Tolerability of Utidelone Capsule in Patients With Advanced Solid Tumors

Phase I Clinical Study on the Tolerability of Utidelone Capsule in Patients With Advanced Solid Tumors

The purpose of this trial is to evaluate the safety and tolerability of Utidelone Capsule in patients with advanced solid tumors and determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). The secondary objectives are to evaluate the pharmacokinetic profile of Utidelone Capsule in patients with advanced solid tumors, preliminarily assess the anti-tumor activity of Utidelone Capsule in patients with advanced solid tumors via objective radiologic tumor response using RECIST 1.1, and to recommend the dose and dosage regimen for subsequent clinical trials.

At least 4 dose cohorts are planned, and 16-28 cases are expected.

1. Cohort 1 and 2: 2 cases are planned for each.
2. Other dose-escalation cohorts: 3-6 cases are planned in each cohort, following the 3 + 3 design.

Inclusion Criteria:

1. Willing and able to sign a written informed consent;

2. Patients with histologic or pathologic documentation of incurable, locally advanced, or metastatic solid tumors for which standard therapies are not available, no longer effective, and not tolerated, and for those patients who have declined the standard therapies;

3. Male or female subjects aged ≥18, with ECOG performance status scored 0-1;

4. Expected survival time ≥ 12 weeks;

5. Adequate organ and marrow function as defined below:

   1. neutrophil count (ANC) ≥ 1.5 × 109/L
   2. platelet count (PLT) ≥ 100 × 109/L
   3. hemoglobin ≥ 9 g/dL
   4. total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN)
   5. alanine transaminase (ALT) ≤ 2.5 × ULN
   6. aspartate transaminase (AST) ≤ 2.5 × ULN
   7. Creatinine clearance ≥ 60 mL/min

6. Female patients of childbearing potential must have negative serum or urine pregnancy test at screening;

7. Sexually active women, unless surgically sterile (at least 6 months prior to study drug administration) or postmenopausal for at least 12 consecutive months, must use an effective method of avoiding pregnancy (including oral, transdermal, or implanted contraceptives [any hormonal method in conjunction with a secondary method], intrauterine device, female condom with spermicide, diaphragm with spermicide, absolute sexual abstinence, use of condom with spermicide by sexual partner or sterile [at least 6 months prior to Study drug administration] sexual partner) for at least 4 weeks prior to study drug administration, during study and up to 30 days or till next chemotherapy cycle. Cessation of birth control after this point should be discussed with a responsible physician. Investigator will discuss with patient on the above points and the patient agreement will be documented in the source document. The investigator should ensure that the patient is using an effective method of avoiding pregnancy as per protocol. In case of Male patients: Either patient partners or patients themselves must use an effective method of avoiding pregnancy for at least 4 weeks prior to study drug administration, during study and up to 30 days or till next chemotherapy cycle.

Exclusion Criteria:

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. Patients with hypersensitivity reaction caused by previous anti-microtubule drugs;
3. Patients who have known brain metastasis; patients whose CNS metastases have been treated by surgery or radiotherapy, who are no longer on corticosteroids, and who are neurologically stable are eligible;
4. Patients with a history of the following within 6 months prior to Cycle 1 Day 1: a myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, New York Heart Association (NYHA) Class III-IV heart failure, uncontrolled hypertension, clinically significant cardiac dysrhythmia or ECG abnormality, cerebrovascular accident, transient ischemic attack, or seizure disorder. Atrial fibrillation is allowed if rate is controlled;
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements;
6. Patients with baseline QTc interval > 470 msec;
7. Patients with known history of human immunodeficiency virus (HIV) infection with an exception that if they have not had an opportunistic infection within the past 12 months, they are eligible;
8. Patients who are HBV DNA positive;
9. Patients with pre-existing > Grade 1 peripheral sensory neuropathy (NCI CTCAE 5.0) ;
10. 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);
11. 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 first cycle of treatment;
12. Patients who have received other investigational treatments within 4 weeks prior to administration of the investigational product.