PARADIGM: Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC
Study Details
Study Description
Brief Summary
The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 3 |
Detailed Description
The purpose of this study is to verify the efficacy of mFOLFOX6 + panitumumab combination therapy and mFOLFOX6 + bevacizumab combination therapy in first-line treatment of chemotherapy-naive patients with KRAS/NRAS wild-type, incurable/unresectable, advanced/recurrent colorectal cancer.
This study will enroll a total of approximately 800 participants (400 per group).
Participants will be randomized to either the mFOLFOX6 + panitumumab arm (Group P) or mFOLFOX6 + bevacizumab arm (Group B) at 1:1 ratio at the time of registration.
Group P and Group B treatment regimen shown below should be administered once every two weeks, following dose, schedule and route of administration.
Group P; mFOLFOX6 + panitumumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg
Group B; mFOLFOX6 + bevacizumab combination therapy, once every two weeks OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg
This trial is conducted by multicenter and is scheduled for 12 months as whole administration period.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Group P; mFOLFOX6 + panitumumab combination therapy OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 panitumumab: 6 mg/kg mFOLFOX6 + panitumumab combination therapy, once every two weeks |
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
|
Active Comparator: Group B; mFOLFOX6 + bevacizumab combination therapy OXA: 85 mg/m2/day 1 l-LV: 200 mg/m2/day 1 5-FU iv: 400 mg/m2/day 1 5-FU civ: 2400 mg/m2/day 1-3 bevacizumab: 5 mg/kg/ mFOLFOX6 + bevacizumab combination therapy, once every two weeks |
Drug: oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab
oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion
|
Outcome Measures
Primary Outcome Measures
- Overall Survival (OS) for All Participants [Up to approximately 63 months]
OS will be measured as the time from the date of randomization to the date of death due to any cause.
- OS for Participants with Left-sided Tumors [Up to approximately 63 months]
OS will be measured as the time from the date of randomization to the date of death due to any cause. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
Secondary Outcome Measures
- Progression-Free Survival (PFS) [Up to approximately 63 months]
PFS is defined as the time from the date of randomization to the earlier of Progressive Disease (PD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or death due to any cause. The outcome will be reported per all participants and those with left-sided tumors. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
- Response Rate (RR) [Approximately 12 months]
RR is defined as percentage of participants who achieve Complete Response (CR) and Partial Response (PR) as the best overall response per RECIST version 1.1. The outcome will be reported per all participants and those with left-sided tumors. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
- Duration of Response (DOR) [Up to approximately 63 months]
DOR means that the period from the day when either CR or PR is first confirmed until the day of documented PD or the day of death due to all causes, whichever occurs earlier. The outcome will be reported per all participants and those with left-sided tumors. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
- Percentage of Participants Treated with Curative Surgical Resection after Chemotherapy [Up to approximately 63 months]
Curative surgical resection is defined as complete resection. The outcome will be reported per all participants and those with left-sided tumors. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
- Percentage of Participants with Treatment-emergent Adverse Events [Until 28 days after the discontinuation of protocol treatment or the start subsequent therapy (up to approximately 63 months)]
Adverse event (AE) is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. A TEAE is defined as an adverse event with an onset that occurs in the treatment period after receiving the protocol treatment. The outcome will be reported per all participants and those with left-sided tumors. The left-sided tumors are defined as primary tumors occupying a left-sided site include the descending colon, sigmoid colon, and rectum.
Eligibility Criteria
Criteria
Inclusion Criteria:
- Investigator and subinvestigator judge a candidate is understand clinical trial and comply this protocol.
Investigator is those who participate in conducting a study and oversight the study duties at a site.
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Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment
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Aged ≥20 to <80 years at the time of informed consent
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Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
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Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1.
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Patients who have not received chemotherapy for colorectal cancer. Patients who experience relapse more than 24 weeks (168 days) after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled. Patients who have received perioperative adjuvant chemotherapy including oxaliplatin are excluded.
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Patients classified as KRAS/NRAS wild-type by KRAS/NRAS testing. KRAS/NRAS test will be performed using the in vitro diagnostic listed in the National Health Insurance.
Patients with no mutation in any of the codons shown below are considered wild type. It is not considered wild type if either of the codons are not evaluable or not tested.
KRAS: EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146) NRAS:EXON2 (codon 12, 13), EXON3 (codon 59, 61), EXON4 (codon 117, 146)
- Patients who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment
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Neutrophil count ≥ 1.5×10^3/µL
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Platelet count ≥ 1.0×10^4/µL
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Hemoglobin ≥ 9.0 g/dL
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Total bilirubin ≤ 2.0 mg/dL
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AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)
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ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)
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Serum creatinine ≤ 1.5 mg/dL
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PT-INR < 1.5 (< 3.0 for patients treated with oral warfarin)
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Satisfies at least one of these conditions
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Urine protein (dip stick method) ≤ 1+
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UPC (urine protein creatinine) ratio ≤ 1.0
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Urinary protein ≤ 1000 mg/ 24hours
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ECOG performance status (PS) of 0 or 1
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Life expectancy of ≥ 3 months (90 days) after enrollment
Exclusion Criteria:
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Radiotherapy received within 4 weeks (28 days) prior to enrollment. Treatments aimed at relieving pain for bone metastases are excluded.
