| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Estrogen-receptor positive, human epidermal growth factor receptor-2 negative advanced breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1
• Monotherapy Dose Escalation: Determine a maximum tolerated
dose (MTD) or recommended Phase 2 dose (RP2D) for ZN-c5 as a
monotherapy
• Monotherapy Expansion: Investigate the safety and tolerability of
ZN-c5 as a monotherapy in subjects with Estrogen Receptor (ER)
positive, Human Epidermal Growth Factor Receptor-2 (HER2)
negative advanced breast cancer
• Combination Dose Escalation: Determine an MTD or RP2D for
ZN-c5 when administered in combination with palbociclib
Phase 2
• Monotherapy Phase 2: Determine preliminary anti-tumor efficacy
(Clinical Benefit Rate [CBR]) for ZN-c5 as a monotherapy
• Combination Phase 2: Determine preliminary anti-tumor efficacy
(CBR) for ZN-c5 when administered in
combination with palbociclib |
|
| E.2.2 | Secondary objectives of the trial |
• Monotherapy Dose Escalation and Monotherapy Phase 2: Investigate
the safety and tolerability of ZN-c5 as a monotherapy in subjects with ER
positive, HER2 negative advanced breast cancer
• Combination Dose Escalation and Combination Phase 2: Investigate the
safety and tolerability of ZN-c5 in combination with palbociclib in
subjects with ER positive, HER2 negative advanced breast cancer
• Monotherapy Expansion Phase 1: Investigate the preliminary antitumor
efficacy (CBR) for ZN-c5 as a monotherapy
• All Cohorts: Assess preliminary efficacy of ZN-c5 alone and in
combination with palbociclib by Objective Response Rate (ORR), CBR,
Duration of Response (DOR), Progression-Free Survival (PFS) and
Overall Survival (OS) using Response Evaluation Criteria in Solid Tumors
(RECIST v.1.1) as assessed by investigators
• Monotherapy Dose Escalation and Monotherapy Expansion Phase 1 and
Monotherapy Phase 2: Characterize the pharmacokinetics (PK) of ZN-c5 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Male or female
2) Age ≥ 18 years
3) Menopausal Status [Female subjects]:
Postmenopausal, as defined by at least one of the following
a) Age ≥ 60 years;
b) Age < 60 years and cessation of regular menses for at least 12
consecutive months with no alternative pathological or physiological
cause; and serum estradiol and FSH level within the laboratory's
reference range for postmenopausal females;
c) Documented bilateral oophorectomy;
or
Pre- or peri-menopausal, who must receive a gonadotropin-releasing
hormone agonist beginning at least 4 weeks prior to first dose of study
medication.
4) Histologically or cytologically confirmed diagnosis of advanced
adenocarcinoma of the breast, not amenable to any potential curative
intervention
5) Estrogen Receptor (ER) positive disease defined as follows
documented by a local laboratory:
a) [Monotherapy Escalation and Combination Dose Escalation Cohorts]:
> 1% positive stained cells based on medical record, archival tumor
biopsy, or de novo tumor biopsy
b) [Monotherapy Expansion/Monotherapy Phase 2/Combination Phase 2
Cohorts]: > 10% positive stained cells
6) Human Epidermal Growth Factor Receptor 2 (HER2) negative disease
as documented by a local laboratory
a) [Monotherapy Escalation and Combination Dose Escalation Cohorts]:
Documentation by medical record or archival tumor tissue allowed
b) [Monotherapy Expansion/Monotherapy Phase 2/Combination Phase 2
Cohorts]: Based on analysis of archival tumor biopsy or de novo biopsy
with HER2-negativity defined as: 1) Immunohistochemistry score 0/1+
or 2) Negative by in situ hybridization (FISH/CISH/SISH) defined as a
HER2/CEP17 ratio < 2, or for single probe assessment a HER2 copy
number < 4
7) [Monotherapy Escalation and Combination Dose Escalation Cohorts]:
Refractory to or intolerant of established therapy(ies) known to provide
clinical benefit for their malignancy
8) Prior Hormonal Therapy:
a) [Monotherapy Expansion Cohort]: up to 2 prior lines of endocrine
therapy for advanced or metastatic breast cancer
b) [Monotherapy Phase 2]: 1 or 2 prior lines of endocrine therapy for
advanced or metastatic breast cancer
c) [Combination Phase 2]: up to 1 prior line of endocrine therapy for
advanced or metastatic breast cancer
d) Subjects who will undergo a FES-PET must have discontinued all prior
ER blocking therapy (e.g., tamoxifen or fulvestrant) for ≥ 60 days before
the day of the examination at baseline.
