A clinical trial to assess effects of Trastuzumab deruxtecan in Hormone Receptor positive and HER-2 low breast cancer patients who have progressed on previous Hormonal therapies

Phase 3

Recruiting

• Conditions: Malignant neoplasm of breast of unspecified site,

• Registration Number: CTRI/2020/09/028041
• Lead Sponsor: AstraZeneca AB

Brief Summary

The study is an open-label,multi-center, randomized study in HR+, HER2-low breast cancer patients whosedisease has progressed on at least 2 lines of prior ET in the metastaticsetting.

 The primary purpose of thestudy is to determine the efficacy and safety of T-DXd compared withinvestigator’s choice single agent chemotherapy in the target population.Approximately 850 patients (700 patients with HER2 IHC 2+/ISH- and IHC 1+[HER2-low] expression and 150 patients with HER2 IHC >0 <1+ expression)will be randomized 1:1 across approximately 300 centers globally to receiveeither T-DXd or investigator’s choice single agent chemotherapy (capecitabine,paclitaxel or nab-paclitaxel) until RECIST 1.1 defined disease progression(PD), unless there is unacceptable toxicity, withdrawal of consent, or anothercriterion for discontinuation is met. To ensure adequate representation of eachsubgroup of the HER2-low

population, at least 240patients in each HER2 IHC group (IHC 2+/ISH- and IHC 1+) across both treatmentarms (120 patients per arm) will be randomized.

 Tumor evaluation scans willbe performed at screening (as baseline) with follow-ups every 6 weeks (q6w ± 1week) from the date of randomization for 48 weeks, and then every 9 weeks (q9w± 1 week, starting at Week 57) thereafter until objective disease progression.

The study will compare PFS,OS and other measures of efficacy between the study treatment groups andfurther characterize the safety and tolerability profile of T-DXd.

 Duration of Treatment:Unless specific treatment discontinuation criteria are met or the patientwithdraws consent, all patients will continue receiving treatment until diseaseprogression. For patients randomized to the investigator’s choice single agentchemotherapy arm, crossover to T-DXd will not be permitted.

 Follow-up of Patients postDiscontinuation of Study Treatment: After discontinuation of study treatment,all patients will have post-treatment follow-up scheduled at 40 days (± 7 days)after their last dose of study treatment. Patients who have discontinuedtreatment for reasons other than progressive disease will also be followed upwith tumor assessments until radiological progression (or death). All patientswill be followed up for PFS2 and survival

status, unless consent waswithdrawn.

 Survival: All patientsrandomized should be followed up for survival unless consent was withdrawn.Long-term/survival follow-up visits will be performed every 3 months (±14 days)from the date of the 40-day (±7 days) follow-up visit until death, withdrawalof consent, or study closure, whichever occurs first.

Detailed Description

Not available

Study Timeline

• Study Start: 2020-11-19
• Last Update Posted: 2024-02-26

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 850

Inclusion Criteria

• 1Male or female patients: a) ≥ 18 years of age – applicable for all countries participating in the study except Japan, b) ≥ 20 years of age – applicable for Japan only 2Pathologically documented breast cancer that: a)Is advanced or metastatic b)Has a history of HER2-low or negative expression, defined as IHC 2+/ISH- or IHC 1+ (ISH- or untested) or IHC 0 (ISH- or untested) with a validated assay c)Patients with historical HER2-low or HER2 IHC 0 expression must be confirmed by central laboratory testing to have HER2 low expression or HER2 IHC >0 <1+ expression, respectively.
• If the local HER2 result is not confirmed by the central laboratory result (i.e., must be HER2 low by most recent local HER2 test and HER2 low by central test or HER2 IHC 0 by most recent local HER2 test and HER2 IHC >0 <1+ by central test), the patient will not be eligible for the study.
• oIf a patient has had multiple historical/local HER2 results, the most recent result will be compared with the central laboratory HER2 results to confirm eligibility.
• oThe most recent historical/local HER2 result that will be used to compare with the central laboratory HER2 result must be from metastatic disease or later.
• oIf most recent local HER2 testing only classified the patient’s tumor as HER2 negative (IHC status not available), eligibility will be determined by the central laboratory testing results.
• d)Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per ASCO/CAP guidelines.
• e)Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) per ASCO/CAP guidelines (Hammond et al, 2010) in the metastatic setting.
• If a patient has had multiple ER/PgR results after metastatic disease, the most recent test result will be used to confirm eligibility 3Must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses and is preferred in FFPE blocks based on a mandatory FFPE tumor sample obtained at the time of metastatic disease or later; the most recently collected pre-randomization tumor sample from the time of metastatic disease or later that meets the tissue requirements specified in Section 8.6.1 is required.
• (see Section 8.6.1 and the laboratory manual for additional details).
• 4ECOG performance status of 0 or 1 5Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment 6Must have had disease progression on at least 2 previous lines of ET with or without a targeted therapy (such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatment of metastatic disease.
• Of note: a)Single agent anti-CDK4/6 therapy for the treatment of metastatic disease is considered a line of therapy b)Disease progression within 24 months of starting adjuvant ET is considered a line of therapy c)Any progression after completing a course of adjuvant ET will not be considered a line of therapy d)Changes in dosing schedules, or discontinuations/re-starting of the same drugs or the addition of a targeted therapy to an ET without progression (e.g., adding a CDK4/6 to a current aromatase inhibitor regimen) will not be considered separate lines of therapy.
• 7No prior chemotherapy for advanced or metastatic breast cancer.
• Patients who have received chemotherapy in the neo-adjuvant or adjuvant setting are eligible, as long as they have had a disease-free interval (defined as completion of systemic chemotherapy to diagnosis of advanced or metastatic disease) of >12 months.
• Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-Ray in the absence of measurable disease as defined above is acceptable; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
• 10LVEF ≥ 50% within 28 days before randomization.
• 11Adequate organ and bone marrow function within 14 days before randomization.
• 12Adequate treatment washout period before randomization/enrollment, defined as: a)Major surgery: ≥ 4 weeks b)Radiation therapy including palliative stereotactic radiation therapy to chest: ≥ 4 weeks (palliative stereotactic radiation therapy to other areas ≥ 2 weeks).
• c)Hormonal therapy: ≥ 3 weeks (≥ 2 weeks or 5 half-lives, whichever is longer for small molecule targeted agents) d)Antibody-based anti-cancer therapy: ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g., denosumab for the treatment of complications resulting from bone metastases) e)Chloroquine/Hydroxychloroquine: ≥ 14 days 13Evidence 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 study treatment.
• Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
• The following age-specific requirements apply: women aged ≥ 50 years would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the site.
• Women aged ≤ 50 years would be considered post menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with >1 year interval since last menses, or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• 14Female 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 and must agree to continue using such precautions for 7 months after the last dose of study treatment.
• Not all methods of contraception are highly effective.Female patients must refrain from egg cell donation and breastfeeding while on study treatment and for at least 7 months after the last dose of study treatment.
• Not engaging in sexual activity for the duration of the study treatment and the drug wash out period (7 months) is an acceptable practice; however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.
• 15Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of study treatment.

