| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Brain Metastasis from Estrogen Receptor Positive, HER-2 Negative Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Brain Metastasis from Estrogen Receptor Positive, HER-2 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 | 27.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 1b
Determine the recommended Phase 2 dose (RP2D) of elacestrant in combination with abemaciclib in patients with metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER-2) negative breast cancer.
Phase 2
Evaluate the efficacy of elacestrant in combination with abemaciclib, in terms of ORR (per RECIST version 1.1) in ER positive, HER-2 negative breast cancer in patients with brain metastases. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b
• Characterize the safety of elacestrant in combination with abemaciclib.
• Describe the plasma pharmacokinetics (PK) of elacestrant and abemaciclib when administered in combination.
• Evaluate the efficacy of elacestrant in combination with abemaciclib, in terms of objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1, duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS).
Phase 2
• Evaluate the efficacy of elacestrant in combination with abemaciclib:
o Intracranial response rate (RR), per RECIST version 1.1.
o Intracranial RR, per the Response Assessment in Neuro-Oncology (RANO) Working Group criteria (Wen et al., 2017) as adapted to the assessment of brain metastases (RANO-BM).
o DoR, CBR, PFS and OS.
• Describe the plasma PK of elacestrant and abemaciclib when administered in combination. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient has signed the informed consent form before any study-related activities according to local guidelines.
2. Women or men aged ≥18 years, at the time of informed consent signature.
− Female patients may be either postmenopausal or pre/perimenopausal. Postmenopausal status is defined by:
a) Age ≥60 years
b) Age <60 years and amenorrhea for 12 or more months (without any alternative reason) and follicle-stimulating hormone (FSH) and estradiol in postmenopausal ranges per local reference ranges
c) Documentation of prior bilateral oophorectomy, at least 1 month before first dose of trial therapy.
− Pre/perimenopausal women and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist starting at least 3-4 weeks before the start of trial therapy and is planning to continue LHRH during the study.
3. Patient must have ER positive, HER-2 negative tumor status as confirmed by local laboratory testing in the following manner:
o Documentation of ER positive tumor with ≥ 1% staining by immunohistochemistry (IHC) as defined in the 2010 or 2020 American Society for Clinical Oncology (ASCO) recommendations for ER testing (Hammond, et al, 2010; Allison, et al, 2020), with or without progesterone receptor (PGR) positivity
o HER-2 negative tumor with an IHC result of 0 or 1+ for cellular membrane protein expression or an in situ hybridization negative result as defined in the 2013 or 2018 ASCO recommendations for HER-2 testing (Wolff, et al, 2013; Wolff, et al, 2018)
4. In Phase 2, patients must have at least one active and measurable brain metastasis per RECIST version 1.1
− Any of the following qualifies brain metastases as active:
a) Newly diagnosed brain metastasis in patients who never received prior central nervous system (CNS)-directed therapy
b) Newly diagnosed brain metastasis outside any area that was previously subjected to CNS-directed therapy
c) Brain metastases that are clearly progressing in an area that has previously been subjected to CNS-directed therapy.
− For lesions, including brain metastases, to qualify as measurable, and possibly be selected as target lesions, per RECIST version 1.1, the longest diameter must be ≥10 mm by CT or MRI).
− In Phase 1b, the presence of brain metastases is allowed but not required for eligibility, in this case, at least 1 measurable lesion outside the brain is required.
5. Patients receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 7 days prior to baseline and not receiving doses higher than 4 mg of dexamethasone per day or equivalent.
6. Any neurological symptoms of brain metastases must be stable for at least 2 weeks before starting trial therapy. Fluctuations of the previously known symptoms deemed to be due to clinical intercurrent processes
(e.g. electrolytes alterations, fever) are admissible if fully resolved before the first dose of study drugs.
7. Patient prior therapy received in the metastatic setting includes:
− At least one endocrine therapy
− Up to two chemotherapy regimens
− Up to two prior cyclin-dependent kinase (CDK) 4/6 inhibitors, not including abemaciclib
Note 1: Toxicity from prior therapy must be resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤1, with the exception of alopecia and peripheral sensory neuropathy (Grade ≤2).