In counting lines of treatment for advanced/metastatic disease, any
change in regimen due to PD or toxicity will be counted as a separate
line of treatment.
9) Documented prior response to endocrine therapy for advanced or
metastatic disease (SD, PR, or CR) lasting > 6 months or disease
recurrence after at least 24 months of adjuvant endocrine treatment.
(not required for treatment naïve patients)
10) Prior Chemotherapy:
a) [Monotherapy Dose Escalation Cohort]: Up to 2 prior lines of
chemotherapy for the treatment of advanced breast cancer
b) [Monotherapy Phase 2]: No prior chemotherapeutic regimens for the
treatment of advanced breast cancer
c) [Monotherapy Expansion, Combination Dose Escalation and
Combination Phase 2 Cohorts]: Up to 1 prior line of chemotherapy for the
treatment of advanced breast cancer
In counting lines of treatment for advanced/metastatic disease, any
change in regimen due to PD or toxicity will be counted as a separate
line of treatment.
11) Prior treatment with a CDK4/6 inhibitor is allowed
12) Evaluable or measurable disease per RECIST v1.1.
13) Eastern Cooperative Oncology Group (ECOG) Performance Status of
≤ 2
14) All acute toxic effects of any prior anti-tumor therapy resolved to
Grade ≤ 1 or baseline (with the exception of alopecia [any grade
permitted])
15) Adequate organ function defined as follows:
a) Hematologic: Platelets ≥ 100 × 109/L; Hemoglobin ≥ 9.0 g/dL;
Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L (without platelet
transfusion or any growth factors within previous 7 days of the
hematologic laboratory values obtained at Screening visit).
b) Hepatic: Aspartate transaminase (AST) and Alanine transaminase
(ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN in case of liver
metastases; Total or conjugated bilirubin ≤ 1.5 × ULN.
c) Renal: Creatinine clearance (CrCl) ≥ 30 mL/min as calculated by the
Cockcroft Gault method or serum creatinine ≤ 1.5 × ULN
16) [Premenopausal and perimenopausal female subjects]: Negative
serum pregnancy test
17) Male and female subjects of childbearing potential or partners of
subjects who engage in intercourse must agree to use protocol specified
method(s) of contraception.
|
|
| E.4 | Principal exclusion criteria |
1) Any of the following within the specified window prior to the first
dose of study drug:
a) Tamoxifen, AI, fulvestrant or other anti-cancer endocrine therapy <
14 days
b) Any chemotherapy < 28 days (or 5 half-lives, whichever is shorter)
c) Any investigational drug therapy < 28 days or 5 half-lives (whichever
is shorter)
d) Prior radiotherapy < 14 days (except for palliative radiotherapy to
peripheral sites without residual toxicity)
e) Major surgery < 28 days
f) Minor surgery < 7 days (placement of central venous catheter, fine
needle aspiration, or endoscopic biliary stent < 1 day is acceptable)
2) Prior hematopoietic stem cell or bone marrow transplantation
3) Prior radiotherapy to > 25% of bone marrow
4) Brain metastases that require immediate treatment or are clinically or
radiologically unstable (i.e., have been stable for < 1 month). If
receiving steroids, subjects must be receiving a stable to decreasing
corticosteroid dose during at least 1 week before enrollment.
