Clinical trial NCT02394795: Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Colorectal Cancer
Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, Bevacizumab
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-03-20
Enrollment: 823
Sex: ALL
Minimum age (years): 20
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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.
2. Patients who have given written consent to take part in the study after detailed explanation of the study prior to enrollment
3. Aged ≥20 to \<80 years at the time of informed consent
4. Patients with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
5. Patients with lesion(s) that can be evaluated. It is not essential to be evaluated the tumor according to the RECIST ver. 1.1.
6. 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.
7. 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)
8. 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
9. ECOG performance status (PS) of 0 or 1
10. 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).

Primary outcomes:
measure: OS in Participants With Left-sided Tumors
timeFrame: Up to approximately 60 months
measure: Overall Survival (OS) in All Participants
timeFrame: Up to approximately 60 months
Secondary outcomes:
measure: Progression-Free Survival (PFS) in Participants With Left-sided Tumors
timeFrame: Up to approximately 60 months
measure: Progression-Free Survival (PFS) in All Participants
timeFrame: Up to approximately 60 months
measure: Response Rate (RR) in All Participants
timeFrame: Up to approximately 60 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 60 months
measure: Number of Participants Treated With Curative Surgical Resection After Chemotherapy
timeFrame: Up to approximately 60 months
measure: Number of Participants With Treatment-emergent Adverse Events (TEAE)
timeFrame: Up to approximately 60 months
Other outcomes:
Locations:
city: Ichinomiya
country: Japan
state: Aichi
city: Komaki
country: Japan
state: Aichi
city: Konan
country: Japan
state: Aichi
city: Nagakute
country: Japan
state: Aichi
city: Nagoya
country: Japan
state: Aichi
city: Okazaki
country: Japan
state: Aichi
city: Toyoake
country: Japan
state: Aichi
city: Toyohashi
country: Japan
state: Aichi
city: Toyokawa
country: Japan
state: Aichi
city: Toyota
country: Japan
state: Aichi
city: Yatomi
country: Japan
state: Aichi
city: Daisen
country: Japan
state: Akita
city: Hirosaki
country: Japan
state: Aomori
city: Misawa
country: Japan
state: Aomori
city: Kashiwa
country: Japan
state: Chiba
city: Yachiyo
country: Japan
state: Chiba
city: Matsuyama
country: Japan
state: Ehime
city: Toon
country: Japan
state: Ehime
city: Tsuruga
country: Japan
state: Fukui
city: Yoshida
country: Japan
state: Fukui
city: Kitakyushu
country: Japan
state: Fukuoka
city: Koga
country: Japan
state: Fukuoka
city: Kurume
country: Japan
state: Fukuoka
city: Omuta
country: Japan
state: Fukuoka
city: Onga
country: Japan
state: Fukuoka
city: Aizuwakamatsu
country: Japan
state: Fukushima
city: Iwaki
country: Japan
state: Fukushima
city: Koriyama
country: Japan
state: Fukushima
city: Shirakawa
country: Japan
state: Fukushima
city: Hashima
country: Japan
state: Gifu
city: Kakamigahara
country: Japan
state: Gifu
city: Minokamo
country: Japan
state: Gifu
city: Ogaki
country: Japan
state: Gifu
city: Okazai
country: Japan
state: Gifu
city: Maebashi
country: Japan
state: Gunma
city: Ota
country: Japan
state: Gunma
city: Fukuyama
country: Japan
state: Hiroshima
city: Hakodate
country: Japan
state: Hokkaido
city: Kitami
country: Japan
state: Hokkaido
city: Kushiro
country: Japan
state: Hokkaido
city: Obihiro
country: Japan
state: Hokkaido
city: Otaru
country: Japan
state: Hokkaido
city: Sapporo
country: Japan
state: Hokkaido
city: Akashi
country: Japan
state: Hyogo
city: Amagasaki
country: Japan
state: Hyogo
city: Himeji
country: Japan
state: Hyogo
city: Kobe
country: Japan
state: Hyogo
city: Nishinomiya
country: Japan
state: Hyogo
city: Hitachi
country: Japan
state: Ibaraki
city: Kasama
country: Japan
state: Ibaraki
city: Ryugasaki
country: Japan
state: Ibaraki
city: Tsuchiura
country: Japan
state: Ibaraki
city: Tsukuba
country: Japan
state: Ibaraki
city: Hakusan
country: Japan
state: Ishikawa
city: Kaga
country: Japan
state: Ishikawa
city: Kahoku
country: Japan
state: Ishikawa
city: Kanazawa
country: Japan
state: Ishikawa
city: Nanao
country: Japan
state: Ishikawa
city: Morioka
country: Japan
state: Iwate
city: Kida
country: Japan
state: Kagawa
city: Marugame
country: Japan
state: Kagawa
city: Takamatsu
country: Japan
state: Kagawa
city: Fujisawa
country: Japan
state: Kanagawa
city: Hiratsuka
country: Japan
state: Kanagawa
city: Isehara
country: Japan
state: Kanagawa
city: Kamakura
country: Japan
state: Kanagawa
city: Kanazawa
country: Japan
state: Kanagawa
city: Sagamihara
country: Japan
state: Kanagawa
city: Yokohama
country: Japan
state: Kanagawa
city: Yokosuka
country: Japan
state: Kanagawa
city: Nankoku
country: Japan
state: Kochi
city: Matsuzaka
country: Japan
state: Mie
city: Tsu
country: Japan
state: Mie
city: Yokkaichi
country: Japan
state: Mie
city: Ishinomaki
country: Japan
state: Miyagi
city: Natori
country: Japan
state: Miyagi
city: Osaki
country: Japan
state: Miyagi
city: Sendai
country: Japan
state: Miyagi
city: Shibata
country: Japan
state: Miyagi
city: Matsumoto
country: Japan
state: Nagano
city: Saku
country: Japan
state: Nagano
city: Omura
country: Japan
state: Nagasaki
city: Sasebo
country: Japan
state: Nagasaki
city: Ikoma
country: Japan
state: Nara
city: Tenri
country: Japan
state: Nara
city: Yamatotakada
country: Japan
state: Nara
city: Yufu
country: Japan
state: Oita
city: Kurashiki
country: Japan
state: Okayama
city: Naha
country: Japan
state: Okinawa
city: Tomigusuku
country: Japan
state: Okinawa
city: Urasoe
country: Japan
state: Okinawa
city: Hirakata
country: Japan
state: Osaka
city: Kawachinagano
country: Japan
state: Osaka
city: Moriguchi
country: Japan
state: Osaka
city: Neyagawa
country: Japan
state: Osaka
city: Osakasayama
country: Japan
state: Osaka
city: Suita
country: Japan
state: Osaka
city: Kawagoe
country: Japan
state: Saitama
city: Kitaadachi
country: Japan
state: Saitama
city: Koshigaya
country: Japan
state: Saitama
city: Moriyama
country: Japan
state: Shiga
city: Otsu
country: Japan
state: Shiga
city: Izumi
country: Japan
state: Shimane
city: Izumo
country: Japan
state: Shimane
city: Hamamatsu
country: Japan
state: Shizuoka
city: Izunokuni
country: Japan
state: Shizuoka
city: Sunto
country: Japan
state: Shizuoka
city: Shimotsuga
country: Japan
state: Tochigi
city: Shimotsuke
country: Japan
state: Tochigi
city: Utsunomiya
country: Japan
state: Tochigi
city: Komatsushima
country: Japan
state: Tokushima
city: Bunkyo-ku
country: Japan
state: Tokyo
city: Chiyoda-ku
country: Japan
state: Tokyo
city: Chuo-ku
country: Japan
state: Tokyo
city: Itabashi-ku
country: Japan
state: Tokyo
city: Koto-ku
country: Japan
state: Tokyo
city: Machida
country: Japan
state: Tokyo
city: Meguro-ku
country: Japan
state: Tokyo
city: Minato-ku
country: Japan
state: Tokyo
city: Musashino
country: Japan
state: Tokyo
city: Ota-ku
country: Japan
state: Tokyo
city: Shinagawa-ku
country: Japan
state: Tokyo
city: Shinjuku-ku
country: Japan
state: Tokyo
city: Yonago
country: Japan
state: Tottori
city: Kurobe
country: Japan
state: Toyama
city: Takaoka
country: Japan
state: Toyama
city: Sakata
country: Japan
state: Yamagata
city: Tsuruoka
country: Japan
state: Yamagata
city: Iwakuni
country: Japan
state: Yamaguchi
city: Ube
country: Japan
state: Yamaguchi
city: Kofu
country: Japan
state: Yamanashi
city: Akita
country: Japan
city: Aomori
country: Japan
city: Chiba
country: Japan
city: Fukui
country: Japan
city: Fukuoka
country: Japan
city: Gifu
country: Japan
city: Ibaraki
country: Japan
city: Kagoshima
country: Japan
city: Kochi
country: Japan
city: Kumamoto
country: Japan
city: Kyoto
country: Japan
city: Miyazaki
country: Japan
city: Nagano
country: Japan
city: Nagasaki
country: Japan
city: Niigata
country: Japan
city: Okayama
country: Japan
city: Okinawa
country: Japan
city: Osaka
country: Japan
city: Saga
country: Japan
city: Saitama
country: Japan
city: Shizuoka
country: Japan
city: Tokushima
country: Japan
city: Toyama
country: Japan
city: Yamagata
country: Japan
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Yoshino T, Uetake H, Tsuchihara K, Shitara K, Yamazaki K, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Yamanaka K, Iwasaki K, Soeda J, Hihara M, Yamanaka T, Ochiai A, Muro K. Rationale for and Design of the PARADIGM Study: Randomized Phase III Study of mFOLFOX6 Plus Bevacizumab or Panitumumab in Chemotherapy-naive Patients With RAS (KRAS/NRAS) Wild-type, Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2017 Jun;16(2):158-163. doi: 10.1016/j.clcc.2017.01.001. Epub 2017 Jan 24.