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Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Participants With Chemotherapy-naïve Unresectable Advanced Recurrent Colorectal Carcinoma (SAPPHIRE)

Primary Purpose

Colorectal Carcinoma

Status

Completed

Phase

Phase 2

Locations

Japan

Study Type

Interventional

Intervention

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

About this trial

This is an interventional treatment trial for Colorectal Carcinoma focused on measuring Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria for enrollment:

Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
Participants with measurable lesion(s) according to the RECIST ver. 1.1
Participants who have not received chemotherapy for colorectal cancer. Participants who experience relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled.
Aged ≥ 20 years at the time of enrollment
Participants classified as KRAS wild-type. However, the criteria will be changed to all patients who are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by National Health Insurance, and the tests become feasible at medical institutions.
Participants who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment
1. Neutrophil count ≥ 1.5 × 10^3/μL
2. White blood cell count ≥ 3.0 × 10^3/μL
3. Platelet count ≥ 10.0 × 10^4/μL
4. Hemoglobin ≥ 9.0 g/dL
5. Total bilirubin ≤ 2.0 mg/dL
6. AST ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
7. ALT ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
8. Serum creatinine ≤ 1.5 mg/dL
Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1
Life expectancy of ≥ 6 months after enrollment
Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment

Inclusion criteria for randomization:

Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy
Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle.
Participants for whom PD or not evaluable has been denied on the RECIST 1.1 based on imaging tests conducted after the day of administration in the 6th cycle within 14 days (2 weeks).

Exclusion Criteria for enrollment:

Radiotherapy received for a measurable lesion
Radiotherapy received within 28 days (4 weeks) prior to enrollment for a lesion other than measurable lesions. However, treatment to relieve pain associated with metastatic bone tumors was allowed.
Known brain metastasis or strongly suspected of brain metastasis
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.).
Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
Active hemorrhage requiring blood transfusion
Disease requiring systemic steroids for treatment (excluding topical steroids)
Intestinal resection and colostomy within 2 weeks prior to enrollment
History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
Serious drug hypersensitivity
Local or systemic active infection requiring treatment, or fever indicating infection
Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment)
Active hepatitis B and/or active hepatitis C
Known human immunodeficiency virus infection
Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study

Exclusion criteria for randomization:

Participants in whom interstitial pneumonia has been newly diagnosed during the period from registration to randomization
Participants who have received radiotherapy during the period from registration to randomization
Other Participants judged by the investigator or sub-investigator to be ineligible for enrollment in the study

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Group A

Group B

Arm Description

Panitumumab (Pmab) 6 mg/kg, intravenous drip infusion (DIV), at Day 1, oxaliplatin (OXA) 85 mg/m^2, DIV, at Day 1, levofolinate (l LV) 200 mg/m^2, DIV, at Day 1, fluorouracil (5-FU) 400 mg/m^2, intravenous (IV) at Day 1, 5-FU 2400 mg/m^2, continuous intravenous infusion (CIV), at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.

Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6 as protocol treatment 1 followed by Pmab 6 mg/kg, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 7 until progressive disease or intolerance.

Outcomes

Primary Outcome Measures

Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization

PFS rate was defined as the gross percentage of participants who survived with no evidence of progression from the day of randomization (Day 0) until 9 months after Day 0. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Secondary Outcome Measures

Progression-Free Survival (PFS)

The PFS is the period from the date of randomization (Day 0) until the date of judgment of progression from the date of randomization, or until death by all causes, whichever comes first. The presence/absence of progressive disease (PD) was determined based on imaging, consideration of clinical PD, or survival research results. PD based on response evaluation criteria in solid tumors (RECIST) is 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Overall Survival (OS)

OS was defined as the time from the day of randomization (Day 0) until death by all causes.

Response Rate (RR)

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 after randomization. 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 to Treatment Failure (TTF)

TTF was defined as the time from the day of randomization (Day 0) until the day of protocol treatment discontinuation determination, the day of PD decision during protocol treatment, or death from any cause, whichever came the earliest.

Percentage of Participants With Adverse Events

Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.

Percentage of Participants With Adverse Events by Severity Graded Using the Common Terminology Criteria for Adverse Events (CTCAE) Grade

An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to AE.

Percentage of Participants With Grade 2 or Higher Peripheral Neuropathy

Peripheral neuropathy was defined as events classified with a preferred term (PT) of "peripheral neuropathy" according to Standardized MedDRA Queries.

Percentage of Participants With Grade 3 or Higher Skin Toxicity

Skin toxicity was defined as events classified with an system organ class of "Skin and subcutaneous tissue disorders" or a preferred term of "paronychia".