5) Leptomeningeal disease that requires or is anticipated to require
immediate treatment.
6) Presence of life-threatening metastatic visceral disease or
symptomatic pulmonary lymphangitic spread
7) Other known active cancer(s) likely to require treatment in the next
year that would impact the assessment of any study endpoints
8) [Female subjects]: Pregnant or breast-feeding
9) Unexplained symptomatic endometrial disorders (including, but not
limited to endometrial hyperplasia, dysfunctional uterine bleeding, or
cysts)
10) Uncontrolled symptomatic thyroid dysfunction
11) Impairment of gastrointestinal (GI) absorption for oral medications
12) Nausea, vomiting, or diarrhea > Grade 1
13) Myocardial infarction, symptomatic congestive heart failure (NYHA >
Class II), unstable angina, or serious uncontrolled cardiac arrhythmia
within the last 6 months
14) QTc interval > 480 msec (based on the mean value of the triplicate
ECGs), family or personal history of long or short QT syndrome, Brugada
syndrome or history of Torsade de Pointes
15) Concurrent use of food or drugs known to be moderate or strong
CYP3A or CYP2C9 inducers and moderate or strong CYP3A4 or CYP2C9
inhibitors. In addition, for moderate or strong CYP3A or CYP2C9
inducers, there should be a wash-out of 14 days (or 5 half-lives,
whichever is shorter) before the first administration of study drug
16) Any clinically significant disorder, condition, or disease that, in the
opinion of the Investigator or Medical Monitor would pose a risk to
subject safety or interfere with the study evaluations, procedures, or
completion
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Monotherapy Dose Escalation and Combination Dose Escalation:
Observed Dose Limiting Toxicities
• Monotherapy Expansion: Safety and tolerability as measured by
incidence of treatment-emergent adverse events (TEAEs) and lab
abnormalities
• Monotherapy Phase 2 and Combination Phase 2: CBR (CR [+ PR] + SD ≥ 24 weeks). PR will only
be included for patients with measurable disease. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monotherapy Dose Escalation and Monotherapy Expansion: Single agent
ZN-c5 will be evaluated at sequentially escalating doses starting with 50 mg
and up to 1200 mg administered orally, once daily (alternatively, this total
daily dose may be divided by 2 and administered BID [every 12 hours]),
using a 28-day cycle (Dose Escalation). During or on completion of the Dose
Escalation, additional patients may be enrolled onto one or more dose
levels for the Monotherapy Expansion portion of the study. The decision to
expand will be based on the PK, safety and available biomarker data.
|
|
| E.5.2 | Secondary end point(s) |
• All Cohorts: Safety and tolerability as measured by incidence of
treatment-emergent AEs and lab abnormalities
• Monotherapy Expansion: CBR (CR [+ PR] + SD ≥ 24 weeks). PR will
only be included for patients with measurable disease.
• All Cohorts: Tumor response including ORR, DOR, CBR, PFS using
Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) as
assessed by Investigators, and OS
• All Cohorts: ZN-c5 (and its potential metabolites as applicable) and
palbociclib (if applicable) plasma pharmacokinetic (PK) parameters
(including Cmax, Tmax, AUClast, t½ and Ctau, as applicable)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Following the determination of the MTD/RP2D for ZN-c5 in combination with palbociclib, additional
subjects will be enrolled to further assess the safety, tolerability, and preliminary efficacy of ZN-c5 in
combination with palbociclib.
Patients are evaluable for assessment of anti-tumor efficacy (based on CBR) if they were dosed and had
at least 1 post baseline disease/tumor assessment. CBR as measured using RECIST v.1.1
will be assessed to provide a preliminary, anti-tumor activity evaluation.
|
|
| 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 | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Lebanon |
| United States |
| Belarus |
| Bosnia and Herzegovina |
| Georgia |
| Moldova, Republic of |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Belgium |
| Bulgaria |
| Czechia |
| Hungary |
| Lithuania |
| United Kingdom |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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