| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Dose Escalation:
- To assess the incidence rate of dose-limiting toxicity (DLT) and to determine the maximum tolerated dose (MTD) as well as the recommended dose (RD) of amcenestrant
administered as monotherapy and in combination with palbociclib
- To assess the incidence rate of DLT and determine the RD of everolimus or abemaciclib in combination with the selected amcenestrant dose for the combination therapy
Safety Run-In:
- To confirm the RD of amcenestrant in combination with alpelisib
Dose Expansion:
- Antitumor activity using objective response rate (ORR) at the amcenestrant RD administered as a monotherapy
- Overall safety profile of amcenestrant administered in combination with palbociclib, alpelisib, everolimus, and abemaciclib
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| E.2.2 | Secondary objectives of the trial |
-Secondary Objectives:
- Overall safety profile of amcenestrant monotherapy and in combination.
- Pharmacokinetic (PK) profile of amcenestrant administered as monotherapy or in combination and PK profile of palbociclib, alpelisib, everolimus and abemaciclib.
- Antitumor activity using ORR, the clinical benefit rate (CBR)
- Time to first tumor response
- Residual ER availability with positron emission tomography (PET) scan [(18)F] fluoroestradiol (18F-FES) uptake with increasing doses of amcenestrant
- Food effect on PK of amcenestrant.
- Potential induction/inhibition effect of amcenestrant on cytochrome P450 (CYP) 3A using 4b-OH cholesterol.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Participants must be postmenopausal women
-Histological diagnosis of breast adenocarcinoma
-Locally advanced or metastatic disease
-Either primary tumor or any metastatic site to be positive for Estrogen Receptors (ER+) and negative for HER2 (HER2-) receptor
-Participants previously treated with endocrine therapy for advanced disease: at least 6 months exposure to endocrine therapy (participants with early relapse while on adjuvant endocrine therapy that was initiated ≥24 months ago, or who relapsed < 12 months after completion of adjuvant endocrine therapy are eligible); in Arm #2 Part D, no more than 2 prior lines of endocrine therapy are allowed; in Arm #3 Parts F and G, participants must have received and progressed on Aromatase Inhibitor (AI) in combination with CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease prior to receiving the study treatment, and not followed by additional endocrine therapy for advanced disease before entering the study; for Arm #4 (Parts H and I) and Arm #5 (J and K): no more than 1 prior line of a single endocrine therapy for advanced disease is allowed or for Arm #4 Parts H and I: participants must have received and progressed on a non-steroidal Aromatase Inhibitor (AI) in combination with a CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease prior to receiving the study treatment; For Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J and K) participants who relapsed while on adjuvant endocrine therapy that was initiated ≥24 months ago, or relapsed < 12 months after
completion of adjuvant endocrine therapy are eligible.
- Participants previously treated with chemotherapy for advanced disease: no more than 3 prior chemotherapeutic regimens in Arm #1 Part A, and no more than 1 prior chemotherapeutic regimen in Arms #1, #2, #3, #4, and #5 (Parts B, C, D, F, H and J respectively); prior chemotherapy for advanced disease is not allowed in dose expansion of Arms #3, #4, and #5 (Part G, I and K respectively).
-Measurable lesion |
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| E.4 | Principal exclusion criteria |
-Medical history or ongoing gastrointestinal disorders that could affect absorption of oral study drugs (including difficulties with swallowing capsules)
-Participants with any other cancer (except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or any other cancer from which the participant has been disease free for >3 years)
-Participants with known brain metastases
-Treatment with anticancer agents (including investigational drugs) less than 2 weeks before first study treatment starts (less than 4 weeks if the anticancer agents were antibodies)
- Prior treatment with another selective ER down-regulator (SERD), except fulvestrant,with a washout of at least 6 weeks prior to the first study drug administration. In Arms #3, #4, and #5 (Parts F, G, H, I, J and K): prior (last) treatment with any SERD including fulvestrant will not be allowed.
-Inadequate hematological and biochemical lab tests
-Participants with Gilbert disease
-Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts
-Treatment with strong and moderate cytochrome P450 (CYP) 3A or CYP2C8 inducers within 2 weeks before first study treatment
-Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment starts
-More than one prior advanced cyclin-dependent kinase (CDK) 4/6 inhibitor based therapy in Arm #1 (Parts A and B), Arm #2 (Part C), and Arm #3 (Parts F and G)
- Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: participants with concurrent or history of pneumonitis
- Arm #3, #4 and #5 (Parts F, G, H, I, J and K) only: prior treatment therapies that target the PI3K axis (mTOR inhibitors, AKT inhibitors, PI3K inhibitors)
- Arm #3 and #4 (Parts F, G, H and I) only: participants with diabetes mellitus type-I or uncontrolled diabetes mellitus type-II: ie, fasting plasma glucose ≥ 140mg/dl (7.7 mmol/l) or HbA1C > 6.2%
- Arm #3 and #4 (Parts F, G, H and I) only: history of severe cutaneous reaction (eg.Stevens-Johnson syndrome [SJS], erythema multiforme [EM]), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms [DRESS].
- Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw
- Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g. viral, bacterial, fungal etc.)
- Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis, angioedema due to concomitant treatment with ACE inhibitors, impaired wounds
- Arm #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia and hyperglycemia in non-diabetic participants
- Arm #4 (Parts H and I) only: treatment with strong or moderate CYP3A4 inhibitors, strong CYP3A4 inducers and/or P-gp inhibitors within 2 weeks before the first study treatment administration or 5 elimination half-lives, whichever is the longest
- Arm #5 (Parts J and K) only: history or current (controlled/not) venous thromboembolism (i.e. deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1/Dose Limiting Toxicities (DLTs) : Incidence of study treatment-related DLTs at Cycle 1 (Arm #1 Part A, Arm #2 Part C, Arm #3 Part D, Arm #4 Part H, and Arm #5 Part J)
2/Objective Response Rate (ORR): Proportion of participants with confirmed CR or PR according to RECIST 1.1 assessed by independent central reviewer relative to the total number of treated participants (Arm #1 Part B)
3/Adverse Events Number of participants with adverse events according to the National Cancer Institute – Common Toxicity Criteria (NCI-CTC) version 4.03 grade scaling Incidence of Adverse Events, including laboratory test results and electrocardiogram (ECG) findings that were adverse events (Arm #2 Part D, Arm #3 Part G, Arm #4 Part I, Arm #5 Part K) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1/Cycle 1, Day 28 for each treated participant (each cycle is 28 days)
2/Baseline to date of first documentation of progression, assessed up to approximately 6 months after the last entered participant
3/Up to 30 days after last dose of amcenestrant
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| E.5.2 | Secondary end point(s) |
1/Adverse Events:Number of participants with adverse events according to the NCI-CTC version 4.03 grade scaling Incidence of Adverse Events, including laboratory test results and ECG findings that were adverse events in all treatment arms
2/ORR:Proportion of participants with confirmed CR or PR according to RECIST 1.1 assessed by investigator/local radiologist relative to the total number of treated participants in all treatment arms
3/ Time to First Response (TTR): Time from the start of treatment to the first objective tumor response observed for participants who achieved confirmed CR or PR in all treatment arms
4/Clinical Benefit Rate (CBR): Proportion of participants with CR or PR or SD ≥24 weeks according to RECIST v.1.1 relative to the total number of treated participants by investigators/local radiologists in all treatment arms and also by independent central reviewer in Arm #1 Part B
5/ Duration of response:Time from initial response to the first documented tumor progression in all treatment arms
21/Cholesterol concentration ratios:Plasma 4B hydroxy/total cholesterol concentration ratios (Arm #1)
22/ER occupancy at 18F-FES-PET imaging:Inhibition of ER occupancy at 18FES-PET imaging (signal extinction) (Arm #1 Part A)
23/Progression free survival:Time interval from the date of the first IMP intake to the date of the first tumor progression assessed by investigators/local radiologists in all treatment arms and (also by IRC in Arm #1 Part B) per RECIST 1.1, or death (due to any cause), whichever comes first.
24/Observation of tumor changes by FES PET and FDG PET scans:To correlate the changes observed in FES PET scan with the changes in glucose metabolism seen on FDG PET (Arm #1 Part A)
Amcenestrant
6/Tlag after single dose:Tlag is interval between administration time and the sampling time preceding the first concentration above the lower limit of quantification of amcenestrant (Arms #1, #2, #4, and #5)
7/Tmax after single dose:Tmax is time to reach Cmax (Arms #1, #2, #4, and #5)
8/Cmax after single dose:Cmax is maximum concentration observed (Arms #1, #2, #4, and #5)
9/AUC0-24 after single dose:AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) (Arms #1, #2, #4 and #5)
10/Tmax after repeated dose administration:Tmax is time to reach Cmax in all treatment arms
11/Cmax after repeated dose administration:Cmax is maximum concentration observed in all treatment arms
12/AUC0-24 after repeated dose administration :AUC0-24 is area under the plasma concentration versus time curve calculated using the trapezoidal method over the dosing interval (24 hours) in all treatment arms
13/Ctrough during repeated dose administration:Ctrough is plasma concentration observed just before treatment administration during repeated dosing in all treatment arms
20/ Urine excretion of amcenestrant during the monotherapy expansion phase (Arm #1 Part B)
Palbociclib(Arm #2)
14/Tmax after single dose
15/Cmax after single dose
16/ AUC0-24 after single dose
17/ Tmax after repeated dose administration
18/ Cmax after repeated dose administration
19/AUC0-24 after repeated dose administration
Alpelisib(Arm # 3)
25/Tmax after third dose
26/Cmax after third dose
27/AUC0-24 after third dose
28/Tmax after repeated dose administration
29/Cmax after repeated dose administration
30/AUC0-24 after repeated dose administration
Everolimus(Arm #4)
31/ Tmax after single dose
32/ Cmax after first dose
33/AUC0-24 after single dose
34/Tmax after repeated dose administration
35/Cmax after repeated dose administration
36/AUC0-24 after repeated dose administration
Abemaciclib(Arm #5)
37/Tmax after single dose
38/Cmax after single dose
39/AUC0-24 after single dose
40/Tmax after repeated dose administration
41/Cmax after repeated dose administration
42/AUC0-24 after repeated dose administration |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/Up to 30 days after last dose of amcenestrant
2/3/4/5/23/Baseline to the date of first documentation of progression, assessed approximately up to 6 months after the last entered participant
6/7/8/9/Cycle 1, Day 1 and Day 3 (each cycle is 28 days)
10/11/12/ Cycle 1, Day 21 or 22
13/Cycle 1, Day 8, Day 21 or 22 and Cycle 2, Day 1
14/15/16/31/32/33/37/38/39/Cycle 1, Day 1
17/18/19/20/Cycle 1, Day 21
21/Up to Cycle 2
22/Baseline and one assessment in Cycle 1 on Day 11 to 15
24/Baseline and approximately at Day 15 of Cycle 1 in Part A
25/26/27/Cycle 1, Day 3
28/29/30/34/35/26/40/41/42/Cycle 1, Day 22
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| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Dose escalation and expansion |
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| 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 | 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 | No |
| 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.8.3 |
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 | 26 |
| 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 |
| Belgium |
| Canada |
| France |
| Italy |
| Poland |
| Portugal |
| Spain |
| United Kingdom |
| United States |
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| 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
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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