Safety and Tolerability Study for T-1201 Injection 100 Mg Kit in Patients with Advanced Solid Tumors

This clinical development plan for T-1201 will begin with a first-in-human (FIH), open label, multi-center Phase I dose-escalation to evaluate the safety, tolerability, and human pharmacokinetics of T-1201 and determine the maximum tolerated dose (MTD) levels in patients with advanced solid cancer. The further Phase II study will then be designed based on the safety, pharmacokinetics, and preliminary efficacy results from the FIH Phase I study.

The initial part of the Phase I study is a safety, tolerability, and pharmacokinetic phase wherein T-1201 Injection will be intravenous administered to patients with advanced solid cancers. The study will be an open label, multi-center Phase I dose-escalation study. Approximately 30-40 patients will be enrolled for the dose-escalation phase. Actual number of patients will be determined by the number of dose cohorts until maximum tolerated dose (MTD) is reached. The modified accelerated titration design will be used for dose escalation.

The initial dose regimen will be 18 mg/m 2 of T-1201 Injection once every 4 weeks in 28-day cycles. Doses will escalate in the following sequence: 18, 36, 71, 119, 178 and 249 mg/m 2 of T-1201 Injection. Dose escalation will cease when 2/3 or 2/6 patients experience a DLT, or a dose of 249 mg/m 2 is reached. A DLT must occur within the first cycle (Cycle 1) to determine dose escalation between cohorts. If 2/3 or 2/6 patients experience DLTs at the initial dose level of 18 mg/m 2 , 2 more dose levels lower than 18 mg/m 2 will be added to the study.

No human study has been conducted for product T-1201, the benefits/risks of T-1201 is therefore not available at this stage. Since T-1201 is a prodrug of SN-38 with target delivery design, the benefits/risks ratio of T-1201 would thus be expected to be more favorable than irinotecan product (CAMPTOSAR ® , Pfizer).


Eligibility Criteria:
Inclusion Criteria:

Subjects must meet all of the following criteria to be eligible for enrollment in the study:

1. Signed and dated informed consent form.
2. Histologically and cytologically confirmed advanced malignancies that are refractory to standard therapy or have no accepted standard therapy.
3. Solid tumors that are measurable or evaluable as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Target lesions that have been previously irradiated will not be considered measurable (lesion).
4. Female or male, 20 years of age or older.
5. ECOG performance status 0 or 1.
6. QTcF ≤ 470 ms at screening.

Exclusion Criteria:

Subjects presenting with any of the following will not be included in the study:

1. Clinically significant comorbidity such as unstable angina, congestive heart failure (NYHA Grade III or IV), uncontrolled hypertension (\>160/100 mmHg despite optimal medical treatment), chronic obstructive pulmonary disease (COPD) with frequent exacerbations, refractory asthma, inflammatory bowel disease or intestinal obstruction.
2. Acute myocardial infarction or cerebrovascular accident (CVA) within 6 months prior the first dose of study drug.
3. Central nervous system (CNS) metastasis or seizure disorder due to underlying malignancy except those who have been treated and have stable CNS metastases or are asymptomatic.
4. AIDS-defining opportunistic infections within the past 12 months.
5. HBV infection (positive HBsAg) except for carrier of inactive HBV as defined by negative HBeAg with normal ALT and HBV DNA \< 2,000 IU/mL or HCV infection (positive anti-HCV antibody) except for those with undetectable HCV RNA.
6. Inadequate bone marrow reserve, hepatic or renal function as defined by any of the following laboratory values:

   1. absolute neutrophil count (ANC) \< 1500/µL
   2. platelet count \< 100 x 10\^9 /µL
   3. hemoglobin \< 9 g/dL
   4. total bilirubin \> 1.5 x the upper limit of normal (ULN)
   5. aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 3 x ULN if no hepatic metastases are present; \> 5 x ULN if hepatic metastases are present
   6. Estimated (Cockroft-Gault formula) creatinine clearance (CrCl) \< 60 mL/min CrCl = \[(140 - age (year)) x weight (kg)\] / (serum creatinine x 72) (x 0.85 for females)
7. Toxicities resulting from prior therapy or surgical procedures not yet resolved to ≤ NCI CTCAE v5.0 Grade 1 with the exception of alopecia, skin hyperpigmentation or hypopigmentation.
8. Major surgical procedures (as defined by Investigator) within 4 weeks prior to the first dose of study drug or any ongoing post-operative complications.
9. Receiving any (investigational or approved) anti-cancer therapy (including chemotherapy or targeted therapy) within 28 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
10. A history of apparent allergic reactions to irinotecan, Tween 80 (dosed with prior treatment with prophylactic drug), and/or ethanol.
11. If female, is pregnant or breastfeeding.
12. If men or women with childbearing potential, unwilling to use effective contraceptive methods during the study and for at least 3 months (men) or 1 month (women) after the last dose of study drug. Effective contraceptive methods include implants, injectables, combined oral contraceptives, intra-uterine devices (IUDs), sexual abstinence, surgical sterilization or a partner who is sterile.
13. Receiving live attenuated vaccine within 28 days prior to the first dose of study drug.
14. Life expectancy \< 3 months
15. Other prior or ongoing condition(s) that, in Investigator's opinion, could affect the safety of the subject, compromise the subject's ability to comply with the study requirements or impair the assessment of study results.