Regorafenib and Nivolumab Simultaneous Combination Therapy

Study Overview
=================
Brief Summary
-----------------
the efficacy and safety ofhe use of regorafenib in combination with nivolumab

Detailed Description
-----------------
The present trial consists of a dose-escalation cohort to verify the tolerability of nivolumab and regorafenib when used in combination for patients with solid tumors, and to examine the clinical recommended dose(RD). The trial also consists of an expansion cohort to examine the safety and efficacy when the clinical RD is administered for several advanced solid tumors. In the dose-escalation cohort, three patients with solid tumors will be administered 3.0 mg/kg of nivolumab once every 2 weeks and regorafenib daily for 21days, with a 1-week washout period at dose of 80 mg (level 1), 120 mg (level 2), or 160 mg (level 3). As a general rule, one cycle will last 28 days (day 1-29); however, in the event of treatment prolongation, the cycle period will be extended. The Dose Limiting Toxicity(DLT) evaluation period will be 28 days. Furthermore, for each level, three additional subjects will be added depending on the state of DLT. In the expansion cohort, the target subject sample will consist of approximately 30 patients who will be administered 3.0 mg/kg of nivolumab once every 2 weeks, and the clinical RD of regorafenib will be determined in the dose-escalation cohort.

Official Title
-----------------
Regorafenib and Nivolumab Simultaneous Combination Therapy for Advanced and Metastatic Solid Tumors: Phase I Clinical Trial

Conditions
-----------------
Advanced and Metastatic Solid Tumor

Intervention / Treatment
-----------------
* Drug: Regorafenib
* Drug: Nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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 Urinary protein: It satisfies one of the following (if any of the inspection criteria are satisfied, other examination may not be carried out) (i) urinary protein (test paper method) is 2+ or less (ii) Urine Protein Creatinine(UPC) ratio <3.5 (iii) 24-hour urine protein was measured, urinary protein ≦ 3500 mg Prothrombin time (PT)- International normalized ratio(INR): ≤ 1.5 (≦ 3.0 in case of anticoagulant administration) For women who are likely to become pregnant (including those without menstruation due to medical reasons such as chemical menopause) Note 1, we agreed to double contraceptive Note 2 for at least 5 months from consent acquisition patient to the final administration of the investigational product. Also, patients who agreed not to breast feeding for at least 5 months from acquiring consent to the final investigational drug administration. For men, patients agreeing to double contraceptive for at least 7 months from the time of starting investigational drug administration to the final investigational drug administration. Note 1): A woman who is likely to become pregnant is a woman who has experienced menarche and is not undergoing sterilization surgery (such as hysterectomy, bilateral salpingo ligation or bilateral oophorectomy), a woman without menopause Everything is included. The definition after menopause shall be amenorrhea continuously for 12 months or more even though there is no noteworthy reason. Women who are using oral contraceptives or mechanical contraceptive methods (such as intrauterine contraceptive devices or barrier methods) are considered to be pregnant. Note 2): With regard to contraception, it is necessary to use two of the vasectomy or condom of a male patient or male male, the uterine tube ligation of a female patient or the other woman, a contraceptive pessary, an intrauterine contraceptive device or an oral contraceptive I need to agree to heavy contraception. Exclusion Criteria: 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 Patients with a seizure disorder who require pharmacotherapy Patients who had grade 3 or higher bleeding during 4 weeks before enrollment Patients undergoing major surgery (thoracotomy or laparotomy, etc.), laparotomy biopsy, trauma within 28 days before registration. The same day of the week before 4 weeks can be registered (However, in case of an artificial anastomosis without intestinal resection, it shall be within 14 days before registration). Patients with non-healing wound, non-healing ulcer, or non-healing bone fracture. Patients with a history of hypersensitivity to any of the study drugs, similar drugs, or excipients. Women who are pregnant or breastfeeding, or with the potential for pregnancy.

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab + Regorafenib<br>Nivolumab and Regorafenib | Drug: Regorafenib<br>* One course will last 28 days. Oral administration at a dose of 80 mg/day, 120mg/day or 160 mg/day for 21 consecutive days, with a 1-week washout period.<br>* Other names: Regorafenib (BMS-936558, MDX1106, ONO-4538);Drug: Nivolumab<br>* One course will last 28 days. Given once every 2 weeks at a dose of 3.0 mg/kg.<br>* Other names: Nivolumab (BAY73-4506);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RD | Recommended Dose of Regorafenib | 4 weeks | 
| Maximum Tolerated Dose(MTD) | Maximum tolerated dose | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST) version. 1.1, and immune-related (ir) RECIST | 1year | 
| Progression-Free Survival(PFS) | Progression-free survival | 1year 6 months | 
| Overall Survival(OS) | Overall survival | 1year 6 months | 
| Disease Control Rate(DCR) | Disease control rate | 1year | 
| Incidence of Treatment-Emergent Adverse-Events [Safety and Tolerability] | Incidence of adverse events | 1year 6 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Regorafenib, Nivolumab, Phase I clinical trial