Full Information

NCT ID

NCT02337946

First Posted

September 30, 2014

Last Updated

August 28, 2019

Sponsor

Takeda

1. Study Identification

Unique Protocol Identification Number

NCT02337946

Brief Title

Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Participants With Chemotherapy-naïve Unresectable Advanced Recurrent Colorectal Carcinoma

Acronym

SAPPHIRE

Official Title

A Phase 2 Randomized Study Comparing the Efficacy and Safety of mFOLFOX6+Panitumumab Combination Therapy and 5-FU/LV+Panitumumab Combination Therapy in the Patients With Chemotherapy-Naive Unresectable Advanced Recurrent Colorectal Carcinoma of KRAS Wild-Type After 6 Cycles of Combination Therapy With mFOLFOX6+Panitumumab

Study Type

Interventional

2. Study Status

Record Verification Date

August 2019

Overall Recruitment Status

Completed

Study Start Date

October 16, 2014 (Actual)

Primary Completion Date

March 31, 2017 (Actual)

Study Completion Date

August 31, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Takeda

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to exploratorily examine efficacy and safety in the participants with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of Kirsten rat sarcoma-2 virus (KRAS) wild-type who have been treated with 6 cycles (2 weeks/cycle) of first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups i.e., a group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination therapy.

Detailed Description

The drug being tested in this study is called panitumumab. Panitumumab is being tested to treat people who have advanced/recurrent colorectal carcinoma of KRAS wild-type. This study will look at the efficacy and safety of 5-FU/LV + panitumumab(Pmab) combination therapy or mFOLFOX6 + Pmab combination therapy in the participants. The study will enroll 164 patients. All participants will receive 6 cycles of Protocol Treatment [1]: Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m^2, DIV, at Day 1, l LV 200 mg/m^2, DIV, at Day 1, 5-FU 400 mg/m^2, IV, at Day 1, 5-FU 2400 mg/m^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6. Then they will be randomly assigned (by chance, like flipping a coin) to one of the treatment groups. Group A Group B This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 20 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Carcinoma

Keywords

Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

164 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Group A

Arm Type

Active Comparator

Arm Description

Arm Title

Group B

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

Intervention Description

oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

Intervention Type

Drug

Intervention Name(s)

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

Primary Outcome Measure Information:

Title

Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization

Description

Time Frame

Up to 9 months after randomization

Secondary Outcome Measure Information:

Title

Progression-Free Survival (PFS)

Description

Time Frame

Up to approximately 31 months

Title

Overall Survival (OS)

Description

OS was defined as the time from the day of randomization (Day 0) until death by all causes.

Time Frame

Up to approximately 31 months

Title

Response Rate (RR)

Description

Time Frame

Up to approximately 31 months

Title

Time to Treatment Failure (TTF)

Description

Time Frame

Up to approximately 31 months

Title

Percentage of Participants With Adverse Events

Description

Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.

Time Frame

Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)

Title

Percentage of Participants With Adverse Events by Severity Graded Using the Common Terminology Criteria for Adverse Events (CTCAE) Grade

Description

Time Frame

Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)

Title

Percentage of Participants With Grade 2 or Higher Peripheral Neuropathy

Description

Peripheral neuropathy was defined as events classified with a preferred term (PT) of "peripheral neuropathy" according to Standardized MedDRA Queries.

Time Frame

Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)

Title

Percentage of Participants With Grade 3 or Higher Skin Toxicity

Description

Skin toxicity was defined as events classified with an system organ class of "Skin and subcutaneous tissue disorders" or a preferred term of "paronychia".

Time Frame

Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria for enrollment: Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer) Participants with measurable lesion(s) according to the RECIST ver. 1.1 Participants who have not received chemotherapy for colorectal cancer. Participants who experience relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled. Aged ≥ 20 years at the time of enrollment Participants classified as KRAS wild-type. However, the criteria will be changed to all patients who are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by National Health Insurance, and the tests become feasible at medical institutions. 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 White blood cell count ≥ 3.0 × 10^3/μL Platelet count ≥ 10.0 × 10^4/μL Hemoglobin ≥ 9.0 g/dL Total bilirubin ≤ 2.0 mg/dL AST ≤ 100 U/L (≤ 200 U/L if liver metastases are present) ALT ≤ 100 U/L (≤ 200 U/L if liver metastases are present) Serum creatinine ≤ 1.5 mg/dL Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1 Life expectancy of ≥ 6 months after enrollment Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment Inclusion criteria for randomization: Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle. Participants for whom PD or not evaluable has been denied on the RECIST 1.1 based on imaging tests conducted after the day of administration in the 6th cycle within 14 days (2 weeks). Exclusion Criteria for enrollment: Radiotherapy received for a measurable lesion Radiotherapy received within 28 days (4 weeks) prior to enrollment for a lesion other than measurable lesions. However, treatment to relieve pain associated with metastatic bone tumors was allowed. Known brain metastasis or strongly suspected of brain metastasis 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.). Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.) Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy Active hemorrhage requiring blood transfusion Disease requiring systemic steroids for treatment (excluding topical steroids) Intestinal resection and colostomy within 2 weeks prior to enrollment History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.) Serious drug hypersensitivity Local or systemic active infection requiring treatment, or fever indicating infection Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment) Active hepatitis B and/or active hepatitis C Known human immunodeficiency virus infection Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study Exclusion criteria for randomization: Participants in whom interstitial pneumonia has been newly diagnosed during the period from registration to randomization Participants who have received radiotherapy during the period from registration to randomization Other Participants judged by the investigator or sub-investigator to be ineligible for enrollment in the study

