Panitumumab and RAS, Diagnostically-useful Gene Mutation for mCRC

NCT ID: NCT02394795

Last Updated: 2023-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 823 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-29
• Study Completion Date: 2022-01-14

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, panitumumab

Intervention Type: DRUG

oxaliplatin (OXA), levofolinate calcium (l-LV), panitumumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

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.

Group Type: ACTIVE_COMPARATOR

oxaliplatin (OXA), levofolinate calcium (l-LV), 5-FU, bevacizumab

Intervention Type: DRUG

oxaliplatin (OXA), levofolinate calcium (l-LV), bevacizumab: intra-venous infusion 5-FU: bolus and continuous intra-venous infusion

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

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).

• Minimum Eligible Age: 20 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Takeda

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Takeda

Locations

Ichinomiya, Aichi-ken, Japan

Komaki, Aichi-ken, Japan

Kōnan, Aichi-ken, Japan

Nagakute, Aichi-ken, Japan

Nagoya, Aichi-ken, Japan

Okazaki, Aichi-ken, Japan

Toyoake, Aichi-ken, Japan

Toyohashi, Aichi-ken, Japan

Toyokawa, Aichi-ken, Japan

Toyota, Aichi-ken, Japan

Yatomi, Aichi-ken, Japan

Daisen, Akita, Japan

Hirosaki, Aomori, Japan

Misawa, Aomori, Japan

Kashiwa, Chiba, Japan

Yachiyo, Chiba, Japan

Matsuyama, Ehime, Japan

Tōon, Ehime, Japan

Tsuruga, Fukui, Japan

Yoshida, Fukui, Japan

Kitakyushu, Fukuoka, Japan

Koga, Fukuoka, Japan

Koga, Fukuoka, Japan

Kurume, Fukuoka, Japan

Omuta, Fukuoka, Japan

Aizu-Wakamatsu, Fukushima, Japan

Iwaki, Fukushima, Japan

Kōriyama, Fukushima, Japan

Shirakawa, Fukushima, Japan

Hashima, Gifu, Japan

Kakamigahara, Gifu, Japan

Minokamo, Gifu, Japan

Okazai, Gifu, Japan

Ōgaki, Gifu, Japan

Maebashi, Gunma, Japan

Ōta, Gunma, Japan

Fukuyama, Hiroshima, Japan

Hakodate, Hokkaido, Japan

Kitami, Hokkaido, Japan

Kushiro, Hokkaido, Japan

Obihiro, Hokkaido, Japan

Otaru, Hokkaido, Japan

Sapporo, Hokkaido, Japan

Akashi, Hyōgo, Japan

Amagasaki, Hyōgo, Japan

Himeji, Hyōgo, Japan

Kobe, Hyōgo, Japan

Nishinomiya, Hyōgo, Japan

Hitachi, Ibaraki, Japan

Kasama, Ibaraki, Japan

Ryūgasaki, Ibaraki, Japan

Tsuchiura, Ibaraki, Japan

Tsukuba, Ibaraki, Japan

Hakusan, Ishikawa-ken, Japan

Kaga, Ishikawa-ken, Japan

Kahoku, Ishikawa-ken, Japan

Kanazawa, Ishikawa-ken, Japan

Nanao, Ishikawa-ken, Japan

Morioka, Iwate, Japan

Kida, Kagawa-ken, Japan

Marugame, Kagawa-ken, Japan

Takamatsu, Kagawa-ken, Japan

Fujisawa, Kanagawa, Japan

Hiratsuka, Kanagawa, Japan

Isehara, Kanagawa, Japan

Kamakura, Kanagawa, Japan

Kanazawachō, Kanagawa, Japan

Sagamihara, Kanagawa, Japan

Yokohama, Kanagawa, Japan

Yokosuka, Kanagawa, Japan

Nankoku, Kochi, Japan

Matsuzaka, Mie-ken, Japan

Tsu, Mie-ken, Japan

Yokkaichi, Mie-ken, Japan

Ishinomaki, Miyagi, Japan

Murata, Miyagi, Japan

Natori-shi, Miyagi, Japan

Ōsaki, Miyagi, Japan

Sendai, Miyagi, Japan

Matsumoto, Nagano, Japan

Saku, Nagano, Japan

Ōmura, Nagasaki, Japan

Sasebo, Nagasaki, Japan

Ikoma, Nara, Japan

Tenri, Nara, Japan

Yamatotakada, Nara, Japan

Yufu, Oita Prefecture, Japan

