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)

• ClinicalTrials.gov Identifier: NCT02337946
• Recruitment Status: Completed
• First Posted: January 14, 2015
• Results First Posted: March 1, 2019
• Last Update Posted: September 10, 2019
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: September 30, 2014
• First Posted Date: January 14, 2015
• Results First Submitted Date: March 27, 2018
• Results First Posted Date: March 1, 2019
• Last Update Posted Date: September 10, 2019
• Actual Study Start Date: October 16, 2014
• Actual Primary Completion Date: March 31, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 26, 2018)

Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization [ Time Frame: Up to 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.

Original Primary Outcome Measures (submitted: January 13, 2015)

Progression-Free Survival rate (PFS rate) at 9 months after randomization [ Time Frame: 9 months ]

The 9-month PFS rate is defined as the number of subjects who had not progressed or died prior to 9 months from the date of randomization, divided by the number of subjects in each arm.

Current Secondary Outcome Measures (submitted: March 20, 2019)

• Progression-Free Survival (PFS) [ Time Frame: Up to approximately 31 months ]
  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) [ Time Frame: Up to approximately 31 months ]
  OS was defined as the time from the day of randomization (Day 0) until death by all causes.
• Response Rate (RR) [ Time Frame: Up to approximately 31 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 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) [ Time Frame: Up to approximately 31 months ]
  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 [ 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) ]
  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 [ 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) ]
  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 [ 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) ]
  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 [ 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) ]
  Skin toxicity was defined as events classified with an system organ class of "Skin and subcutaneous tissue disorders" or a preferred term of "paronychia".

Original Secondary Outcome Measures (submitted: January 13, 2015)

• Progression-Free Survival (PFS) [ Time Frame: From the date of randomization (Day 0) until the date of judgment of progression or date of death by all causes, whichever comes first, assessed after the last participant enrollment (up to 24 months) ]
  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.
• Overall survival (OS) [ Time Frame: From the date of randomization (Day 0) until the date of death by all causes, whichever comes first, assessed up to 24 months after the last participant enrollment ]
  OS will be measured as the time from the date of randomization to the date of death by all causes.
• Response rate (RR) [ Time Frame: After randomization up to 24 months ]
  RR is defined as the percentage of subjects who have shown complete response or partial response as the best overall response in RECIST ver 1.1 after randomization. The overall response will be complete response, followed by partial response, stable disease, progression, and nonevaluable in this order.
• Time to treatment failure (TTF) [ Time Frame: up to 24 months ]
  TTF is defined as the period from the date of randomization (counted as Day 0) to the date of judgment of discontinuation of protocol treatment, the date of judgment of progression, or the date of death for all causes, whichever has come earliest (up to 24 months).
• Frequency of adverse events rate [ Time Frame: After initiation of protocol treatment after randomization up to 24 months ]
  Adverse events are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The frequencies of all adverse events which developed after initiation of protocol treatment after randomization will be tabulated by type and seriousness, and causal relationship to panitumumab

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Colorectal Carcinoma

Intervention

• 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

Study Arms

• 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.
  Intervention: 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.
  Intervention: Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 7, 2017): 164
• Original Estimated Enrollment (submitted: January 13, 2015): 100
• Actual Study Completion Date: August 31, 2017
• Actual Primary Completion Date: March 31, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Japan

Administrative Information

• NCT Number: NCT02337946
• 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 )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• 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.

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: August 2019