"DEMETER": Milademetan and fulvestrant in GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer patients: a multicenter phase II trial
- Trial ID
- 2022-502360-21-00
- Protocol
- IC 2022-05
- Sponsor
- Institut Curie
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **efficacy** of the combination of milademetan and fulvestrant by assessing the clinical benefit rate at 6 months (6mCBR) in patients with GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer. This is clinically relevant as it aims to evaluate the potential of this combination therapy to provide a meaningful therapeutic benefit in a specific subset of breast cancer patients, potentially leading to improved treatment outcomes.
Secondary objectives include:
- To determine the safety and tolerability of milademetan and fulvestrant.
- To further assess the efficacy of the combination in terms of progression-free survival (PFS), overall response rate (ORR), duration of response (DoR), and overall survival (OS).
- To describe changes in Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) in patients treated with the combination.
- To identify potential biomarkers of response and resistance mechanisms through circulating tumor DNA (ctDNA) analyses and immunohistochemistry (IHC) analyses.
- To explore innovative tools to detect GATA3 mutant cancers.
Participants
The clinical trial involves participants diagnosed with **GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer**. The study population includes both male and female subjects, with an age range of 18 years and older. Participants are required to have a good general health status, as indicated by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include individuals who have progressed on CDK4/6 inhibitor therapy and have received at least one prior line of endocrine therapy. Participants must have a life expectancy of at least 3 months and adequate organ function. Lifestyle considerations such as the ability to swallow capsules and willingness to adhere to study procedures are also required. The trial population was selected based on specific genetic and clinical criteria, ensuring the presence of a GATA3 frameshift or truncating mutation confirmed by genetic analysis.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **milademetan** in combination with **fulvestrant** for patients with GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer. This is a multicenter, phase II trial with a randomized, double-blind, controlled design. The trial aims to assess the clinical benefit rate at six months, with the primary endpoint being the proportion of patients achieving a confirmed complete or partial response, or stable disease for at least 24 weeks as per RECIST 1.1 criteria. Secondary endpoints include the evaluation of serious adverse events, progression-free survival, objective response rate, duration of response, and overall survival.
The trial is expected to last until December 31, 2026, with recruitment having commenced on June 30, 2023. Participants will be involved in the study for a maximum treatment period of 36 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The inclusion visit involves molecular screening to confirm GATA3 mutational status and other eligibility criteria, such as age, performance status, and prior treatment history. Follow-up visits will occur at regular intervals to evaluate treatment efficacy and monitor for adverse events. The end-of-study visit will conclude the participant's involvement, with a comprehensive assessment of their response to the treatment regimen.
Participants are expected to adhere to the study protocol, including attending all scheduled visits and complying with treatment regimens. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are covered by a health insurance plan. The study's rigorous design and comprehensive monitoring aim to provide valuable insights into the treatment of this specific breast cancer subtype.
Treatment
The clinical trial involves the administration of **Milademetan**, an experimental medication provided in the form of a capsule. The active substance, milademetan, is chemically derived and is manufactured by Rain Therapeutics, Inc. The pharmaceutical form is a capsule, and the medication is administered orally. The maximum daily dose is 260 mg, with a total maximum dose of 60,793 mg over a treatment period of up to 36 weeks. The medication is not formulated for pediatric use and is not classified as an orphan drug. Participant compliance with the dosing schedule is monitored throughout the trial.
In addition to Milademetan, the trial includes the administration of **Fulvestrant**, a non-experimental treatment used as a comparator. Fulvestrant is provided as a 250 mg solution for injection in a pre-filled syringe, manufactured by Sandoz Ltd. The active substance, fulvestrant, is also chemically derived. The administration route is via intramuscular injection, with a maximum daily dose of 500 mg and a total maximum dose of 13,000 mg over a treatment period of up to 86 days. This treatment is not formulated for pediatric use and is not classified as an orphan drug. Compliance with the administration schedule is similarly monitored to ensure adherence to the protocol.
Efficacy
The efficacy of the combination of **milademetan** and fulvestrant in patients with GATA3-mutant, ER-positive, HER2-negative advanced or metastatic breast cancer will be assessed primarily by evaluating the clinical benefit rate at 6 months (6mCBR). The primary endpoint is defined as the proportion of patients who achieve a confirmed complete or partial response, or stable disease for at least 24 weeks after treatment initiation, as per RECIST 1.1 criteria based on local investigator assessment.
Secondary endpoints include the evaluation of serious adverse events (SAEs) and adverse events (AEs) according to NCI CTCAE v5.0, progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS). Additionally, the study will measure the mean difference in change from baseline to specific visits in total/subscale scores of the EQ-5D-5L scale. Quantitative and qualitative analyses of circulating tumor DNA (ctDNA) collected at baseline, during therapy, and at tumor progression will be conducted, along with GATA3 and MDM2 immunohistochemistry (IHC) on tumor tissue. Digital pathology analyses on tumor tissue will also be performed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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).
- 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
- Molecular screening step • Patient whose disease has not yet progressed on CDK4/6 inhibitor therapy
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Jun 2023 | 48 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204760 |
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204761 |
Fulvestrant 250 mg solution for injection in pre-filled syringe | Test | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | INTRAMUSCULAR INJECTION | 500 | 86 | PRD3261730 |
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204757 |
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204756 |
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204758 |
Milademetan | Test | CAPSULE | ORAL USE | 260 | 36 | PRD9204759 |