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Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naïve Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer

Open AccessPublished:January 24, 2017DOI:https://doi.org/10.1016/j.clcc.2017.01.001

      Abstract

      Background

      It remains unclear whether an anti-VEGF or anti-EGFR antibody with standard doublet chemotherapy is the optimal first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer (mCRC). Here we outline the PARADIGM study (NCT02394795), designed to evaluate the superiority of panitumumab over bevacizumab, in combination with oxaliplatin/5-fluorouracil/leucovorin (mFOLFOX6) in patients with RAS wild-type chemotherapy-naïve mCRC.

      Patients and Methods

      Eligible patients are aged 20 to 79 years with an ECOG performance status of 0-1 and histologically/cytologically confirmed RAS wild-type mCRC. A total of 800 patients are to be randomly assigned (1:1 ratio) to mFOLFOX6 plus panitumumab (n = 400) or bevacizumab (n = 400) and stratified according to institution, age (20-64 vs. 65-79 years), and liver metastases (present vs. absent). Each treatment regimen includes oxaliplatin 85 mg/m2, l-leucovorin 200 mg/m2, and 5-fluorouracil (5-FU) I.V. 400 mg/m2 on day 1; 5-FU continuous I.V. 2400 mg/m2 on days 1 to 3; and either panitumumab 6 mg/kg or bevacizumab 5 mg/kg on day 1 every 2 weeks. The primary endpoint is overall survival forming the basis to detect a hazard ratio of 0.76 with a 1-sided type I error rate of 0.025 and 80% power. Secondary efficacy endpoints include progression-free survival, response rate, duration of response, and curative resection rate. A comprehensive biomarker analysis (NCT02394834) using archival tumor tissue and circulating tumor DNA samples collected at different time points (pretreatment and confirmed progressive disease) will investigate potential biomarkers related to primary and secondary resistance. The first patient was enrolled in May 2015 and the study is anticipated to complete in 2020.

