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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02394795
Recruitment Status : Completed
First Posted : March 20, 2015
Last Update Posted : February 18, 2022
Sponsor:
Information provided by (Responsible Party):
Takeda

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
Colorectal Cancer 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.

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Study Type : Interventional  (Clinical Trial)
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 : January 14, 2022
Actual Study Completion Date : January 14, 2022

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Overall Survival (OS) for All Participants [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02394795


Locations
Show Show 155 study locations
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02394795    
Other Study ID Numbers: Panitumumab-3001
U1111-1164-9167 ( Other Identifier: WHO )
JapicCTI-142731 ( Registry Identifier: JapicCTI )
jRCTs031180246 ( Registry Identifier: Japan Registry of Clinical Trials )
UMIN000016776 ( Registry Identifier: UMIN Clinical Trials Registry )
First Posted: March 20, 2015    Key Record Dates
Last Update Posted: February 18, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Metastatic colorectal cancer, Panitumumab, mFOLFOX6, Bevacizumab
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Calcium, Dietary
Leucovorin
Bevacizumab
Panitumumab
Oxaliplatin
Fluorouracil
Calcium
Levoleucovorin
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Calcium-Regulating Hormones and Agents
Bone Density Conservation Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action