Kurashiki, Okayama-ken, Japan

Naha, Okinawa, Japan

Tomigusuku, Okinawa, Japan

Urasoe, Okinawa, Japan

Hirakata, Osaka, Japan

Kawachi-Nagano, Osaka, Japan

Moriguchi, Osaka, Japan

Neyagawa, Osaka, Japan

Sayama, Osaka, Japan

Suita, Osaka, Japan

Kawagoe, Saitama, Japan

Kitaadachi, Saitama, Japan

Koshigaya, Saitama, Japan

Moriyama, Shiga, Japan

Ōtsu, Shiga, Japan

Izumi, Shimane, Japan

Izumo, Shimane, Japan

Hamamatsu, Shizuoka, Japan

Izunokuni, Shizuoka, Japan

Sunto, Shizuoka, Japan

Shimotsuga, Tochigi, Japan

Shimotsuke, Tochigi, Japan

Utsunomiya, Tochigi, Japan

Komatsushimachō, Tokushima, Japan

Bunkyo-ku, Tokyo, Japan

Chiyoda-ku, Tokyo, Japan

Chuo-ku, Tokyo, Japan

Itabashi-ku, Tokyo, Japan

Koto-ku, Tokyo, Japan

Machida, Tokyo, Japan

Meguro-ku, Tokyo, Japan

Minato-ku, Tokyo, Japan

Musashino, Tokyo, Japan

Ōta-ku, Tokyo, Japan

Shinagawa-ku, Tokyo, Japan

Shinjuku-ku, Tokyo, Japan

Yonago, Tottori, Japan

Kurobe-shi, Toyama, Japan

Takaoka, Toyama, Japan

Sakata, Yamagata, Japan

Tsuruoka, Yamagata, Japan

Iwakuni, Yamaguchi, Japan

Ube, Yamaguchi, Japan

Kofu, Yamanashi, Japan

Akita, , Japan

Aomori, , Japan

Chiba, , Japan

Fukui, , Japan

Fukuoka, , Japan

Gifu, , Japan

Ibaraki, , Japan

Kagoshima, , Japan

Kochi, , Japan

Kumamoto, , Japan

Kyoto, , Japan

Miyazaki, , Japan

Nagano, , Japan

Nagasaki, , Japan

Niigata, , Japan

Okayama, , Japan

Okinawa, , Japan

Osaka, , Japan

Saga, , Japan

Saitama, , Japan

Shizuoka, , Japan

Tokushima, , Japan

Toyama, , Japan

Yamagata, , Japan

Countries

Japan

References

Shitara K, Muro K, Watanabe J, Yamazaki K, Ohori H, Shiozawa M, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Mori I, Yamanaka K, Hihara M, Soeda J, Misumi T, Yamamoto K, Yamashita R, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Baseline ctDNA gene alterations as a biomarker of survival after panitumumab and chemotherapy in metastatic colorectal cancer. Nat Med. 2024 Mar;30(3):730-739. doi: 10.1038/s41591-023-02791-w. Epub 2024 Feb 12.

Reference Type: DERIVED

PMID: 38347302 (View on PubMed)

Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, Ojima H, Yuasa Y, Miwa K, Yasui H, Oki E, Sato T, Naitoh T, Komatsu Y, Kato T, Hihara M, Soeda J, Misumi T, Yamamoto K, Akagi K, Ochiai A, Uetake H, Tsuchihara K, Yoshino T. Panitumumab vs Bevacizumab Added to Standard First-line Chemotherapy and Overall Survival Among Patients With RAS Wild-type, Left-Sided Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2023 Apr 18;329(15):1271-1282. doi: 10.1001/jama.2023.4428.

Reference Type: DERIVED

PMID: 37071094 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28237539 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://clinicaltrials.takeda.com/study-detail/5f6b60294db2bf003ab499d1

To obtain more information on the study, click here/on this link

Other Identifiers

U1111-1164-9167

Identifier Type: OTHER

Identifier Source: secondary_id

JapicCTI-142731

Identifier Type: REGISTRY

Identifier Source: secondary_id

jRCTs031180246

Identifier Type: REGISTRY

Identifier Source: secondary_id

UMIN000016776

Identifier Type: REGISTRY

Identifier Source: secondary_id

Panitumumab-3001

Identifier Type: -

Identifier Source: org_study_id