I/II Phase Study Evaluating M1774 in Combination With Fulvestrant in HR+ and HER2- Advanced Breast Cancers — MATRIX  

Breast Cancer Clinical Trial

Official title: A Phase I/II Study Evaluating M1774, an ATR Inhibitor, in Combination With Fulvestrant in Hormone Receptor-positive and HER2-negative, Advanced Breast Cancers, Resistant to CDK4/6 Inhibitor Plus Aromatase Inhibitor-based Endocrine Treatment

Status Not yet recruiting

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

• NCT number: NCT05986071
• Study type: Interventional
• Source: Institut Paoli-Calmettes
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: May 1, 2024
• Completion date: October 15, 2027