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

NCT05986071 | Not Yet Recruiting Phase 1 DMC

• 1 other identifier: MATRIx-IPC 2022-029
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Breast Cancer

Keywords

M1774; fulvestrant; CDK4/6; breast cancer; homologous recombination deficiency

Outcome Measures

Primary Outcomes (1)

• dose-limiting toxicity

  incidence of dose-limiting toxicity as defined as considered to be related or possi-bly related to M1774 or fulvestrant treatment

  28 days after the first dose of treatment

Secondary Outcomes (1)

• Tolerance

  18 months after the first dose of treatment

Study Arms (1)

study arm

EXPERIMENTAL

administration of M1774 in combination with fulvestrant

Drug: M1774; Drug: Fulvestrant injection

Interventions

M1774 DRUG

• 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

study arm

Fulvestrant injection DRUG

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

study arm

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 18 years of age (or \> 18, depending on countries' legal age of majority) at the time of signing the informed consent.
• 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.
• Patient has advanced (loco regionally recurrent not amenable to curative therapy or metastatic) breast cancer.
• 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
• 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.
• 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).
• Tumor site accessible for baseline biopsy or archival tissue available without any specific anticancer treatment after collection
• No more than one previous chemotherapy regimen for advanced disease (including antibody drug conjugates) ; (neo)adjuvant chemotherapy is allowed
• 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
• Patient has Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Patient must have normal organ and marrow function

You may not qualify if:

• Has received previous fulvestrant
• Any investigational therapy within ≤ 21 days or 5 half-lives prior treatment, whichever is longer, prior treatment
• 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 (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
• 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 \[without bone marrow involvement\]).
• 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.
• Any of the following cardiac diseases currently or within the last 6 months
• Unstable angina pectoris
• Congestive heart failure ≥ Class 2 as defined by the New York Heart Association
• Acute myocardial infarction
• 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)
• Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible)
• Other clinically significant heart disease
• 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).

Sponsors & Collaborators

• Institut Paoli-Calmettes: lead
• National Cancer Institute, France: collaborator
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (1)

Institut Paoli Calmettes

Marseille, 13009, France

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Fulvestrant

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: August 2, 2023
• First Posted: August 14, 2023
• Study Start: May 1, 2024
• Primary Completion (Estimated): April 1, 2027
• Study Completion (Estimated): October 15, 2027
• Last Updated: March 29, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)