Clinical Trial of TB511 in Advanced Solid Tumors

Prostate Cancer Clinical Trial

Official title: Phase I/IIa Clinical Trial to Assess the Maximum Tolerated Dose (MTD), Safety, and the Anti-tumor Effect of TB511 Monotherapy and Pembrolizumab Combination Therapy in Patients With Advanced Solid Tumors

Status Not yet recruiting

Clinical Trial Summary

1. Study population [TB511 Monotherapy Cohort for Phase I and Phase IIa Clinical Trial] Participants with an advanced solid tumor who are either refractory or intolerant to standard of care (SoC).

[Immune checkpoint inhibitors (ICIs) Combination Therapy Cohort for Phase IIa Clinical Trial] Participants with advanced solid tumor who have either not responded to or have relapsed after ICIs that are anti-PD-1 or PD-L1 inhibitors and who have no standard of care available.

2. Objectives of the Clinical Trial [Phase I Clinical Trial] 1) Primary Objective

• To evaluate the safety and tolerability of TB511 monotherapy in Participants with advanced solid tumor to determine maximum tolerated dose (MTD) and recommended Phase IIa dose (RP2D).

2) Secondary Objectives

• To evaluate the safety of TB511 monotherapy.

• To evaluate the objective response rate (ORR) and anti-tumor effect (based on Response Evaluation Criteria in Solid Tumors Version 1.1, RECIST v1.1) of TB511 monotherapy.

• To evaluate the pharmacokinetic characteristics of TB511 monotherapy. 3) Exploratory Objectives

• To compare the changes in biomarker levels of TB511 monotherapy.

• To evaluate immunogenicity by measuring anti-drug antibodies against TB511 [Phase IIa Clinical Trial]

1) Primary Objective

• To evaluate the ORR of TB511 monotherapy and combination therapy with Pembrolizumab in Participants with advanced solid tumors (based on RECIST v1.1).

2) Secondary Objectives

• To evaluate the disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) of TB511 monotherapy and combination therapy with Pembrolizumab.

• To evaluate the safety and tolerability of TB511 monotherapy and combination therapy with Pembrolizumab.

• To evaluate the pharmacokinetic characteristics of TB511 monotherapy and combination therapy with Pembrolizumab.

3) Exploratory Objectives

• To compare the changes in biomarker levels of TB511 monotherapy.

• To evaluate immunogenicity by measuring anti-drug antibodies against TB511

Clinical Trial Description

1. Number of participants

Phase I Clinical Trial: 3 to 6 participants per dose group Phase IIa Clinical Trial:

Approximately 20 participants per cohort (Cohort 1: Approximately 20 participants, Cohort 2: Approximately 20 participants)

2. Study Duration

Total clinical trial duration: Approximately 36 months from the IRB approval date (however, this may change depending on the time taken by participants to enroll.) Duration of participation of individual participants Screening period: Up to 4 weeks (28 days) Treatment period: 1 cycle consists of 3 weeks (21 days), and administration is continued until there are reasons to suspend administration.

Safety follow-up period: 6 weeks after the end of treatment (EOT)

3. Investigational Product

1. Study drug Product name or code: TB511 Injection (8 mg) Formulation and appearance:

White or off-white color of lyophilized powder Main ingredient: TB511 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 liquid contained in a colorless and transparent vial.

Main ingredient: Pembrolizumab 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 I Clinical Trial]

1. TB511 Initial dose: 4 mg Dose escalation: 4 mg, 8 mg, 16 mg, 24 mg Administration method: 1 cycle consists of 3 weeks (21 days). Administer subcutaneously into the abdomen once every 7 days for 3 weeks (21 days). Avoid repeat injection at the same site during subcutaneous injection, and administer injections while changing the location within the same area (abdomen). In addition, do not inject into the skin that is irritated or abnormal (scar, rash, redness, tenderness, etc.).

Administration plan: Administration is continued until intolerable toxicity, verification of progressive disease (PD) under RECIST v1.1 or other reasons for discontinuing administration occur.

