Tolerability and Bioavailability of Utidelone Capsule in Patients With Advanced Solid Tumors

This study has three parts. Part 1 is a dose-escalation trial, Part 2 is a pharmacokinetic comparison and food effect study, and Part 3 is extended trial of combination of utidelone capsule and capecitabine. The primary objectives are 1. To evaluate the safety and tolerability of utidelone capsules in patients with advanced solid tumors and to determine the Maximum Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT). 2. To evaluate the objective response rate in patients with advanced metastatic breast cancer treated with the combination of utidelone capsule and capecitabine. The secondary objectives are: 1. to evaluate the absolute bioavailability of utidelone capsules relative to utidelone injection; 2. to evaluate the pharmacokinetic profile of utidelone capsules in patients with advanced solid tumors; 3. to preliminarily evaluate the efficacy and safety of utidelone capsules in patients with advanced solid tumors; and 4. to recommend doses and dosing regimens for subsequent clinical trials. 5. To evaluate the Progression-Free Survival (PFS), safety and pharmacokinetics of utidelone capsule combined with capecitabine in the treatment of patients with advanced metastatic breast cancer.

Part 1 is a dose-escalation trial, and it's an open design; Part 2 is a pharmacokinetic comparison and food effect study, and it's an open, controlled study;Part 3: Extended trial of combination of utidelone capsule and capecitabine.

Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all of the following criteria to be enrolled into the study:

1. Patients who have fully understood the objectives, content, process of the study and possible adverse events, voluntarily serves as a subject and signs the informed consent form.
2. Part 1 and Part 2: Patients with definitive histopathological diagnosis of advanced solid tumors. Part 3: Patients were diagnosed with advanced metastatic breast cancer by pathology and/or cytology.
3. Part 1 and Part 2: Male or female subjects aged ≥18 and ≤65, Part 3: Male or female subjects aged ≥18 and ≤70, with ECOG performance status scored 0-1.
4. Expected survival time ≥ 12 weeks;
5. At least one measurable lesion present according to RECIST 1.1 criteria.
6. Baseline routine blood tests within 1 week prior to enrollment is normal (not received blood transfusions or hematopoietic-stimulating factors within 14 days), with CTCAE grade ≤1 (based on normal values at each site's laboratory): a) Neutrophil count (ANC) ≥ 1.5 × 109/L; b) platelet count (PLT ) ≥ 100 × 109/L; c) Hemoglobin ≥9.0 g/dL.
7. Liver and kidney function test results are normal within 1 week prior to enrollment, with CTCAE grade ≤1 (based on normal values at each site's laboratory): a) Total bilirubin (TBIL) ≤ 1.5× the upper limit of normal value (ULN); b) Serum Glutamic Pyruvic Transaminase/Alanine Aminotransferease (SGPT /ALT) ≤ 2.5× ULN (Part 3 allowed ≤5×ULN in patients with liver metastases); c) Serum Glutamic-oxaloacetic Transaminase/Aspartate Aminotransferase (SGOT /AST) ≤ 2.5× ULN (Part 3 allowed ≤5×ULN in patients with liver metastases); d) Creatinine clearance (Ccr) ≥60 ml/min.
8. Patients with no functional disorders of major organs.
9. Fertile males and females of childbearing potential must agree to use effective contraception (so do their partners, using hormonal or barrier contraception, or abstinence) during the study and within at least 12 weeks after the last dose. The blood or urine pregnancy test for female patients of childbearing potential prior to enrollment must be negative.
10. Part 3: breast cancer patients who had received ≤4 previous chemotherapy regimens (adjuvant chemotherapy/neoadjuvant chemotherapy was considered as one chemotherapy regimen);
11. Part 3: history of prior treatment with at least one anthracycline or one taxane as neoadjuvant/adjuvant or advance therapy or both.

Exclusion Criteria:

Subjects who fulfill any one of the following exclusion criteria will be excluded from the study:

1. Patients who have received non-investigational anti-tumor therapies (such as chemotherapy, radiotherapy, immunotherapy, biological therapy or traditional Chinese medicine treatment) within 2 weeks prior to study drug administration.
2. Subjects with severe hypersensitivity to castor oil (this criteria is applicable to Part 2 of the study), and subjects who had hypersensitivity reaction caused by previous anti-microtubule drugs.
3. Patients with uncontrollable brain metastases (brain metastatic lesion confirmed by examination within 2 months after radiotherapy or other localized treatment); patients with uncontrollable bone metastases (patients who have had fracture or have the risk of fracture in recent days, patients who need surgery or localized radiotherapy in recent days, patients with other critical conditions)
4. Patients with serious comorbidities, such as severe heart disease, cerebrovascular disease, uncontrolled diabetes, uncontrolled hypertension, severe infections, active peptic ulcers, etc.
5. Patients with mental illnesses which are hard to control, patients who lack legal capacity or have limited legal capacity.
6. Patients with gastrointestinal diseases such as esophageal obstruction, pyloric obstruction, intestinal obstruction, or who are post-operative of gastrointestinal resection, or who have difficulty in swallowing due to other factors, interfering with oral administration and absorption of the drug.
7. Patients with active hepatitis B infections.
8. Patients with peripheral neuropathy grade\>1 within 4 weeks prior to enrollment (NCI CTCAE 5.0).
9. Patients who still experience ≥ Grade 2 acute toxicities caused by previous anti-tumor therapies (e.g. chemotherapy, radiotherapy, immunotherapy, biological therapy or TCM treatment) prior to enrollment (NCI-CTCAE 5.0, except alopecia).
10. Patients who have undergone any major surgery or have major trauma within 4 weeks prior to administration of the investigational product or are expected to undergo major surgery during the treatment.
11. Patients who have participated in another clinical trial or have received other investigational treatments within 4 weeks prior to administration of the investigational product.
12. Patients who, in the opinion of the investigator, are not suitable to participate in this study.
13. Part 3: other malignant tumors within 5 years before enrollment, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma, thyroid papillary carcinoma;
14. Part 3: previous or current capecitabine therapy (except if capecitabine was used in neoadjuvant/adjuvant therapy and progression occurred \> 12 months after completion of treatment, inclusion was allowed);
15. Part 3: patients with previous fluorouracil medication history with severe allergy or known dihydropyrimidine dehydrogenase (DPD) deficiency;
16. Part 3: previous or current use of utidelone (including utidelone injection and utidelone capsule); 17) Part 3: pregnant or lactating patients; 18) Part 3: uncontrolled pleural effusion, pericardial effusion or ascites (drainage once a month or more); 19) Part 3: a history of immunodeficiency, including positive HIV antibody test, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation.