MATRIX-IPC 2022-029 A phase I/II study evaluating 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)
- Conditions
- advanced breast cancer
- Registration Number
- 2023-507485-10-00
- Lead Sponsor
- Institut Paoli-Calmettes, Institut Paoli-Calmettes
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- Temporarily halted
- Sex
- Not specified
- Target Recruitment
- 57
- Age ≥ 18 years
Patient must have normal organ and marrow function
Adequate renal function
Female participant must have a negative serum pregnancy test.
Use of contraceptive if applicable
Measurable disease, i.e., at least one measurable lesion as per RECIST 1.1.
. Patient affiliated to regimen of social security
Are capable of giving signed informed consent (or a trusted person).
Man or postmenopausal woman due to either surgical/natural menopause or chemical ovarian suppression.
Patient has advanced breast cancer
Patient has pathologically confirmed hormone receptors (HR)-positive and HER2-negative advanced BC. HER2- negative breast
Patient has disease progression while receiving aromatase inhibitor therapy in combination with CDK4/6 inhibitors
No more than one previous chemotherapy regimen for advanced disease.
No more than 1 previous endocrine therapy administered for metastatic disease.
Patient with gBRCA1/2 must have received PARP inhibitors and have experienced disease progression during or after treatment
ECOG Performance Status of 0 or 1.
Has received previous fulvestrant
Concomitant use of known strong or moderate CYP3A inducers
Persistent toxicities (≥ CTCAE grade 2) caused by previous cancer therapy
Major surgery within 2 weeks of starting study treatment.
Visceral crisis or impending visceral crisis at time of screening.
HIV, HBV or HCV infection
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
Live vaccines within 4 weeks of first dose of study intervention and while receiving study intervention.
Patients unable to swallow orally administered medication
History or known hypersensitivity to the active substances or to any excipients of the study interventions.
Pregnant or breast feeding women.
Any investigational therapy within ≤ 21 days or 5 half-lives prior treatment, whichever is longer, prior treatment
Patient considered socially or psychologically unable to comply with the treatment and the required medical follow-up
Any hormonal therapy within 7 days prior treatment (except ovarian function suppression)
Any cytotoxic therapy within 21 days (3-weekly regimen), 14 days (weekly or oral regimen) prior treatment.
Previous treatment with ATR or CHK1 inhibitors. Prior treatment with PARP inhibitor is allowed.
Patients with second primary cancer
Mean resting corrected QTc interval using the Fridericia formula
Cardiac or vascular diseases currently or within the last 6 months
Concomitant use of known strong cytochrome P (CYP) 3A inhibitors or moderate CYP3A inhibitors.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method incidence of dose-limiting toxicity incidence of dose-limiting toxicity
- Secondary Outcome Measures
Name Time Method Tolerance: incidence of AEs and Serious Adverse Events (SAE) presented by grade according to the NCI-CTCAE v5.0. Tolerance: incidence of AEs and Serious Adverse Events (SAE) presented by grade according to the NCI-CTCAE v5.0.
overall response rate (ORR) as defined as the percent of patients with a complete response (CR) or a partial response (PR) (RECIST v1.1). overall response rate (ORR) as defined as the percent of patients with a complete response (CR) or a partial response (PR) (RECIST v1.1).
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. 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.
PK evaluation will be performed on typical individual pharmacokinetics parameters ( PK evaluation will be performed on typical individual pharmacokinetics parameters (
Trial Locations
- Locations (9)
Hopital Jean Minjoz
🇫🇷Besançon, France
Institut De Cancerologie De L Ouest
🇫🇷St Herblain, France
Institut Paoli-Calmettes
🇫🇷Marseille, France
Centr Georges Francois Leclerc
🇫🇷Dijon, France
Centre Oscar Lambret
🇫🇷Lille, France
Institut Universitaire Du Cancer Toulouse‐ Oncopole
🇫🇷Toulouse, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Benite, France
Centre Leon Berard
🇫🇷Lyon, France
Institut Curie
🇫🇷Paris, France
Hopital Jean Minjoz🇫🇷Besançon, FranceLaura MANSISite contact0370632403lmansi@chu-besancon.fr