Clinical Trial of TB511 in Advanced Solid Tumors

Trial Title: Clinical Trial of TB511 in Advanced Solid Tumors

NCT ID: NCT06400160

Condition: NSCLC
Prostate Cancer
Colorectal Cancer
Hepatocellular Carcinoma

Conditions: Official terms:
Carcinoma, Hepatocellular
Pembrolizumab

Study type: Interventional

Study phase: Phase 1/Phase 2

Overall status: Not yet recruiting

Study design:

Allocation: Non-Randomized

Intervention model: Parallel Assignment

Intervention model description: An Open-label, Multi-center, and Dose-escalation, Phase I/IIa Clinical Trial to Assess the Maximum Tolerated Dose (MTD), Safety, and the Anti-tumor Effect of TB511 Monotherapy in Patients with Advanced Solid Tumors Refractory or Intolerant to Standard of Care (SoC) and Pembrolizumab Combination Therapy in Patients with Advanced Solid Tumors Relapsed or Refractory

Primary purpose: Treatment

Masking: None (Open Label)

Masking description: Open Label

Intervention:

Intervention type: Drug
Intervention name: TB511
Description: TB511 is a peptide drug conjugate (PDC) which composed of TAMpep826 peptide. TB511 is a white amorphous powder used for subcutaneous injections. TB511 is a peptide drug conjugate that combines a transporter peptide with a specific targeting of M2 macrophages and an apoptosis-inducing peptide (dKLA). As a transporter, the M2 binding peptide acts as a drug conjugate, explicitly binding to M2 macrophages and inducing cell penetration. In the cells, the dKLA component of TB511 binds to the mitochondrial membrane, destroys the mitochondrial membrane, and induces apoptosis by causing cytochrome release, leading to the destruction of the mitochondria and subsequent death of M2 macrophages.
Arm group label: TB511

Intervention type: Drug
Intervention name: Keytruda
Description: KEYTRUDA binds to the PD - 1 receptor, blocking both immune-suppressing ligands, PD L1 and PD L2, from interacting with PD - 1 to help restore T-cell response and immune response.
Arm group label: Concomitant drug

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

Detailed 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.

Criteria for eligibility:
Criteria:
Inclusion Criteria: 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 or evaluable 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 the use of interceptive birth-control methods (i.e., condoms) and must agree that appropriate contraception is used by himself and his partner for 6 months after the end of administration of the investigational product. *Appropriate means of birth control: Complete abstinence, contraception hormonal agent of unknown drug interactions [levonorgestrel intrauterine system (IUS) (Mirena), medroxyprogesterone (Provera)], copper intrauterine device, and vasectomy by the male partner. Provided, however, that occasional abstinence (for example, abstinence based on ovulation time or symptomatic thermometry) is not considered an appropriate 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. Exclusion Criteria: 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 ≥ 450 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. 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 systemic corticosteroid administration (provided, however, that local use of corticosteroid, such as in joints, nasal cavity, eyes, or inhalation, and temporary systemic corticosteroid administration to treat and prevent the subject's contrast medium allergy or adverse event is permitted). 17. Patients who had been administered with live vaccine or attenuated live vaccine within 4 weeks prior to the screening. Laboratory tests 18. Patients whose laboratory levels are as follows as of the screening. - ANC < 1,500/mm³ - Platelet count < 100,000/mm³ - Hemoglobin < 9.0 g/dL (if hemoglobin level is recovered to over 9.0 g/dL during the screening period, the patient can be enrolled. Provided, however, that blood transfusion conducted 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 who are positive on a pregnancy test at the screening. 20. Patients whose remaining life expectancy is determined to be less than 12 weeks by the investigator. 21. Patients who have been treated with another investigational product within 4 weeks to the screening (patients who have not been treated with the investigational product or participated in a non-interventional study can be enrolled) 22. Patients with a history of drug or alcohol abuse 23. Patients whose participation in the clinical trial is deemed inappropriate by the investigator.

Gender: All

Minimum age: 19 Years

Maximum age: N/A

Healthy volunteers: No

Start date: October 2024

Completion date: October 2025

Lead sponsor:
Agency: Twinpig Biolab, Inc.
Agency class: Industry

Source: Twinpig Biolab, Inc.

Record processing date: ClinicalTrials.gov processed this data on November 12, 2024

Source: ClinicalTrials.gov page: https://clinicaltrials.gov/ct2/show/NCT06400160