| Eligibility |
Inclusion Criteria:
1. Age = 18 years of age (or > 18, depending on countries' legal age of majority) at the
time of signing the informed consent.
2. Man or postmenopausal woman due to either surgical/natural menopause or chemical
ovarian suppression (maintained during all the study treatment) with a
gonadotropin-releasing hormone (GnRH) agonist or radiation-induced ovarian
suppression.
3. Patient has advanced (loco regionally recurrent not amenable to curative therapy or
metastatic) breast cancer.
4. Patient has pathologically confirmed hormone receptors (HR)-positive (ER+ and/or PgR+)
and HER2-negative advanced BC by local laboratory on the last tissue examined.
HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC
status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or
SISH) test is required by local laboratory testing
5. Patient has disease progression while receiving aromatase inhibitor therapy (i.e.
letrozole, anastrozole, exemestane) in combination with CDK4/6 inhibitors
(palbociclib, ribociclib, abemaciclib) administered in the advanced setting or
patients has recurrence while receiving aromatase inhibitor therapy (i.e. letrozole,
anastrozole, exemestane) in combination with CDK4/6 inhibitors (palbociclib,
ribociclib, abemaciclib) or within 12 months of the end of CDK4/6 inhibitors when
administered in the early setting.
6. For phase 2 part only : patient whose tumor displays (according to local tumor boards)
either
- Germline or somatic BRCA1, BRCA2 or PALB2 mutations and prior exposure and
resistance to PARP inhibitors (cohort 1).
- Documented deleterious germline or somatic alterations associated with HRD :
BARD1 BRIP1, CDK12, CHEK2, FANCA, FANCD2, FANCL, MRE11A, NBN, PPP2R2A, RAD51B,
RAD51C, RAD51D and RAD54L (cohort 2). Patients with sBRCA1, sBRCA2 and g/sPALB2,
without previous exposure to PARP inhibitors, may be enrolled in this cohort.
- Oncogenic driver amplification (such as MYC, RAS, Cycin E1) or mutations of the
following genes: ATM, ARID1A, ERCC4, XRCC1, RB1, ATRX, DAXX, suspected to favor
RS and thereby sensitivity to ATR inhibitors as determined by a local molecular
tumor board and validated by the central molecular tumor board (cohort 3).
7. Tumor site accessible for baseline biopsy or archival tissue available without any
specific anticancer treatment after collection
8. No more than one previous chemotherapy regimen for advanced disease (including
antibody drug conjugates) ; (neo)adjuvant chemotherapy is allowed
9. No more than 1 previous endocrine therapy administered for metastatic disease
10. Patient with gBRCA1/2 must have received PARP inhibitors and have experienced disease
progression during or after treatment
11. Patient has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
12. Patient must have normal organ and marrow function
Adequate hematologic function as indicated by:
- Platelet count = 100,000/mm3
- Absolute neutrophil count > 1,500/µL with no growth factor treatment within the
last 14 days
- Hemoglobin = 10.0 g/dL, with no erythropoietin or red blood cell transfusion
within the last 14 days.
Adequate hepatic function as indicated by:
- Total bilirubin = 1.5 × ULN. In the case of documented Gilbert's syndrome, total
bilirubin = 2.0 × ULN is allowed.
- AST and ALT levels = 3 × ULN or = 5 × ULN in presence of liver metastases.
13. Adequate renal function defined as: serum creatinine = 1.5 × ULN. If serum creatinine
is > 1.5 × ULN, creatinine clearance needs to be = 60 mL/min by calculation using the
Cockcroft-Gault formula or by measured 24-hour urine collection. The Cockcroft-Gault
formula is (glomerular filtration rate [mL/min] = {(l40-age) × weight/(72 × serum
creatinine [mg/dL])} × 0.85 [if female]).
14. A female participant must have a negative serum pregnancy test, as required by local
regulations, before the first dose of study intervention).
Contraceptive use will be consistent with local regulations on contraception methods
for those participating in clinical studies.
Female participants of childbearing potential will be using highly effective
contraception for throughout the study and for at least 6 months after last M1774
treatment administration. Women should not breastfeed during the study and for at
least 1 month after the study period, (i.e., after the last dose of study intervention
is administered).
Male participants will be using highly effective contraception for throughout the
study and for at least 3 months after last M1774 treatment administration.
15. Patient has measurable disease, i.e., at least one measurable lesion as per RECIST 1.1
criteria
16. Patient affiliated to the national "Social Security" regimen or beneficiary of this
regimen or any other regimen of social security
17. Are capable of giving signed informed consent(or a trusted person) , which includes
compliance with the requirements and restrictions listed in the ICF and this protocol.
Exclusion Criteria:
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 (unless treatment was for less than 3
weeks duration and at least 12 months have elapsed between the last dose and
randomization. Patients that did not tolerate prior treatment are excluded). Prior
treatment with PARP inhibitor is allowed
6. . .
