Overview

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.

Eligibility

Inclusion Criteria:

1. 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.
2. 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.
3. 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.

4. 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)
5. Female or male patient aged ≥18 years on the day of the ICF signature
6. Patient who has histologically confirmed diagnosis of breast cancer with unresectable loco regional or metastatic disease
7. Patient must have an ECOG PS ≤1 at the time of screening
8. 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
9. 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
10. 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
11. 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
12. 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:
    1. Intrauterine device (IUD)
    2. Bilateral tubal occlusion
    3. Vasectomized partner
    4. 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
13. 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

14. 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
15. 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.
16. 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
17. Patient must be affiliated to a social security system or beneficiary of the same

Exclusion Criteria:

        The following exclusion criteria are applicable for all modules. Patients will be excluded
        if they present one of them:
          1. Patient with a breast cancer amenable for resection or radiation therapy with curative
             intent
          2. 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
          3. Patient with clinically severe pulmonary compromise (based on investigator's
             assessment) resulting from intercurrent pulmonary illnesses including, but not limited
             to:
               1. Any underlying pulmonary disorder (eg, pulmonary embolism, severe asthma, severe
                  chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural
                  effusion) OR
               2. Any autoimmune, connective tissue or inflammatory disorder with pulmonary
                  involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR
               3. Prior pneumonectomy
          4. 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
          5. Patient with evidence of any leptomeningeal disease
          6. Patient with clinically significant corneal disease
          7. 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
          8. 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
          9. Inadequate washout period prior to Cycle 1 Day 1, defined as:
               1. Whole brain radiation therapy or stereotactic brain radiation therapy <14 days
               2. Previous treatment with T-DXd < 28 days
               3. 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
               4. Endocrine therapy <21 days
               5. Monoclonal antibodies <28 days including immune checkpoint inhibitors (ICIs)
               6. Major surgery (excluding placement of vascular access) <28 days
               7. 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
               8. Live virus vaccination <28 days
         10. Prior treatment with an anti-HER3 antibody
         11. 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
               -  Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2
                  endocrinopathies provided they are clinically stable and receiving hormone
                  replacement therapy when applicable which may include:
                    1. Hypothyroidism/ hyperthyroidism
                    2. Type I diabetes
                    3. Hyperglycemia
                    4. Adrenal insufficient
                    5. Adrenalitis
                    6. Skin hypopigmentation (vitiligo)
         12. Has known hypersensitivity to either the drug substances or the inactive ingredients
             of HER3-DXd and/or T-DXd
         13. Patient with a history of severe hypersensitivity reactions to other monoclonal
             antibodies or PARP inhibitors
         14. Has any malignancy other than locally advanced or ABC within 3 years prior to Cycle 1
             Day 1, except adequately resected non-melanoma skin cancer or curatively treated
             in-situ disease or other curatively treated solid tumors
         15. Documented uncontrolled or significant cardiovascular disorder prior to Cycle 1 Day 1,
             including:
               1. Corrected QT interval >450 ms according to Fridericia's formula (QTcF) based on
                  triplicate 12-lead ECGs, approximately 1 minute apart
               2. LVEF <45% by either ECHO or MUGA or cardiac MRI if clinically indicated according
                  to the investigator or consulting cardiologist
               3. Resting systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg
               4. Myocardial infarction within 6 months
               5. Symptomatic congestive heart failure (NYHA class from III to IV)
               6. Uncontrolled angina pectoris within 6 months
               7. Cardiac arrhythmia not controlled by ongoing antiarrhythmic treatment
               8. Diagnosed or suspected long QT syndrome, or known family history of long QT
                  syndrome
               9. History of clinically relevant ventricular arrhythmias, such as ventricular
                  tachycardia, ventricular fibrillation, or Torsade de Pointes
              10. Patient has bradycardia of less than 50 bpm (as determined by central reading)
                  unless the subject has a pacemaker
              11. History of second or third degree heart block. Candidates with a history of heart
                  block may be eligible if they currently have pacemakers, and have no history of
                  fainting or clinically relevant arrhythmia with pacemakers
              12. Coronary/peripheral artery bypass graft within 6 months
              13. Complete left bundle branch block
         16. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic evidence
             of active viral infection within 28 days of Cycle 1, Day 1. Patients with past or
             resolved Hepatitis B virus (HBV) infection are eligible if:
               1. Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody
                  (anti-HBc) positive; OR
               2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to be
                  ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12
                  weeks prior to the viral load evaluation with normal transaminases (in the
                  absence of liver metastasis); OR
               3. HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in the
                  absence of anti-viral therapy and during the previous 12 weeks prior to the viral
                  load evaluation with liver metastasis and abnormal transaminases AST/ALT <3 ULN
                  For patients with HBsAg positive, if abnormal liver function is detected during
                  study drug treatment, viral load should be tested to rule out reactivation.
             Patients with a history of Hepatitis C infection will be eligible for enrollment only
             if the viral load according to local standards of detection, is documented to be below
             the level of detection in the absence of anti-viral therapy during the previous 12
             weeks (ie, sustained viral response according to the local product label but not less
             than 12 weeks, whichever is longer)
         17. Female patient who is pregnant or breastfeeding or intends to become pregnant during
             the study
         18. Has a known human immunodeficiency virus (HIV) infection that is not well controlled.
             All the following criteria are required to define an HIV infection that is well
             controlled: undetectable viral ribonucleic acid (RNA) load, CD4+ counts/levels of >350
             cells/μL, no history of acquired immunodeficiency syndrome (AIDS)-defining
             opportunistic infection within the past 12 months, and stable for at least 3 weeks on
             same anti-HIV retroviral medications. If an HIV infection meets the above criteria,
             the patient's viral RNA load and CD4+ cell count should be monitored per local
             standard of care (eg, every 3 months). Patients with a well-controlled HIV infection
             may only be enrolled into Part 2 (dose expansion) of the study.
         19. Prior or ongoing clinically relevant illness, medical condition, surgical history,
             physical finding, or laboratory abnormality that, in the Investigator's judgment,
             could affect the safety of the patient; alter the absorption, distribution, metabolism
             or excretion of the study drug; or confound the assessment of study results
         20. Adult under legal protection: guardianship, curatorship, or legal protection; or
             patient deprived of his/her liberty by a judicial or administrative decision; or
             patient incapable of giving his/her consent, or patient under psychiatric care
         21. Participation in another clinical trial evaluating an experimental drug during the
             last 4 weeks (except non-interventional research) Specific exclusion criteria for each
             module
             Module 0:
             There are no specific exclusion criteria for module 0 (HER3-DXd monotherapy). Module 1
             (olaparib)
         22. History of hypersensitivity to excipients of olaparib
         23. Inadequate washout period prior to Cycle 1 Day 1, defined as:
               1. Strong CYP3A inhibitors < 1 week
               2. CYP3A inducers for olaparib and phenobarbital < 5 weeks and for any other drug <
                  3 weeks