[Phase 2a Clinical Trial]

1. TB511 Dose: Recommended dose for Phase IIa determined in Phase I Administration method:

1 cycle consists of 3 weeks (21 days). Administer subcutaneously into the abdomen once every 7 days for 3 weeks (21 days). Avoid repeat injection at the same site during subcutaneous injection, and administer injections while changing the location within the same area (abdomen). In addition, do not inject into the skin that is irritated or abnormal (scar, rash, redness, tenderness, etc.).

Administration plan: Administration is continued until intolerable toxicity, verification of progressive disease (PD) under RECIST v1.1 or other reasons for discontinuing administration occur.

2. Pembrolizumab Dose: 200 mg or dose adjusted in accordance with the label Administration method: Pembrolizumab is administered by continuous intravenous infusion for 30 minutes, once every 3 weeks (if pembrolizumab is administered with TB511, TB511 is administered at least 30 minutes after Pembrolizumab injection).

Administration plan: Administration is continued until intolerable toxicity, verification of progressive disease (PD) under RECIST v1.1 or other reasons for discontinuing administration occur.

5. Study Method

This clinical trial comprises a Phase I dose-escalation study to determine the maximum tolerated dose (MTD) of TB511 in participants with an advanced solid tumor who are either refractory or intolerant to standard of care and to determine the recommended Phase 2a dose (RP2D) and a Phase IIa study to verify the anti-tumor effect of TB511 monotherapy in dose determined in Phase I (Cohort 1) and in combination with Pembrolizumab (Cohort 2) in participants with an advanced solid tumor with no standard of care who have refractory or have relapsed after treatment with anti-PD-1 or PD-L1 ICIs.

Participants who have voluntarily signed the written informed consent form undergo a screening test to verify eligibility of participation in this clinical trial during the screening period. Participants who have been determined to be eligible in accordance with the inclusion and exclusion criteria are enrolled into this clinical trial and receive the determined dose of the investigational product. 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) under RECIST v1.1 or other reasons for discontinuing administration occur. RECIST (CT/MRI) is performed on Day 1 of cycle 1 and every 2 cycles thereafter. Pharmacokinetic evaluation is performed on Day 1 and Day 21 of Cycle 1, and exploratory evaluation is conducted at the screening and Day 21 of Cycle 1.

[Phase I Clinical Trial] TB511 Monotherapy Phase I clinical trial is conducted on a 3 + 3 basis beginning with the lowest-dose cohort until MTD is determined. Depending on the method of determining MTD, 3 to 6 participants are enrolled in the order for each dose level (TB511: 4 mg, 8 mg, 16 mg, 24 mg) with a minimum interval of 3 days, and TB511 is administered for Cycle 1 in order to determine DLT. DLT assessment is conducted in Cycle 1, and whether to escalate dose is determined by the Safety Review Committee (SRC) after the Cycle 1 DLT assessment has been completed for the last participant. RP2D of Phase IIa clinical trial is determined through MTD and overall toxicity assessment.

[Phase IIa Clinical Trial] Phase IIa clinical trial is conducted in approximately 20 participants with an advanced solid tumor for which there is no standard of care, who is subject to TB511 monotherapy cohort (Cohort 1) and approximately 20 participants with advanced solid tumor who have refractory or have relapsed after treatment with anti-PD-1 or ICIs that are PD-L1 inhibitors and for whom there is no standard of care, who is subject to TB511 and Pembrolizumab combination therapy cohort (Cohort 2).

Cohort 1 (TB511 Monotherapy Cohort) For Cohort 1, participants are enrolled consecutively and treated with the RP2D dose of TB511 determined in the Phase I clinical trial.

Cohort 2 (TB511 and Pembrolizumab Combination Cohort) For Cohort 2, the first 3 participants are enrolled serially with a minimum interval of 3 days and administered in combination of the RP2D dose of TB511 and Pembrolizumab for Cycle 1 to evaluate DLT. If DLT occurs, the 3 + 3 design is applied, and the SRC, thereby evaluate the safety of a total of 6 participants. When DLT occurs in 2 out of 3 to 6 subjects, the safety of combination therapy of a TB511 dose lower than the RP2D determined in Phase I and Pembrolizumab may be evaluated by the SRC in the same manner as above. If the safety of combination therapy of TB511 and Pembrolizumab is determined per the decision of the SRC, the remaining participants are simultaneously enrolled and participate in the clinical trial.

