Trial of Trastuzumab Deruxtecan in Previously Treated HER2

The purpose of this study is to test the good and bad effects of a drug called trastuzumab deruxtecan (T-DXd) in adult patients with metastatic HER2-negative breast cancer and which patients might benefit the most from T-DXd.

HER2 (human epidermal growth factor receptor 2) is a gene that can play a role in the development of breast cancer. Genes like HER2 and the proteins they make influence how a breast cancer behaves and how it might respond to a specific treatment.

A score of 0 on the HER2 immunohistochemistry (IHC) test indicates that breast tissue is HER2-negative. Drugs that fight cancer by targeting the growth of HER2 genes, such as the monoclonal antibody trastuzumab, have not traditionally been used in patients with HER2-negative tumors because trastuzumab works by attaching to HER2 and stopping cancer cells from growing and dividing. However, about half of breast cancers that are categorized as HER2-negative like yours, actually have low expression of HER2. and recent research has shown that newer generations of antibody-drug conjugates like trastuzumab show considerable survival benefit even in tumors that are not classified as HER2-positive.

An antibody-drug conjugates is a combination of a monoclonal antibody like trastuzumab with an anticancer agent like deruxtecan. This combination that interrupts DNA replication in cancer cells. Antibody-drug conjugates like (T-DXd) are designed to target and kill cancer cells while sparing healthy cells.

Prior research that has shown that the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has outstanding activity and survival benefit in HER2-low breast cancers.

The purpose of this study is to help us learn more about which patients might benefit most from T-DXd through a single-arm, open-label, phase 2 study to assess the safety and efficacy of T-DXd in HER2-negative subjects with unresectable and/or metastatic breast cancer.

The researchers will measure the response to the T-DXd (the percentage of patients with complete response, partial response, stable disease, and progressive disease). Researchers will also look for biomarkers to determine the most accurate way to predict which patients without HER2-positive breast cancer will benefit the most from T-DXd.

T-DXd has been FDA approved to treat adults with unresectable or metastatic HER2-low breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

Each treatment cycle is 21 days.

Eligibility Criteria:
Inclusion Criteria:

1. Must be competent and able to comprehend, sign, and date an Institutional Review Board (IRB) approved ICF before performance of any study-specific procedures or tests.
2. Men or women ≥18 years old.
3. Pathologically documented breast cancer that:

   1. Is unresectable or metastatic.
   2. Has always been HER2-IHC 0 and never previously HER2-positive (IHC 3+ or ISH+) or HER2-low (1+, or 2+ ISH-) on prior pathology testing according to American Society of Clinical Oncology College of American Pathologists (ASCO-CAP) guidelines.
   3. Is either HR-positive or HR-negative per ASCO-CAP guidelines
   4. If HR-positive, has or has not been treated with a CDK4/6 inhibitor.
   5. Has been treated with 1 or 2 prior lines of systemic therapy (which includes either standard cytotoxic chemotherapy and/or antibody-drug conjugates \[e.g sacituzumab-govitecan, datopotamab-deruxtecan, or others\]) in the metastatic setting. If recurrence occurred within 6 months of the last dose of (neo)adjuvant chemotherapy, (neo)adjuvant chemotherapy would count as 1 line of therapy. Endocrine therapies, immune checkpoint inhibition without systemic chemotherapy, and targeted-therapies (e.g. olaparib, or others) do not count as systemic cytotoxic chemotherapy lines and are unlimited prior to enrolment.
   6. Was never previously treated with anti-HER2 therapy.
4. Documented radiologic progression (during or after most recent treatment).
5. Adequate archival tumor sample \<3 years-old available for assessment of HER2 status by IHC and by HS-HER2 quantitative assay. If archival tissue is not available or inadequate for assessment (e.g. decalcified bone, cytology, or other), a newly obtained biopsy from a metastatic site (or breast tissue if locally advanced/unresectable disease as the only site of advanced disease) is required on enrolment.
6. Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per modified Response Evaluation Criteria in Solid Tumors (mRECIST) version 1.1
7. ECOG PS 0 or 1.
8. Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to C1D1.
9. Adequate bone marrow function within 28 days before C1D1, defined as:

   * Platelet count ≥100,000/mm3 (Platelet transfusion is not allowed within 1 week prior to Screening assessment)
   * Hemoglobin level ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 week prior to Screening assessment)
   * Absolute neutrophil count ≥1500/mm3 (granulocyte colony-stimulating factor administration is not allowed within 1 week prior to Screening assessment)
10. Adequate renal function within 28 days before C1D1, defined as:

    - Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault Equation.
11. Adequate hepatic function (Table 1) within 28 days before C1D1, defined as:

    * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3×ULN (\< 5×ULN in participants with liver metastases)
    * Total bilirubin ≤1.5 × ULN if no liver metastases or \<3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
12. Adequate blood clotting function within 28 days before C1D1, defined as:

    - International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN
13. Adequate treatment washout period before C1D1, defined as:

    * Major surgery, minimum washout period ≥ 4 weeks
    * Radiation Therapy including palliative stereotactic radiation therapy to chest, minimum washout period ≥ 4 weeks
    * Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation, minimum washout period ≥ 2 weeks
    * Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], hormonal therapy, antibody-based therapy, or retinoid therapy, minimum washout period ≥ 3 weeks
    * Targeted agents and small molecules, minimum washout period ≥ 2 weeks or 5 half-lives, whichever is longer
    * Cell-free and Concentrated Ascites Reinfusion Therapy (CART), peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion, minimum washout period ≥2 weeks prior to screening assessment
14. Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of T-DXd. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
15. Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening (those using hormonal methods must have been stable on their chosen form of contraception for 3 months prior to study entry) and must agree to continue using such precautions for 7 months after the last dose of T-DXd. Not all methods of contraception are highly effective. Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of T-DXd. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable.
16. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom from screening to 4 months after the final dose of T-DXd. Complete heterosexual abstinence for the duration of the study and drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use at least one highly effective method of contraception throughout this period, as described in Table 3. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of enrolment, throughout the study and for 4 months after the last dose of T-DXd. Preservation of sperm should be considered prior to enrolment in this study.
17. Female subjects must not donate, or retrieve for their own use, ova from the time of enrolment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrolment in this study.

Exclusion Criteria:

1. Uncontrolled or significant cardiovascular disease, including any of the following:

   1. History of myocardial infarction within 6 months before enrolment.
   2. History of symptomatic congestive heart failure (New York Heart Association Class II to IV).
   3. Corrected QT interval (QTc) prolongation to \>470 ms (females) or \>450 ms (male) based on average of Screening 12 lead ECG.
2. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
3. Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids to control associated symptoms.

   * Subjects with clinically inactive brain metastases may be included in the study.
   * Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrolment.
4. Has multiple primary malignancies within 3 years, except adequately resected nonmelanoma skin cancer, curatively treated in situ disease, or contralateral breast cancer.
5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
6. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
7. Has an uncontrolled infection requiring ongoing IV antibiotics, antivirals, or antifungals.
8. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that would, in the opinion of the Investigator, increase the safety risk to the subject or interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
9. Social, familial, or geographical factors that would interfere with study participation or follow-up.
10. Has known history of human immunodeficiency virus (HIV) infection with detectable viral load or CD4 count \< 200 cells per cubic millimeter or active hepatitis B (HBsAg positive) or C (HCV positive RNA) infection.
11. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Sponsor-Investigator \[eg, Grade 2 chemotherapy-induced neuropathy, fatigue, residual endocrinopathies from use of immunotherapy such as hypothyroidism/hyperthyroidism, type 1 diabetes, hyperglycemia, adrenal insufficiency, adrenalitis, skin hypopigmentation (vitiligo)\].
12. Therapeutic radiation therapy or major surgery within 4 weeks before study treatment or palliative stereotactic radiation therapy (other than abdominal radiation) within 2 weeks before study treatment.
13. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study treatment; or treatment with small-molecule targeted agents within 2 weeks, or 5 half-lives before study treatment, whichever is longer.
14. Current treatment with strong cytochrome P450 (CYP3A4) and organic anion transporting polypeptide (OATP) inhibitors and any monoclonal antibody treatment (washout period of ≥3 elimination half-lives of the inhibitor/antibody is required).
15. Participation in a therapeutic clinical study within 3 weeks before study treatment (for small-molecule targeted agents, this nonparticipation period is 2 weeks or 5 half-lives, whichever is longer), or current participation in other investigational procedures.
16. Is pregnant or breastfeeding or planning to become pregnant.
17. Subject must not be study site personnel directly involved in the clinical trial, or an immediate family member of someone directly involved.
18. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study intervention. Note: Participants, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study intervention.

20. Lung criteria:

* Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disorder, restrictive lung disease, pleural effusion etc.)
* Any autoimmune, connective tissue or inflammatory disorders, including Rheumatoid arthritis, Sjogren's, and sarcoidosis, where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the study.
* Prior pneumonectomy (complete) 21. Otherwise considered inappropriate for the study by the Investigator.