CAPOXIRI+Bevacizumab vs. FOLFOXIRI+Bevacizumab for mCRC (QUATTRO-II)

Quadruplet 1st Line Treatment of CAPOXIRI Plus Bevacizumab Versus FOLFOXIRI Plus Bevacizumab for mCRC, Multicenter Randomised Phase II Study (QUATTRO-II)

The objective is to compare the efficacy and safety of CAPOXIRI+BEV therapy versus FOLFOXIRI+BEV therapy as first-line therapy in patients with metastatic colorectal cancer (mCRC).

Study Overview

• Status: Unknown
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Biological: Bevacizumab; Drug: Oxaliplatin; Drug: Capecitabine; Drug: 5-fluorouracil; Drug: Irinotecan hydrochloride; Drug: Leucovorin calcium

Detailed Description

QUATTRO-II is an open-label, multicenter, randomised, phase II study to investigate the efficacy and safety of CAPOXIRI+BEV versus FOLFOXIRI+BEV in 1st line mCRC.

This study is composed two steps because of confirming of recommended dose (RD) for CAPOXIRI+BEV regimen.

1. Dose finding step (Step1): CAPOXIRI+BEV doses findings were planned by 3+3 cohort design, register up to maximum of 12 cases.
2. Randomised step (Step2): After confirmation of RD regarding CAPOXIRI+BEV, we will move to Step2 to compare the efficacy and safety between FOLFOXIRI+BEV and CAPOXIRI+BEV, register up to 65 cases.

• Study Type: Interventional
• Enrollment (Anticipated): 112
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tsunehiko Tateuchi; Phone Number: +81-3-6304-5495; Email: quattro-2_jimukyoku@acmedical.co.jp

Study Locations

• Japan
  • Tokyo
    • Chuo Ku, Tokyo, Japan, 104-0053
      • Recruiting
      • Ac Medical Inc.
      • Contact: Tsunehiko Tateuchi; Phone Number: +81-3-6304-5495; Email: quattro-2_jimukyoku@acmedical.co.jp
      • Principal Investigator: Takeshi Kato, M.D.,Ph.D.
      • Principal Investigator: Akihito Tsuji, M.D.,Ph.D.
      • Sub-Investigator: Takayuki Yoshino, M.D.,Ph.D.
      • Sub-Investigator: Eiji Oki, M.D.,Ph.D.
      • Sub-Investigator: Masahito Kotaka, M.D.,Ph.D.
      • Sub-Investigator: Yoshito Komatsu, M.D.,Ph.D.
      • Sub-Investigator: Hiroya Taniguchi, M.D.,Ph.D.
      • Sub-Investigator: Kei Muro, M.D.
      • Sub-Investigator: Kentaro Yamazaki, M.D.,Ph.D.
      • Sub-Investigator: Takeharu Yamanaka, Ph.D.
      • Sub-Investigator: Hironaga Satake, M.D.,Ph.D.
      • Sub-Investigator: Hideaki Bando, M.D.,Ph.D.

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:

1. Personal written informed consent is obtained after the study has been fully explained

2. Histologically confirmed colon or rectal adenocarcinoma

   *Excluding appendix cancer and anal canal cancer

3. Clinically unresectable
4. ≥20 years of age at enrollment
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 (≥71 years of age: PS score of 0)
6. Measurable lesion according to RECIST ver. 1.1 criteria on contrast-enhanced chest, abdominal, or pelvic (trunk) CT (required within 28 days of enrollment)

7. No previous chemotherapy for colon or rectal cancer

   *Patients with confirmed relapse ≥24 weeks after completion of post-operative adjuvant chemotherapy can be enrolled

8. Ras/Braf mutation analysis at enrollment identifies Ras/Braf status as either the wild type or mutant type.

9. Vital organ functions meet the following criteria within 14 days before enrollment.

   If multiple test results are available in that period, the results closest to enrollment will be used. No blood transfusions or hematopoietic factor administration will be permitted within 2 weeks before the date on which measurements are taken.

   i. Neutrophil count: ≥1,500 /cu.mm

   ii. Platelet count: ≥10.0 × 104/cu.mm

   iii. Hemoglobin concentration: ≥9.0 g/dL

   iv. Total bilirubin: ≤1.5 times upper limit of normal (ULN)

   v. Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP): ≤2.5 times ULN (≤5 times ULN for metastases to liver)

   vi. Serum creatinine: ≤1.5 times ULN, or creatinine clearance: ≥30 mL/min

   vii. Urine protein: ≤2+ (if ≥3+, urine protein/creatinine ratio: <2.0)

10. UGT1A1 polymorphism is wild type or single heterozygous type -

Exclusion Criteria:

