Trial Title:
I/II Phase Study Evaluating M1774 in Combination With Fulvestrant in HR+ and HER2- Advanced Breast Cancers
NCT ID:
NCT05986071
Condition:
Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Fulvestrant
Conditions: Keywords:
M1774
fulvestrant
CDK4/6
breast cancer
homologous recombination deficiency
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Phase I : we will examine the safety and determine the recommended phase II dose (RP2D)
of the combination of M1774 with Fulvestrant in ER+/HER2- ABC with progressive disease
under or after CDK4/6 inhibitor and aromatase inhibitor.
Phase II: Administration of M1774 ar RP2D with fulvestrant
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
M1774
Description:
• Phase I part = administration of M1774 in combination with fulvestrant in ER+/HER2- ABC
resistant to CDK4/6 inhibitor and aromatase inhibitor-based endocrine therapy in order to
detemine the recommended phase II dose Phase II part = administration of M1774 at RP2D in
combination with fulvestrant
Arm group label:
study arm
Intervention type:
Drug
Intervention name:
Fulvestrant injection
Description:
Phase I part = administration of M1774 in combination with fulvestrant in ER+/HER2- ABC
resistant to CDK4/6 inhibitor and aromatase inhibitor-based endocrine therapy in order to
detemine the recommended phase II dose Phase II part = administration of M1774 at RP2D in
combination with fulvestrant
Arm group label:
study arm
Summary:
CDK4/6 inhibitor in combination with endocrine treatment is the standard of care in
advanced breast cancer (ABC) with expression of hormone receptors and without HER2
overexpression (ER+/HER2-). When patients experience disease progression under this
strategy, options of second-line endocrine treatment in combination with other targeted
therapies are limited and have failed to improve overall survival to date over endocrine
treatment alone. A significant fraction of ER+/HER2- ABC display genetic alterations
associated with homologous recombination deficiency (HRD) which may be associated with
efficacy of therapeutic targeting DNA damage response (DDR) pathways. Moreover, other
molecular alterations associated with replicative stress may be found in ER+/HER2- ABC
patients which may also favor antitumor activity of DDR targeting therapeutics. M1774 is
a novel orally administered inhibitor of ataxia telangiectasia and rad3-related (ATR), a
protein kinase with key activity in DDR pathway. MATRIx is a phase I/II study aiming to
determine the recommended phase II dose (RP2D, phase I) as well as efficacy and safety
(phase II) of M1774 in combination with fulvestrant in ER+/HER2-ABC patients whose
disease has become resistant to aromatase inhibitor plus CDK4/6 inhibitor, and whose
tumor displays molecular alterations associated with HRD, oncogenic driver activation
and/or replicative stress. Primary endpoints will include: maximum tolerated dose (MTD)
of M1774 in combination with fulvestrant (phase I), the clinical benefit rate and
toxicity of the combination at RP2D of M1774 in the molecularly selected population
(phase II). Baseline, on-treatment and post-treatment blood and tumor tissue samples will
be collected for pharmacokinetics and translational analyses including genomic
characterization of tumor tissue and ctDNA as well as functional studies focusing on DDR
pathways.
Detailed description:
Approximately 5% among all types of breast cancers are associated with germline breast
cancer susceptibility gene BRCA 1 or 2 mutations (gBRCA). These mutations lead to
homologous recombination deficiency (HRD) and inability for cancer cells to repair DNA
double-strand break (DDSB), making gBRCA-ABC exquisitely sensitive to poly(adenosine
diphosphate-ribose) polymerase (PARP) inhibitors (22). Indeed, PARP is a pivotal actor in
the repair of DNA single-strand breaks (DSSB), and PARP inhibition will generate
accumulating DSSB leading to DDSB and ultimately cell death if let unrepaired, as it is
in the context of HRD. In OlympiAD and EMBRACA trials assessing the efficacy of olaparib
or talazoparib, respectively compared to physician's choice single-agent, non
platin-based, chemotherapy in gBRCA HER2- ABC patients, a significant increase in PFS and
an improvement in QOL was shown with both PARP inhibitors (23, 24) . Of note, around 50%
of the patients in these trials had ER+/HER2- breast cancer. Among these patients the PFS
was 7 month and 8.6 month with olaparib and talazoparib respectively. Yet, either in this
subgroup or in the overall population, there was no OS improvement (25, 26).
Nevertheless, according to guidelines (3), PARP inhibitors should be part of the
treatment sequence in gBRCA, ER+ /HER2- ABC patients when the disease becomes resistant
to CDK4/6 inhibitor-based first-line ET.
