Ignite Creation Date:
2024-05-06 @ 7:22 PM
Last Modification Date:
2024-10-26 @ 3:05 PM
Study NCT ID:
NCT05986071
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-29
First Post:
2023-08-02
Brief Title:
III Phase Study Evaluating M1774 in Combination With Fulvestrant in HR and HER2- Advanced Breast Cancers
Sponsor:
Institut Paoli-Calmettes
Organization:
Institut Paoli-Calmettes
Study Overview
Official Title:
A Phase III Study Evaluating M1774 an ATR Inhibitor in Combination With Fulvestrant in Hormone Receptor-positive and HER2-negative Advanced Breast Cancers Resistant to CDK46 Inhibitor Plus Aromatase Inhibitor-based Endocrine Treatment
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MATRIX
Brief Summary:
CDK46 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 ERHER2- 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 ERHER2- 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 ERHER2- 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 III 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 ERHER2-ABC patients whose disease has become resistant to aromatase inhibitor plus CDK46 inhibitor and whose tumor displays molecular alterations associated with HRD oncogenic driver activation andor 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 polyadenosine 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 physicians 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 ERHER2- breast cancer Among these patients the PFS was 7 month and 86 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 CDK46 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 ERHER2- 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 BRCA12 or somatic BRCA12 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-PKPRKDC 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 33While 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 andor 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 M1774s IB V20 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 35 hours and mean T12 ranged from 3 to 56 hours
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 ERHER2- 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 BRCA12 or somatic BRCA12 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-PKPRKDC 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 33While 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 andor 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 M1774s IB V20 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 35 hours and mean T12 ranged from 3 to 56 hours
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None