8. Patient has documented intra- and/or extra-cranial clear radiological progression or recurrence while on or after the most recent therapy.
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
10. Patient has adequate bone marrow and organ function, as defined by the following laboratory values:
a. Absolute neutrophil count (ANC) ≥1.5 × 109/L
b. Platelets ≥100 × 109/L
c. Hemoglobin ≥9.0 g/dL
d. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE Grade ≤1
e. Creatinine clearance (per Cockcroft-Gault formula [Appendix E]) ≥50 mL/min
f. Serum albumin ≥3.0 g/dL (≥30 g/L)
g. Liver function tests:
• In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper limit of normal (ULN).
• If the patient has liver metastases, ALT and AST ≤5 × ULN.
h. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤1.5 × ULN.
Please see the protocol for further incl criteria |
|
| E.4 | Principal exclusion criteria |
1. Immediate CNS-specific treatment is likely to be required, per the
treating physician's assessment.
2. Patient with imminent organ failure and/or visceral crisis.
3. Patient has leptomeningeal metastases, defined as having positive
CSF cytology or unequivocal radiologic and clinical evidence of
leptomeningeal involvement.
4. Breast cancer treatment-naïve patients in the advanced/metastatic
setting.
5. Prior therapy with abemaciclib in the metastatic setting. Note: use of
abemaciclib in the adjuvant setting is allowed if the last treatment
administration was more than 12 months prior to first recurrence.
6. Prior therapy with elacestrant or other investigational selective
estrogen receptor degraders (SERDs), or investigational alike agents
such as selective estrogen receptor modulators (SERM), selective
estrogen receptor covalent antagonists (SERCANs), complete estrogen
receptor antagonists (CERANs), and proteolysis-targeting chimeras
(PROTACs), in the metastatic setting.
7. Patient has a concurrent malignancy or malignancy within 3 years of
enrollment, with the exception of adequately treated basal or squamous
cell skin cancer, superficial bladder cancer, carcinoma in situ of the
cervix or second primary breast cancer.
8. Currently participating in another breast cancer intervention clinical
study. Patients who are being followed for overall survival for another
clinical trial with no therapy and study intervention are allowed after the
washout period for any prior therapy.
9. Prior anti-cancer or investigational drug treatment within the
following windows:
• Fulvestrant treatment (last injection) <42 days before first dose of
study drug.
• Any other endocrine therapy <14 days before first dose of study drug.
Note: LHRH agonists alone should not be counted as endocrine therapy.
• Chemotherapy or other anti-cancer therapy <14 days before first dose
of study drug.
• Any investigational anti-cancer drug therapy within <28 days or <5
half-lives, whichever is shorter.
• Bisphosphonates or RANKL inhibitors initiated, or dose changed <1
month prior to first dose of study drug.
10. Radiation therapy (other than CNS directed) within 14 days before
the first dose of study drug. CNS directed radiation therapy within 28
days before the first dose of study drug.
11. Uncontrolled significant active infections.
• Patients with hepatitis B virus (HBV) and/or hepatitis C virus (HCV)
infection must have undetectable viral load during screening.
• Patients known to be HIV+ are allowed as long as they have
undetectable viral load at baseline.
12. Major surgery within 4 weeks of starting trial therapy.
13. Inability to take oral medication, or history of malabsorption
syndrome or any other uncontrolled gastrointestinal condition.
14. Females of childbearing potential who do not agree to use a highly
effective non-hormonal method of contraception and to abstain from
donating ova within 28 days of the first dose of study treatment through
120 days after the last dose of study treatment. Highly effective nonhormonal
method of contraception includes any of the following:
a. Intrauterine device (non-hormonal).
b. Sexual abstinence.
c. Bilateral tubal occlusion/ligation.
d. Have a vasectomized partner with confirmed azoospermia.
Note: Please refer to Appendix F for further details.
15. Male patients (including males with a vasectomy) with a pregnant or
non-pregnant female of childbearing potential partner who do not agree
to use a highly effective barrier contraception method (condoms) within
28 days of the first dose of study treatment until 120 days of the last
dose of study treatment. And male patients who do not agree to abstain
from donating sperm within the same period.
