PARADIGM: Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC

Sponsor
Takeda (Industry)
Overall Status
Completed
CT.gov ID
NCT02394795
Collaborator
(none)
823
155
2
79.6
5.3
0.1

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

Study Type:
Interventional
Actual Enrollment :
823 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase III, Randomized, Controlled Study of mFOLFOX6 + Bevacizumab Combination Therapy Versus mFOLFOX6 + Panitumumab Combination Therapy in Chemotherapy-naive Patients With KRAS/NRAS Wild-type, Incurable/Unresectable, Advanced/Recurrent Colorectal Cancer
Actual Study Start Date :
May 29, 2015
Actual Primary Completion Date :
Jan 14, 2022
Actual Study Completion Date :
Jan 14, 2022

Arms and Interventions

Arm Intervention/Treatment
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

  1. 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.

  2. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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

Ages Eligible for Study:
20 Years to 79 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  1. 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.

  1. Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment

  2. Aged ≥20 to <80 years at the time of informed consent

  3. Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)

  4. Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1.

  5. 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.

  6. 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)

  1. Patients who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment
  • Neutrophil count ≥ 1.5×10^3/µL

  • Platelet count ≥ 1.0×10^4/µL

  • Hemoglobin ≥ 9.0 g/dL

  • Total bilirubin ≤ 2.0 mg/dL

  • AST ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)

  • ALT ≤ 100 IU/L (≤ 200 IU/L if liver metastases are present)

  • Serum creatinine ≤ 1.5 mg/dL

  • PT-INR < 1.5 (< 3.0 for patients treated with oral warfarin)

  • Satisfies at least one of these conditions

  1. Urine protein (dip stick method) ≤ 1+

  2. UPC (urine protein creatinine) ratio ≤ 1.0

  3. Urinary protein ≤ 1000 mg/ 24hours

  4. ECOG performance status (PS) of 0 or 1

  5. Life expectancy of ≥ 3 months (90 days) after enrollment

Exclusion Criteria:
  1. Radiotherapy received within 4 weeks (28 days) prior to enrollment. Treatments aimed at relieving pain for bone metastases are excluded.

  2. Known brain metastasis or strongly suspected of brain metastasis

  3. 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.).

  4. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)

  5. Patients 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. The patient who has placed colonic stent

  10. Intestinal resection within 4 weeks prior to enrollment or colostomy within 2 weeks prior to enrollmentt

  11. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)

  12. 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)

  13. Serious drug hypersensitivity

  14. Local or systemic active infection requiring treatment, or fever indicating infection

  15. NYHA class II or higher heart failure or serious heart disease

  16. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhoea (incapacitating symptoms despite adequate treatment)

  17. Poorly controlled hypertension

  18. Poorly controlled diabetes mellitus

  19. Active hepatitis B

  20. Known HIV infection

  21. Peripheral neuropathy of ≥ Grade 2 by CTCAE (Japanese edition JCOG version 4.03)

  22. 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
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.
Responsible Party:
Takeda
ClinicalTrials.gov Identifier:
NCT02394795
Other Study ID Numbers:
  • Panitumumab-3001
  • U1111-1164-9167
  • JapicCTI-142731
  • jRCTs031180246
  • UMIN000016776
First Posted:
Mar 20, 2015
Last Update Posted:
Feb 18, 2022
Last Verified:
Feb 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Takeda
Additional relevant MeSH terms:

Study Results

No Results Posted as of Feb 18, 2022