7. Patients with second primary cancer, EXCEPTIONS: adequately treated non melanoma skin
cancer, curatively treated in-situ cancer of the cervix, Ductal carcinoma in Situ
(DCIS), stage 1 grade 1 endometrial carcinoma, or other solid tumours curatively
treated with no evidence of disease for = 3 years prior to study entry (including
lymphomas [without bone marrow involvement]).
8. Mean resting corrected QTc interval using the Fridericia formula (QTcF) = >470
msec/female patients and >450 msec for male patients obtained from 3 ECGs Uncontrolled
or poorly controlled arterial hypertension, symptomatic congestive heart failure (New
York Heart Association Classification = Class III), uncontrolled cardiac arrhythmia,
calculated QTc average using the QTcF > 470 msec; unstable angina pectoris, myocardial
infarction or a coronary revascularization procedure, cerebral vascular accident,
transient ischemic attack, or any other significant vascular disease within 180 days
of study intervention start.
9. Any of the following cardiac diseases currently or within the last 6 months
10. Unstable angina pectoris
11. Congestive heart failure = Class 2 as defined by the New York Heart Association
12. Acute myocardial infarction
13. Conduction abnormality not controlled with pacemaker or medication (patients with a
conduction abnormality controlled with pacemaker or medication at the time of
screening are eligible)
14. Significant ventricular or supraventricular arrhythmias (patients with chronic
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are
eligible)
15. Other clinically significant heart disease
16. Concomitant use of known strong cytochrome P (CYP) 3A inhibitors (eg itraconazole,
telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or
cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate
CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem,fluconazole, verapamil).
17. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil).
18. Persistent toxicities (= CTCAE grade 2) caused by previous cancer therapy, excluding
alopecia and CTCAE grade 2 peripheral neuropathy.
19. Major surgery within 2 weeks of starting study treatment: patients must have recovered
from any effects of any major surgery.
20. Immunocompromised patients, eg, patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
21. Patients with known active hepatitis (ie, hepatitis B or C).
22. Visceral crisis or impending visceral crisis at time of screening.
23. CNS complications for whom urgent neurosurgical intervention is indicated (e.g.,
resection, shunt placement).
24. uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the
previous 6 months, chronic liver or renal disease, or severe malnutrition.
25. Active infection requiring antibiotics at day 1 of cycle 1
26. Active and/or uncontrolled infection. The following exceptions apply:
- Participants with HIV infection are eligible if they are on effective
antiretroviral therapy with undetectable viral load within 6 months, provided
there is no expected drug-drug interaction.
- Participants with evidence of chronic HBV infection are eligible if the HBV viral
load is undetectable on suppressive therapy (if indicated), and if they have ALT,
AST, and total bilirubin levels < ULN, and provided there is no expected
drug-drug interaction.
- Participants with a history of HCV infection are eligible if they have been
treated and cured. For participants with HCV infection who are currently on
treatment, they are eligible if they have an undetectable HCV viral load, and if
they have ALT, AST, and total bilirubin levels < ULN.
27. Participants with clinically controlled brain metastases, which is defined as
individuals with central nervous system metastases that have been treated for, are
asymptomatic, and have discontinued corticosteroids for > 14 days or are on a stable
or decreasing steroid dose (for the treatment of brain metastases) may be enrolled.
Participants with meningeal carcinomatosis are excluded.
28. A scan to confirm the absence of brain metastases is not required. Patients with
spinal cord compression unless considered to have received definitive treatment for
this and evidence of clinically stable disease (SD) for 28 days.
29. Patients with a history of treated central nervous system (CNS) metastases are
eligible, provided they meet all of the following criteria: Disease outside the CNS is
present. No clinical evidence of progression since completion of CNS-directed therapy.
Minimum of 3 weeks between completion of radiotherapy and Cycle 1 Day 1 and recovery
from significant (Grade =3) acute toxicity with no ongoing requirement for >10 mg of
prednisone per day or an equivalent dose of other corticosteroid. If on
corticosteroids, the patient should be receiving a stable dose of corticosteroids,
started at least 4 weeks prior to treatment
30. 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 such as (but not limited
to) significant small bowel resection, gastric surgery, or exocrine pancreatic
insufficiency requiring pancreatic enzyme replacement therapy.
31. Live vaccines within 4 weeks of first dose of study intervention and while receiving
study intervention. Administration of inactivated vaccines (i.e., inactivated
influenza vaccine) is permitted. Inactivated RNA or nonreplicating viral vector-based
SARS-CoV-2 vaccines are allowed, as approved by local/regional Health Authorities.
Novel live attenuated SARS CoV-2 vaccines are not permitted.
32. Persistence of AEs related to any prior treatments that have not recovered to Grade =
1 unless AEs are clinically non significant (e.g. alopecia) and /or stable on
supportive therapy in the opinion of the Investigator.
33. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
34. History or known hypersensitivity to the active substances or to any excipients of the
study interventions.
35. Pregnant or breast feeding women.
36. Patient considered socially or psychologically unable to comply with the treatment and
the required medical follow-up
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