Clinical trial NCT02337946: Safety and Efficacy Study of mFOLFOX6 + Panitumumab Combination Therapy and 5-FU/LV + Panitumumab Combination Therapy in Participants With Chemotherapy-naïve Unresectable Advanced Recurrent Colorectal Carcinoma
Official title: A Phase 2 Randomized Study Comparing the Efficacy and Safety of mFOLFOX6+Panitumumab Combination Therapy and 5-FU/LV+Panitumumab Combination Therapy in the Patients With Chemotherapy-Naive Unresectable Advanced Recurrent Colorectal Carcinoma of KRAS Wild-Type After 6 Cycles of Combination Therapy With mFOLFOX6+Panitumumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Carcinoma
Keywords: Metastatic colorectal cancer, Panitumumab, mFOLFOX6, First-line
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-01-14
Enrollment: 164
Sex: ALL
Minimum age (years): 20
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 exploratorily examine efficacy and safety in the participants with chemotherapy-naïve unresectable, advanced/recurrent colorectal carcinoma of Kirsten rat sarcoma-2 virus (KRAS) wild-type who have been treated with 6 cycles (2 weeks/cycle) of first-line mFOLFOX6 + panitumumab combination therapy and then assigned to two groups i.e., a group receiving 5-FU/LV + panitumumab combination therapy and a group receiving mFOLFOX6 + panitumumab combination therapy.

Detailed description: The drug being tested in this study is called panitumumab. Panitumumab is being tested to treat people who have advanced/recurrent colorectal carcinoma of KRAS wild-type. This study will look at the efficacy and safety of 5-FU/LV + panitumumab(Pmab) combination therapy or mFOLFOX6 + Pmab combination therapy in the participants.

The study will enroll 164 patients. All participants will receive 6 cycles of Protocol Treatment \[1\]: Pmab 6 mg/kg, DIV, at Day 1, OXA 85 mg/m\^2, DIV, at Day 1, l LV 200 mg/m\^2, DIV, at Day 1, 5-FU 400 mg/m\^2, IV, at Day 1, 5-FU 2400 mg/m\^2, CIV, at Day 2 once every two weeks from cycle 1 through cycle 6.

Then they will be randomly assigned (by chance, like flipping a coin) to one of the treatment groups.

* Group A
* Group B

This multi-center trial will be conducted in Japan. The overall time to participate in this study is approximately 20 months.

Eligibility criteria: Inclusion Criteria for enrollment:

1. Participants with unresectable adenocarcinoma originating in the large intestine (excluding carcinoma of the appendix and anal canal cancer)
2. Participants with measurable lesion(s) according to the RECIST ver. 1.1
3. Participants who have not received chemotherapy for colorectal cancer. Participants who experience relapse more than 6 months after the final dose of perioperative adjuvant chemotherapy with fluoropyrimidine agents may be enrolled.
4. Aged ≥ 20 years at the time of enrollment
5. Participants classified as KRAS wild-type. However, the criteria will be changed to all patients who are verified to be of KRAS and NRAS wild-type when the KRAS and NRAS tests come to be covered by National Health Insurance, and the tests become feasible at medical institutions.
6. Participants who satisfy the following criteria for the major organ function in tests performed within 14 days prior to enrollment

   1. Neutrophil count ≥ 1.5 × 10\^3/μL
   2. White blood cell count ≥ 3.0 × 10\^3/μL
   3. Platelet count ≥ 10.0 × 10\^4/μL
   4. Hemoglobin ≥ 9.0 g/dL
   5. Total bilirubin ≤ 2.0 mg/dL
   6. AST ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
   7. ALT ≤ 100 U/L (≤ 200 U/L if liver metastases are present)
   8. Serum creatinine ≤ 1.5 mg/dL
7. Participants who are assessed at Eastern Cooperative Oncology Group (ECOG) performance status (P.S.) of 0 or 1
8. Life expectancy of ≥ 6 months after enrollment
9. Participants who have given written consent to take part in the study after detailed explanation of the study prior to enrollment

Inclusion criteria for randomization:

1. Participants who have received 6 cycles of mFOLFOX6 + panitumumab combination therapy
2. Participants who are assessed at ECOG P.S. of 0-1 in the 6th cycle.
3. Participants for whom PD or not evaluable has been denied on the RECIST 1.1 based on imaging tests conducted after the day of administration in the 6th cycle within 14 days (2 weeks).

Exclusion Criteria for enrollment:

1. Radiotherapy received for a measurable lesion
2. Radiotherapy received within 28 days (4 weeks) prior to enrollment for a lesion other than measurable lesions. However, treatment to relieve pain associated with metastatic bone tumors was allowed.
3. Known brain metastasis or strongly suspected of brain metastasis
4. 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.).
5. Body cavity fluid that requires treatment (pleural effusion, ascites, pericardial effusion, etc.)
6. Participants who do not want to use contraception to prevent pregnancy, and women who are pregnant or breast-feeding, or test positive for pregnancy
7. Active hemorrhage requiring blood transfusion
8. Disease requiring systemic steroids for treatment (excluding topical steroids)
9. Intestinal resection and colostomy within 2 weeks prior to enrollment
10. History or obvious and extensive CT findings of interstitial pulmonary disease (interstitial pneumonia, pulmonary fibrosis, etc.)
11. Serious drug hypersensitivity
12. Local or systemic active infection requiring treatment, or fever indicating infection
13. Intestinal paralysis, gastrointestinal obstruction, or uncontrollable diarrhea (incapacitating symptoms despite adequate treatment)
14. Active hepatitis B and/or active hepatitis C
15. Known human immunodeficiency virus infection
16. Other patients judged by the investigator or subinvestigator to be ineligible for enrollment in the study

