Purpose : To evaluate the safe dose range and confirm the effectiveness and safety of the maximum tolerated dose of Docetaxel In combination with SH003

Background: In the participation of chemotherapy of a patient, it is common that anticipated chemotherapy cannot be continued due to toxicity. Therefore, the need for the reduction of the toxicity has increased which can help complete the anticipated chemotherapy and raise the quality of life of a patient with the use of herbal medicine. According to this need, various clinical trials have been conducted in China and etc.
Also, the effectiviness of combination of SH003 and several anti-cancer drugs including taxane-based drugs which are commonly used in breast cancer patients has been proved in the experiment which has been conducted in this lab. 
The safe dose range for the combination therapy of SH003 has not yet established. Therefore, starting with a phase 1 clinical trial by setting a starting dose based on the results of toxicity studies, Phase 2 trials will be conducted in order to evaluate the effectiveness of the doses obtained from phase 1 trials.
In a 13-week repeated, oral toxicity study, No abnormal findings related to the test substances were observed. NOAEL(No Observed Adverse Effect Level) of test substances are judged to be 2,500 mg / kg among both sexes. When divided by human/animal factor, according to FDA guideline (Guidance of Human Equivalent Doses), 2,500 mg/kg NOAEL of a rat can be equaled to 400 mg/kg in humans. When setting the safety factor at 10, Max Recommended Starting Dose (MRSD) will be 40 mg/kg and it can be calculated into 2,400 mg in a 60 kg human body.

Study design
(1)Phase 1 : 
The study is designed as a single Group, Dose Elevating trial which evaluates safety to confirm the final maximum tolerated dose by the combination of oral administration of SH003 to docetaxel administered patients. 
Firstly, 3 subjects is recruited and administered for 21 days for the starting dose of 2,400 mg / day. If no DLT occurs, raise the dose to a secondary dose of 3,600 mg / day. If DLT occurs, additional 3 subjects are recruited and administered for 2,400mg / day. After, If two or more of the six subjects shows DLT, stop the capacity increase, whereas if DLT occurs in less than 1 person, increase the dose to 3,600 mg / day. Next, 3 subjects is recruited and administered for 21 days for a dose of 3,600 mg / day. If no DLT occurs, raise the dose to 4,800 mg / day. If DLT occurs, 3 subjects are additionally recruited and administered for 3,600 mg / day. After, If two or more of the six subjects shows DLT, stop the capacity increase, whereas if DLT occurs in less than 1 person, increase the dose to 4,800 mg / day. Finally, 3 subjects is recruited and administered for a dose of 4,800 mg / day. If no DLT occurs, complete the study. If DLT occurs, additional 3 subjects are recruited and administered for 4,800mg / day and complete the study after observation.

(2) Phase 2
A total of 101 subjects were recruited and docetaxel / SH003 combination therapy is performed to evaluate the efficacy and safety of the maximum tolerated dose identified in phase I clinical trial. The selected subject visits the clinical laboratory at each cycle’s D0 or D1, undergoes examination by a person in charge, and conducts blood collection. Next, subject visits the institution at D7 (+-3days) to check and collect blood for Nadir. If no specificity appears in C1 and C2, the D7 later visit can be omitted by the discretion of the researcher. Docetaxel is given on each day of the cycle and 3 weeks amount of SH003 is prescribed. As diarrhea may occur as a side effect of docetaxel, researchers will prescribe PRN loperamide and take it when needed. After 2 cycles, the administration is completed.(6 weeks of investigational drug administration schedule)

Treatment

1. Experimental Group
Patients with histologically and cytologically confirmed lung or breast cancer with docetaxel indication

2. Starting dose, administration method and administration period
1) Starting dose
- SH003 : 2 tablets at a time (SH003 800mg)
No abnormalities related to the test substance were observed in the Single dose toxicity test and repeated administration toxicity test. Also, No Observed Adverse Effect Level (NOAEL) of the test substance was determined to be 2,500 mg / kg for both sexes. NOAEL(No Observed Adverse Effect Level) of test substances are judged to be 2,500 mg / kg among both sexes. When divided by human/animal factor, according to FDA guideline (Guidance of Human Equivalent Doses), 2,500 mg/kg NOAEL of a rat can be equaled to 400 mg/kg in humans. When setting the safety factor at 10, Max Recommended Starting Dose (MRSD) will be 40 mg/kg and it can be calculated into 2,400 mg in a 60 kg human body.

3) Administration period
- Phase 1 dose escalation group : 3 weeks for dose group 1,2,3
- Phase 2 : Continue administration of the maximum tolerated dose until it meets the criteria for interruption / dropout
- Follow-Up period
When the administration of the investigational product is suspended, the subject will respectively be followed-up in the follow-up period from last administration date to the end of clinical study. In this period, disease assessment will be performed on the subject, subjects will be followed-up every 4 weeks to monitor progression-free and overall survival, and tumor assessment will be performed until disease lesions are identified.

Arm Label

Target Number of Participant

Arm Type

Arm Description

1) Starting dose
- SH003 : 2 tablets at a time (SH003 800mg)
No abnormalities related to the test substance were observed in the Single dose toxicity test and repeated administration toxicity test. Also, No Observed Adverse Effect Level (NOAEL) of the test substance was determined to be 2,500 mg / kg for both sexes. NOAEL(No Observed Adverse Effect Level) of test substances are judged to be 2,500 mg / kg among both sexes. When divided by human/animal factor, according to FDA guideline (Guidance of Human Equivalent Doses), 2,500 mg/kg NOAEL of a rat can be equaled to 400 mg/kg in humans. When setting the safety factor at 10, Max Recommended Starting Dose (MRSD) will be 40 mg/kg and it can be calculated into 2,400 mg in a 60 kg human body.

2) Administration method
Docetaxel: Intravenously administer 75mg / m2 for 1 hour every 3 weeks
SH003 : Take 3 times a day. orally administer with water for each dose 30 minutes after breakfast, lunch and dinner
- Phase 1 1st dose group: SH003 2 tablets once (800 mg once, 2,400 mg / day)
- Phase 1 2nd dose group: SH003 2 tablets once (1200 mg once, 3,600 mg / day)
- Phase 1 3rd dose group: SH003 2 tablets once (1600 mg once, 4,800 mg / day)
- Phase 2 : Maximum tolerated dose determined in Phase 1

3) Administration period
- Phase 1 dose escalation group : 3 weeks for dose group 1,2,3
- Phase 2 : Continue administration of the maximum tolerated dose until it meets the criteria for interruption / dropout
- Follow-Up period
When the administration of the investigational product is suspended, the subject will respectively be followed-up in the follow-up period from last administration date to the end of clinical study. In this period, disease assessment will be performed on the subject, subjects will be followed-up every 4 weeks to monitor progression-free and overall survival, and tumor assessment will be performed until disease lesions are identified.

Gender

Age

Description

1.Phase 1
1) Adults over 19
2)  Patients with histologically and cytologically confirmed lung or breast cancer who failed previous treatment or did not respond to established treatment
3) A person whose previous treatment has terminated at least 4 weeks in advance and do not have persistent toxicity (Grade 1 or higher adverse events according to NCI CTCAE v 5.0) associated with previous treatment (Excluding a grade 2 or less hair loss or sensory neuropathy that is not considered a safety risk to the patient according to the investigator's judgment)
4) Patient whose Eastern Cooperative Oncology Group (ECOG) functional status index is 0-2
5) Patients who have a minimum life expectancy of 12 weeks or more from the expected initial dosing date
6) Person who can swallow pills
7) Patients with measurable lesions based on the RECIST 1.1 scale
8) Proper organ function
i. Bone marrow function : Hb ≥ 8.0 g/dL, ANC ≥ 1,500/㎣, PLT ≥100,000/㎣
ii. Liver Function : bilirubin ≤ 2.5 times the upper limit of normal, AST / ALT ≤ 2.5 times the upper limit of normal (with liver metastasis ≤ 5 times the upper limit of normal)
iii. Kidney function : Serum creatinine ≤ 1.5 times the upper limit or calculated CCr (Cockroft) ≥ 60 ml / min
9) No chance of pregnancy in the case of female.(60 years old or older and have had no menstrual period for more than one year, or have had hysterectomy or bilateral ovarian resection) If there is a possibility of pregnancy, pregnancy test should be performed before participation in the study
10) male and female patients of childbearing age who can follow appropriate contraceptives during the study administration period and for at least eight weeks after discontinuation.
11) Applicants who have fully been explained of the test, the purpose, content, and characteristics of the test drug prior to participation and agreed to participate in the examination at their discretion
12)  A person who can understand and follow the instructions and can participate in the whole process of the clinical trial.