      Keywords

      Introduction

      The treatment of metastatic colorectal cancer (mCRC) has evolved greatly over the past 2 decades. Building on backbone chemotherapy with 5-fluorouracil (5-FU)/leucovorin (LV) with oxaliplatin (FOLFOX), irinotecan (FOLFIRI), or both oxaliplatin and irinotecan (FOLFOXIRI) targeted agents have shown clinical benefit as first-line or subsequent therapy, including antiangiogenesis inhibitors (bevacizumab, ziv-aflibercept, ramucirumab); anti-epidermal growth factor receptor (anti-EGFR) antibodies (cetuximab, panitumumab); the multi-tyrosine kinase inhibitor regorafenib; and the combination agent of trifluridine/tipiracil hydrochloride (TAS-102).
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      • Clarke S.
      • Díaz-Rubio E.
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      Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.
      • Van Cutsem E.
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      • et al.
      Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.
      • Tabernero J.
      • Yoshino T.
      • Cohn A.L.
      • et al.
      Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study.
      • Van Cutsem E.
      • Köhne C.-H.
      • Hitre E.
      • et al.
      Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.
      • Douillard J.Y.
      • Siena S.
      • Cassidy J.
      • et al.
      Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
      • Grothey A.
      • Van Cutsem E.
      • Sobrero A.
      • et al.
      Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial.
      • Mayer R.J.
      • Van Cutsem E.
      • Falcone A.
      • et al.
      Randomized trial of TAS-102 for refractory metastatic colorectal cancer.
      Retrospective analyses of randomized clinical trials have demonstrated no survival benefit with anti-EGFR antibody therapy in patients with KRAS exon 2 mutation, or in patients with any mutation in KRAS exons 3 and 4 and NRAS exons 2, 3, and 4
      • Douillard J.Y.
      • Oliner K.S.
      • Siena S.
      • et al.
      Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer.
      • Van Cutsem E.
      • Lenz H.J.
      • Köhne C.-H.
      • et al.
      Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
      ; thus, in Western countries, cetuximab and panitumumab are indicated only in patients with wild-type RAS (Europe) or KRAS (United States).
      In Japan, oxaliplatin-based therapy is more frequently selected as first-line treatment for mCRC than irinotecan-based therapy, at a similar frequency to that seen in the United States, and bevacizumab is an accepted first-line treatment regardless of RAS mutational status.
      • Yamazaki K.
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      • Tamagawa H.
      • et al.
      Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).
      • Venook A.P.
      • Niedzwiecki D.
      • Lenz H.-J.
      • et al.
      CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
      The Japanese Society of Medical Oncology recently revised its clinical guidelines to recommend RAS mutation testing,
      • Taniguchi H.
      • Yamazaki K.
      • Yoshino T.
      • et al.
      Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients.
      and the RASKET kit (MEBGEN; Medical & Biological Laboratories Co, Ltd) for determining RAS mutations is approved as the validated in vitro diagnostic kit for the use of anti-EGFR therapy.
      • Yoshino T.
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      • Yamaguchi K.
      • et al.
      Clinical validation of a multiplex kit for RAS mutations in colorectal cancer: results of the RASKET (RAS KEy testing) prospective, multicenter study.
      Japanese indications for panitumumab and cetuximab were revised to mandate RAS mutation testing before anti-EGFR therapy.
      It is unclear whether bevacizumab or an anti-EGFR antibody should be used in first-line treatment of RAS (KRAS/NRAS) wild-type mCRC. The FIRE-3 phase III study demonstrated a significant improvement in overall survival (OS) with cetuximab versus bevacizumab plus FOLFIRI in patients with KRAS (exon 2) wild-type mCRC (median OS, 28.7 vs. 25.0 months; hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.62-0.96; P = .017).
      • Heinemann V.
      • von Weikersthal L.F.
      • Decker T.
      • et al.
      FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
      However, the CALGB/SWOG 80405 phase III study demonstrated no OS difference between cetuximab and bevacizumab plus chemotherapy in this setting (median OS 29.9 vs. 29.0 months; HR 0.925; 95% CI, 0.78-1.09; P = .34).
      • Venook A.P.
      • Niedzwiecki D.
      • Lenz H.-J.
      • et al.
      CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC).
      In subsequent post hoc analyses in RAS wild-type populations, FIRE-3 showed a greater OS improvement with cetuximab versus bevacizumab (median, 33.1 vs. 25.6 months; HR 0.70; 95% CI, 0.53-0.92; P = .011), whereas CALGB/SWOG 80405 again showed no OS difference between the groups (median 32.0 vs. 31.2 months; HR 0.9; 95% CI, 0.7-1.1; P = .40).
      • Heinemann V.
      • von Weikersthal L.F.
      • Decker T.
      • et al.
      FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
      • Lenz H.
      • Niedzwiecki D.
      • Innocenti F.
      • et al.
      CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with untreated metastatic adenocarcinoma of the colon or rectum (mCRC): expanded RAS analyses.
      Additionally, in a subset of patients with KRAS/NRAS wild-type mCRC from the phase II PEAK study, a trend toward improved OS was seen with panitumumab versus bevacizumab plus FOLFOX-based chemotherapy.
      • Schwartzberg L.S.
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      • et al.
      PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer.
      Given these inconsistent findings, the optimal sequencing of agents remains to be determined. Of note, it has recently been reported that the EGFR pathway is not comparably activated in left- and right-sided primary tumors, and an EGFR inhibitor-sensitive phenotype appears to be more prevalent in left-sided primary tumors, leading to the hypothesis that EGFR inhibitors may exhibit differential activity based on primary tumor location.
      • Missiaglia E.
      • Jacobs B.
      • D'Ario G.
      • et al.
      Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features.
      Duration of treatment is limited mainly by primary and secondary resistance. Recent evidence has suggested that in RAS wild-type mCRC, potential primary resistance mechanisms include BRAF, PIK3CA mutations, and ERBB-2 overexpression/amplification; and secondary resistance mechanisms include acquired RAS mutations, c-MET amplification, and so on.
      • Bronte G.
      • Silvestris N.
      • Castiglia M.
      • et al.
      New findings on primary and acquired resistance to anti-EGFR therapy in metastatic colorectal cancer: do all roads lead to RAS?.
      Thus, there is a focus on liquid biopsy, especially for circulating tumor DNA (ctDNA) analysis that may enable comprehensive pretreatment biomarker analysis as well as resistance monitoring; a key focus of current research is development of clinically meaningful thresholds that may be used for identifying and implementing treatment changes. Evolving technologies, such as Next Generation Sequencing (NGS) and digital polymerase chain reaction, are expanding the potential of ctDNA analysis, and studies have used these in investigating resistance mechanisms against targeted therapy in mCRC.
      • Bettegowda C.
      • Sausen M.
      • Leary R.J.
      • et al.
      Detection of circulating tumor DNA in early- and late-stage human malignancies.
      • Misale S.
      • Yaeger R.
      • Hobor S.
      • et al.
      Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
      • Bertotti A.
      • Papp E.
      • Jones S.
      • et al.
      The genomic landscape of response to EGFR blockade in colorectal cancer.
      To date, no phase III study has been conducted to prospectively compare bevacizumab and panitumumab combination therapies for RAS wild-type mCRC. The objective of the PAnitumumab and RAS, DIagnostically useful Gene Mutation for mCRC (PARADIGM) study (clinicaltrials.gov identifier NCT02394795) is therefore to assess mFOLFOX6 plus panitumumab or bevacizumab in the first-line treatment of RAS wild-type mCRC. Another objective is to investigate primary and secondary resistance mechanisms by collecting blood samples and archival formalin-fixed paraffin-embedded (FFPE) tissue for comprehensive biomarker analysis.