In addition, female partners of childbearing potential of male patients
(who has not undergone vasectomy) must use highly effective methods
of contraception, as described in Appendix F.
16. Females who are pregnant or breastfeeding. Females should not get
pregnant during study treatment and for 120 days after last dose of
study treatment. Females should not breastfeed during administration of
elacestrant and for 1 week after receiving the last dose.
17. Known intolerance to either study drug or any of the excipients.
18. Patient is currently receiving or received any of the following
medications prior to first dose of trial therapy:
a. Known strong or moderate inducers or inhibitors of cytochrome P450
(CYP) 3A4 (including foods and herbal preparations) within 14 days or 5
half-lives, whichever is shorter, (Refer to Section 5.2.3).
b. Herbal preparations/medications (which are not strong or moderate
inducers or inhibitors of CYP3A4). These include, but are not limited to,
kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone
(DHEA), yohimbe, saw palmetto, and ginseng within 7 days prior to
initiating trial therapy.
Please see the protocol for further excl criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
The primary study endpoint is determination of the RP2D based on the observed number of DLTs during the first cycle.
Phase 2:
− ORR per blinded independent central review; defined as the proportion of patients achieving a best overall response of confirmed partial response (PR) or confirmed complete response (CR), per RECIST version 1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b: Cycle 1 (28 days)
Phase 2: throughout the study duration (based on CT/MRI scans performed every 8 weeks until radiological disease progression) |
|
| E.5.2 | Secondary end point(s) |
Phase 1b:
− AEs and serious adverse events (SAEs) as well as changes in clinical laboratory values, vital signs measurements and ECG parameters.
− Plasma PK parameters including, but not limited to, the area under the plasma concentration-time curve over the dosing interval (AUC0-tau), Cmax, time of the maximum observed plasma concentration (Tmax), and Ctrough.
− ORR, DoR, CBR at 16 weeks, CBR at 24 weeks, and PFS as per local investigator's assessment and per blinded independent central review.
− OS
Phase 2:
− Intracranial RR per blinded independent central review; defined as the proportion of patients achieving a best overall response of confirmed PR+CR, based on intracranial lesions (per RECIST version 1.1).
− Intracranial RR per blinded independent central review; defined as the proportion of patients achieving a best overall response of confirmed PR+CR, based on intracranial lesions (per RANO criteria [Wen et al., 2017]). All radiological measurements and assessments will be provided by independent central review; the clinical components required by RANO criteria will be derived from the electronic case report form.
− DoR, CBR at 16 weeks, CBR at 24 weeks, and PFS per blinded independent central review.
- OS.
− ORR, intracranial RR (per RECIST version 1.1 [Appendix C]), intracranial RR (per RANO criteria [Wen et al., 2017]), DoR, CBR at 16 weeks, CBR at 24 weeks, PFS per local investigator's assessment.
− Plasma PK parameters including, but not limited to AUC0-tau, Cmax, Tmax, and Ctrough.
− Change in patients’ responses to EORTC QLQ-C30, EQ5D-5L, and
EORTC QLQ-BN20.
− Change in patients’ scores in MMSE-2 SV, and NANO scale.
− AEs and SAEs as well as changes in clinical laboratory values, vital signs measurements and ECG parameters. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1b:
Safety throughout the study duration
Plasma PK based on samples collected on Cycle 1 Day 15
Radiological response throughout the study duration (based on CT/MRI scans performed every 8 weeks until radiological disease progression)
Phase 2:
Radiological response throughout the study duration (based on CT/MRI scans performed every 8 weeks until radiological disease progression)
Plasma PK based on samples collected on Cycle 1 Day 15 (first 10 patients)
QoL and neurocognitive questionnaires administered on each cycle Day 1 and at the end of treatment visit
Safety throughout the study duration |
|
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1b evaluation of elacestrant in combination with abemaciclib |
|
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 47 |
| 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 |
| Korea, Republic of |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Greece |
| Italy |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The study will be closed within 6 months of the cutoff date for the survival analysis. If a patient is still receiving trial therapy, he/she will continue to be provided with study treatment (if permitted by the local regulations), until treatment discontinuation or until elacestrant is approved for marketing in his/her country. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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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