2. Phase 2
1)Adults over 19
2) Patients with histologically and cytologically confirmed lung or breast cancer with docetaxel indication
3) Patient with indication of Docetaxel administration
- Patients without Taxane-based Treatment for Metastatic / Recurrent Cancer
- Patient who have a disease-free survival of at least one year after receiving taxane as an adjuvant
- Patients with two or less previous treatments in treatment of metastatic / recurring cancer (Excluding the history of previous hormonal combination therapies based on hormonal receptor-positive cancer
4) A person whose previous treatment has terminated at least 4 weeks in advance and do not have persistent toxicity (Grade 1 or higher adverse events according to NCI CTCAE v 5.0) associated with previous treatment (Excluding a grade 2 or less hair loss or sensory neuropathy that is not considered a safety risk to the patient according to the investigator's judgment)
5) Patient whose Eastern Cooperative Oncology Group (ECOG) functional status index is 0-2
6) Patients who have a minimum life expectancy of 12 weeks or more from the expected initial dosing date
7) Person who can swallow pills
8) Patients with measurable lesions based on the RECIST 1.1 scale
9) Proper organ function
i. Bone marrow function : Hb ≥ 8.0 g/dL, ANC ≥ 1,500/㎣, PLT ≥100,000/㎣
ii. Liver Function : bilirubin ≤ 2.5 times the upper limit of normal, AST / ALT ≤ 2.5 times the upper limit of normal (with liver metastasis ≤ 5 times the upper limit of normal)
iii. Kidney function : Serum creatinine ≤ 1.5 times the upper limit or calculated CCr (Cockroft) ≥ 60 ml / min
10) No chance of pregnancy in the case of female.(60 years old or older and have had no menstrual period for more than one year, or have had hysterectomy or bilateral ovarian resection) If there is a possibility of pregnancy, pregnancy test should be performed before participation in the study
11) male and female patients of childbearing age who can follow appropriate contraceptives during the study administration period and for at least eight weeks after discontinuation.
12) Applicants who have fully been explained of the test, the purpose, content, and characteristics of the test drug prior to participation and agreed to participate in the examination at their discretion
13)  A person who can understand and follow the instructions and can participate in the whole process of the clinical trial.

1) Patients undergoing any topical chemotherapy, including systemic drug therapy or radiation therapy for cancer treatment (Steroid preparations are allowed at or below 10 mg of prednisolone, a physiological maintenance dose, Short-term use of steroids to prevent side effects is allowed, but further systemic steroid therapy is not allowed)
2) Person with known or suspected hypersensitivity or serious adverse events to material, material belonging to same kind(Astragalus, Angelica, Golse root, Cremophor R EL (polyoxyethylated castor oil) or docetaxel
3) Patients with a history of severe hypersensitivity to polysorbate 80
4) Subject with evidence of active infection (HBV, HCV, HIV, TB, etc.) that needs treatment
5) subjects with known past history of positive of immunodeficiency virus (HIV) infection test
6) Patients with Uncontrolled Cardiovascular Disease(patient with symptoms of unstable angina pectoris, heart failure, myocardial infarction, hypertension uncontrolled below 140/90 )
7) Patients with active CMV disease or infection within 4 weeks
8) Patients who have undergone major surgery requiring acute hepatic artery syndrome, cerebrovascular diseases such as stroke, or other assisted breathing devices within one year
9) Patient who is Pregnant or breastfeeding 
10) Patient with Metastatic Brain Lesions accompanying Symptoms(Including meninges metastases, patient with no symptoms after previous surgery or radiation surgery and with no recent progress is permitted) 
11) Participants in blood donation or other clinical trials of drugs and medical devices within one month prior to the start of the study
12) Organ-transplanted patients, including allogeneic stem-cell transplantation
13) Person who abused of substance which are considered to interfere with research participation and interpretation of research results and have neurological / medical / psychiatric / social diseases
14) Patients with a recent (within last year) severe abnormalities that may increase the risk due to the administration of the investigational drug and participation in the study by the discretion of the researcher, or may interfere with interpretation of the test results 
15) Patients who are judged to have lost their ability to consent due to accompanying diseases including dementia
16) Patients with complications of infectious diseases
17)  Patients suspected of infectious fever

Phase 1 clinical trial - safety and tolerability assessment

At every visit(Visit 1, Visit 2(D0), Visit 3(D8), Visit 4(D15),Visit 5(D22), Visit 6(D29))

Phase 2 - Objective Overall Response Rate by RECIST 1.1 criteria or PCWG3 of all cancers

Check tumor response rate every 2 cycles(6weeks)

Phase 2 - Objective Overall Response Rate of each type of cancer

Check tumor response rate every 2 cycles(6weeks)

Phase 2 - frequency rate of Peripheral Neuritis and Fatigue among adverse events

Visits after administration of Investigational Product (Visit 2(D0), Visit 3(D21), Within 30 days after the last dose, 30 days after disease progression, follow-up visit every 4 weeks)

Phase 2 - ECOG performance status change

At every visit (Screening, Visit 2(D0), Visit 3(D21), Within 30 days after the last dose, 30 days after disease progression, follow-up visit every 4 weeks)

Phase 2 - Progression Free Survival(PFS)

Visits after administration of Investigational Product (Visit 2(D0), Visit 3(D21), Within 30 days after the last dose, 30 days after disease progression, follow-up visit every 4 weeks)