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Quadruplet 1st line Treatment of CAPOXIRI plus Bevacizumab versus FOLFOXIRI plus Bevacizumab for mCRC, Multicenter Randomised Phase II study (QUATTRO-II)

A randomized phase II Study of CAPOXIRI plus Bevacizumab versus FOLFOXIRI plus Bevacizumab for mCRC

112

Arm A (FOLFOXIRI+BEV) 51 patients vs Arm B (CAPOXIRI+BEV) 52 patients Age: Median (range) Arm A 60.0 (38-75) vs Arm B 60.0 (35-77) Sex: Male/Female (%) Arm A 36/15 (70.6/29.4) vs Arm B 27/25 (51.9/48.1) Primary tumor: Arm A (%) vs Arm B (%) Cecum 3 (5.9%) vs 1 (1.9%), Ascending colon 4 (7.8%) vs 10 (19.2%), Transverse colon 4 (7.8) %) vs 1(1.9%), Descending colon 5(9.8%) vs 3(5.8%), Sigmoid colon 11(21.6%) vs 21(40.4%), Rectal 24(47.1%) vs 16(30.8%) Site of primary lesion (right and left) : Left/Right (%) Arm A 40/11 (78.4/21.6) vs Arm B 40/12 (76.9/23.1) ECOG PS: 0/1(%) Arm A 46/5 (90.2/9.8) vs Arm B 49/3 (94.2/5.8) RAS/BRAF gene status: Wild type/Mutant type (%) Arm A 19/32 (37.3/62.7) vs Arm B 22/30 (42.3/57.7) UGT1A1 *6/*28: Wild type/Single heterozygote(%) Arm A 30/21 (58.8/41.2) vs Arm B 29/23 (55.8/44.2) Status of distant metastasis: Synchronous/Metachronous/Other (%) Arm A 43/7/1 (84.3/13.7/2.0) vs Arm B 39/11/2 (75.0/21.2/3.8) Number of organs with metastases: Median (range) Arm A 2.0 (1-5) vs Arm B 2.0 (1-5) Metastatic lesions (overlapped): Arm A (%) vs Arm B (%) Liver 36 (70.6%) vs 34 (65.4%), Lung 13 (25.5%) vs 22 (42.3%), Bone 4 (7.8%) vs 2(3.8%), Lymph node 25(49.0%) vs 13(25.0%), Pleura 1(2.0%) vs 2(3.8%), Peritoneum 11(21.6%) vs 19(36.5%), Other 8( 15.7%) vs 7(13.5%) Primary tumor status: Remaining/Resected (%) Arm A 27/24 (52.9/47.1) vs Arm B 27/25 (51.9/48.1) Adjuvant chemotherapy: Yes(%) Arm A 6 (11.8) vs Arm B 8 (15.4)

This clinical study consists of STEP 1: drug dose confirmation phase for CAPOXIRI+BEV therapy, and STEP 2: efficacy and safety evaluation phase of CAPOXIRI+BEV therapy compared with FOLFOXIRI+BEV therapy. In STEP 1, we confirmed the occurrence of adverse events in 3 patients each, and considered whether to add patients (3 patients) or increase or reduce the dose of each drug based on the occurrence of DLT. Safety was confirmed in 3 patients who started treatment at the LEVEL 0 dose, so 3 patients were added at the LEVEL+1 dose, and since there were no safety issues, 3 more patients were added at the LEVEL+1 dose. Therefore, it was decided to implement STEP 2 at a dose of LEVEL+1. A total of 9 patients were registered in STEP 1. Enrollment in STEP 2 began in June 2020, and approximately 10 patients were enrolled every month. Registration ended at the end of June 2021 when 100 patients were reached. A total of 103 patients were registered in STEP 2.

[STEP1] The serious AE incidence rate was 66.7% (2/3) during induction therapy and 0% (0/3) during maintenance therapy at Level 0, and 33.3% (2/6) during induction therapy and 25.0% (1/4) during maintenance therapy at Level +1. No deaths due to AE were observed. Serious AEs during induction therapy at Level 0 included ``decreased neutrophil count'' in 1 patient and ``diarrhea, anorexia, and dehydration'' in 1 patient. At Level+1, there were 2 patients of enteritis. [STEP2] The incidence of serious AEs was 29.4% (15/51) during induction therapy and 0% (0/32) during maintenance therapy in Arm A, and 17.3% (9/52) during induction therapy and 2.9% (1/35) during maintenance therapy in Arm B. The incidence of serious AEs during induction therapy was 1.7 times higher in Arm A than in Arm B (29.4% vs. 17.3%). There were no deaths due to AEs in both Arm. Serious AEs during induction therapy in Arm A included decreased neutrophil count in 7 patients, febrile neutropenia in 3 patients, encephalopathy in 2 patients, diarrhea, anorexia, gastrointestinal perforation, decreased white blood cell count, decreased platelet count, There was one patient each of constipation, back pain, intestinal obstruction, epilepsy, medical device-related infection, bacteremia, vertebral compression fracture, and unstable angina. In Arm B, there were 4 patients of diarrhea, anorexia, febrile neutropenia, 2 patients each, nausea, dehydration, enterocolitis, ileus, shock, pneumothorax, acute kidney injury, re-expansion pulmonary edema, and abdominal abscess in 1 patient each.

Primary endpoint (PFS): Median PFS was 10.61 (7.66 - 13.34) months in Arm A and 10.91 (9.26 - 14.29) months in Arm B, and the point estimate of HR in Arm B using Arm A as reference The value (95% CI) was 1.114 (0.695 - 1.784), with no significant difference (P = 0.654), and the point estimate of HR in Arm B, X, satisfied 0.8<X<1.25, indicating that the treatment results of the two arms were were equivalent. Secondary endpoints: ORR The number of patients responding to induction therapy [ORR (95% CI)] was 36 patients [70.6% (56.2% - 82.5%)] in Arm A and 41 patients [78.8% (65.3% - 88.9%)] in Arm B. The number of patients responding to induction therapy + maintenance therapy [ORR (95% CI)] was 39 patients [76.5% (62.5% - 87.2%)] in Arm A and 44 patients [84.6% (71.9% - 93.1%)] in Arm B. OS Median OS cannot be calculated due to insufficient follow-up period in Arm A, and cannot be calculated due to insufficient follow-up period in Arm B. HR in Arm B using Arm A as reference was 0.771 (0.371 - 1.602), with no significant difference (P=0.485). Tumor response The proportion of patients with comprehensive tumor response (CR+PR) was approximately half of the patients in both arms at 32 weeks +- 2 weeks, 60.0% (15/25) in Arm A and 84.0% in Arm B. (21/25). PRO assessment (FACT/GOG-Ntx4 PSN) In both arms A and B, the measured values for four types of evaluation items increased from baseline to 48 weeks after the start of treatment, but overall there was no difference in PRO assessment (FACT/GOG-Ntx4/PSN) between the two arms.

Compared to FOLFOXIRI+BEV therapy for patients with unresectable advanced/recurrent colorectal cancer treated for the first time, CAPOXIRI+BEV therapy is equivalent in terms of PFS and safety. The low incidence of AEs suggested the usefulness of CAPOXIRI+BEV therapy.