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Takeda

Official's Role

Study Director

Facility Information:

City

Nagakute

State/Province

Aichi

Country

Japan

City

Nagoya

State/Province

Aichi

Country

Japan

City

Okazaki

State/Province

Aichi

Country

Japan

City

Toyoaki

State/Province

Aichi

Country

Japan

City

Yachiyo

State/Province

Chiba

Country

Japan

City

Kitakyushu

State/Province

Fukuoka

Country

Japan

City

Tagawa

State/Province

Fukuoka

Country

Japan

City

Aizuwakamatsu

State/Province

Fukushima

Country

Japan

City

Kakamigahara

State/Province

Gifu

Country

Japan

City

Tajimi

State/Province

Gifu

Country

Japan

City

Hakodate

State/Province

Hokkaido

Country

Japan

City

Kushiro

State/Province

Hokkaido

Country

Japan

City

Amagasaki

State/Province

Hyogo

Country

Japan

City

Kakogawa

State/Province

Hyogo

Country

Japan

City

Kobe

State/Province

Hyogo

Country

Japan

City

Nishinomiya

State/Province

Hyogo

Country

Japan

City

Kahoku

State/Province

Ishikawa

Country

Japan

City

Kanazawa

State/Province

Ishikawa

Country

Japan

City

Morioka

State/Province

Iwate

Country

Japan

City

Kida-gun

State/Province

Kagawa

Country

Japan

City

Marugame

State/Province

Kagawa

Country

Japan

City

Takamatsu

State/Province

Kagawa

Country

Japan

City

Kawasaki

State/Province

Kanagawa

Country

Japan

City

Yokohama

State/Province

Kanagawa

Country

Japan

City

Nangoku

State/Province

Kochi

Country

Japan

City

Sendai

State/Province

Miyagi

Country

Japan

City

Matsumoto

State/Province

Nagano

Country

Japan

City

Suwa

State/Province

Nagano

Country

Japan

City

Sasebo

State/Province

Nagasaki

Country

Japan

City

Higashiosaka

State/Province

Osaka

Country

Japan

City

Hirakata

State/Province

Osaka

Country

Japan

City

Izumisano

State/Province

Osaka

Country

Japan

City

Izumi

State/Province

Osaka

Country

Japan

City

Sakai

State/Province

Osaka

Country

Japan

City

Tondabayashi

State/Province

Osaka

Country

Japan

City

Hidaka

State/Province

Saitama

Country

Japan

City

Izumo

State/Province

Shimane

Country

Japan

City

Fujioka

State/Province

Shizuoka

Country

Japan

City

Shimonoseki

State/Province

Yamaguchi

Country

Japan

City

Akita

Country

Japan

City

Fukui

Country

Japan

City

Fukuoka

Country

Japan

City

Gifu

Country

Japan

City

Hiroshima

Country

Japan

City

Kyoto

Country

Japan

City

Nagasaki

Country

Japan

City

Okinawa

Country

Japan

City

Osaka

Country

Japan

City

Saga

Country

Japan

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

Citations:

PubMed Identifier

31445198

Citation

Munemoto Y, Nakamura M, Takahashi M, Kotaka M, Kuroda H, Kato T, Minagawa N, Noura S, Fukunaga M, Kuramochi H, Touyama T, Takahashi T, Miwa K, Satake H, Kurosawa S, Miura T, Mishima H, Sakamoto J, Oba K, Nagata N. SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer. Eur J Cancer. 2019 Sep;119:158-167. doi: 10.1016/j.ejca.2019.07.006. Epub 2019 Aug 21.

Results Reference

background

PubMed Identifier

28284575

Citation

Nagata N, Mishima H, Kurosawa S, Oba K, Sakamoto J. mFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)-Study Design and Rationale. Clin Colorectal Cancer. 2017 Jun;16(2):154-157.e1. doi: 10.1016/j.clcc.2017.02.001. Epub 2017 Mar 1.

Results Reference

derived

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