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)

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Carcinoma
• Intervention / Treatment: Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab; Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

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.

• Study Type: Interventional
• Enrollment (Actual): 164
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Akita, Japan
  • Fukui, Japan
  • Fukuoka, Japan
  • Gifu, Japan
  • Hiroshima, Japan
  • Kyoto, Japan
  • Nagasaki, Japan
  • Okinawa, Japan
  • Osaka, Japan
  • Saga, Japan
  • Aichi
    • Nagakute, Aichi, Japan
    • Nagoya, Aichi, Japan
    • Okazaki, Aichi, Japan
    • Toyoaki, Aichi, Japan
  • Chiba
    • Yachiyo, Chiba, Japan
  • Fukuoka
    • Kitakyushu, Fukuoka, Japan
    • Tagawa, Fukuoka, Japan
  • Fukushima
    • Aizuwakamatsu, Fukushima, Japan
  • Gifu
    • Kakamigahara, Gifu, Japan
    • Tajimi, Gifu, Japan
  • Hokkaido
    • Hakodate, Hokkaido, Japan
    • Kushiro, Hokkaido, Japan
  • Hyogo
    • Amagasaki, Hyogo, Japan
    • Kakogawa, Hyogo, Japan
    • Kobe, Hyogo, Japan
    • Nishinomiya, Hyogo, Japan
  • Ishikawa
    • Kahoku, Ishikawa, Japan
    • Kanazawa, Ishikawa, Japan
  • Iwate
    • Morioka, Iwate, Japan
  • Kagawa
    • Kida-gun, Kagawa, Japan
    • Marugame, Kagawa, Japan
    • Takamatsu, Kagawa, Japan
  • Kanagawa
    • Kawasaki, Kanagawa, Japan
    • Yokohama, Kanagawa, Japan
  • Kochi
    • Nangoku, Kochi, Japan
  • Miyagi
    • Sendai, Miyagi, Japan
  • Nagano
    • Matsumoto, Nagano, Japan
    • Suwa, Nagano, Japan
  • Nagasaki
    • Sasebo, Nagasaki, Japan
  • Osaka
    • Higashiosaka, Osaka, Japan
    • Hirakata, Osaka, Japan
    • Izumi, Osaka, Japan
    • Izumisano, Osaka, Japan
    • Sakai, Osaka, Japan
    • Tondabayashi, Osaka, Japan
  • Saitama
    • Hidaka, Saitama, Japan
  • Shimane
    • Izumo, Shimane, Japan
  • Shizuoka
    • Fujioka, Shizuoka, Japan
  • Yamaguchi
    • Shimonoseki, Yamaguchi, Japan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for enrollment:

1. Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
2. Participants with measurable lesion(s) according to the RECIST ver. 1.1
3. 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.
4. Aged ≥ 20 years at the time of enrollment
5. 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.

6. 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
7. Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1
8. Life expectancy of ≥ 6 months after enrollment
9. 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:

1. Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy
2. Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle.
3. 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:

1. Radiotherapy received for a measurable lesion
2. 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.
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. Active hemorrhage requiring blood transfusion
8. Disease requiring systemic steroids for treatment (excluding topical steroids)
9. Intestinal resection and colostomy within 2 weeks prior to enrollment
10. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
11. Serious drug hypersensitivity
12. Local or systemic active infection requiring treatment, or fever indicating infection
13. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment)
14. Active hepatitis B and/or active hepatitis C
15. Known human immunodeficiency virus infection
16. Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study

Exclusion criteria for randomization:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Group A; 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.	Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab; oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion; Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab
Experimental: Group B; 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.	Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab; oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion; Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 9 months after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to approximately 31 months
Overall Survival (OS)	OS was defined as the time from the day of randomization (Day 0) until death by all causes.	Up to approximately 31 months
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).	Up to approximately 31 months
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.	Up to approximately 31 months
Percentage of Participants With Adverse Events	Safety population was defined as all participants who received at least one dose of protocol treatment after randomization.	Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
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.	Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
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.	Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
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".	Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2014
• Primary Completion (Actual): March 31, 2017
• Study Completion (Actual): August 31, 2017

Study Registration Dates

• First Submitted: September 30, 2014
• First Submitted That Met QC Criteria: January 13, 2015
• First Posted (Estimate): January 14, 2015

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: August 28, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin; Calcium, Dietary; Panitumumab
• Other Study ID Numbers: Panitumumab-2003; U1111-1161-8871 (Registry Identifier: UTN (WHO)); 183/NRP-005 (Other Identifier: Secondary Takeda ID); JapicCTI-142668 (Registry Identifier: JapicCTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No