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Advanced or Metastatic Breast CancerPhase 2DEMETERNCT05932667

Milademetan and Fulvestrant in GATA3-mutant, ER+HER- Advanced or Metastatic Breast Cancer

A Phase 2 study testing Milademetan and Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) in people with Advanced or Metastatic Breast Cancer, run by Institut Curie at 6 sites in France.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is a single arm, multicentric phase II study of milademetan plus fulvestrant in patients with ER+, HER2- ABC harboring GATA3 mutation(s) in the tumor and/or in ctDNA who have progressed on or after prior treatments including a CDK4/6 inhibitor. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced or Metastatic Breast Cancer
What is being tested?
Milademetan and Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1 participants
Where
6 sitesFrance
Study dates
12 Oct 2023to 30 Nov 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Molecular screening step -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.
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  • 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-).
  • HER2 negative is defined as having an IHC of 0 or 1+ without ISH OR IHC 2+ and ISH non-amplified.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.
  • For patients with germline BRCA mutation: having received a prior treatment with PARP inhibitor.
  • Evaluable disease per investigator assessment (RECIST v1.1).
  • Willingness to provide access to archived tumor block (or 12 unstained FFPE slides of 10 and 4 µm). 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 supplemented by a hormonal contraception) 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.
  • Capable of giving signed informed consent (per local law).

Who cannot join

  • 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.
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  • 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.
  • Visceral crisis defined as severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of 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 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 (ILD), 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.
  • Inability to comply with medical monitoring of the trial for geographic, social or psychological reasons
  • Hypersensitivity to the active substance or to any excipients of milademetan.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

France6 sites

  • Centre Leon Berard

    Lyon, 69008

  • Institut Du Cancer Montpellier

    Montpellier, 34298

  • Hopital Tenon Ap-Hp

    Paris, 75020

  • Institut Curie

    Paris, 75248 Cedex

  • Centre Eugene Marquis

    Rennes, 35000

  • Institut Curie

    Saint-Cloud, 92210

Other trials in France

About this study

Official title: Milademetan and Fulvestrant in GATA3-mutant, ER-positive, HER2-negative Advanced or Metastatic Breast Cancer Patients: a Multicenter Phase II Trial

This is a single arm, multicentric phase II study of milademetan plus fulvestrant in patients with ER+, HER2- ABC harboring GATA3 mutation(s) in the tumor and/or in ctDNA who have progressed on or after prior treatments including a CDK4/6 inhibitor.

Frameshift or truncating GATA3 mutations will be identified by next generation sequencing (NGS) performed on either tissue or circulating DNA. Given the well-known safety profile of fulvestrant and the absence of significant toxicity expected from the association of fulvestrant and milademetan, a safety run-in is planned. During the course of the study, the Steering Committee will specifically review the occurrence of toxicities defined as DLTs in the safety run-in.

Read the detailed description

This is a single arm, multicentric phase II study designed to evaluate the efficacy and safety of milademetan-fulvestrant combination in patients with ER+ advanced breast cancer. The trial is dedicated to patients experiencing disease progression after one prior line of endocrine therapy, including a prior CDK4/6 inhibitor, but no more than 2 prior lines of endocrine therapy for metastatic disease. No more than 2 prior lines of chemotherapy for metastatic disease is allowed.

The study selection step includes the confirmation of GATA3 mutational status, either with a result already available, or following informed consent form signature, and mutationnal and analysis of FFPE block available as per inclusion criteria.

The study treatment step is divided into two successive parts: a safety run-in part followed by a phase II part.

In the safety run-in, 6 patients will be included at dose D (milademetan 260mg qdx3 every 14 days twice in a 28-day cycle and fulvestrant 500mg IM at Day1, Day15 of cycle 1, then Day1 of every 28 day-cycle. In case of unacceptable toxicity at the D-dose, a D-1 dose will be investigated, followed by a D-2 dose in case of unacceptable toxicity at D-1 dose.

In the phase II, patients will be treated at the milademetan dose recommended in the safety run-in. Dose reductions will be allowed on subsequent cycles in case of toxicity.

Patients will continue to receive study drug treatment until progression of disease, unacceptable toxicity, patient withdrawal of consent, Investigator decision, lost to follow-up, death, patient non-compliance, or study termination by Sponsor.

