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

ConditionsAnatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IV Breast Cancer AJCC v8 Locally Advanced Triple-Negative Breast Carcinoma Metastatic Triple-Negative Breast Carcinoma Unresectable Triple-Negative Breast Carcinoma

Trial statusRecruiting

Trial phasePhase 1

Trial typeInterventional

Biological sexAll

Age18+

SponsorNational Cancer Institute (NCI)

About this trial

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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

Estrogen receptor (ER) and progesterone receptor (PR) < 10% by immunohistochemistry (IHC), and HER2-negative (per current American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines)

If there is more than one histological result available, the most recent sample with ER, PR and HER2 results will be considered for inclusion

Patients who have not had ER, PR and HER2 testing and thus, ER, PR and HER2 status is unknown, are not eligible

Participants without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation

Disqualifiers

History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694), nab-paclitaxel, or pembrolizumab

Patients with uncontrolled intercurrent illness

Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

Any gastrointestinal (GI) disorder that may affect absorption of oral medications in the opinion of the treating investigator, such as malabsorption syndrome or major bowel or stomach resection

Trial design

Design model

Sequential

Treatments tested in this trial

BET Bromodomain Inhibitor ZEN-3694
Drug
Given PO
Biopsy Procedure
Procedure/Surgery
Undergo biopsy
Biospecimen Collection
Procedure/Surgery
Undergo collection of blood samples
Computed Tomography
Procedure/Surgery
Undergo CT
Magnetic Resonance Imaging
Procedure/Surgery
Undergo MRI
Nab-paclitaxel
Drug
Given IV
Pembrolizumab
Biological/Vaccine
Given IV

Treatment groups

57 Participants

are divided into 2 treatment groups

Group A: Dose Escalation (ZEN003694, nab-paclitaxel, pembrolizumab)Experimental treatment 6 interventions

Group B: Dose Expansion (ZEN003694, nab-paclitaxel, pembrolizumab)Experimental treatment 7 interventions

Trial outcomes

Primary outcomes

Maximum tolerated dose (MTD) of ZEN003694 (ZEN-3694) used in combination with pembrolizumab and nab-paclitaxel

A Bayesian optimal interval design will be used to identify the MTD.

Time frame

Up to 28 days from start of treatment

Recommended phase 2 dose (RP2D) of ZEN003694 (ZEN-3694) used in combination with pembrolizumab and nab-paclitaxel

Will be for adverse events consistent with a dose-limiting toxicity definition.

Time frame

Up to 28 days from start of treatment

Incidence of adverse events

Toxicity will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Toxicities will be summarized by maximum grade and by treatment dose level. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.

Time frame

Up to 3 years from treatment start date

Secondary outcomes

Pharmacokinetics profile of the combination of ZEN003694 (ZEN-3694), pembrolizumab and nab-paclitaxel

Given the potential for interactions via CYP3A4, the pharmacokinetics of both ZEN003694 (ZEN-3694) and paclitaxel are assessed to confirm whether a clinically relevant drug-drug interaction occurs. Plasma concentration-time curves will be analyzed by noncompartmental methods using routines supplied in the Phoenix WinNonlin. For pembrolizumab, the primary assessment will be individual baseline pembrolizumab clearance as a continuous variable in uni-variate and multi-variate Cox proportional hazards models for progression free survival (PFS).

Time frame

Pre-dose & 2 hours (h) post-dose on cycle 0 day 1 (C0D1), C2D15, C4D1, & C6D8; pre-dose & 0.5h post-dose on C1D1; pre-dose & 0.5, 1, 2, 4, 6, 8 & 24h post-dose on C1D15

Recommended phase 2 dose (RP2D)

Will confirm the 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. Toxicity will be graded according to NCI CTCAE, Version 5.0. Toxicities will be summarized by maximum grade and by treatment dose level. Incidence rate of each toxicity will be reported with 95% exact confidence intervals.

Time frame

Up to 3 years

Overall response rate

Radiographic response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be graded as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). All patients (dose escalation, triple negative breast cancer \[TNBC\] unselected by PD-L1 status; dose expansion, TNBC PD-L1-negative) who receive at least one dose of study treatment will be included in the efficacy analyses.

Time frame

From start of the treatment until disease progression/ recurrence, or for up to 3 years

PFS

Radiographic response will be assessed by RECIST 1.1 criteria and will be graded as CR, PR, SD, and PD. Subjects without disease progression or death at the time of analysis will be censored at the date of last known alive. All patients (dose escalation, TNBC unselected by PD-L1 status; dose expansion, TNBC PD-L1-negative) who receive at least one dose of study treatment will be included in the efficacy analyses.

Time frame

From the time of study enrollment until the identification of disease progression or death, or for up to 3 years

Other outcomes

Potential biomarker indicators of response and resistance to the triplet combination

To characterize the expression of tumor markers by immunohistochemistry and/or IF, descriptive statistics and agglomerative hierarchical clustering techniques will be used to summarize the distribution and patterns of profiles observed in baseline samples. Descriptive statistics will be used to summarize the change in markers and inferences on treatment-effects will use non-parametric tests (e.g. Wilcoxon rank sum) with two-sided alpha 0.05.

Time frame

Baseline up to on-treatment and post-treatment biopsies

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

National Cancer Institute (NCI)

Lead sponsor

Source ClinicalTrials.gov

Apply now