[Phase IIa Study Scheme]

1) Definition and Assessment of Dose Limiting Toxicity (DLT) DLT is an adverse event or abnormal laboratory level unrelated to the progress of the disease or intercurrent disease that limits dose escalation and is consistent with one or more of the following criteria: DLT assessment is conducted only at Cycle 1 after completion of Cycle 1. However, even during Cycle 1, DLT can be immediately evaluated if toxicity is determined to be DLT. DLT assessment is conducted in accordance with NCI-CTCAE v5.0 based on individual assessment items on hematological/non-hematological toxicity and other toxicities.

6. Endpoints

1. Safety Endpoints Adverse Events Vital signs Physical examination Electrocardiogram Laboratory test

2. Primary endpoint (Response Evaluation Criteria in Solid Tumors - RECIST) [Phase I Clinical Trial] Solid tumor response is evaluated in accordance with RECIST v1.1. Objective response rate (ORR): Fraction of participants whose best overall response is Complete Response (CR) or Partial Response (PR) Disease control rate (DCR): Fraction of participants whose best overall response is CR, PR or Stable Disease (SD) Duration of response (DoR): From the point of time when response occurs to (CR or PR) PD or death due to any reason.

[Phase IIa Clinical Trial] Solid tumor response is evaluated in accordance with RECIST v1.1 and immune RECIST (iRECIST).

Objective response rate (ORR): Fraction of participants whose best overall response is CR or PR Disease control rate (DCR): Fraction of participants whose best overall response is CR, PR or SD Duration of response (DoR): From the point of time when response occurs to (CR or PR) PD or death due to any reason.

Progression-free survival (PFS) period: Period from the initial date of administration of the investigational product to the date when objective progressive disease (PD) is verified by the investigator, or the date of death, whichever occurs first.

3. Pharmacokinetic endpoint Blood is collected on Day 1 and Day 21 of Cycle 1 from available participants among the participants of this clinical trial for pharmacokinetic evaluation. In all clinical trials, blood collection for pharmacokinetic evaluation is performed prior to the administration of the investigational product (- 60 minutes), and after the administration of the investigational product, at 0.16 h (± 3 minutes), 0.5 h (± 3 minutes), 1 h (± 5 minutes), 2 h (± 10 minutes), 4 h (± 10 minutes), 8 h (± 30 minutes), and 24 h (± 30 minutes).

Cycle 1, Day 1: AUClast, AUCinf, Cmax, Tmax, t1/2, CL/F, Vd/F Cycle 1, Day 21:

AUClast,ss, AUCtau,ss, AUCinf,ss, Cmax,ss, Tmax,ss, t1/2,ss, CLss/F, Vd,ss/F

4. Exploratory endpoints Compare changes of the biomarker from the value before TB511 treatment (screening visit) to the post-treatment value (Day 21).

Category Analysis method Examination items Tumor tissue ELISA CD18, CD163, TGF-ß1, IL-10, VEGF, IFN-γ, Granzyme B Blood ELISA TGF-ß1, VEGF, TNF-α, IFN-γ, IL-2 Flow cytometer (Tcell, NK cell) CD45, CD3(CD45+CD3+: T cells), CD4, IFN-γ (Activation), CD25, CD8, Granzyme B(Activation), CD56 (CD45+CD3-CD19-CD56: NK), CD19(CD45+CD3-CD19+: B cell)

Anti-drug antibody (ADA) to TB511 is measured on Day 1 of Cycle 1 and every 2 cycles, both before and after the administration of TB511, end of study, and safety follow-up (if needed), to compare changes. ;

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Colorectal Cancer
• Hepatocellular Carcinoma
• NSCLC
• Prostate Cancer

• NCT number: NCT06400160
• Study type: Interventional
• Source: Twinpig Biolab, Inc.
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: October 2024
• Completion date: October 2025