Regorafenib and Nivolumab Simultaneous Combination Therapy

NCT03406871 | Completed Phase 1 Results DMC

• 1 other identifier: EPOC 1603 study
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

the efficacy and safety ofhe use of regorafenib in combination with nivolumab

Conditions

Advanced and Metastatic Solid Tumor

Keywords

Regorafenib; Nivolumab; Phase I clinical trial

Outcome Measures

Primary Outcomes (1)

• The Number of Dose Limiting Toxicity (DLT) for RD Determination

  The procedure for DLT assessment was as follows: 1. When DLT is observed in 1 out of 3 cases, 3 additional cases are added to the administration level. 2. When DLT is observed in more than 2 of 3 cases, it is judged that the administration level exceeds Maximum Tolerated Dose (MTD). 3. If the number of DLT is 1 case or less in 6 cases, shift to the next level. 4. If MTD is exceeded, shift to the next lower level. At the relevant dose, if only 3 people are evaluating DLT, add 3 cases. When the number of DLT is 1 or less out of 6, the dose is defined as MTD and RD. If it is judged that Level 1 exceeds the MTD, review the dose or consider stopping the trial. 5. MTD should be the highest dose level of DLT expression less than 1 in 6 cases. - After the RD was determined and the patient moved to the expansion cohort, G3 skin toxicity occurred, so based on the recommendation of the Data and Safety Monitoring Committee, the RD was reduced by one level and the trial was resumed.

  4 weeks

Secondary Outcomes (5)

• Objective Response Rate (ORR)

  2year

• Progression-Free Survival(PFS)

  6 months

• Overall Survival(OS)

  2year

• Disease Control Rate(DCR)

  2year

• Adverse-Events

  2 year

Study Arms (4)

Level 1

ACTIVE COMPARATOR

Regorafenib: Oral administration at a dose of 80 mg given once per day for 21 consecutive days, with a 1-week washout period. Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg via an intravenous infusion. When it is deemed that there is no problem with safety at the doses described above, tolerability will be verified at the level-2 dosages described below.

Drug: Regorafenib; Drug: Nivolumab

Level 2

ACTIVE COMPARATOR

Regorafenib: Oral administration at a dose of 120 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. When it is deemed that there is no problem with safety at the doses described above, tolerability will be verified at the level-3 dosages described below.

Drug: Regorafenib; Drug: Nivolumab

Level 3

ACTIVE COMPARATOR

Regorafenib: Oral administration at a dose of 160 mg/day for 21 consecutive days, with a 1-week washout period. Nivolumab: Given once every 2 weeks at a dose of 3.0 mg/kg. After starting the trial, three cases are registered at level 1, and temporary case registration is suspended until safety evaluation of the first course is completed in all cases. If there are cases in which evaluation of DLT can not be performed properly, such as being canceled due to reasons other than safety during the course of the first course, the necessary number of cases is appropriately added to the administration level.

Drug: Regorafenib; Drug: Nivolumab

Expansion cohort

ACTIVE COMPARATOR

After completion of the final DLT evaluation period of the subjects in the dose escalating cohort, the decision to move the subjects into the expansion cohort will be determined once it is decided, upon deliberation between the sponsor and the principal investigator, that there are no problems associated with moving on. Furthermore, the opinion of the Data and Safety Monitoring Committee (DSMC) can be sought as required . Regarding the review of RD in the expansion cohort, please refer to "Analysis Population Description" in Primary Outcome Measures.

Drug: Regorafenib; Drug: Nivolumab

Interventions

Regorafenib DRUG

One course will last 28 days. Oral administration for 21 consecutive days, with a 1-week washout period. As for the expansion cohort, implemented using the RD estimated in the dose-escalation cohort.

Also known as: Identification code of the investigational drug; BAY73-4506

Expansion cohort; Level 1; Level 2; Level 3

Nivolumab DRUG

One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg.