Feb. 27, 2024

May. 31, 2023

https://doi.org/10.1200/JCO.2023.41.16_suppl.3565

No

-

https://jrct.mhlw.go.jp/latest-detail/jRCTs041190072

Tsuji Akihito

Kagawa University Hospital

1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa-ken

atsuji@med.kagawa-u.ac.jp

Tsuji Akihito

Kagawa University Hospital

1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa-ken

+81-87-898-5111

atsuji@med.kagawa-u.ac.jp

Complete

Sept. 01, 2019

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1.Obtaining informed consent prior to study-specific screening procedures
2.Histologically-confirmed colorectal adenocarcinoma excluding vermiform appendix cancer and anal canal cancer
3.Clinically-confirmed metastatic colorectal cancer
4.Age>=20 years at the time of informed consent
5.ECOG performance status (PS) of 0,1
6.Patients who has one or more lesion(s) of diameter 1 cm or larger (RECEST v1.1) be able to assess continuously on the basis of the protocol by contrast enhanced CT.
7.Untreated metastatic colorectal cancer. Patients who underwent to adjuvant chemotherapy can be enrolled after 24 weeks from last administration.
8.RAS / BRAF testing was performed and confirmed RAS / BRAF wild type or mutation type
9.Adequate organ function according to following laboratory values obtained within 14 days before enrolment (excluding patients who received blood transfusions or hematopoietic growth factors within 14 days before the laboratory test)
i. Neutrophil count: >= 1200/mm3
ii. Platelet count: >= 10.0 x 104/mm3
iii. Hemoglobin: >= 9.0 g/dL
iv. Total bilirubin: =< 1.5 x ULM
v. AST, ALT, ALP: =< 2.5 x ULM (<5 x ULM if liver metastases present)
vi. Serum creatinine: =<1.5 x ULM or Ccr >30 ml/min
vii. Protein Urea: =< 2+ (In case of >= 3+, UPC (Urine protein / creatinine ratio: < 2.0)
10.Confirmed UGT1A1 wild type or UGT1A1 single hetero type

1.Previously treated with irradiation to bone marrow constituting 20% or more of irradiation field.
2.Untreated brain metastases or spinal cord compression or primary brain tumors.
3.History of CNS disease.(except for asymptomatic lacunar stroke)
4.Requiring chronic systemic corticosteroid treatment.
5.Patients who have uncontrolled anticoagulant therapy.
6.History / Presence of thrombosis within 1 year requiring medication.
7.Previously participated in any clinical trials and treatment with any investigational drug within 28 days.
8.Patient with i) Uncontrolled hypertension, ii) Uncontrolled diabetes, iii) Uncontrolled diarrhea, iv) >grade 1 peripheral neuropathy, v) Active peptic ulcer, vi) Non-healing wound (except for central venous port), vii) Clinically significant cardiovascular disease (for example cerebrovascular accidents, myocardial infarction, unstable angina, congestive heart failure, serious cardiac arrhythmia requiring medication), viii) Uncontrolled venous thromboembolism, xi) Evidence or requiring systemic treatment for Infectious disease, x) Clinically important diseases.
9.Major surgical procedure within 28 days prior to study treatment start, open biopsy, or significant traumatic injury, or anticipation of the need for major surgical procedure. (except for central venous port)
10.Lack of physical integrity of the upper gastrointestinal tract.
11.Pregnant women, lactating woman, positive by pregnancy test, wishing to become pregnant, and Sexually active males.
12.Hepatitis B or hepatitis C or Evidence of HIV infection.
13.History / Presence of paralytic ileus, obstruction or gastrointestinal perforation.
14.Other active co-existing malignancies.
15.History / Presence of paralytic ileus, obstruction or gastrointestinal perforation.
16.With massive pleural effusion or ascites
17.History of allergy to the drug of fluorouracil, oxaliplatin, irinotecan, bevacizumab and Chinese hamster ovary cell proteins of any components of the study medications.
18.History of fluoropyrimidine severe side effects caused by DPD defect.
19.Patients who underwent colonic stent.
20.Patient who is judged by the investigator to be inappropriate for study participation for any reason.