Exclusion Criteria

• Patients must NOT meet the following criteria at screening: 1.Ineligible for all options in the investigator’s choice chemotherapy arm 2.Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• 3.Uncontrolled or significant cardiovascular disease includes any of the following: a.Patients with a medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (NYHA Class II to IV).
• Patients with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial infarction related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
• b.Uncontrolled hypertension c.Uncontrolled and/or clinically important cardiac arrhythmias d.Corrected QT interval by Fredericia’s method (QTcF) prolongation to >470 ms (females) or >450 ms (male) based on average of screening triplicate 12-lead electrocardiogram (ECG) 4.Has as a history of (non-infectious) ILD/pneumonitis, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• 5.Patients with prior use of immunosuppressive medication within 14 days prior to first study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less than 10 mg/day of prednisone or equivalent.
• 6.Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study enrollment, severe asthma, severe chronic obstructive pulmonary disorder [COPD], restrictive lung disease, significant pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy.
• 7.Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 8.Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants 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 or anticonvulsants 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 enrollment.
• 9.Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection.
• Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Participants should be tested for HIV prior to randomization if required by local regulations or by the IRB/IEC.
• 10.Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment.
• Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study treatment.
• 11.Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
• Patients with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the AstraZeneca Study Physician or designee (e.g., Grade 2 chemotherapy-induced neuropathy).
• 12.Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment.
• 13.Pregnant or breastfeeding female patients.
• 14.Has a history of severe hypersensitivity reactions to either the drug substances, inactive ingredients in the drug product or to other monoclonal antibodies 15.History of another primary malignancy within 3 years, except adequately resected non melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated, or contralateral breast cancer.
• 16.Previous treatment with anti-HER2 therapy 17.Prior treatment with antibody drug conjugate that comprised an exatecan derivative that is a topoisomerase I inhibitor 18.Prior randomization or treatment in a previous trastuzumab deruxtecan clinical study regardless of treatment arm assignment.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
PFS by BICR according to RECIST 1.1 in the HR positive, HER2 low population	PFS in the HER2 low population and ITT population will be tested once, when PFS reaches approximately 65 percent maturity (456 events) in the HER2 low population. This is estimated to occur 29 months after the first patient is randomized (4 months after randomization is completed) assuming a non-uniform accrual of patients with a duration of 25 months. At this time, it is expected that at least 553 events (65 percent maturity) will have been observed in the ITT population

Secondary Outcome Measures

Name	Time	Method
To assess the efficacy of T DXd compared with investigators choice chemotherapy in terms of PFS by BICR	Approximately 29 months after first patient is randomized (456 events in the HER2 low population and at least 553 events have been observed in the ITT population)
I. To assess the efficacy of T DXd compared with investigators choice chemotherapy in terms of OS in the HR PLUS, HER2-low population	ii. OS in the ITT population (HER2 IHC greater than 0 less than 1 PLUS and HER2-low)

Trial Locations

Locations (12)

Aakash Healthcare Super Speciality Hospital; 🇮🇳 Delhi, DELHI, India

Bhagwan Mahaveer Jain Cancer Hospital & Research Centre; 🇮🇳 Jaipur, RAJASTHAN, India

Chittaranjan National Cancer Institute; 🇮🇳 Kolkata, WEST BENGAL, India

Dr. B.L.Kapur Memorial Hospital; 🇮🇳 Delhi, DELHI, India

Manipal Hospital; 🇮🇳 Bangalore, KARNATAKA, India

Max Super Speciality Hospital, Saket; 🇮🇳 Delhi, DELHI, India

Mazumdar Shaw Medical Center (A unit of Narayana Health); 🇮🇳 Bangalore, KARNATAKA, India

MVR Cancer Centre & Research Institute; 🇮🇳 Kozhikode, KERALA, India

Rajiv Gandhi Cancer Institute and Research Centre; 🇮🇳 Delhi, DELHI, India

Regional Cancer Centre; 🇮🇳 Thiruvananthapuram, KERALA, India

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Aakash Healthcare Super Speciality Hospital

🇮🇳Delhi, DELHI, India

Dr Parveen Jain

Principal investigator

9811775324

drparveen1010@gmail.com