Milademetan and fulvestrant in GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer patients (DEMETER)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Curie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

12 Oct 2023 → 24 Nov 2023

Decision date (initial)

2023-06-06

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Institut Curie - Ensemble Hospitalier · RAIN Therapeutics

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Others, Safety

Determine the efficacy of milademetan + fulvestrant by assessment of the clinical benefit rate at 6 months (6mCBR).

Secondary objectives 5

1. To determine the safety and tolerability of milademetan + fulvestrant.
2. To further assess the efficacy of milademetan + fulvestrant. In terms of PFS, ORR, DoR and OS
3. To describe the changes in Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) in patients treated with milademetan + fulvestrant.
4. To identify potential biomarkers of response and resistance mechanisms by circulating tumor DNA (ctDNA) analyses and immunohistochemistry (IHC) analyses.
5. To explore innovative tools to detect GATA3 mutant cancers

Conditions and MedDRA coding

GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Molecular screening step – for French sites only; patients with unknown GATA3 mutational status will be identified either locally or centrally (Institut Curie core Genetics facility) after consenting for this molecular screening. • Availability of a formalin-fixed paraffin-embedded (FFPE) block with >10% tumor tissue (it is recommended to provide the most recently collected tumor sample). • Patients who progressed on CDK4/6 inhibitor therapy • Prior signature of a written informed molecular screening consent. • Patients should be eligible to the treatment step according to the investigator’s opinion. • Patients must be covered by a health insurance plan (French centers). • Capable of giving signed informed consent (per local law).
2. Treatment step • Breast cancer should have a GATA3 frameshift or truncating mutation, retrieved by either tissue or circulating DNA sequencing, which eligibility must be confirmed by the study geneticist prior to any treatment or study procedure. • Age > 18 years. • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. • Stage IV, histologically-confirmed metastatic breast cancer. Locally-advanced breast cancer not amenable to local curative therapy are also eligible. • Most recent tumor tissue analyzed must be estrogen receptor-positive (ER+) (≥10% tumor cell staining by IHC per ASCO/CAP guidelines) and HER2-negative (HER2-). • Having received at least one prior line of endocrine therapy, including a prior CDK4/6 inhibitor in the absence of any contraindication, but no more than 2 prior lines of endocrine therapy for metastatic disease. • No more than 2 prior lines of chemotherapy for metastatic disease. • Evaluable disease per investigator assessment (RECIST v1.1). • Willingness to provide access to archived tumor block (or 10 unstained FFPE slides) for retrospective central assessment of GATA3 mutational status. • Have a life expectancy of at least 3 months. • Adequate organ function (obtained within 14 days prior to treatment start) as evidenced by: • Absolute neutrophil count (ANC) ≥ 1.0 X 109/L, • Hemoglobin (Hgb) ≥ 9 g/dL, • Platelet count ≥ 100 X 109/L, • Bilirubin ≤ 1.5 X upper limit of normal (ULN); for patients with Gilbert’s disease, ≤ 2 X ULN • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 X ULN; for patients with liver metastases, ≤ 5 X ULN, • Calculated creatinine clearance (MDRD) ≥ 50 mL/min, • For female of childbearing potential (WCBP): negative serum or urinary pregnancy test • Patients must be postmenopausal, surgically infertile, or willing to use a highly effective contraception methods until at least 2 years after completion of study treatment. Highly effective contraception methods include: - Placement of an intrauterine device (IUD). - Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception. - Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. - Male partner sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient. - Male patients must agree to use an acceptable method of contraception (e.g., condom) during the study and for 2 years after completion of investigational treatment. • Participants must be able to swallow capsules. • Participants must be able and willing to be available for the duration of the study and are willing to follow study procedures. • Patients must be covered by a health insurance plan (French centers). • Capable of giving signed informed consent (per local law).

Exclusion criteria 2

1. Molecular screening step • Patient whose disease has not yet progressed on CDK4/6 inhibitor therapy
2. Treatment step • Somatic deleterious inactivating TP53 mutation. • Any prior therapy with an MDM2 inhibitor. • Unable or unwilling to avoid prescription medications, over-the-counter medications, dietary/herbal supplements, and/or foods (eg, grapefruit, pomelos, star fruit, Seville oranges and their juices) that are moderate/strong inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the medication, supplements, and/or foods are discontinued for at least 5 half-lives or 14 days (whichever is longer) prior to study entry and for the duration of the study. • Symptomatic or actively progressing central nervous system (CNS) metastases. Asymptomatic patients since at least 3 months before cycle 1 day 1 with treated CNS lesions are eligible, provided that all of the following criteria are met: - Evaluable disease, per RECIST v1.1, must be present outside the CNS. - Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord). - The patient has no history of intracranial hemorrhage or spinal cord hemorrhage. - Anticonvulsant therapy at a stable dose is permitted. - No ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of >2 mg of dexamethasone (or equivalent). Subjects on a chronic stable dose of ≤2 mg total daily dose of dexamethasone can enter the trial. • History of leptomeningeal disease. • Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1 at time of treatment start, with the following exceptions: Alopecia (any grade) and neuropathy (must have resolved to ≤ Grade 2); Congestive Heart Failure (must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely); Anemia (must have resolved to ≤ Grade 2) • Patients who have had a last dose of IV chemotherapy within 21 days, last dose of oral cytotoxic chemotherapy, radiotherapy, biological therapy, endocrine therapy, targeted therapy including a CDK4/6 inhibitor or investigational therapy within 14 days prior to treatment start. • Patients who have had any major surgery within 28 days prior to inclusion. • Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment. • Concomitant use of other agents for the treatment of cancer or any investigational agent(s). LH-RH agonists are allowed per standard of care and investigator’s opinion. • Women who are either pregnant, lactating, planning to get pregnant. • Have a serious concomitant systemic disorder (eg, active infection or a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, diarrhea, or profound immune suppression) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol, including but not limited to the following: - Known active hepatitis B or C virus infection. - Severe renal impairment, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, liver disease diagnosed with Child-Pugh A or higher cirrhosis or history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in clinically significant diarrhea. ability to comply with medical monitoring of the trial for geographic, social or psychological reasons.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The proportion of patients who have achieved either a confirmed complete or partial response, or stable disease for at least 24 weeks after treatment start per RECIST 1.1 based on local investigator assessment

Secondary endpoints 5

1. SAEs (serious adverse events) and AEs (adverse events) according to NCI CTCAE v5.0, by grade and their relationship to milademetan and/or fulvestrant.
2. PFS (Progression-free survival), ORR (objective response rate), DoR (duration of response), OS (overall survival)
3. The measure of interest is the mean difference in the change from baseline to different specific visits (each disease radiological assessment, disease progression and/or treatment discontinuation) in total/subscale scores of the 5 Dimension 5 Level (EQ-5D-5L) scale.
4. Quantitative and qualitative analyses of ctDNA collected at baseline, during therapy and at tumor progression; GATA3 and MDM2 IHC on tumor tissue
5. Digital pathology analyses on tumor tissue.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Curie

Sponsor organisation

Institut Curie

Address

26 Rue D Ulm

City

Paris

Postcode

75005

Country

France

Scientific contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Public contact point

Organisation

Institut Curie

Contact name

François-Clément Bidard

Third parties 1

Sponsor responsibilities

Article 77 compliance

Institut Curie

Contact point sponsor

Institut Curie

Article 77 implementation

Institut Curie

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 2 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications