Triple Negative Breast Cancer
Conditions
Brief summary
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.
Interventions
* 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)
Sponsors
PharmAbcine
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female and male patients ≥18 years old 2. 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. 3. At least one confirmed measurable lesion by RECIST 1.1 criteria 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1 5. 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
1. 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) 2. 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 3. Has a history of (non-infectious) pneumonitis/interstitial lung diseases that required steroids or current pneumonitis/interstitial lung disease. 4. Has an active infection requiring systemic therapy 5. Uncontrolled hypertension (systolic blood pressure \[SBP\]\> 150 or diastolic blood pressure \[DBP\]\> 90 mmHg) 6. Uncontrolled seizures 7. Class III or IV heart failure by New York Heart Association (NYHA) classification 8. Has oxygen-dependent chronic disease 9. Active psychiatric disorder (schizophrenia, major depressive disorder, bipolar disorder etc.). Treated depression with ongoing antidepressant medication is not an exclusion 10. History of abdominal fistula or gastrointestinal perforation within 6 months prior to start of study drug 11. History of serious gastrointestinal haemorrhage within 6 months prior to start of study drug 12. History of severe arterial thromboembolic event within 12 months of start of study drug 13. Serious grade 4 venous thromboembolic event including pulmonary embolism 14. History of hypertensive crisis or hypertensive encephalopathy 15. History of posterior reversible encephalopathy syndrome 16. Planned surgery within 4 weeks post last dose 17. Moderate to severe proteinuria 18. Requiring therapeutic anticoagulation with warfarin at baseline 19. Not recovered below National Cancer Institute -Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 1 or baseline from AEs due to previous therapy 20. Treatment with systemic chemotherapy, hormonal therapy, immunotherapy or biologic therapy within 2 weeks prior to the baseline visit 21. Has received prior radiotherapy within 2 weeks of start of study treatment. 22. Undergone major surgery requiring general anaesthesia or a respiratory assistance device within 4 weeks prior to the baseline visit 23. Treated with other investigational drugs within 4 weeks prior to the baseline visit for this study 24. Female who is pregnant\* or lactating and of childbearing potential who does not agree to a reliable and adequate method of contraception 25. A known history of severe drug hypersensitivity or hypersensitivity to a therapy similar to the study drugs 26. Unable to participate in the trial according to the investigator's decision. 27. Previous therapy with vascular endothelial growth factor (VEGF)-targeted agents including (but not limited to) bevacizumab 28. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose limiting toxicities | During the first cycle (every cycle is 21 days) of treatment | The frequency and percentage of DLT will be presented by dose level |
| Adverse events | 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 | The frequency and percentage of AEs will be presented by dose level |
| Immunogenicity | 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 | Presence anti-drug antibody (ADA) will be listed |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate | 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)] | complete response (CR) or partial response (PR) by RECIST criteria |
| Overall survival | 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 | Period from the date of the drug administration to the patient's death |
| Disease control rate | 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) | complete response (CR), partial response (PR) or stable disease (SD) by RECIST criteria |
| Progression free survival | 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 | Period from the date of the drug administration to the disease progression time point |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic parameters - T½ | 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 | Half-life by dose level |
| Pharmacokinetic parameters - Cmax | 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 | Maximum concentration of drug by dose level |
| PD-L1, VEGFR-2 expression 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 | PD-L1, VEGFR-2 expression level in tumour environment such as tumour, tumour vessel and parenchymal tissue |
| Change in concentration of serum angiogenic factor or receptor | 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 | VEGF, placental growth factor \[PLGF\], soluble vascular endothelial growth factor receptor \[sVEGFR\]-2, sVEGFR-1, etc. |
| Pharmacokinetic parameters - Cmin | 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 | Minimum concentration of drug by dose level |
| Pharmacokinetic parameters - AUC0-t | 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 | Area under the curve from baseline to each timepoint by dose level |
| Pharmacokinetic parameters - Tmax | 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 | Time of Cmax by dose level |
| Pharmacokinetic parameters - CL | FFrom 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 | Clearance by dose level |
| Pharmacokinetic parameters - Vd | 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 | Volume of distribution by dose level |
| Pharmacokinetic parameters - Ke | 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 | Elimination rate constant by dose level |
Countries
Australia
Outcome results
None listed