Testing the Addition of Anti-Cancer Drug, ZEN003694 (ZEN-3694) and PD-1 Inhibitor (Pembrolizumab), to Standard Chemotherapy (Nab-Paclitaxel) Treatment in Patients With Advanced Triple-Negative Breast Cancer

Anatomic Stage III Breast Cancer AJCC v8 Clinical Trial

Official title: A Phase 1b Trial of ZEN003694 (ZEN-3694) With Pembrolizumab and Nab-Paclitaxel in Patients With Metastatic Triple-Negative Breast Cancer

Status Suspended

Clinical Trial Summary

This phase Ib trial tests the safety and tolerability of ZEN003694 in combination with an immunotherapy drug called pembrolizumab and the usual chemotherapy approach with nab-paclitaxel for the treatment of patients with triple negative-negative breast cancer that has spread to other parts of the body (advanced). Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Immunotherapy with monoclonal antibodies, such as pembrolizumab may help the body's immune system attach the cancer and may interfere with the ability of tumor cells to grow and spread. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Combination therapy with ZEN003694 pembrolizumab immunotherapy and nab-paclitaxel chemotherapy may help shrink or stabilize cancer for longer than chemotherapy alone.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694) used in combination with pembrolizumab and nab-paclitaxel in patients with locally advanced or metastatic triple negative-negative breast cancer (TNBC).

II. Evaluate the safety and tolerability of ZEN003694 used in combination with pembrolizumab and nab-paclitaxel in patients with locally advanced or metastatic TNBC.

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity. II. Confirm the recommended phase 2 dose (RP2D) from the trial by assessing the totality of the evidence (i.e., safety, tolerability, pharmacokinetic, and activity data) from this trial to select an optimal dosage(s) for future trials with registrational intent.

III. Evaluate the pharmacokinetic (PK) profile of the combination of ZEN003694, pembrolizumab and nab-paclitaxel.

IV. Determine the preliminary efficacy of the combination of ZEN003694, pembrolizumab and nab-paclitaxel, as assessed by overall response rate (ORR), progression-free survival (PFS), overall survival (OS), duration of response (DoR) and time to objective response (TTOR), utilizing Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, in patients with locally advanced or metastatic TNBC.

V. Quantify changes in PD-L1 pre- and post-exposure to BET bromodomain inhibitor (BBDI) and determine correlations that occur with response to the triplet combination.

VI. Quantify cytotoxic T cell populations, T cell activation, checkpoint expression, and angiogenesis and determine if location or absolute number of CD8+ T cells pre- and post-exposure to BBDI is predictive of response to immunotherapy with the triplet combination.

VII. Determine whether differential gene expression of immune-activating and immunosuppressive pathways occurs with exposure to single-agent BBDI and/or to the triplet combination of BBDI, PD-1 inhibition and taxane-based chemotherapy, and whether these changes correlate with response or resistance to treatment.

EXPLORATORY OBJECTIVES:

I. Explore potential biomarker indicators of response and resistance to the triplet combination in tumor tissue, blood, and stool samples.

OUTLINE: This is a dose-escalation study of ZEN003694 in combination with fixed-dose pembrolizumab and nab-paclitaxel, followed by a dose-expansion study.

DOSE ESCALATION: Patients receive ZEN003694 orally (PO) once daily (QD) on days 1-21, nab-paclitaxel intravenously (IV) over 30 minutes on day 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) scan and collection of blood samples throughout the trial.

DOSE EXPANSION: Patients receive ZEN003694 PO QD on days 1-7 prior to combination therapy. Patients then receive ZEN003694 PO QD on days 1-21, nab-paclitaxel IV over 30 minutes on days 1, 8, and 15, and pembrolizumab IV over 30 minutes every 21 days of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity with a maximum of 35 doses of pembrolizumab administered. Patients also undergo biopsies on study, and CT or MRI scans and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up for 30 days after the last dose of study medication and then every 6 months for a maximum of 3 years or until death, whichever occurs first. ;

Related Conditions & MeSH terms

• Anatomic Stage III Breast Cancer AJCC v8
• Anatomic Stage IV Breast Cancer AJCC v8
• Breast Neoplasms
• Carcinoma
• Metastatic Triple-Negative Breast Carcinoma
• Triple Negative Breast Neoplasms
• Unresectable Triple-Negative Breast Carcinoma

• NCT number: NCT05422794
• Study type: Interventional
• Source: National Cancer Institute (NCI)
• Status: Suspended
• Phase: Phase 1
• Start date: May 18, 2023
• Completion date: December 31, 2025