Clinical Trial of TB511 in Advanced Solid Tumors

1. Study population

   \[TB511 Monotherapy Cohort for Phase 1 and Phase 2a Clinical Trial\] Patients with advanced solid tumors who are either refractory or intolerant to standard of care (SoC).

   \[Immune checkpoint inhibitors (ICIs) Combination Therapy Cohort for Phase 2a Clinical Trial\] Patients with advanced solid tumors who are refractory to immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 inhibitors or who have no available standard of care.
2. Objectives of the Clinical Trial

2.1 Primary Objectives \[Phase 1 Clinical Trial\]

* To evaluate the safety and tolerability of TB511 monotherapy in patients with advanced solid tumors and to determine the Maximum Tolerated Dose (MTD) and the Recommended Phase II Dose (RP2D).

\[Phase 2a Clinical Trial\]

* To evaluate the Objective Response Rate (ORR) of TB511 monotherapy and TB511 in combination with Pembrolizumab in patients with advanced solid tumors (based on Response Evaluation Criteria In Solid Tumors Version 1.1, RECIST v1.1).

2.2 Secondary Objectives \[Phase 1 Clinical Trial\]

* To evaluate the safety of TB511 monotherapy.
* To assess the Objective Response Rate (ORR) and anti-tumor activity of TB511 monotherapy (based on RECIST v1.1).
* To characterize the pharmacokinetic (PK) profile of TB511 monotherapy.

\[Phase 2a Clinical Trial\]

* To evaluate the Disease Control Rate (DCR), Duration of Response (DoR), and Progression-Free Survival (PFS) of TB511 monotherapy and TB511 in combination with Pembrolizumab.
* To assess the safety and tolerability of TB511 monotherapy and TB511 in combination with Pembrolizumab.
* To characterize the pharmacokinetic (PK) profile of TB511 monotherapy and TB511 in combination with Pembrolizumab.

2.3 Exploratory Objectives

* To compare changes in biomarker levels of TB511 monotherapy.
* To assess immunogenicity of TB511 by measuring anti-drug antibodies (ADA).

1. Number of participants

   \[Phase 1 Clinical Trial\] 3 to 6 patients per dose group

   \[Phase 2a Clinical Trial\] Approximately 20 patients per cohort (Cohort 1: Approximately 20 patients, Cohort 2: Approximately 20 patients)
2. Study Duration

   * Total clinical trial duration: Approximately 36 months from the date of IRB approval (however, this may be adjusted depending on the enrollment rate of participants.)
   * Participation duration for individual participants
   * Screening period: Up to 4 weeks (28 days)
   * Treatment period: Each cycle consists of 3 weeks (21 days), and administration will continue until a reason for discontinuation occurs.
   * Safety follow-up period: 6 weeks after the End of Treatment (EOT)
3. Investigational Product

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1. Study drug

   * Product name or code: TB511 Injection (8 mg)

     * Formulation and appearance: White or off-white color of lyophilized powder ③ Main ingredient: TB511 ④ Storage method: Store in a hermetic container in a freezer (-20℃); protect from light
2. Concomitant drug

   * Product name or code: Keytruda

     * Formulation and appearance: An injection comprised of clear to slightly opalescent, colorless to slightly yellow solution contained in a colorless and transparent vial.

       * Main ingredient: Pembrolizumab ④ Storage method: Store in a hermetic container, refrigerated at 2 to 8℃; protect from light; do not freeze

         4. Dosage and method of administration

\[Phase 1 Clinical Trial\]

1. TB511

   * Starting Dose group: 4 mg

     * Dose Escalation groups: 4 mg, 8 mg, 16 mg, 24 mg

       ③ Dose De-escalation: 12 mg, 20 mg

       ④ Administration method: 1 cycle consists of 3 weeks (21 days). TB511 will be administered subcutaneously into the abdomen once every 7 days for 3 weeks (21 days). Repetitive injections at the same site should be avoided; instead, rotate injection sites within the abdominal area. Do not inject into sensitive or abnormal skin areas (e.g., wounds, rashes, redness, induration, etc.).

       ⑤ Administration Plan: Administration will continue until unacceptable toxicity, disease progression (PD) per RECIST v1.1, or other reasons requiring discontinuation occur.

\[Phase 2a Clinical Trial\]

1. TB511

   * Dose: Recommended dose for Phase 2a determined in Phase 1.

     ② Administration method: 1 cycle consists of 3 weeks (21 days). TB511 will be administered subcutaneously into the abdomen once every 7 days for 3 weeks (21 days). Repetitive injections at the same site should be avoided; instead, rotate injection sites within the abdominal area. Do not inject into sensitive or abnormal skin areas (e.g., wounds, rashes, redness, induration, etc.).

     ③ Administration Plan: Administration will continue until unacceptable toxicity, disease progression (PD) per RECIST v1.1, or other reasons requiring discontinuation occur.
2. Pembrolizumab

   * Dose: 200 mg or dose adjusted according to the approved labeling.