Both

Metastatic colorectal cancer

Step1: Confirmation of dosage of each drug (Oxaliplatin and Irinotecan)
i)Induction treatment
The following drugs will be administered in 3week/cycle for 6cycles (maximum 8cycle, if investigator required). With regard to determination of oxaliplatin (OX) and Irinotecan (IRI) dosage, initial 3patients (pts) will be enrolled of level0. After finishing initial enrollment, Steering committee (SC) will evaluate safety of 3pts at the time of starting of cycle2 and will decide whether the proceeding same level (add 3 pts) or other level (level+1 or level-0.5). Final decision of Recommended Dose (RD) of OX and IRI will be required 6pts of safety evaluation in same level and will be endorsed by SC and Independent Data monitoring committee (IDMC).

1) Each drug dosage of CAPOXIRI+Bevacizumab
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: 130 mg/m2, i.v., 90 min, Day 1)
Oxaliplatin (OX: 200 mg/m2, i.v., 120 min, Day 1)
Capecitabine (CAP: 800 mg/m2 p.o., twice daily, 14 days consecutively)

2) OX and IRI dose level
Level +1: IRI: 200 mg/m2, OX:130mg/m2
Level 0: IRI: 200 mg/m2, OX:100mg/m2
Level -0.5: IRI: 180 mg/m2, OX:100mg/m2
Level -1: IRI: 150 mg/m2, OX:100mg/m2

ii)Maintenance treatment
After finishing the induction treatment, investigator will select 1) 5-FU/LV+BEV (2weeks cycle) or 2) CAP+BEV treatment (3weeks/cycle).

1)5-FU/LV+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of 5-FU/LV+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)CAP+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of CAP+BEV -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Capecitabine (CAP: 800 mg/m2, p.o., twice daily 14 days consecutively)

Step2: Evaluation efficacy and safety of CAPOXIRI+BEV treatment in randomized setting.
i)Induction treatment
Patient who meet the criteria will be randomized Arm A (FOLFOXIRI+BEV treatment) or Arm B (CAPOXIRI+BEV treatment).

1)Arm A: FOLFOXIRI+BEV treatment
The following drugs will be administered in 3week/cycle for 8 cycles (maximum 12cycle, if investigator required).

- Each drug dosage of FOLFOXIRI+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: 165 mg/m2, i.v., 60 min, Day 1)
Oxaliplatin (OX: 85 mg/m2, i.v., 120 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)Arm B: CAPOXIRI+BEV treatment
The following drugs will be administered in 3week/cycle for 6 cycles (maximum 8cycle, if investigator required).

- Each drug dosage of CAPOXIRI+Bevacizumab -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Irinotecan (IRI: See below 2) dose level, i.v., 90 min, Day 1)
Oxaliplatin (OX: See below 2)dose level, i.v., 120 min, Day 1)
Capecitabine (CAP: 800 mg/m2 p.o., twice daily, 14 days consecutively)

ii)Maintenance treatment
After finishing the induction treatment, investigator will select 1)5-FU/LV+BEV (2weeks cycle) or 2) CAP+BEV treatment (3weeks/cycle).

1)5-FU/LV+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of 5-FU/LV+BEV -
Bevacizumab (BEV: 5.0 mg/kg, i.v., 90, 60, 30 min, Day 1)
Leucovorin (LV: 200 mg/m2, i.v., 120 min, Day 1)
5-FU (3200 mg/m2, c.i.v., 48 hours, Day 1-3)

2)CAP+BEV treatment
The following drugs will be administered in 2week/cycle until meeting discontinuation criteria.

- Each drug dosage of CAP+BEV -
Bevacizumab (BEV: 7.5 mg/kg, i.v., 90, 60, 30 min, Day 1)
Capecitabine (CAP: 800 mg/m2, p.o., twice daily 14 days consecutively)

Colorectal cancer

Progression-free survival (PFS)

Overall response rate (ORR)
Overall survival (OS)
Safety (Adverse event:Type, Grade)
Patient reported outcome assessment (FACT/GOG-Ntx4)

+81-55-989-5222

Aug. 29, 2019

none