Also known as: Identification code of the investigational drug; BMS-936558, MDX1106, ONO-4538

Expansion cohort; Level 1; Level 2; Level 3

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who provided written informed consent to be subjects in this trial
• Patients at least 20 years of age on the day of providing consent
• Dose-escalation cohort: Patients with histologically or cytologically confirmed advanced or metastatic solid tumors.
• Expansion cohort: Patients with histologically or cytologically confirmed advanced or metastatic solid tumors (gastric, colorectal, or hepatocellular cancer).
• Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Patients capable of taking oral medication
• Patients with evaluable or measurable lesions as per RECIST version 1.1
• Patients with adequate organ function at the time of enrollment as defined below:
• Neutrophil count ≥1500mm3
• Platelet count ≥10.0 × 104/mm3
• Hemoglobin (Hb) ≥ 9 g/dL,
• aspartate transaminase (AST), alanine transaminase (ALT) ≤100 U/L (≤100 U/L in patients with Hepatocellular carcinoma, ≤250 U/L in patients with liver metastasis)
• Total bilirubin ≤1.5-mg /dL
• Creatinine ≤1.5--mg /dL
• Lipase ≤ 80 IU/L

You may not qualify if:

• Patients who have undergone systemic chemotherapy, radiotherapy, surgery, hormone therapy, or immunotherapy \<2 weeks before enrollment. Immune checkpoint blockade as pretreatment is permitted.
• Patients with a history of taking regorafenib.
• Patients with hypertension that is difficult to control (systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg) despite treatment with several hypotensive agents
• Patients with acute coronary syndrome (including myocardial infarction and unstable angina), and with a history of coronary angioplasty or stent placement performed within 6 months before enrollment
• Patients with a large amount of pleural effusion or ascites requiring drainage.
• Patients with a ≥grade 3 active infection according to NCI-CTCAE version 4.03
• Patients with symptomatic brain metastasis
• Patients with partial or complete gastrointestinal obstruction
• Patients with interstitial lung disease with symptoms or signs of activity
• Patients who test positive for either anti-HIV-1 antibodies, anti-HIV-2 antibodies, hepatitis B surface antigen (HBsAg), or anti-hepatitis C virus (HCV) antibodies\*
• \*Patients who test positive for either anti-Hepatitis B surface(HBs) or anti- Hepatitis B core(HBc) antibodies, and those who have hepatitis B virus (HBV)-DNA measurements greater than the detection sensitivity will also be excluded.
• (However, patients with hepatocellular carcinoma in the expansion cohort will not be excluded even if they test positive for HBsAg and anti-HCV antibodies.)
• Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
• Patients who require systemic corticosteroids (excluding temporary usage for tests, prophylactic administration for allergic reactions, or to alleviate swelling associated with radiotherapy) or immunosuppressants, or who have received such a therapy \<14 days before enrollment in the present study
• Patients with a history or findings of ≥grade III congestive heart failure according to the New York Heart Association functional classification

Sponsors & Collaborators

• Kohei Shitara: lead
• Ono Pharmaceutical Co. Ltd: collaborator
• Bayer Yakuhin, Ltd.: collaborator

Study Sites (1)

NationalCCHE

Kashiwa, Chiba, 277-8577, Japan

Location

Related Publications (1)

• Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, Yoshii T, Kotani D, Tamura H, Mikamoto Y, Hirano N, Wakabayashi M, Nomura S, Sato A, Kuwata T, Togashi Y, Nishikawa H, Shitara K. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603). J Clin Oncol. 2020 Jun 20;38(18):2053-2061. doi: 10.1200/JCO.19.03296. Epub 2020 Apr 28.

  PMID: 32343640 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

regorafenib; Nivolumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr.Kohei Shitara
• Organization: NationalCCHE,JAPAN

regonivo_core@east.ncc.go.jp

+81-4-7133-1111

Study Officials

• Kohei Shitara, Dr

  National Cancer Center Hospital East

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: Dose-escalation cohort: A total of 3-6 patients per level, for a total of 9-18 patients(Anticipated), 14(Actual) Expansion cohort: Approximately 30 patients in total, 36(Actual)
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Chief of Gastrointestinal Oncology Division

Study Record Dates

• First Submitted: January 12, 2018
• First Posted: January 23, 2018
• Study Start: January 15, 2018
• Primary Completion: December 15, 2020
• Study Completion: December 15, 2020
• Last Updated: January 24, 2025
• Results First Posted: January 24, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

JP (1)