Dose-Expansion Modular Study To Explore the Safety, Tolerability, and Anti-tumor Activity of HER3- DXd Monotherapy and Combinations in Patients With Inoperable Advanced Breast Cancer (ABC) After Progression on T-DXd

Recruiting now · Phase 1/Phase 2

Conditions studied: Breast Cancer Metastatic, HER2-positive Metastatic Breast Cancer, HER2 Low Breast Carcinoma, Advanced Breast Cancer

In brief

ICARUS-BREAST02 is an open-label, multicenter, phase 1b/2, platform study that aims to evaluate the safety, tolerability, and efficacy of HER3-DXd monotherapy and in combination with other anti-cancer agents in patients with ABC. The first 2 modules will evaluate: i. safety and efficacy of HER3-DXd with olaparib in patients with HER2-low and HER2-positive ABC progressed on T-DXd (Module 1) and HER3-DXd monotherapy in patients with HER2-low ABC progressed on T-DXd (Module 0). The main objective of Part 1 is to assess the safety and tolerability of HER3-DXd monotherapy and combination and to determine the recommended phase 2 dose (RP2D) of the combination containing HER3-DXd. The main objective of Part 2 is to assess the efficacy of study therapies in each module based on investigator assessment as evaluated by the objective response rate (ORR) at 6 months.

Key facts

Study ID

NCT06298084

Run by

Gustave Roussy, Cancer Campus, Grand Paris

People needed

152

Starts

2024-03-21

Expected to finish

2029-06-01

Last updated by the study team

2024-03-29

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

• Patients must have received prior treatment with T-DXd and presented disease progression while on T-DXd treatment or within 2 months from T-DXd interruption/discontinuation for any reason, without requiring to be the last line of treatment. Patients who have received other lines of treatment after T-DXd and before study entry is capped at 10 patients for each cohort.
• Patients with HER2-positive tumors must have received prior treatment with trastuzumab and taxanes. They may have received prior treatment with T-DM1 and pertuzumab.
• Patients with HER2-low tumors must have been treated with taxanes. Patients with HR-positive tumors must have received ET and CDK4/6 inhibitors (patients may have received prior treatment with sacituzumab govitecan) If a patient has a tumor that was previously HER2-pos and became HER2-low, she/he will be included in cohort 2 and meet the inclusion criteria for HER2-low tumors.
• If a patient has a tumor that was previously HR-pos and became HR-neg, prior therapy with CDK4/6 inhibitors is not mandatory.
• Patients with germline pathogenic BRCA1/2 mutations and HER2-positive or HER2-low breast cancer are eligible to the study but must have received a prior treatment with PARP inhibitor (olaparib or talazoparib)
• Female or male patient aged ≥18 years on the day of the ICF signature
• Patient who has histologically confirmed diagnosis of breast cancer with unresectable loco regional or metastatic disease
• Patient must have an ECOG PS ≤1 at the time of screening
• Patients must have HER2-pos (IHC 3+ or IHC2+/ISH positive) or HER-2 low (IHC2+/ISH negative or IHC 1+) tumors with any HR status, any time before T-DXd exposure
• Patient must have at least one radiologically measurable lesion (different from the biopsy site) according to response evaluation criteria in solid tumors (RECIST) V1.1 criteria. At least one predominantly lytic or mixed lytic-blastic bone lesion with identifiable soft tissue component that can be evaluated by Computerized Tomography (CT)/Magnetic Resonance Imaging (MRI) must be present in patients with only bone metastasis
• Patient must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patients must have accepted to perform pre-treatment, on-treatment, and end-of-treatment biopsies
• Patient must have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1, defined per the protocol
• Female patients of reproductive/childbearing potential must have a negative pregnancy test at screening (serum test within 24 hours before C1D1 or urine test within 72 hours of C1D1) and must and must agree to use a highly effective form of contraception or avoid intercourse during and till the end of treatment and for at least 8 months after the last dose of study drug. The following contraception methods are considered highly effective:
• Intrauterine device (IUD)
• Bilateral tubal occlusion
• Vasectomized partner
• Complete sexual abstinence defined as refraining from heterosexual intercourse during and till the end of treatment and for at least 8 months for females after the last dose of study drug. Periodic abstinence not an acceptable method of contraception
• Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 8 months after the final study drug administration
• Male patients must be surgically sterile or must withhold heterosexual intercourse, or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 5 months following the last dose of study drug
• Male patients must not freeze or donate sperm starting at screening and throughout the study period, and for at least 5 months after the final study drug administration.
• Patient must understand, sign and date the written informed consent form (ICF) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedure as per protocol
• Patient must be affiliated to a social security system or beneficiary of the same

You may not qualify if…

• The following exclusion criteria are applicable for all modules. Patients will be excluded if they present one of them:
• Patient with a breast cancer amenable for resection or radiation therapy with curative intent
• Patient with any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has current ILD, or is suspected to have ILD as assessed by imaging during screening
• Patient with clinically severe pulmonary compromise (based on investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
• Any underlying pulmonary disorder (eg, pulmonary embolism, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion) OR
• Any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR
• Prior pneumonectomy
• Patient receiving chronic systemic corticosteroids dosed at >10 mg/day prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1 Day 1. Patients who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study
• Patient with evidence of any leptomeningeal disease
• Patient with clinically significant corneal disease
• Patient with any evidence of severe or uncontrolled systemic diseases (e.g. active bleeding diatheses, active infection, or psychiatric illness) which in the investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required for eligibility
• Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Patients with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1
• Inadequate washout period prior to Cycle 1 Day 1, defined as:
• Whole brain radiation therapy or stereotactic brain radiation therapy <14 days
• Previous treatment with T-DXd < 28 days
• Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s) from a previous cancer treatment regimen or clinical study <14 days or 5 half-lives, whichever is longer
• Endocrine therapy <21 days
• Monoclonal antibodies <28 days including immune checkpoint inhibitors (ICIs)
• Major surgery (excluding placement of vascular access) <28 days
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <14 days
• Live virus vaccination <28 days
• Prior treatment with an anti-HER3 antibody
• Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Patients with chronic Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the Investigator deems related to previous anticancer therapy, comprising the following, may be enrolled at the discretion of the Investigator:
• Chemotherapy-induced neuropathy
• Fatigue

Where it is running

• Gustave Roussy Institut — Villejuif, France (enrolling)

Full record on ClinicalTrials.gov

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