Exclusion criteria for randomization:

1. Participants in whom interstitial pneumonia has been newly diagnosed during the period from registration to randomization
2. Participants who have received radiotherapy during the period from registration to randomization
3. Other Participants judged by the investigator or sub-investigator to be ineligible for enrollment in the study

Primary outcomes:
measure: Progression-Free Survival Rate (PFS Rate) at 9 Months After Randomization
timeFrame: Up to 9 months after randomization
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 31 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 31 months
measure: Response Rate (RR)
timeFrame: Up to approximately 31 months
measure: Time to Treatment Failure (TTF)
timeFrame: Up to approximately 31 months
measure: Percentage of Participants With Adverse Events
timeFrame: Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
measure: Percentage of Participants With Adverse Events by Severity Graded Using the Common Terminology Criteria for Adverse Events (CTCAE) Grade
timeFrame: Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
measure: Percentage of Participants With Grade 2 or Higher Peripheral Neuropathy
timeFrame: Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
measure: Percentage of Participants With Grade 3 or Higher Skin Toxicity
timeFrame: Up to 28 days after discontinuation of study drug or start of subsequent therapy (data cut off: 31 August 2017; Overall study completion date)
Other outcomes:
Locations:
city: Nagakute
country: Japan
state: Aichi
city: Nagoya
country: Japan
state: Aichi
city: Okazaki
country: Japan
state: Aichi
city: Toyoaki
country: Japan
state: Aichi
city: Yachiyo
country: Japan
state: Chiba
city: Kitakyushu
country: Japan
state: Fukuoka
city: Tagawa
country: Japan
state: Fukuoka
city: Aizuwakamatsu
country: Japan
state: Fukushima
city: Kakamigahara
country: Japan
state: Gifu
city: Tajimi
country: Japan
state: Gifu
city: Hakodate
country: Japan
state: Hokkaido
city: Kushiro
country: Japan
state: Hokkaido
city: Amagasaki
country: Japan
state: Hyogo
city: Kakogawa
country: Japan
state: Hyogo
city: Kobe
country: Japan
state: Hyogo
city: Nishinomiya
country: Japan
state: Hyogo
city: Kahoku
country: Japan
state: Ishikawa
city: Kanazawa
country: Japan
state: Ishikawa
city: Morioka
country: Japan
state: Iwate
city: Kida-gun
country: Japan
state: Kagawa
city: Marugame
country: Japan
state: Kagawa
city: Takamatsu
country: Japan
state: Kagawa
city: Kawasaki
country: Japan
state: Kanagawa
city: Yokohama
country: Japan
state: Kanagawa
city: Nangoku
country: Japan
state: Kochi
city: Sendai
country: Japan
state: Miyagi
city: Matsumoto
country: Japan
state: Nagano
city: Suwa
country: Japan
state: Nagano
city: Sasebo
country: Japan
state: Nagasaki
city: Higashiosaka
country: Japan
state: Osaka
city: Hirakata
country: Japan
state: Osaka
city: Izumisano
country: Japan
state: Osaka
city: Izumi
country: Japan
state: Osaka
city: Sakai
country: Japan
state: Osaka
city: Tondabayashi
country: Japan
state: Osaka
city: Hidaka
country: Japan
state: Saitama
city: Izumo
country: Japan
state: Shimane
city: Fujioka
country: Japan
state: Shizuoka
city: Shimonoseki
country: Japan
state: Yamaguchi
city: Akita
country: Japan
city: Fukui
country: Japan
city: Fukuoka
country: Japan
city: Gifu
country: Japan
city: Hiroshima
country: Japan
city: Kyoto
country: Japan
city: Nagasaki
country: Japan
city: Okinawa
country: Japan
city: Osaka
country: Japan
city: Saga
country: Japan
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: Munemoto Y, Nakamura M, Takahashi M, Kotaka M, Kuroda H, Kato T, Minagawa N, Noura S, Fukunaga M, Kuramochi H, Touyama T, Takahashi T, Miwa K, Satake H, Kurosawa S, Miura T, Mishima H, Sakamoto J, Oba K, Nagata N. SAPPHIRE: a randomised phase II study of planned discontinuation or continuous treatment of oxaliplatin after six cycles of modified FOLFOX6 plus panitumumab in patients with colorectal cancer. Eur J Cancer. 2019 Sep;119:158-167. doi: 10.1016/j.ejca.2019.07.006. Epub 2019 Aug 21.
citation: Nagata N, Mishima H, Kurosawa S, Oba K, Sakamoto J. mFOLFOX6 Plus Panitumumab Versus 5-FU/LV Plus Panitumumab After Six Cycles of Frontline mFOLFOX6 Plus Panitumumab: A Randomized Phase II Study of Patients With Unresectable or Advanced/Recurrent, RAS Wild-type Colorectal Carcinoma (SAPPHIRE)-Study Design and Rationale. Clin Colorectal Cancer. 2017 Jun;16(2):154-157.e1. doi: 10.1016/j.clcc.2017.02.001. Epub 2017 Mar 1.