1. Previous radiation therapy in which ≥20% bone marrow was exposed to the radiation field
2. Untreated brain metastases, spinal cord compression, or primary brain tumor
3. History of central nervous system (CNS) disease (excluding asymptomatic lacunar infarction)
4. Continuous systemic corticosteroid treatment is required
5. Oral or parenteral (such as low molecular weight heparin) anticoagulant dose is not consistently (≥14 days) controlled. (Oral anticoagulants: conditions at high risk for bleeding, such as prothrombin time (PT)-international normalized ratio (INR) ≥3, clinically significant active bleeding (within 14 days of enrollment))
6. Evidence of cardiovascular disease, cerebrovascular disorder (within 24 weeks), myocardial infarction (within 24 weeks), unstable angina pectoris, New York Heart Association (NYHA) classification ≥Grade II congestive heart failure, serious arrhythmias requiring drug therapy
7. Previous treatment with an investigational drug within 28 days prior to enrollment, or participation in a study of an unapproved drug

8. Any of the following comorbidities

   i. Uncontrolled hypertension

   ii. Uncontrolled diabetes mellitus

   iii. Uncontrolled diarrhea

   iv. Peripheral sensory neuropathy (≥Grade 1)

   v. Active peptic ulcer

   vi. Unhealed wound (except for suturing associated with implanted port placement)

   vii. Other clinically significant disease (such as interstitial pneumonia or renal impairment)

9. Major surgical procedure within 28 days prior to study treatment initiation (such as open chest, laparoscopy, thoracoscopic surgery, laparoscopic surgery), unless only colostomy is performed; open biopsy or suturing for major trauma within 14 days of study treatment initiation; or planned major surgical procedure during the study (open chest, laparoscopy) ("major surgical procedures" does not include central venous (CV) port insertion)
10. Physical defects of the upper gastrointestinal tract; malabsorption syndrome or difficulty taking oral medication
11. Pregnant, breastfeeding, positive pregnancy test (women who have menstruated in the last year will be tested), or women who are unwilling to use contraception; men who are unwilling to use contraception during the study
12. Active hepatitis B or C, or evidence of HIV infection
13. Previous chemotherapy for other malignancies (excluding hormone therapy for breast cancer)
14. Other active malignancies (synchronous malignancies, and asynchronous malignancies separated by a 5-year disease-free interval) (excluding malignancies that are expected to be completely cured, such as intramucosal carcinoma and carcinoma in situ)
15. Uncontrolled venous thromboembolism (unless clinically stable, asymptomatic, or appropriately treated with an anticoagulant)
16. Arterial thrombosis or arterial thromboembolism such as myocardial infarction, transient ischemic attack, or cerebrovascular attack in the last year prior to enrollment
17. Complications such as intestinal paralysis, intestinal obstruction, or gastrointestinal perforation, current or within 1 year prior to enrollment
18. Pleural effusion, ascites, or pericardial effusion requiring drainage
19. History of hypersensitivity to fluorouracil, levofolinate, oxaliplatin, irinotecan, bevacizumab and their excipients or Chinese hamster ovary cell proteins
20. History of adverse reactions to fluoropyrimidine drugs indicative of dihydropyrimidine dehydrogenase (DPD) deficiency
21. Systemic treatment required for, or evidence of, infections
22. Endoluminal stenting
23. Otherwise unsuitable for the study in the opinion of investigators -

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

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Step 1 (CAPOXIRI+ BEV); Induction therapy is followed by the maintenance therapy. [Induction treatment: CAPOXIRI+BEV] Administered for 6 cycles (a maximum of 8 cycles). BEV: 7.5mg/kg (d.i.v.) oxaliplatin (OX): 100/130 mg/sq.m (d.i.v.) irinotecan (IRI):150/180/200mg/sq.m (d.i.v.) CAP 1,600 mg/sq.m /day (p.o. day1-15) Administered every 3 weeks. OX/IRI dose is applied according to the progress of Step 1. [Maintenance treatment: 5-fluorouracil (FU)/Levofolinate calcium (LV)+BEV or CAP+BEV] The following 5-FU/LV+BEV therapy will be repeated in 2-week cycles, or the following CAP+BEV therapy will be repeated in 3-week cycles (Physician's choice). No change in treatment regimen will be permitted after the selection of maintenance therapy (5-FU/LV+BEV or CAP+ BEV). 5-FU/LV+BEV: BEV:5mg/kg (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks. CAP+BEV: BEV: 7.5mg/kg (d.i.v.) CAP 1,600 mg/sq.m /day (po. day1-15) Administered every 3 weeks.	Biological: Bevacizumab; Given IV; Other Names: BEV; Drug: Oxaliplatin; Given IV; Other Names: OX; Drug: Capecitabine; Given PO; Other Names: CAP; Drug: Irinotecan hydrochloride; Given IV; Other Names: IRI
Experimental: Step 2 Arm A (FOLFOXIRI+ BEV); Induction therapy is followed by the maintenance therapy. [Induction treatment: FOLFOXIRI+BEV] Administered for 8 cycles (a maximum of 12 cycles). BEV: 5mg/kg (d.i.v.) OX: 85 mg/sq.m (d.i.v.) IRI:165mg/sq.m (d.i.v.) LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks. [Maintenance treatment: 5-FU/LV+BEV or CAP+BEV] The following 5-FU/LV+BEV therapy will be repeated in 2-week cycles, or the following CAP+BEV therapy will be repeated in 3-week cycles (Physician's choice). No change in treatment regimen will be permitted after the selection of maintenance therapy (5-FU/LV+BEV or CAP+ BEV). 5-FU/LV+BEV: BEV:5mg/kg (d.i.v.) LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks. CAP+BEV: BEV: 7.5mg/kg (d.i.v.) CAP 1,600 mg/sq.m /day (po. Day1-15) Administered every 3 weeks.	Biological: Bevacizumab; Given IV; Other Names: BEV; Drug: Oxaliplatin; Given IV; Other Names: OX; Drug: 5-fluorouracil; Given IV; Other Names: 5-FU; Drug: Irinotecan hydrochloride; Given IV; Other Names: IRI; Drug: Leucovorin calcium; Given IV; Other Names: LV
Experimental: Step 2 Arm B (CAPOXIRI+ BEV); Induction therapy is followed by the maintenance therapy. [Induction treatment: CAPOXIRI+BEV] Administered for 6 cycles (a maximum of 8 cycles). BEV: 7.5mg/kg (d.i.v.) OX: 100/130 mg/sq.m (d.i.v.) IRI:150/180/200mg/sq.m (d.i.v.) CAP 1,600 mg/sq.m /day (p.o. day1-15) Administered every 3 weeks. Regarding to OX/IRI dose, RD will be confirmed at Step 1. [Maintenance treatment: 5-FU/LV+BEV or CAP+BEV] The following 5-FU/LV+BEV therapy will be repeated in 2-week cycles, or the following CAP+BEV therapy will be repeated in 3-week cycles (Physician's choice). No change in treatment regimen will be permitted after the selection of maintenance therapy (5-FU/LV+BEV or CAP+ BEV). 5-FU/LV+BEV: BEV:5mg/kg (d.i.v.) l-LV:200mg/sq.m (d.i.v.) 5-FU:3,200mg/sq.m (c.i.v.) Administered every 2 weeks. CAP+BEV: BEV: 7.5mg/kg (d.i.v.) CAP 1,600 mg/sq.m /day (po. day1-15) Administered every 3 weeks.	Biological: Bevacizumab; Given IV; Other Names: BEV; Drug: Oxaliplatin; Given IV; Other Names: OX; Drug: Capecitabine; Given PO; Other Names: CAP; Drug: Irinotecan hydrochloride; Given IV; Other Names: IRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS by investigator-reported measurements according to CT image. PFS was calculated from the day of treatment start to the first observation of progression disease (PD) or death from any cause.PD was defined as Overall Response by RECIST criteria v1.1 according to CT image.	Up to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)		Up to 36 months
Overall survival (OS)		Up to 36 months
Incidence of adverse events	Adverse events were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. All adverse events was collected in duration from starting treatment to whichever shorter "after 30 days from withdrawal treatment" or "later treatment	Up to 36 months
Functional Assessment of Cancer Therapy (FACT) / Gynaecologic Oncology Group (GOG) Neurotoxicity 4		Up to 18 months

Collaborators and Investigators

• Sponsor: Chugai Pharmaceutical
• Investigators: Principal Investigator: Takeshi Kato, M.D., Ph.D., Department of Surgery, National Hospital Organization Osaka National Hospital.; Principal Investigator: Akihito Tsuji, M.D., Ph.D., Department of Medical Oncology, Kagawa University Hospital.

Publications and helpful links

General Publications

• Kotani D, Yoshino T, Kotaka M, Kawazoe A, Masuishi T, Taniguchi H, Yamazaki K, Yamanaka T, Oki E, Muro K, Komatsu Y, Bando H, Satake H, Kato T, Tsuji A. Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first-line treatment for metastatic colorectal cancer: Safety lead-in results from the QUATTRO-II study. Invest New Drugs. 2021 Dec;39(6):1649-1655. doi: 10.1007/s10637-021-01125-2. Epub 2021 May 21.
• Miyo M, Kato T, Yoshino T, Yamanaka T, Bando H, Satake H, Yamazaki K, Taniguchi H, Oki E, Kotaka M, Oba K, Miyata Y, Muro K, Komatsu Y, Baba H, Tsuji A. Protocol of the QUATTRO-II study: a multicenter randomized phase II study comparing CAPOXIRI plus bevacizumab with FOLFOXIRI plus bevacizumab as a first-line treatment in patients with metastatic colorectal cancer. BMC Cancer. 2020 Jul 23;20(1):687. doi: 10.1186/s12885-020-07186-5.

Study record dates

Study Major Dates

• Study Start (Actual): October 11, 2019
• Primary Completion (Anticipated): August 31, 2022
• Study Completion (Anticipated): August 31, 2022

Study Registration Dates

• First Submitted: September 18, 2019
• First Submitted That Met QC Criteria: September 19, 2019
• First Posted (Actual): September 20, 2019

Study Record Updates

• Last Update Posted (Actual): October 31, 2019
• Last Update Submitted That Met QC Criteria: October 29, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: bevacizumab; Metastatic colorectal cancer; FOLFOXIRI; CAPOXIRI
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Capecitabine; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Calcium; Levoleucovorin
• Other Study ID Numbers: QUATTRO-II

Drug and device information, study documents

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