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

NCT05932667 | Terminated Phase 2

• 1 other identifier: IC 2022-05
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 6

Brief 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. 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.

Conditions

Advanced or Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (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.

  24 weeks

Secondary Outcomes (7)

• Safety follow-up

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

• Progression-free survival (PFS) measurement

  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

• Objective Response Rate (ORR) measurement

  Until 24 months

• Duration of Response (DoR) measurement

  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

• Overall Survival (OS)

  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

Study Arms (1)

Single arm: combination of Milademetan at the recommended dose and fulvestrant

EXPERIMENTAL

In 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.

Drug: Milademetan; Behavioral: Patient Reported Outcomes (PROs) and Health-Related Quality of Life (HRQOL)

Interventions

Milademetan DRUG

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.

Also known as: Fulvestrant

Single arm: combination of Milademetan at the recommended dose and fulvestrant

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

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

Single arm: combination of Milademetan at the recommended dose and fulvestrant

Eligibility Criteria

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

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• Institut Curie: lead
• Rain Oncology Inc: collaborator

Study Sites (6)

Centre Leon Berard

Lyon, 69008, France

Location

Institut Du Cancer Montpellier

Montpellier, 34298, France

Location

Hopital Tenon Ap-Hp

Paris, 75020, France

Location

Institut Curie

Paris, 75248 Cedex, France

Location

Centre Eugene Marquis

Rennes, 35000, France

Location

Institut Curie

Saint-Cloud, 92210, France

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

milademetan; Fulvestrant; Patient Reported Outcome Measures; Quality of Life

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; Health Care Surveys; Surveys and Questionnaires; Data Collection; Epidemiologic Methods; Investigative Techniques; Health Services Research; Health Planning; Health Care Economics and Organizations; Patient Outcome Assessment; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation; Health Care Evaluation Mechanisms; Public Health; Environment and Public Health; Health Status; Demography; Epidemiologic Measurements

Study Officials

• François-Clément Bidard

  Institut Curie

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: June 13, 2023
• First Posted: July 6, 2023
• Study Start: October 12, 2023
• Primary Completion: November 24, 2023
• Study Completion: November 30, 2023
• Last Updated: December 21, 2023

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data requests can be submitted starting 9 months after last article publication and will be made accessible for up to 12 months.
• Access Criteria: Access to trial individual participant data can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a data sharing agreement (DSA).

Locations

FR (6)