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

Triple Negative Breast Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03720431
• Other study ID #: PMC_TTAC-0001_05
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: January 3, 2019
• Est. completion date: October 26, 2022

Study information

• Verified date: August 2022
• Source: PharmAbcine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 11
• Est. completion date: October 26, 2022
• Est. primary completion date: March 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Drug:
• TTAC-0001 and pembrolizumab combination
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)

Locations

Country	Name	City	State
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Hollywood Private Hospital	Nedlands	Western Australia

Sponsors (1)

Lead Sponsor	Collaborator
PharmAbcine

Country where clinical trial is conducted

Australia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacokinetic parameters - Cmax	Maximum concentration of drug 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
Other	Pharmacokinetic parameters - Cmin	Minimum concentration of drug 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
Other	Pharmacokinetic parameters - AUC0-t	Area under the curve from baseline to each timepoint 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
Other	Pharmacokinetic parameters - Tmax	Time of Cmax 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
Other	Pharmacokinetic parameters - CL	Clearance by dose level	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
Other	Pharmacokinetic parameters - Vd	Volume of distribution 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
Other	Pharmacokinetic parameters - Ke	Elimination rate constant 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
Other	Pharmacokinetic parameters - T½	Half-life 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
Other	Change in concentration of serum angiogenic factor or receptor	VEGF, placental growth factor [PLGF], soluble vascular endothelial growth factor receptor [sVEGFR]-2, sVEGFR-1, etc.	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
Other	PD-L1, VEGFR-2 expression level	PD-L1, VEGFR-2 expression level in tumour environment such as tumour, tumour vessel and parenchymal tissue	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
Primary	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
Primary	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
Primary	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	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)]
Secondary	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)
Secondary	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
Secondary	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