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Known brain metastasis or strongly suspected of brain metastasis
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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.).
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Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
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Patients who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
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Nonhealing surgical wound (excluding implanted venous reservoirs)
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Active hemorrhage requiring blood transfusion
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Disease requiring systemic steroids for treatment (excluding topical steroids)
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The patient who has placed colonic stent
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Intestinal resection within 4 weeks prior to enrollment or colostomy within 2 weeks prior to enrollmentt
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History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
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Patients with unstable angina, myocardial infarction, cerebral hemorrhage, arterial thromboembolism such as cerebral infarction, or have history of these desease less than 24 weeks (168 days) before registration (except for lacunar infarction asymptomatic)
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Serious drug hypersensitivity
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Local or systemic active infection requiring treatment, or fever indicating infection
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NYHA class II or higher heart failure or serious heart disease
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Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms despite adequate treatment)
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Poorly controlled hypertension
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Poorly controlled diabetes mellitus
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Active hepatitis B
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Known HIV infection
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Peripheral neuropathy of ≥ Grade 2 by CTCAE (Japanese edition JCOG version 4.03)
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Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study (e.g. Patients who might agree to participate under compulsion).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Ichinomiya | Aichi | Japan | ||
2 | Komaki | Aichi | Japan | ||
3 | Konan | Aichi | Japan | ||
4 | Nagakute | Aichi | Japan | ||
5 | Nagoya | Aichi | Japan | ||
6 | Okazaki | Aichi | Japan | ||
7 | Toyoake | Aichi | Japan | ||
8 | Toyohashi | Aichi | Japan | ||
9 | Toyokawa | Aichi | Japan | ||
10 | Toyota | Aichi | Japan | ||
11 | Yatomi | Aichi | Japan | ||
12 | Daisen | Akita | Japan | ||
13 | Hirosaki | Aomori | Japan | ||
14 | Misawa | Aomori | Japan | ||
15 | Kashiwa | Chiba | Japan | ||
16 | Yachiyo | Chiba | Japan | ||
17 | Matsuyama | Ehime | Japan | ||
18 | Toon | Ehime | Japan | ||
19 | Tsuruga | Fukui | Japan | ||
20 | Yoshida | Fukui | Japan | ||
21 | Kitakyushu | Fukuoka | Japan | ||
22 | Koga | Fukuoka | Japan | ||
23 | Kurume | Fukuoka | Japan | ||
24 | Omuta | Fukuoka | Japan | ||
25 | Onga | Fukuoka | Japan | ||
26 | Aizuwakamatsu | Fukushima | Japan | ||
27 | Iwaki | Fukushima | Japan | ||
28 | Koriyama | Fukushima | Japan | ||
29 | Shirakawa | Fukushima | Japan | ||
30 | Hashima | Gifu | Japan | ||
31 | Kakamigahara | Gifu | Japan | ||
32 | Minokamo | Gifu | Japan | ||
33 | Ogaki | Gifu | Japan | ||
34 | Okazai | Gifu | Japan | ||
35 | Maebashi | Gunma | Japan | ||
36 | Ota | Gunma | Japan | ||
37 | Fukuyama | Hiroshima | Japan | ||
38 | Hakodate | Hokkaido | Japan | ||
39 | Kitami | Hokkaido | Japan | ||
40 | Kushiro | Hokkaido | Japan | ||
41 | Obihiro | Hokkaido | Japan | ||
42 | Otaru | Hokkaido | Japan | ||
