Phase 1 / 2 study of amcenestrant (SAR439859) single agent and in combination with other anti-cancer therapies in postmenopausal women with estrogen receptor positive advanced breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Sanofi-Aventis Recherche & Developpement

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Jan 2019 → 8 Nov 2024

Decision date (initial)

2024-10-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Sanofi-Aventis Recherche et Développement

External identifiers

EU CT number

2024-512997-89-00

EudraCT number

2017-000690-36

WHO UTN

U1111-1189-4896

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacogenomic, Pharmacokinetic, Efficacy, Dose response, Therapy, Pharmacodynamic, Pharmacogenetic, Others

• 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

Secondary objectives 7

1. Overall safety profile of amcenestrant monotherapy and in combination
2. Pharmacokinetic (PK) profile of amcenestrant administered as monotherapy or in combination and PK profile of palbociclib, alpelisib, everolimus and abemaciclib
3. Antitumor activity using ORR, the clinical benefit rate (CBR) and progression free survival (PFS)
4. Time to first tumor response
5. Residual ER availability with positron emission tomography (PET) scan [(18)F] fluoroestradiol (18F-FES) uptake with increasing doses of amcenestrant
6. Food effect on PK of amcenestrant
7. Potential induction/inhibition effect of amcenestrant on cytochrome P450 (CYP) 3A using 4b-OH cholesterol

Conditions and MedDRA coding

Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Participants must be postmenopausal women
2. Histological diagnosis of breast adenocarcinoma
3. Locally advanced or metastatic disease
4. Either primary tumor or any metastatic site to be positive for Estrogen Receptors (ER+) and negative for HER2 (HER2-) receptor
5. Participants must have been previously treated with at least 6 months of endocrine therapy for advanced disease: - Dose Escalation study parts: Arm #3 - Part F and Arm #5 - Part J: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy Arm #4 -H: up to 2 prior lines of either single endocrine therapy and/or endocrine-based therapy (exemestane not allowed) - Dose Expansion study parts: Arm #2: - Part D: no more than 2 prior lines of advanced endocrine therapy for advanced disease are allowed Arm #3, - Part G: patients must have received and progressed on the combination of Aromatase Inhibitors (AI) + CDK4/6 inhibitor as the first line (1L) treatment for advanced disease Arm #4 - Part I: participants must have received and progressed on the combination of Aromatase Inhibitors (AI) +CDK4/6 Inhibitor as the first line (1L) treatment for advanced disease (exemestane not allowed) Arm #5: - Part K: up to 1 prior line of a single endocrine therapy for advanced disease Note: Additional patients who relapsed while on previous adjuvant endocrine therapy that was initiated ≥24 months ago, or relapsed < 12 months after completion of adjuvant endocrine therapy are also allowed for Arms #2, #3, #4, and #5 (Parts C, D, F, G, H, I, J and K).
6. 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).
7. Measurable lesion

Exclusion criteria 24

1. Medical history or ongoing gastrointestinal disorders that could affect absorption of oral study drugs (including difficulties with swallowing capsules)
2. 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)
3. Participants with known brain metastases
4. 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)
5. Prior treatment with another selective ER down-regulator (SERD)
6. Dose Escalation study parts (Parts F, H and J): SERDs are not allowed except for fulvestrant which will need a washout of at least 6 weeks prior to the first study drug administration
7. Dose Expansion study parts (Parts G, I and K): prior (last) treatment with any SERD including fulvestrant will not be allowed
8. Inadequate hematological and biochemical lab tests
9. Participants with Gilbert disease
10. Treatment with HIV-antiviral, antifungal and antioxidant agents less than 2 weeks before study treatment starts
11. Treatment with strong P450 (CYP) 3A inducers within 2 weeks before first study treatment
12. Treatment with OATP1B1/B3 sensitive substrates and which cannot be replaced
13. Arm #2 Treatment with strong CYP3A inhibitors within 2 weeks before first study treatment starts
14. More than one prior advanced cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy in Arm #1, Arm #2 (Part C), Arm #3 (Parts F and G), and Arm#4 (Part H).
15. Arm #2, #3, #4 and #5 (Parts C, D, F, G, H, I, J and K) only: participants with concurrent or history of pneumonitis
16. 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)
17. 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%
18. 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].
19. Arm #3 (Parts F and G) only: ongoing osteonecrosis of jaw
20. Arm #4 (Parts H and I) only: any active, untreated or uncontrolled infection (e.g. viral, bacterial, fungal etc.)
21. Arm #4 (Parts H and I) only: participants with active and uncontrolled stomatitis, angioedema due to concomitant treatment with ACE inhibitors, impaired wounds
22. Arm #4 (Parts H and I) only: uncontrolled hypercholesterolemia, hypertriglyceridemia and hyperglycemia in non-diabetic participants
23. 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
24. Arm #5 (Parts J and K) only: history or current (controlled/not controlled) venous thromboembolism (i.e. deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Dose Limiting Toxicities (DLTs)
2. Objective Response Rate (ORR)
3. Adverse Events

Secondary endpoints 42

1. Adverse Events
2. ORR
3. Time to First Response (TTR)
4. Clinical Benefit Rate (CBR)
5. Duration of response
6. Tlag of amcenestrant after single dose
7. Tmax of amcenestrant after single dose
8. Cmax of amcenestrant after single dose
9. AUC0-24 of amcenestrant after single dose
10. Tmax of amcenestrant after repeated dose administration
11. Cmax of amcenestrant after repeated dose administration
12. AUC0-24 of amcenestrant after repeated dose administration
13. Ctrough of amcenestrant during repeated dose administration
14. Tmax of palbociclib after single dose
15. Cmax of palbociclib after single dose
16. AUC0-24 of palbociclib after single dose
17. Tmax of palbociclib after repeated dose administration
18. Cmax of palbociclib after repeated dose administration
19. AUC0-24 of palbociclib after repeated dose administration
20. Urine excretion of amcenestrant
21. Cholesterol concentration ratios
22. ER occupancy at 18F-FES-PET imaging
23. Progression free survival
24. Observation of tumor changes by FES PET and FDG PET scans
25. Tmax of alpelisib after third dose
26. Cmax of alpelisib after third dose
27. AUC0-24 of alpelisib after third dose
28. Tmax of alpelisib after repeated dose administration
29. Cmax of alpelisib after repeated dose administration
30. AUC0-24 of alpelisib after repeated dose administration
31. Tmax of everolimus after single dose
32. Cmax of everolimus after first dose
33. AUC0-24 of everolimus after single dose
34. Tmax of everolimus after repeated dose administration
35. Cmax of everolimus after repeated dose administration
36. AUC0-24 of everolimus after repeated dose administration
37. Tmax of abemaciclib after single dose
38. Cmax of abemaciclib after single dose
39. AUC0-24 of abemaciclib after single dose
40. Tmax of abemaciclib after repeated dose administration
41. Cmax of abemaciclib after repeated dose administration
42. AUC0-24 of abemaciclib after repeated dose administration

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Sanofi-Aventis Recherche & Developpement

Sponsor organisation

Sanofi-Aventis Recherche & Developpement

Address

82 Avenue Raspail

City

Gentilly

Postcode

94250

Country

France

Scientific contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Services and operations

Public contact point

Organisation

Sanofi-Aventis Recherche & Developpement

Contact name

Clinical Services and operations

Third parties 1

Locations

2 EU/EEA countries · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 28 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications