TTAC-0001 and Pembrolizumab Phase Ib Combination Trial in Metastatic Triple-negative Breast Cancer

Study Overview
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Brief Summary
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This is a phase 1b, open-Label clinical trial to determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) of TTAC-0001 administered in combination with pembrolizumab in patients with metastatic triple-negative breast cancer.

Official Title
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A Phase 1b, Open-Label, Safety and Tolerability Study of TTAC-0001 in Combination With Pembrolizumab in Patients With Metastatic Triple-Negative Breast Cancer

Conditions
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Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: TTAC-0001 and pembrolizumab combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female and male patients ≥18 years old Histologically proven metastatic breast carcinoma with triple negative receptor status (Estrogen receptor, Progesterone receptor and human epidermal growth factor receptor 2 [HER2] negative) by IHC and Fluorescence in situ hybridization (FISH) according to ASCO-CAP guideline3. At least one confirmed measurable lesion by RECIST 1.1 criteria Eastern Cooperative Oncology Group (ECOG) performance status 0-1 A person who satisfies the following criteria in hematologic, renal, and hepatic function tests performed within 7 days prior to screening: (1) Hematologic tests Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Haemoglobin ≥ 9.0 g/dL (2) Blood coagulation tests Prothrombin time (PT) ≤ 1.5 x Upper limit of normal (UNL) Activated partial thromboplastin Time (aPTT) ≤ 1.5 x UNL (3) Hepatic function tests Total bilirubin ≤ 1.5 x UNL Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN in case of liver metastasis) (4) Renal function test ≤1.5 × ULN or creatinine clearance (CrCl) ≥30 mL/min for patient with creatinine levels >1.5 × institutional ULN 6) At least 12 weeks of expected life expectancy 7) The patient (or legally acceptable representative if applicable) is able and willing to provide written informed consent for the trial. Exclusion Criteria: Has a known additional malignancy that is progressing or has required active treatment within the past 2 years. (Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) controlled by curative therapy are not excluded) Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment Has a history of (non-infectious) pneumonitis/interstitial lung diseases that required steroids or current pneumonitis/interstitial lung disease. Has an active infection requiring systemic therapy Uncontrolled hypertension (systolic blood pressure [SBP]> 150 or diastolic blood pressure [DBP]> 90 mmHg) Uncontrolled seizures Class III or IV heart failure by New York Heart Association (NYHA) classification Has oxygen-dependent chronic disease Active psychiatric disorder (schizophrenia, major depressive disorder, bipolar disorder etc.). Treated depression with ongoing antidepressant medication is not an exclusion History of abdominal fistula or gastrointestinal perforation within 6 months prior to start of study drug History of serious gastrointestinal haemorrhage within 6 months prior to start of study drug History of severe arterial thromboembolic event within 12 months of start of study drug Serious grade 4 venous thromboembolic event including pulmonary embolism History of hypertensive crisis or hypertensive encephalopathy History of posterior reversible encephalopathy syndrome Planned surgery within 4 weeks post last dose Moderate to severe proteinuria Requiring therapeutic anticoagulation with warfarin at baseline Not recovered below National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 1 or baseline from AEs due to previous therapy Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologic therapy within 2 weeks prior to the baseline visit Has received prior radiotherapy within 2 weeks of start of study treatment. Undergone major surgery requiring general anaesthesia or a respiratory assistance device within 4 weeks prior to the baseline visit Treated with other investigational drugs within 4 weeks prior to the baseline visit for this study Female who is pregnant* or lactating and of childbearing potential who does not agree to a reliable and adequate method of contraception A known history of severe drug hypersensitivity or hypersensitivity to a therapy similar to the study drugs Unable to participate in the trial according to the investigator's decision. Previous therapy with vascular endothelial growth factor (VEGF)-targeted agents including (but not limited to) bevacizumab Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TTAC-0001 and pembrolizumab<br>TTAC-0001 and pembrolizumab combination therapy will be administered. | Drug: TTAC-0001 and pembrolizumab combination<br>* Investigational product (IP): TTAC-0001 and Pembrolizumab (Merck, Keytruda®) Treatment groups: 3 dose levels Dose level 1 (optimal starting dose): TTAC-0001 12 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 Dose level 2 (first escalation dose): TTAC-0001 16 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 Dose level 0 (de-escalation dose): TTAC-0001 8 mg/kg on D1, D8 and D15 + Pembrolizumab 200 mg on D1 Cycle: 3 weeks (21 days per cycle)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities | The frequency and percentage of DLT will be presented by dose level | During the first cycle (every cycle is 21 days) of treatment | 
| Adverse events | The frequency and percentage of AEs will be presented by dose level | From date of screening visit until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Immunogenicity | Presence anti-drug antibody (ADA) will be listed | From date of screening visit until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | complete response (CR) or partial response (PR) by RECIST criteria | At every 2nd cycles until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years (every cycle is 21 days)] | 
| Disease control rate | complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria | At every 2nd cycles until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years (every cycle is 21 days) | 
| Progression free survival | Period from the date of the drug administration to the disease progression time point | From date of screening visit until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Overall survival | Period from the date of the drug administration to the patient's death | From date of screening visit until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years |