Even in the absence of gBRCA, HRD may still exist in tumors due to somatic defects in
BRCA genes as well as alterations in other genes involved in homologous recombination
repair such as ATM, BARD1, CHEK1, CHEK2, RAD51C, RAD51D, BRIP1, NBN, PALB2, and the
Fanconi anemia complementation group (FANC) family of genes (FANCA, FANCC, FANCD2, FANCE,
FANCF, FANCG, and FANCL): the so-called "BRCAness" phenotype (27). In whole-exome studies
focusing on ABC samples, we and others found that more than approximately 15% of
ER+/HER2- ABC may display such a BRCAness phenotype (28-30). Although it should be
theoretically associated with similar sensitivity to PARP inhibitors, clinical data
examining anti-tumor activity of this latter class remain relatively sparse. In a recent
study investigating antitumor activity of olaparib in ABC with either germline mutations
in HR-related genes other than BRCA1/2 or somatic BRCA1/2 mutations, only patients with
gPALB2 or somatic BRCA mutations but not those with mutations in other homologous
recombination-associated genes had high response rates and clinical benefit (31). Thus,
developing alternative therapeutic targeting DNA damage response (DDR) pathways in BRCA
and non BRCA-driven HRD is urgently needed.
DNA damage repair pathway :
The DDR pathway, which coordinates the detection of cellular DNA damage with cell-cycle
adaptation and repair processes, primarily involves ataxia telangiectasia and
rad3-related (ATR), ataxia telangiectasia mutated (ATM), and DNA-dependent protein kinase
(DNA-PK/PRKDC). ATR, the key DDR kinase, is activated by accumulated DSSB, primarily
induced by oncogene-driven dysregulated replication, leading to the so-called replication
stress (RS) and associated genomic instability. Once activated, ATR phosphorylates
checkpoint kinase 1 (CHK1), leading to cell-cycle arrest, pausing of DNA synthesis and
initiation of DNA repair. Loss of ATR function leads to the inability to resolve stalled
replication forks, the accumulation of DNA damage and rapid cell death (32, 33).While
normal cells can generally tolerate inhibition of ATR by activating compensatory DNA
repair pathways, such pathways are frequently defective in cancer cells, rendering them
highly dependent on ATR for survival. Due to its major implication in RS-induced DDR
pathway activation, ATR has been recently considered as a potential target in various
cancer models and several ATR inhibitors are under clinical evaluation. Classically,
tumors with high level of RS have been suggested to be the most sensitive to ATR
inhibitors, including RS-induced by oncogenic amplification such as MYC, RAS or Cyclin
E1. Other potential molecular alterations that may sensitize to ATR inhibitors are those
associated with HRD (33, 34) as well as those associated with DDR such as loss of
expression of ATM, ARID1A, ERCC4, XRCC1, RB133, (35-39). Of note, recent works have
revealed that treatment with ATR inhibitors can overcome the resistance to PARP
inhibition (40), suggesting the potential of ATR inhibitors as a second-line treatment in
patients who have developed resistance to PARP inhibitors (33).
ATR inhibitors and M1774:
First early-phase studies have been initiated using ATR inhibitors as monotherapy or in
combination with various therapeutics including chemotherapy and PARP inhibitors in
various tumor types. Tolerance was favorable and preliminary proofs of activity have been
obtained, notably in patients with DDR and/or HR pathway alterations (41-43). M1774
(substance code MSC2584415A; also known as VXc-400 or VRT-1363004) is an orally
administered small molecule inhibitor of ATR kinase; it is a potent and selective
inhibitor of ATR, with a mean half maximal inhibitory concentration (IC50) of 4 nM, as
measured by inhibition of the phosphorylation of the proximal target CHK1 in cells
(M1774's IB V2.0, Nov 2020). Pre-clinical pharmacology, pharmacokinetic (PK), and
toxicology studies support development of M1774 for the treatment of patients with
advanced cancers and a phase I study is currently ongoing.
As of 21 APR 2022, 55 participants received doses of M1774 ranging from 5 mg to 270 mg
once daily (QD). Dose-limiting toxicities (DLT) were observed at dose levels of 130 mg QD
and above. DLT included grade 2 and 3 anemia requiring transfusion in 7 patients, as well
as one grade 4 thrombopenia associated with upper gastro-intestinal hemorrhage. Most
frequent toxicities also included gastro-intestinal disorders (nausea, vomiting,
constipation, diarrhea and abdominal pain). The recommended phase 2 dose as monotherapy
was 180 mg QD, 2 weeks on/ 1 week off. Of note, preliminary data showed that PK was
approximately dose proportional up to 180 mg and slightly more than dose proportional
beyond 180 mg. Absorption was fast with median Tmax ranging from 1 to 3.5 hours and mean
T1/2 ranged from 3 to 5.6 hours.
Criteria for eligibility:
Criteria:
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
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut Paoli Calmettes
Address:
City:
Marseille
Zip:
13009
Country:
France
Start date:
May 1, 2024
Completion date:
October 15, 2027
Lead sponsor:
Agency:
Institut Paoli-Calmettes
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute, France
Agency class:
Other
Collaborator:
Agency:
Merck KGaA, Darmstadt, Germany
Agency class:
Industry
Source:
Institut Paoli-Calmettes
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05986071
