Regorafenib and Nivolumab Simultaneous Combination Therapy

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

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.

Eligibility Criteria:
Inclusion Criteria:

1. Patients who provided written informed consent to be subjects in this trial
2. Patients at least 20 years of age on the day of providing consent
3. 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).
4. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
5. Patients capable of taking oral medication
6. Patients with evaluable or measurable lesions as per RECIST version 1.1
7. 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)
8. 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:

1. Patients who have undergone systemic chemotherapy, radiotherapy, surgery, hormone therapy, or immunotherapy \<2 weeks before enrollment. Immune checkpoint blockade as pretreatment is permitted.
2. Patients with a history of taking regorafenib.
3. 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
4. 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
5. Patients with a large amount of pleural effusion or ascites requiring drainage.
6. Patients with a ≥grade 3 active infection according to NCI-CTCAE version 4.03
7. Patients with symptomatic brain metastasis
8. Patients with partial or complete gastrointestinal obstruction
9. Patients with interstitial lung disease with symptoms or signs of activity
10. 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.)
11. Patients with concurrent autoimmune disease, or a history of chronic or recurrent autoimmune disease
12. 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
13. Patients with a history or findings of ≥grade III congestive heart failure according to the New York Heart Association functional classification
14. Patients with a seizure disorder who require pharmacotherapy
15. Patients who had grade 3 or higher bleeding during 4 weeks before enrollment
16. 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).
17. Patients with non-healing wound, non-healing ulcer, or non-healing bone fracture.
18. Patients with a history of hypersensitivity to any of the study drugs, similar drugs, or excipients.
19. Women who are pregnant or breastfeeding, or with the potential for pregnancy.

Definition of DLT:

In principle, a DLT was any of the following Adverse Drug Reactions (ADRs) observed during Cycle 1 (28 days), which was the DLT evaluation period, and was finally determined after discussion in the coordinating committee. According to need, the opinion of the data and safety monitoring committee was to be sought.

* Hematological toxicity Grade 4 neutropenia lasting for more than 7 days. Neutrophil count of \<1000/mm3 with a fever of ≥38.0°C. Grade 4 thrombocytopenia or thrombocytopenia with bleeding requiring platelet transfusion. Grade 3 thrombocytopenia with bleeding.
* Non-hematological toxicity. Grade 3 or higher non-hematological toxicity. However, non-hematological toxicities meeting any of the following criteria are classified as DLTs only when the investigator determines it impossible to continue the study even with supportive therapy.

  * Grade 3 diarrhea, nausea, vomiting, or anorexia lasting for at least 5 days.
  * Grade 3 or higher electrolyte abnormality lasting for at least 7 days.
  * Grade 3 or higher skin toxicity lasting for at least 7 days.
  * AST or ALT increased ≥5 to 8 times the upper limit of the institutional reference range that does not improve to ≤5 times the upper limit of the institutional reference range within 7 days, with T-Bil increased ≤2 times the upper limit of the institutional reference range.
  * AST or ALT increased ≥5 to 8 times the upper limit of the institutional reference range, with T-Bil increased ≥2 times the upper limit of the institutional reference range.
  * AST or ALT increased ≥8 times the upper limit of the institutional reference range.
  * T-Bil increased ≥3 times the upper limit of the institutional reference range.
  * Grade 3 or higher immune-related AEs lasting for at least 8 days even with steroid therapy.
* Overall The case in which 70% of the planned dose of regorafenib was not administered due to toxicities during the DLT evaluation period, or the case in which the specified number of nivolumab doses was not administered.

Patients evaluated for DLT:

At least 3 patients were enrolled at each dose level, and the presence or absence of a DLT was evaluated during the DLT evaluation period.

When there were patients not patient to the assessment for proceeding to the next dose level, additional patients were to be enrolled to allow the DLT evaluation specified in Section "6.1.3 Definition of DLT." Patients enrolled who met any of the following criteria were excluded from the DLT analysis set.

1. Patients in whom regorafenib was not administered for 10 days or longer during Cycle 1 for reasons other than toxicity.
2. Patients in whom no dose of nivolumab was administered during Cycle 1 for reasons other than toxicity.
3. Patients in whom adequate data for DLT evaluation were not obtained due to missing essential testing or other reasons.

Whether to include the following patients in the DLT analysis set was determined by discussion in the coordinating committee: patients who had treatment interruption with regorafenib and nivolumab during Cycle 1 for reasons other than Adverse Events (AEs) or patients who were not allowed to initiate Cycle 2 due to toxicities other than DLT.