Being tested
Milademetan, Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL)
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MilademetanDrug

    Also called Fulvestrant

    The study treatment, including a combination of milademetan and fulvestrant, is administered into two successive parts: a safety run-in part followed by a phase II part. Once GATA3 mutational status confirmed, patients will continue to receive study drug treatment until progression of disease, unacceptable toxicity, patient withdrawal of consent, Investigator decision, lost to follow-up, death, patient non-compliance, or study termination by Sponsor.

  • Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL)Behavioural

    Measure of interest is the mean difference in the change from baseline to different specific visit (each disease radiological assessment, disease progression and/or treatment discontinuation) in total/subscale scores of the 5 Dimension 5 Level (EQ-5D-5L) scale and the EORTC-QLQ-C30 questionnaire

Study groups in NCT05932667
Study groupRoleWhat they receive
Single arm: combination of Milademetan at the recommended dose and fulvestrantExperimentalIn the safety run-in, 6 patients will be included milademetan at dose D and fulvestrant 500mg IM at Day1, Day15 of cycle 1, then Day1 of every 28 day-cycle. In case of unacceptable toxicity at the D-dose, a D-1 dose will be investigated, followed by a D-2 dose in case of unacceptable toxicity at D-1 dose. In the phase II, patients will be treated at the milademetan dose recommended in the safety run-in. Dose reductions will be allowed on subsequent cycles in case of toxicity.
Receives: Drug: Milademetan; Behavioral: Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Response per RECIST 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.

    Measured: 24 weeks

Secondary outcomes (7)

  1. Safety follow-up

    SAEs (serious adverse events) and AEs (adverse events) according to NCI CTCAE v5.0, by grade and their relationship to milademetan and/or fulvestrant

    Measured: Until 30 days after the last dose of IMP (24 months + 30 days)

  2. Progression-free survival (PFS) measurement

    PFS defined as the time from the date of inclusion until progression per RECIST 1.1 based on local investigator assessment or death due to any cause

    Measured: From date of Treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

  3. Objective Response Rate (ORR) measurement

    ORR defined as the proportion of patients who have a complete response (CR) or partial response (PR) based on local investigator assessment, per RECIST 1.1 among patients with mesurable disease at baseline. If PR/CR is reported, confirmation of response is required; confirmatory assessment should be performed ≥ 4 weeks after response is first documented.

    Measured: Until 24 months

  4. Duration of Response (DoR) measurement

    DoR defined as the time from the date of first documented response until date of documented progression or death due to any cause per RECIST 1.1 based on local investigator assessment.

    Measured: From date of treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

  5. Overall Survival (OS)

    OS defined as the time from inclusion to the date of death due to any cause.

    Measured: From date of treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

  6. Quality of Life measurement with EQ-5D-5L

    The measure of interest is the mean difference in the change from baseline to different discontinuation in scores of the 5 Dimension 5 Level (EQ-5D-5L) scale

    Measured: From date of treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

  7. Quality of Life measurement with EORTC-QLQ-C30

    The measure of interest is the mean difference in the change from baseline to different discontinuation in scores of the EORTC-QLQ-C30 questionnaire.

    Measured: From date of treatment start until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jul 2023
  2. Study start12 Oct 2023
  3. Primary completion24 Nov 2023
  4. Study completion30 Nov 2023

Why it stopped: Financial partner providing study drug could no longer support the trial

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
This is a single arm, multicentric phase II study designed to evaluate the efficacy and safety of milademetan-fulvestrant combination in patients with ER+ advanced breast cancer. The study treatment step is divided into two successive parts: a safety run-in part followed by a phase II part.
Masking
None (open label)
Enrolment
1 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05932667
Sponsor's protocol ID
IC 2022-05
Acronym
DEMETER
Status last verified
Dec 2023
First submitted
13 Jun 2023
Last updated
21 Dec 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Investigators will share de-identified data sets documents generated under the project will be disseminated in accordance with Institut Curie policies.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Milademetan and Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL) in people with Advanced or Metastatic Breast Cancer, run by Institut Curie at 6 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 38 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 21 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Financial partner providing study drug could no longer support the trial). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Response per RECIST 1.1 (time frame: 24 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05932667.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Dec 2023.

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