43 | Sapporo | Hokkaido | Japan | ||
44 | Akashi | Hyogo | Japan | ||
45 | Amagasaki | Hyogo | Japan | ||
46 | Himeji | Hyogo | Japan | ||
47 | Kobe | Hyogo | Japan | ||
48 | Nishinomiya | Hyogo | Japan | ||
49 | Hitachi | Ibaraki | Japan | ||
50 | Kasama | Ibaraki | Japan | ||
51 | Ryugasaki | Ibaraki | Japan | ||
52 | Tsuchiura | Ibaraki | Japan | ||
53 | Tsukuba | Ibaraki | Japan | ||
54 | Hakusan | Ishikawa | Japan | ||
55 | Kaga | Ishikawa | Japan | ||
56 | Kahoku | Ishikawa | Japan | ||
57 | Kanazawa | Ishikawa | Japan | ||
58 | Nanao | Ishikawa | Japan | ||
59 | Morioka | Iwate | Japan | ||
60 | Kida | Kagawa | Japan | ||
61 | Marugame | Kagawa | Japan | ||
62 | Takamatsu | Kagawa | Japan | ||
63 | Fujisawa | Kanagawa | Japan | ||
64 | Hiratsuka | Kanagawa | Japan | ||
65 | Isehara | Kanagawa | Japan | ||
66 | Kamakura | Kanagawa | Japan | ||
67 | Kanazawa | Kanagawa | Japan | ||
68 | Sagamihara | Kanagawa | Japan | ||
69 | Yokohama | Kanagawa | Japan | ||
70 | Yokosuka | Kanagawa | Japan | ||
71 | Nankoku | Kochi | Japan | ||
72 | Matsuzaka | Mie | Japan | ||
73 | Tsu | Mie | Japan | ||
74 | Yokkaichi | Mie | Japan | ||
75 | Ishinomaki | Miyagi | Japan | ||
76 | Natori | Miyagi | Japan | ||
77 | Osaki | Miyagi | Japan | ||
78 | Sendai | Miyagi | Japan | ||
79 | Shibata | Miyagi | Japan | ||
80 | Matsumoto | Nagano | Japan | ||
81 | Saku | Nagano | Japan | ||
82 | Omura | Nagasaki | Japan | ||
83 | Sasebo | Nagasaki | Japan | ||
84 | Ikoma | Nara | Japan | ||
85 | Tenri | Nara | Japan | ||
86 | Yamatotakada | Nara | Japan | ||
87 | Yufu | Oita | Japan | ||
88 | Kurashiki | Okayama | Japan | ||
89 | Naha | Okinawa | Japan | ||
90 | Tomigusuku | Okinawa | Japan | ||
91 | Urasoe | Okinawa | Japan | ||
92 | Hirakata | Osaka | Japan | ||
93 | Kawachinagano | Osaka | Japan | ||
94 | Moriguchi | Osaka | Japan | ||
95 | Neyagawa | Osaka | Japan | ||
96 | Osakasayama | Osaka | Japan | ||
97 | Suita | Osaka | Japan | ||
98 | Kawagoe | Saitama | Japan | ||
99 | Kitaadachi | Saitama | Japan | ||
100 | Koshigaya | Saitama | Japan | ||
101 | Moriyama | Shiga | Japan | ||
102 | Otsu | Shiga | Japan | ||
103 | Izumi | Shimane | Japan | ||
104 | Izumo | Shimane | Japan | ||
105 | Hamamatsu | Shizuoka | Japan | ||
106 | Izunokuni | Shizuoka | Japan | ||
107 | Sunto | Shizuoka | Japan | ||
108 | Shimotsuga | Tochigi | Japan | ||
109 | Shimotsuke | Tochigi | Japan | ||
110 | Utsunomiya | Tochigi | Japan | ||
111 | Komatsushima | Tokushima | Japan | ||
112 | Bunkyo-ku | Tokyo | Japan | ||
113 | Chiyoda-ku | Tokyo | Japan | ||
114 | Chuo-ku | Tokyo | Japan | ||
115 | Itabashi-ku | Tokyo | Japan | ||
116 | Koto-ku | Tokyo | Japan | ||
117 | Machida | Tokyo | Japan | ||
118 | Meguro-ku | Tokyo | Japan | ||
119 | Minato-ku | Tokyo | Japan | ||
120 | Musashino | Tokyo | Japan | ||
121 | Ota-ku | Tokyo | Japan | ||
122 | Shinagawa-ku | Tokyo | Japan | ||
123 | Shinjuku-ku | Tokyo | Japan | ||
124 | Yonago | Tottori | Japan | ||
125 | Kurobe | Toyama | Japan | ||
126 | Takaoka | Toyama | Japan | ||
127 | Sakata | Yamagata | Japan | ||
128 | Tsuruoka | Yamagata | Japan | ||
129 | Iwakuni | Yamaguchi | Japan | ||
130 | Ube | Yamaguchi | Japan | ||
131 | Kofu | Yamanashi | Japan | ||
132 | Akita | Japan | |||
133 | Aomori | Japan | |||
134 | Chiba | Japan | |||
135 | Fukui | Japan | |||
136 | Fukuoka | Japan | |||
137 | Gifu | Japan | |||
138 | Ibaraki | Japan | |||
139 | Kagoshima | Japan | |||
140 | Kochi | Japan | |||
141 | Kumamoto | Japan | |||
142 | Kyoto | Japan | |||
143 | Miyazaki | Japan | |||
144 | Nagano | Japan | |||
145 | Nagasaki | Japan | |||
146 | Niigata | Japan | |||
147 | Okayama | Japan | |||
148 | Okinawa | Japan | |||
149 | Osaka | Japan | |||
150 | Saga | Japan | |||
151 | Saitama | Japan | |||
152 | Shizuoka | Japan | |||
153 | Tokushima | Japan | |||
154 | Toyama | Japan | |||
155 | Yamagata | Japan |
Sponsors and Collaborators
- Takeda
Investigators
- Study Director: Study Director, Takeda
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- Panitumumab-3001
- U1111-1164-9167
- JapicCTI-142731
- jRCTs031180246
- UMIN000016776