%)
Cancer pain	1/55 (1.8%)
Nervous system disorders
Transient ischaemic attack	1/55 (1.8%)
Product Issues
Device breakage	1/55 (1.8%)
Reproductive system and breast disorders
Female genital tract fistula	1/55 (1.8%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/55 (1.8%)
Pleural effusion	1/55 (1.8%)
Other (Not Including Serious) Adverse Events
	Panitumumab + TAS-102
	Affected / at Risk (%)	# Events
Total	54/55 (98.2%)
Blood and lymphatic system disorders
Anaemia	9/55 (16.4%)
Ear and labyrinth disorders
Vertigo	3/55 (5.5%)
Gastrointestinal disorders
Abdominal pain	6/55 (10.9%)
Diarrhoea	17/55 (30.9%)
Nausea	23/55 (41.8%)
Stomatitis	39/55 (70.9%)
Vomiting	8/55 (14.5%)
Constipation	4/55 (7.3%)
General disorders
Fatigue	27/55 (49.1%)
Malaise	10/55 (18.2%)
Pyrexia	9/55 (16.4%)
Infections and infestations
Paronychia	23/55 (41.8%)
Investigations
Blood bilirubin increased	4/55 (7.3%)
Neutrophil count decreased	36/55 (65.5%)
Platelet count decreased	13/55 (23.6%)
White blood cell count decreased	7/55 (12.7%)
Metabolism and nutrition disorders
Hypomagnesaemia	12/55 (21.8%)
Decreased appetite	30/55 (54.5%)
Musculoskeletal and connective tissue disorders
Back pain	5/55 (9.1%)
Nervous system disorders
Dysgeusia	12/55 (21.8%)
Peripheral sensory neuropathy	11/55 (20%)
Renal and urinary disorders
Proteinuria	3/55 (5.5%)
Skin and subcutaneous tissue disorders
Alopecia	4/55 (7.3%)
Dermatitis acneiform	34/55 (61.8%)
Palmar-plantar erythrodysaesthesia syndrome	14/55 (25.5%)
Dry skin	27/55 (49.1%)
Pruritus	9/55 (16.4%)
Rash	11/55 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.