     ② Administration Method: Pembrolizumab is administered by continuous intravenous infusion for 30 minutes, once every 3 weeks (When used in combination with TB511, Pembrolizumab should be administered first, followed by TB511 at least 30 minutes later).
     * Administration Plan: Administration will continue until unacceptable toxicity, disease progression (PD) per RECIST v1.1, or other reasons requiring discontinuation occur.

       5. Study Method

This clinical trial consists of a Phase 1 dose-escalation study to determine the maximum tolerated dose (MTD) of TB511 and establish the recommended Phase 2a dose (RP2D) in patients with advanced solid tumors who are refractory or intolerant to standard of care, and a Phase 2a study to evaluate the anti-tumor effect of TB511 monotherapy in dose determined in Phase 1 (Cohort 1) and TB511 in combination with Pembrolizumab (Cohort 2) in patients with advanced solid tumors for whom no standard of care is available, including those who are refractory to immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 agents or who have experienced disease progression.

Participants who voluntarily sign the written informed consent form will undergo screening tests to assess eligibility during the screening period. Subjects who meet all inclusion and none of the exclusion criteria will be enrolled in this clinical trial and receive the investigational product at the assigned dose level. 1 cycle of administration of the investigational product is 3 weeks (21 days), and enrolled participants continue to receive the investigational product until intolerable toxicity, verification of progressive disease (PD) as defined by RECIST v1.1, or any other reason for discontinuing administration occur. Tumor response assessments (CT/MRI) will be conducted on Day 1 of Cycle 1 and every 2 cycles thereafter. Pharmacokinetic (PK) evaluation will be performed on Day 1 and Day 15 of Cycle 1, and exploratory evaluation will be performed during screening, and on Day 8 and Day 15 of Cycle 1.

\[Phase 1 Clinical Trial - TB511 Monotherapy\] The Phase I clinical trial will follow a 3+3 design, starting from the lowest dose cohort and continuing until the maximum tolerated dose (MTD) is determined. Depending on the MTD determination method, 3 to 6 participants will be sequentially enrolled in each dose-escalation level (TB511: 4 mg, 8 mg, 16 mg, 24 mg) with at least a 3-day interval and TB511 is administered for 1 cycle to determine dose limiting toxicity(DLT). DLT assessment will be conducted in Cycle 1. Dose escalation or de-escalation will be decided by the Safety Review Committee (SRC) after the completion of DLT evaluation of the last participant in each dose level. If no DLT is observed, the study will proceed to the next higher dose level. If DLT occurs, the trial may proceed with an intermediate dose level, as defined below. After completion of dose escalation or de-escalation, the Recommended Phase 2a Dose (RP2D) will be determined based on the MTD and overall toxicity evaluation. The SRC will also decide whether to continue or discontinue the trial.

\<Dose De-escalation Scheme\>

If DLT is observed at a given dose level, the dose will be de-escalated to an intermediate dose\* as follows:

- If toxicity occurs at 24 mg, the intermediate dose will be 20 mg.

* If toxicity occurs at 16 mg, the intermediate dose will be 12 mg.

  * Intermediate dose: An intermediate dose between the given dose level and one-step lower dose level.

Eligibility Criteria:
Inclusion Criteria:

\[Common\]

1. Male and female adults who are 19 years old or older at the time of obtaining informed consent form.
2. Patients with at least one measurable lesion by RECIST v1.1.
3. Patients whose Eastern Cooperative Oncology Group Performance Status (ECOG PS) is 0 or 1.
4. Female patients of childbearing potential who have not undergone sterilization surgery must agree to use appropriate contraception\* for 6 months after the end of administration of the investigational product and must satisfy one of the following conditions at the time of screening to establish that they are not pregnant.

   • Women over the age of 50 who have had amenorrhea for at least 12 months after the termination of all exogenous hormone treatment.
   * Documented irreversible surgical sterilization by hysterectomy, dual ovariectomy, or oophorectomy (tubal litigation does not satisfy this criteria)
   * Women under the age of 50 who have had amenorrhea for at least 12 months after the termination of all exogenous hormone treatment and whose luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels are within the post-menopause range determined by the clinical trial institution.
5. Male patients who have not undergone vasectomy must agree to use a barrier method of contraception (i.e., condom) and agree that both they and their partners will use an appropriate method of contraception\* through 6 months after the end of administration of the investigational product.

   \*Appropriate methods of contraception include: complete abstinence, hormonal contraceptives not known to have drug interactions \[levonorgestrel-releasing intrauterine system (IUS) (e.g., Mirena), medroxyprogesterone (e.g., Provera)\], copper intrauterine device, and partner's vasectomy. Periodic abstinence (e.g., calendar-based, ovulation tracking, or basal body temperature methods) and withdrawal are not considered appropriate methods of contraception.
6. Patients who have been provided with sufficient explanations on this clinical trial, have voluntarily decided to participate in this clinical trial and have agreed in writing to faithfully comply with the requirements of the clinical trial.

\[Cohort of TB511 Monotherapy in Phase 1 and Phase 2a Clinical Trials\]

1) Patients with cytologically or histologically confirmed advanced solid tumors who are either refractory or intolerant to standard of care (SoC).

\[Cohort of ICIs Combination Therapy in Phase 2a Clinical Trial\] 1) Patients with advanced solid tumors who, at the time of screening, are refractory to or have experienced disease progression during treatment with immune checkpoint inhibitors (ICIs) such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 agents within their approved indications, and for whom no standard therapy is available.

- This includes: melanoma, non-small cell lung cancer, head and neck cancer, classical Hodgkin lymphoma, urothelial carcinoma, gastric cancer, esophageal cancer, renal cell carcinoma, endometrial cancer, microsatellite instability-high (MSI-H) cancer, MSI-H colorectal cancer, triple-negative breast cancer, cervical cancer, biliary tract cancer, and hepatocellular carcinoma.

Exclusion Criteria:

\[Common\] Current Disease and Medical History

1. Patients who have had other malignant tumors within 5 years prior to the screening (provided, however, that patients with basal cell carcinoma that requires only stable long-term follow-up without treatment can be enrolled).
2. Patients who had been subject to chemotherapy, radiotherapy, or biological therapy within 4 weeks prior to the screening.
3. Patients who had undergone major surgery requiring general anesthesia within 4 weeks prior to the screening.
4. Patients with brain metastasis who have symptoms or required treatment (provided, however, that patients with asymptomatic metastasis that does not require treatment \[excluding anticonvulsants used in maintenance therapy\] can be enrolled).
5. Patients with systemic disease for which administration of anti-cancer drugs is deemed inappropriate by the investigator.
6. Patients with the following cardiovascular disease at the screening

   * Myocardial infarction, unstable angina, stroke, or transient ischemic within 6 months.
   * QTc interval ≥ 480 msec or clinically significant electrocardiographic change.
   * Congestive heart failure classified as New York Heart Association (NYHA) class III or above.
7. Patients who are HIV-positive.
8. Patients whose participation in the clinical trial is deemed inappropriate by the investigator based on their results of Hepatitis B virus and Hepatitis C virus test.(Not applicable to patients with hepatocellular carcinoma.)

   However, the following cases are allowed:
   * For patients positive for HBsAg or HBcAb: HBV DNA must be ≤ 2000 IU/mL or undetectable.
   * For patients positive for HCV Ab: HCV RNA must be negative or the patient must have completed antiviral treatment and be stabilized.
9. Patients with acute or severe hepatitis.
10. Patients with autoimmune disease or with history of chronic or recurrent autoimmune disease.
11. Patients with history of organ transplantation.
12. Patients with history of identical hematopoietic stem cell transplantation.
13. Patients with history of interstitial pneumonia requiring steroid treatment.
14. Patients with known hypersensitivity to recombinant drugs (drugs with active ingredients of peptide or protein).
15. Patients with history of hypersensitivity to the components of TB511.

    Prohibited Drugs
16. Patients who require continuous treatment with immunosuppressants or systemic corticosteroid administration (Note: Use of topical corticosteroids such as intra-articular, intranasal, ophthalmic, or inhaled formulations is permitted. Temporary use of systemic corticosteroids administration for the treatment or prevention of contrast agent allergies or adverse reactions is also allowed.)
17. Patients who have received live or attenuated live vaccines within 4 weeks prior to the screening.

    Laboratory tests
18. Patients with the following laboratory levels at the time of screening.

    * ANC \< 1,500/mm³
    * Platelet count \< 100,000/mm³ (for hepatocellular carcinoma: \< 75,000/mm³)
    * Hemoglobin \< 9.0 g/dL (Patients can be enrolled if hemoglobin level is recovered to ≥ 9.0 g/dL during the screening period; however, blood transfusion within 7 days prior to the screening to fulfill this criterion is not allowed.)
    * AST, ALT \> 3 × ULN (provided, however, that if liver metastasis is involved, AST, ALT \> 5 × ULN)
    * Total bilirubin \> 1.5 × ULN
    * Serum creatinine \> 1.5 × ULN

    Others
19. Pregnant, breastfeeding women, or patients with a positive pregnancy test at the time of screening.
20. Patients who, in the investigator's judgment, have an expected survival of less than 12 weeks.
21. Patients who have received other investigational drugs within 4 weeks prior to screening (Patients who did not receive investigational products or who participated only in non-interventional observational studies can be eligible).
22. Any patient deemed unsuitable for participation in this clinical trial at the discretion of the investigator.

\[Only applicable to the cohort of TB511 and ICIs combination therapy in Phase 2a Clinical Trial\]

1. Patients with thyroid-stimulating hormone (TSH) levels above the institutional upper limit of normal (ULN) at the time of screening (Note: patients with abnormal TSH levels may be eligible if free T4 and total T3 levels are within normal ranges).
2. Patients with a history of hypersensitivity to any component of pembrolizumab.