| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Triple Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Triple Negative Breast Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10071115 |
| E.1.2 | Term | Node-negative breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1:
- To determine the safety, tolerability, maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ZEN003694 in combination with talazoparib in patients with locally advanced or metastatic triple-negative breast cancer (TNBC)
Part 2:
- To evaluate the efficacy of ZEN003694 in combination with talazoparib in patients with locally advanced or metastatic TNBC
Expansion
To evaluate the efficacy of ZEN003694 in combination with talazoparib in patients with locally advanced or metastatic TNBC whose cancer was hormone receptor negative (<5%) at the time of initial breast cancer diagnosis and who have received TROP2-ADC therapy in the unresecable locally advanced or metastatic disease setting. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1
- PK of ZEN003694, ZEN003791, talazoparib
- Effects of ZEN003694 +talazoparib on mRNA expression & on patient reported health status
- Clinical activity of ZEN003694 +talazoparib by radiographic response and progression
Part 2
- Safety and tolerability of ZEN003694 + talazoparib
- PK of ZEN003694, ZEN003791, talazoparib
- Effect of ZEN003694 + talazoparib on patient reported health status
Expansion
- Efficacy of ZEN003694 and ZEN003694 + talazoparib in patients TNBC whose cancer was hormone receptor negative and who have not received TROP2-ADC in the unresectable locally advanced or metastatic disease and have received prior TROP2-ADC.
- To further evaluate the safety and tolerability of ZEN003694 in combination with talazoparib
-To determine the pharmacokinetics (PK) of ZEN003694, its metabolite, ZEN003791, and talazoparib
-To determine the effect of ZEN003694 and talazoparib patient reported health status and quality of life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Females or males age ≥ 18 years (at time of signing informed consent)
2. Parts 1 and 2: Histologically confirmed metastatic or recurrent or locally advanced triple-negative breast cancer (estrogen receptor (ER) ≤10%; progesterone receptor (PR) ≤10%; HER2 negative by immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH)
Expansion: Histologically confirmed metastatic or recurrent, or locally advanced triple-negative breast cancer as defined by the most recent American Society of Clinical Oncology/College of American pathologists (ASCO/CAP) guidelines
3. Parts 1 and 2 only: Patient is not a candidate for endocrine based therapy based on Investigator judgement
4. Have a history of progressive disease despite prior therapy
5. Part 1: Have had at least 1 prior cytotoxic chemotherapy. Part 2: Have had no more than 2 prior chemotherapy-inclusive regimens for locally
advanced or metastatic disease, unless approved by the Sponsor (no limit on prior targeted anticancer therapies such as mechanistic target or rapamycin (mTOR) or CDK4/6 inhibitors, immune-oncology agents, tyrosine kinase inhibitors, or monoclonal antibodies against CTL4 or VEGF).
Expansion Cohort A (combination treatment in post-TROP2-ADC patients): Have received TROP2-ADC therapy for unresecable locally advanced or metastatic disease.
Expansion Cohort B (ZEN003694 monotherapy): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease which may or may not have included TROP2-ADC therapy.
Expansion Cohort C (combination treatment in TROP2-ADC-naive patients): Have had at least 1 prior systemic therapy for locally advanced or metastatic disease and who have not received prior TROP2- ADC therapy.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7. Part 2 and Expansion only: Measurable disease per RECIST version 1.1
8. Adequate laboratory parameters at Screening including:
a. Parts 1 and 2: Hemoglobin ≥ 10.0 gm/dL without transfusions during the 4 weeks prior to Screening. Expansion: Hemoglobin ≥ 9.0 gm/dL
b. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
c. Platelet count ≥ 150,000/mm3
d. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x ULN or if liver function abnormalities due to liver metastases AST and ALT ≤ 5.0 x ULN
e. Total bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN for subjects with known Gilbert's syndrome)
f. Calculated (Cockcroft-Gault formula) or measured creatinine clearance ≥ 60 mL/min
g. Prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x ULN
9. Female subjects may be enrolled if they are not of childbearing potential, permanently sterile or who are post-menopausal, defined as no menses for at least 1 year without an alternative medical cause and FSH levels in the post-menopausal range. Female subjects of childbearing potential may be enrolled if they consistently and correctly use a highly effective form of contraception. from the time point of study drug administration until at least 7 months thereafter. Highly effective forms of contraception include: combined (estrogen and progestogen hormonal contraceptives (oral, intravaginal, transdermal) associated with inhibition of ovulation; progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence.