      Discussion

      Study Design and Treatment

      The aim of the PARADIGM phase III, randomized controlled study is to assess the efficacy and safety of mFOLFOX6 + panitumumab (experimental arm) versus mFOLFOX6 + bevacizumab (reference arm) in the first-line treatment of chemotherapy-naïve patients with RAS wild-type, unresectable mCRC. Eligible patients are being randomized centrally in a 1:1 ratio, with randomization stratified by study site, age (20-64 years vs. 65-79 years), and liver metastases (presence vs. absence). Patients receive the following every 2 weeks (Figure 1): oxaliplatin 85 mg/m2 on day 1, l-leucovorin 200 mg/m2 on day 1, bolus 5-FU 400 mg/m2 on day 1, and continuous I.V. 5-FU 2400 mg/m2 on days 1 to 3, plus panitumumab 6 mg/kg (Group P) or bevacizumab 5 mg/kg (Group B) on day 1. Patients receive treatment until progressive disease, unacceptable toxicity, patient withdrawal/physician decision, or planned conversion surgery with the intention of curative resection. Recommended second-line treatment for Group P is bevacizumab plus irinotecan-based chemotherapy, and for Group B, bevacizumab or anti-EGFR antibody therapy plus irinotecan-based chemotherapy. In subsequent lines, all approved drugs are recommended as appropriate across the 2 groups.
      Figure thumbnail gr1
      Figure 1Study Design
      Abbreviations: 5-FU = fluorouracil; Bmab = bevacizumab; civ = continuous intravenous infusion; div = intravenous drip infusion; iv = intravenous; l-LV = levofolinate calcium; mCRC = metastatic colorectal cancer; mFOLFOX6 = fluorouracil/levofolinate calcium in combination with oxaliplatin; OXA = oxaliplatin; Pmab = panitumumab; R = randomization; RAS = rat sarcoma.
      This study is being conducted according to the ethical principles laid down in the Declaration of Helsinki Ethical Guidelines for Clinical Research, and the International Conference on Harmonisation E6 Good Clinical Practice. The ethical committee or institutional review committee at each site approved the protocol before the initiation of the site. All patients are required to sign written informed consent.

