MATRIX-IPC 2022-029 A phase I/II study evaluating Tuvusertib (M1774), an ATR Inhibitor, in combination with fulvestrant in hormone receptors-positive and HER2-negative, advanced breast cancers, resistant to CDK4/6 inhibitor plus aromatase inhibitor-based endocrine treatment and with homologous recombination deficiency, oncogenic driver activation and/or other molecular alterations associated with replication stress (RS)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Paoli-Calmettes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

21 Apr 2026 → ongoing

Decision date (initial)

2024-04-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Institut National du Cancer

External identifiers

EU CT number

2023-507485-10-00

WHO UTN

U1111-1298-2302

ClinicalTrials.gov

NCT05986071

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

Phase I part = to determine the maximum tolerated dose (MTD) and provide a recommended phase
II dose (RP2D) of M1774 in combination with fulvestrant in ER+/HER2- ABC resistant to CDK4/6
inhibitor and aromatase inhibitor-based endocrine therapy
Phase II part = to further determine safety in terms incidence of DLT and preliminary efficacy in
terms of clinical benefit rate (co-primary) of the combination of M1774 with fulvestrant at the RP2D in
ER+/HER2- ABC resistant to CDK4/6 inhibitor and aromatase inhibitor-based endocrine therapy and
whose tumor displays either HRD (including g/sBRCA1,- BRCA2- or PALB2- mutated ABC after
PARP inhibitor-based treatment) and/or or other molecular alterations associated with oncogenic
driver activation and/or high RS.

Secondary objectives 4

1. to determine the tolerance of the combination (phase I and phase II)
2. to determine efficacy in terms of objective response and progression-free survival (Phase I and II)
3. to determine efficacy in terms of objective response and progression-free survival in subgroup of interest (germline or somatic BRCA1-, BRCA2- or PALB2-mutated ABC with previous PARP inhibitor-based treatment, other HRD gene alterations, oncogenic drivers and/or molecular alterations inducing RS) (phase II)
4. to determine pharmacokinetics of M1774 and fulvestrant (Phase I and II)

Conditions and MedDRA coding

advanced breast cancer

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 16

1. 1. Age ≥ 18 years
2. Man or postmenopausal woman due to either surgical/natural menopause or chemical ovarian suppression.
3. Patient has advanced breast cancer
4. Patient has pathologically confirmed hormone receptors (HR)-positive and HER2-negative advanced BC. HER2- negative breast
5. Patient has disease progression while receiving aromatase inhibitor therapy in combination with CDK4/6 inhibitors
6. No more than one previous chemotherapy regimen for advanced disease.
7. No more than 1 previous endocrine therapy administered for metastatic disease.
8. Patient with gBRCA1/2 must have received PARP inhibitors and have experienced disease progression during or after treatment
9. ECOG Performance Status of 0 or 1.
10. Patient must have normal organ and marrow function
11. Adequate renal function
12. Female participant must have a negative serum pregnancy test.
13. Use of contraceptive if applicable
14. Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1.
15. . Patient affiliated to regimen of social security
16. Are capable of giving signed informed consent (or a trusted person).

Exclusion criteria 20

1. Has received previous fulvestrant
2. Any investigational therapy within ≤ 21 days or 5 half-lives prior treatment, whichever is longer, prior treatment
3. Any hormonal therapy within 7 days prior treatment (except ovarian function suppression)
4. Any cytotoxic therapy within 21 days (3-weekly regimen), 14 days (weekly or oral regimen) prior treatment.
5. Previous treatment with ATR or CHK1 inhibitors. Prior treatment with PARP inhibitor is allowed.
6. Patients with second primary cancer
7. Mean resting corrected QTc interval using the Fridericia formula
8. Cardiac or vascular diseases currently or within the last 6 months
9. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or moderate CYP3A inhibitors.
10. Concomitant use of known strong or moderate CYP3A inducers
11. Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy
12. Major surgery within 2 weeks of starting study treatment or an anticipated need for major surgery during the study...
13. Visceral crisis or impending visceral crisis at time of screening.
14. HIV, HBV or HCV infection
15. Any other clinical condition, uncontrolled concurrent illness, or other situations, which in the Investigator’s opinion would not make the patient a good candidate for the study or may potentially impact the absorption of M1774
16. Live vaccines within 4 weeks of first dose of study intervention and while receiving study intervention.
17. Patients unable to swallow orally administered medication
18. History or known hypersensitivity to the active substances or to any excipients of the study interventions.
19. Pregnant or breast feeding women.
20. Patient considered socially or psychologically unable to comply with the treatment and the required medical follow-up

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. incidence of dose-limiting toxicity

Secondary endpoints 4

1. Tolerance: incidence of AEs and Serious Adverse Events (SAE) presented by grade according to the NCI-CTCAE v5.0.
2. overall response rate (ORR) as defined as the percent of patients with a complete response (CR) or a partial response (PR) (RECIST v1.1).
3. The progression-free survival (PFS) as defined as the interval between the date of inclusion and the date of progression or death. A patient alive and without progression will be censored at the last date of follow-up.
4. PK evaluation will be performed on typical individual pharmacokinetics parameters (

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Paoli-Calmettes

Sponsor organisation

Institut Paoli-Calmettes

Address

232 Boulevard De Sainte Marguerite, Bp 156 Bp 156

City

Marseille

Postcode

13009

Country

France

Scientific contact point

Organisation

Institut Paoli-Calmettes

Contact name

investigateur coordonateur

Public contact point

Organisation

Institut Paoli-Calmettes

Contact name

Marina LAROSA

Locations

1 EU/EEA country · 12 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 5 · Art. 38 CTR

Results and documents

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

Documents 17 files

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

Application history

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