Female subjects should not donate eggs from the time point of study drug administration until at least 7 months thereafter.
10. Males with partners of childbearing potential may be enrolled if they use a condom when having sex with a pregnant woman or with a nonpregnant female of childbearing potential from 21 days before the first dose of study drug through 4 months after the last dose of study drug,
and males should not donate sperm from the time point of study drug administration until at least 4 months thereafter. Contraception should
be considered for a non-pregnant female partner of childbearing potential.
11. Females of childbearing potential must have a negative serum or urine pregnancy test before the first dose of study drug and must agree pregnancy tests during the study.
12. Females may not be breast-feeding at the first dose of study drug, during study participation or through 7 months after the last dose of study drug.
13. Ability to swallow capsules and comply with study procedures
14. Ability to understand and willingness to sign informed consent form prior to initiation of any study procedures |
|
| E.4 | Principal exclusion criteria |
1. Documented germline BRCA1 or BRCA2 mutations
2. Parts 1 and 2 only: Evidence of disease progression during platinum treatment either in the neoadjuvant or in the metastatic setting. For patients receiving platinum in the neoadjuvant setting, at least 6 months must have elapsed between the last dose of platinum-based treatment and
enrollment.
3. Part 2 only: Patients with inflammatory breast cancer (in Part 2 only)
4. Current or anticipated use of medications known to be strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow
therapeutic windows. Strong inhibitors, inducers or substrates must be discontinued at least 7 days prior to the first administration of study
drug.
5. Current or anticipated use within 7 days prior to the first administration of study drug, or during the study, of strong P-gp
inhibitors.
6. Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor
IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed.
7. Prior anticancer therapy (chemotherapy, radiation, hormone therapy, immunotherapy or investigational agent) within 3 weeks from the start
of study drug (except for nitrosoureas and mitomycin C within 6 weeks from start of study drug).
8. Parts 1 and 2 only: Radiation to >25% of the bone marrow
9. Treatment with a bone-targeted radionuclide within 6 weeks of first dose of study drug.
10. Have previously received an investigational BET inhibitor (including previous participation in studies with the Sponsor's drug, ZEN003694); except for patients in Expansion Cohort B who received ZEN003694 monotherapy and are eligible to cross-over to combination treatment
11. Prior treatment with a PARP inhibitor.
12. QTcF interval > 470 msec.
13. Insufficient recovery (i.e., has not recovered to at least Grade 1) from prior treatment-related toxicities except for alopecia, fatigue and Grade 2 neuropathy.
14. Non-healing wound, ulcer or bone fracture (not including a pathological bone fracture caused by a pre-existing pathological bone
lesion).
15. Parts 1 and 2 only: Brain metastases not adequately treated and clinically stable (at the discretion of the Investigator) for at least 3 months prior to the start of study treatment, unless a shorter interval is approved by the Sponsor's Medical Monitor
Expansion only: Progressive, symptomatic, or untreated brain metastases. CNS metastases treated definitively with surgery and/or
radiation must be radiographically stable based on imaging at least 3 months after definitive treatment. CNS metastases requiring steroid doses equivalent to prednisone doses >10 mg daily or an increase in steroid doses due to CNS disease prior to consent are not eligible
16. Expansion only: Disease initially diagnosed with expression of estrogen receptor (ER) or progesterone receptor (PR) as ≥5%
17. Expansion only: Patients treated with prior endocrine therapy
18. Known impaired cardiac function or clinically significant cardiac disease such as uncontrolled supraventricular arrhythmia, ventricular
arrhythmia requiring therapy, or congestive heart failure (New York Heart Association functional class III or IV)).
19. Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug.
20. Known myelodysplastic syndrome.
21. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active,
uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, or any other condition that could compromise safety or the
patient's participation in the study,
22. Impairment of gastrointestinal function (i.e., diagnosis of malabsorption syndrome) that may significantly alter the absorption of ZEN003694 or talazoparib.
23. Other known active cancer requiring therapy at time of study entry or that progressed or required treatment within 3 years prior to starting
study drug (except for skin basal cell carcinoma or squamous cell carcinoma or in situ cervical cancer).
24. Historically positive (screening tests not required) for human immunodeficiency virus (HIV); or hepatitis B virus (HBV) with currently
active disease defined as hepatitis Bsurface antigen (HBsAg) positivity; or hepatitis C virus (HCV) unless previously treated and viral load is undetectable.
25. Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior to the first administration of study drug.
26. Concurrent participation in another clinical investigational treatment trial with a systemic therapy
27. Any other reason that in the opinion of the Investigator would prevent the patient from completing participation or following the study
schedule. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
- Safety profile of ZEN003694 in combination with talazoparib
- DLT characteristics and MTD determination for ZEN003694 in combination with talazoparib
- RP2D of ZEN003694 in combination with talazoparib for further clinical investigation
Part 2:
- Clinical benefit rate (CBR) defined as a complete response (CR), partial response (PR) or stable disease (SD ≥ 4 cycles) by RECIST v1.1
Expansion Cohort A (Combination Treatment in post-Trodelvy patients):
-Objective response rate (ORR) by RECIST v1.1 (CR or PR) by investigator and by independent review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Part 1:
- Plasma concentrations of ZEN003694, the active metabolite ZEN003791 and talazoparib. The following PK parameters, at a minimum, will be calculated as appropriate: AUC0-last and AUC0-inf, Cmax and minimum or trough concentration (Cmin), dosing interval, and Tmax and half-life (t1/2)
-Clinical benefit rate (CBR)
- Overall response rate (ORR)
- Progression-free survival (PFS)
- Quality of Life
Part 2:
- Progression-free survival (PFS)
-Objective response rate (ORR)
- Duration of response (DOR)
- Plasma concentrations of ZEN003694, the active metabolite ZEN003791 and talazoparib. The following PK parameters, at a minimum, will be calculated as appropriate: AUC0-last and AUC0-inf, Cmax and minimum or trough concentration (Cmin), dosing interval, and Tmax and half-life (t1/2)
- Quality of Life
- Safety
Expansion Cohort A: Combination Treatment (post-Trodelvy patients)
-Duration of response (DOR)
-Clinical benefit rate (CBR)
-Progression free survival (PFS)
-Safety analyses will include, but are not limited to, AEs, laboratory abnormalities, ECG evaluations, and vital signs
-Pharmacokinetics: AUC0-last and AUC0-inf, Cmax, Cmin, Tmax, and T½ of ZEN003694, ZEN003791, and talazoparib during the first 2 treatment cycles
-Quality of Life
Expansion Cohort B: ZEN003694 Monotherapy
In discussions with the FDA, if there are 1 or 0 patients (out of the 10 evaluable patients enrolled) who show an objective response to ZEN003694 monotherapy, it could be concluded that ZEN003694 as a monotherapy has no clinical benefit.
Expansion Cohort C: Combination Treatment (Trodelvy-naïve patients)
-Objective response rate (ORR) by RECIST v1.1 (CR or PR) by investigator
-Duration of response (DOR)
-Clinical benefit rate (CBR)
-Progression free survival (PFS)
-Safety analyses will include, but are not limited to, AEs, laboratory abnormalities, ECG evaluations, and vital signs
-Pharmacokinetics: AUC0-last and AUC0-inf, Cmax, Cmin, Tmax, and T½ of ZEN003694, ZEN003791, and talazoparib during the first 2 treatment cycles
-Quality of Life |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| China |
| United States |
| Spain |
| Belgium |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 42 |
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