      Patients

      Eligibility criteria are shown in Table 1. RAS testing is done using the validated in vitro diagnosis method that covers both KRAS and NRAS codons 12, 13, 59, 61, 117, and 146, all of which must be determined to be wild-type in the tumor using archival FFPE tissue to be eligible. Patients can receive adequate supportive care for neutropenia, nausea, vomiting, allergic reaction, hypertension, and interstitial lung disease. For panitumumab-related skin toxicities, the following supportive care is strongly recommended: tetracycline antibiotic, external salicylic acid petrolatum, steroid ointment, moisturizer, or sunscreen.
      Table 1PARADIGM Inclusion and Exclusion Criteria
      Inclusion Criteria
       1. Age 20-79 years at the time of informed consent
       2. Unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
       3. Lesions must be evaluable; however, they are not required to be measurable per Response Evaluation Criteria in Solid Tumors (RECIST, ver1.1)
       4. Chemotherapy-naïve:
      a. Patients who experience relapse >24 weeks after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents are eligible
      b. Patients who have received adjuvant chemotherapy including perioperative oxaliplatin are ineligible
       5. KRAS/NRAS wild-type: All codons as listed in Figure 1
       6. Adequate organ function tested within 2 weeks before enrollment:
      a. Neutrophil count ≥1.5 × 103/μL
      b. Platelet count ≥10.0 × 104/μL
      c. Hemoglobin ≥9.0 g/dL
      d. Total blood bilirubin ≤2.0 mg/dL
      e. AST ≤100 IU/L (≤200 IU/L if liver metastases are present)
      f. ALT ≤100 IU/L (≤200 IU/L if liver metastases are present)
      g. Serum creatinine ≤1.5 mg/dL
      h. PT-INR <1.5 (<3.0 for patients treated with oral warfarin)
      i. Urine protein: meet at least 1 of the following:
      i. Urine protein (dip stick method) ≤1 +
      ii. Urine protein:creatinine ratio ≤1.0
      iii. Measurement of 24-hour urine protein ≤1000 mg
      j. Eastern Cooperative Oncology Group performance status 0-1
      k. Life expectancy of ≥3 months after enrollment
      Exclusion Criteria
       1. Radiotherapy within 4 weeks before enrollment, except therapy received for pain relief of bone metastases
       2. Known or strongly suspected brain metastasis
       3. Synchronous or metachronous cancers with a disease-free period of ≤5 years
       4. Body cavity fluid that requires treatment
       5. Women who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
       6. Nonhealing surgical wound (excluding implanted venous reservoirs)
       7. Active hemorrhage requiring blood transfusion
       8. Disease requiring systemic steroids for treatment (excluding topical steroids)
       9. Stent placement in colon
       10. Intestinal resection within 4 weeks or colostomy within 2 weeks before enrollment
       11. History or obvious and extensive computerized tomography findings of interstitial pulmonary disease
       12. Arterial thromboembolism, such as unstable angina pectoris, cardiac infarction, cerebral hemorrhage, or cerebral infarction within 24 weeks before enrollment
       13. Serious drug hypersensitivity
       14. Local or systemic active infection requiring treatment, or fever indicating infection
       15. Heart failure or serious heart disease of ≥class II by New York Heart Association classification
       16. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea
       17. Poorly controlled hypertension or diabetes mellitus
       18. Active hepatitis B or known human immunodeficiency virus infection
       19. Peripheral neuropathy of ≥grade 2
      Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; PARADIGM = PAnitumumab and RAS, DIagnostically useful Gene Mutation for mCRC; PT-INR = prothrombin time-international normalized ratio.

      Endpoints and Assessments

      The primary endpoint is OS, defined as time from randomization until death from any cause. Secondary endpoints include progression-free survival (time from randomization until documented progressive disease or death from any cause), response rate, duration of response, percentage of curative resection (R0 resection), and safety. Response is being assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      Adverse events are being graded according to the Common Terminology Criteria for Adverse Events (Japanese edition, JCOG version v4.03). Exploratory endpoints include percentage of early tumor shrinkage, defined as a ≥20% decrease from baseline in the sum of longest diameter of the target lesions at week 8 by enhanced computed tomography; and maximum tumor shrinkage (depth of response), which also will be determined based on change in the sum of longest diameter of the target lesions.

      Target Sample Size and Statistical Analysis Plan

      For assessment of the difference in OS, a piecewise exponential distribution will be assumed, in which the survival rate of the 2 treatment groups would be the same until 18 months, and then after 48 months would be 22% and 32% for the bevacizumab and panitumumab groups, respectively. To detect an OS hazard ratio of 0.76 based on the log-rank test with a 1-sided significance level of 2.5%, 570 death events will ensure a power of approximately 80%, requiring accrual of 800 patients over a 24-month enrollment period, and a 36-month follow-up period. An interim analysis for OS is planned when 70% (399 events) of the targeted number of events are observed. If the primary endpoint is met, subgroup analysis of patients with left-sided primary tumors will be performed.

      Comprehensive Biomarker Analysis

      Archival FFPE tumor tissue and ctDNA samples taken before treatment and at confirmed progressive disease will be collected in a large-scale biomarker analysis study (NCT02394834), with the aim of investigating potential biomarker candidates related to both primary and secondary resistance mechanisms. Matched pretreatment DNA from primary tissue and ctDNA will be analyzed by a NGS-based platform to investigate potential biomarkers of primary resistance mechanisms, and pre- and posttreatment ctDNA will be analyzed to investigate potential secondary mechanisms of resistance for each treatment arm. An ultra-deep target sequencing panel will be developed using molecular tagging specifically designed for the CRC ctDNA assay; exons of more than 70 genes will be captured so that point mutations and copy number variations can be detected. Genes will be selected to cover previously identified CRC-related pathways (RTK-RAS pathway, WNT pathway, transforming growth factor-beta pathway), CRC-related biological processes (DNA damage repair, CpG island methylation),
      • Cancer Genome Atlas Network
      Comprehensive molecular characterization of human colon and rectal cancer.
      • Guinney J.
      • Dienstmann R.
      • Wang X.
      • et al.
      The consensus molecular subtypes of colorectal cancer.
      and pathways presumed relevant to acquired resistance of EGFR-targeted therapies (apoptosis, JAK-STAT).
      • Bertotti A.
      • Papp E.
      • Jones S.
      • et al.
      The genomic landscape of response to EGFR blockade in colorectal cancer.
      • Siravegna G.
      • Mussolin B.
      • Buscarino M.
      • et al.
      Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.
      For archived FFPE samples, a conventional target sequencing panel covering approximately 1000 cancer-related gene exons will be designed to explore a wider range of potential predictive genome biomarkers.

      Conclusion

      PARADIGM is the first phase III study to prospectively restrict eligibility to RAS wild-type patients and the chemotherapy regimen to mFOLFOX6, to conduct a head-to-head comparison of panitumumab versus bevacizumab, and to incorporate a prespecified subgroup analysis of patients with left-sided primary tumors. The first patient was enrolled in May 2015; 250 sites in Japan are currently open for enrollment. The estimated completion date is 2020. The findings will help to establish the optimal combination of a monoclonal antibody (anti-vascular endothelial growth factor vs. anti-EGFR) in the first-line treatment of patients with mCRC.

      Disclosure

      Takayuki Yoshino has received research funding from GlaxoSmithKline K.K. and Boehringer Ingelheim GmbH. Katsuya Tsuchihara received personal fees from Takeda Pharmaceutical Co, Ltd during the conduct of the study. Kohei Shitara has received research funding from Sumitomo Dainippon Pharma Co Ltd, Daiichi Sankyo Co Ltd, Eli Lilly, MSD Merck, Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co, Ltd, and Sanofi K.K. Kentaro Yamazaki has received lecture fees from Takeda, Chugai, Taiho, Yakult, Daiichi-Sankyo, Merck Serono, Bristol Meyers Squibb, Eli Lilly, and Bayer. Eiji Oki reports honoraria and consulting fees from Takeda Pharmaceutical Co Ltd during the conduct of the study, as well as other activities with Takeda Pharmaceutical Company, Taiho Pharmaceutical Company, Chugai Pharmaceutical Company, Bayer Japan; other relationships with Merck Serono, Eli Lilly Japan, are reported outside the submitted work. Takeo Sato has received honoraria and consulting fees from Takeda Pharmaceutical Co Ltd, during the conduct of this study; personal fees from Johnson & Johnson, Medtronic, Takeda, Stryker, Olympus, Chugai Pharmaceutical Co Ltd, Taiho, Astellas Pharma Inc, Daiichi-Sankyo Co Ltd, Bayer., Merck Serono, and Eli Lilly Japan are outside the submitted work. Takeshi Naitoh has received honoraria and consulting fees from Takeda Pharmaceutical Co Ltd during the conduct of this study; consulting and lecture fees from Johnson & Johnson, Medtronic, TERUMO, MC medical, Olympus, Chugai Pharmaceutical Co Ltd, Intuitive Surgical, Astellas Pharma Inc, Daiichi-Sankyo Co Ltd, grants from Ajinomoto Co Ltd, and Japan Society for the Promotion of Science are outside the submitted work. Yoshito Komatsu has received honoraria and consulting fees from Takeda Pharmaceutical Co Ltd, during the conduct of this study. Takeshi Kato reports personal fees from Takeda Pharmaceutical Co Ltd, during the conduct of the study; personal fees from Takeda Pharmaceutical Co Ltd, personal fees from Chugai Pharmaceutical Co, Ltd, personal fees from Eli Lilly, personal fees from Taiho Pharmaceutical Co, Ltd are outside the submitted work. Kazunori Yamanaka, Kouji Iwasaki, Jumpei Soeda, and Masamitsu Hihara are employees of Takeda Pharmaceutical Company Limited. Takeharu Yamanaka received honoraria from Takeda Pharmaceutical Co Ltd during the conduct of this study and from Chugai Pharmaceutical Co Ltd, Taiho, and Merck Serono, outside the submitted work. Kei Muro received honoraria and consulting fees from Takeda Pharmaceutical Co Ltd, during the conduct of the study; honoraria from Yakult Pharmaceutical Company, Taiho Pharmaceutical Company, Chugai Pharmaceutical Company, Merck Serono, and Eli Lilly Japan are outside the submitted work, as well as research funding from Sumitomo Dainippon Pharma Co Ltd, Daiichi Sankyo Co Ltd, Eli Lilly, MSD Merck, Taiho Pharmaceutical Co, Ltd, Chugai Pharmaceutical Co Ltd, Merck Serono, Kyowa Hakko Kirin Co Ltd, and GlaxoSmithKline K.K. Hiroyuki Uetake and Atsushi Ochiai have nothing to disclose.

      Acknowledgments

      This study was funded by Takeda Pharmaceutical Company Limited. The authors acknowledge the patients who are participating in this study and their families, as well as staff at all investigational sites. The authors also acknowledge Helen Wilkinson of FireKite (an Ashfield Company, part of UDG Healthcare plc), who provided medical writing assistance during the development of this article, which was funded by Takeda Pharmaceutical Company Limited, and complied with Good Publication Practice 3 ethical guidelines (Battisti et al,
      • Battisti W.P.
      • Wager E.
      • Baltzer L.
      • et al.
      International Society for Medical Publication Professionals, Good Publication Practice for Communicating Company-Sponsored Medical Research: GPP3.
      Ann Intern Med 2015). Takeda was involved in the design of this study and contributed to development and approval of the present manuscript. The final decision to submit the paper, however, lay directly with the authors.

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