Phase II Randomized Trial of Datopotamab Deruxtecan Plus Durvalumab Versus Datopotamab Deruxtecan in PD-L1-Negative Metastatic Triple-Negative Breast Cancer

Trial ID: 2024-519913-76-00
Protocol: 1011098
Sponsor: Queen Mary University Of London

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Diseases & Conditions

Triple negative breast cancer

Objectives

The primary objective is to demonstrate the superiority of datopotamab deruxtecan plus durvalumab compared to datopotamab deruxtecan monotherapy in patients with PD-L1-negative metastatic triple-negative breast cancer, as evaluated by progression-free survival. Secondary objectives include the assessment of:

Overall survival;
Objective response rate, clinical benefit rate, duration of response, and duration of clinical benefit;
Changes in quality of life via patient reported outcomes;
Safety and tolerability.

Participants

This clinical trial includes 30 participants diagnosed with PD-L1-negative metastatic triple-negative breast cancer. The study population consists of male and female individuals aged 18 years or older with an ECOG performance status of 0-1. Eligible participants must present with locally advanced unresectable or stage IV disease and possess measurable lesions via computed tomography or magnetic resonance imaging. Selection requires documented PD-L1 negativity, defined by a 22C3 CPS of less than 10, alongside specific estrogen receptor, progesterone receptor, and HER2 status. Inclusion is contingent upon adequate haematologic and end-organ function, a body weight exceeding 30 kg, and the availability of sufficient formalin-fixed paraffin embedded tumor samples for central testing. Additionally, patients must adhere to specific contraception requirements to manage reproductive risks during the study period.

Plans and Procedures

This phase II, open-label, randomised trial is designed to evaluate the efficacy of datopotamab deruxtecan in combination with durvalumab compared to datopotamab deruxtecan monotherapy. The study focuses on patients with PD-L1-negative metastatic triple-negative breast cancer. The primary objective is to demonstrate superiority in progression-free survival. The research methodology involves assigning participants to receive either the combination therapy or the single agent via intravenous administration. The trial is expected to occur between September 2025 and September 2030. The study process begins with a screening visit to confirm eligibility based on criteria such as ECOG performance status, body weight, and specific histopathology requirements. Following randomisation, participants undergo treatment cycles and periodic assessments to monitor for tumour progression or overall survival. Secondary endpoints include objective response rate, duration of response, and changes in quality of life. Clinical assessments are performed to document the incidence and severity of adverse events.

Treatment

Durvalumab is administered via intravenous administration at a dosage of 1120 mg.

Datopotamab deruxtecan is provided as a solution for infusion and is administered via intravenous administration at a dose of 6.0 mg/kg.

This open-label randomised, phase II trial compares the combination of datopotamab deruxtecan and durvalumab against datopotamab deruxtecan monotherapy in patients with metastatic triple-negative breast cancer exhibiting PD-L1-negative status. The primary objective is to evaluate progression-free survival.

Efficacy

The primary efficacy endpoint is progression-free survival (PFS), defined as the time from randomization to the date of the first documented confirmed tumor progression or death from any cause. Tumor progression is assessed using RECIST 1.1.

Secondary efficacy parameters include:

Overall survival (OS), measured as the time from randomization to death due to any cause.
Objective response rate (ORR), representing the proportion of patients achieving a complete response (CR) or partial response (PR) based on RECIST 1.1.
Duration of response (DoR), defined as the time from the first documentation of CR or PR to confirmed disease progression or death from any cause.
Clinical benefit rate (CBR), calculated as the percentage of patients achieving at least one CR, PR, or meeting stable disease (SD) criteria for a minimum interval of 24 weeks.
Duration of clinical benefit (DoCB), measured in months from randomization to progression or death from any cause in patients achieving clinical benefit.
Changes in quality of life, assessed via time to deterioration (TTD) for overall health and global quality of life items, as well as the percentage of patients experiencing a change of ≥ 10 points on the EORTC QLQ-C30 scale.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Willing and able to provide written informed consent
Ability to comply with the protocol
Female and male ≥ 18 years of age
Patients with locally advanced unresectable or metastatic (stage IV) triple-negative breast cancer, defined as tumour cells being o Negative for ER with <10% of tumour cells positive for ER on IHC or IHC score (Allred) of ≤3 o Negative for PR with <10% of tumour cells positive for PR on IHC or IHC score (Allred) of ≤3 or PR unknown, and o Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH.
PD-L1 negative, defined as o 22C3 CPS<10
Patients must have: at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) performed within 28 days prior to randomisation which is suitable for accurate repeated measurements, or o lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible Patients that cannot be assessed by the CT or MRI scan should be excluded.
Representative formalin-fixed paraffin embedded (FFPE) breast tumour samples with an associated pathology report from the primary or recurrent cancer that are determined to be available and sufficient for central testing OR tumour accessible for biopsy.
ECOG performance status 0-1
Adequate haematologic and end-organ function within 28 days prior to the first study treatment defined by the following: o ANC ≥ 1500 cells/μL (1.5 x 109/L) (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1) o WBC > 2500/μL (2.5 x 109/L) o Platelet count ≥ 100,000/μL (100 x 109/L) (transfusion not permitted within 28 days of study medication) o Haemoglobin ≥ 9.0 g/dL (90g/L) with no blood transfusions (packed red blood cells) o Serum albumin ≥ 3g/dL o AST (SGOT) or ALT (SGPT) and ALP ≤ 2.5 times the institutional upper limit of normal (ULN), bilirubin ≤ 1.5 x ULN (patients with liver metastases who have AST or ALT ≤ 5 x the institutional ULN may be enrolled), o aPTT ≤ 1.5 × the institutional ULN, INR <1.5 and absence of evidence of impaired hepatic synthesis function. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose o Serum Creatinine ≤ 1.5 x ULN. o Glomerular filtration rate ≥ 40mL/min as assessed by standard methodology at the investigating center (i.e., CockcroftGault, MDRD or CKD-EPI formulae, EDTA clearance or 24 h urine collection) o No evidence of haematuria: +++ on microscopy or dipstick
Patients of childbearing potential are eligible provided they have a negative serum or urine pregnancy test on Cycle 1, Day 1 (within 72 hours) of study treatment, preferably as close to the first dose as possible. Patients must agree to use adequate contraception, defined as those methods with a failure rate of < 1 % per year beginning 14 days before the first dose of study drug and for 7 months after the last dose of study drug. Also, participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of treatment. Preservation of ova should be considered prior to randomization or the first dose of study intervention. Fertile men with a female partner of childbearing potential must agree to use one barrier method of contraception, such as condom, during treatment on this trial and for up to 4 months after the last dose of treatment. Male participants must not donate sperm from the start of dosing for at least 4 months after the last dose of the treatment.
Body Weight > 30 kg

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Exclusion Criteria

Prior chemotherapy, immunotherapy (including durvalumab) or treatment with PARP inhibitors for advanced or metastatic breast cancer
Prior treatment with immune checkpoint inhibitors (eg atezolizumab, pembrolizumab) or DNA topoisomerase I or TROP2- or HER2-targeting ADCs and TROP2 targeted therapy in the (neo)adjuvant setting within 6 months from the end of treatment and randomisation into this study
Patients with prior allogeneic stem cell or solid organ transplantation
Patients must not have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent), or had oral or IV steroids for 14 days prior to the first dose of study drug; the use of intranasal, inhaled corticosteroids topical steroids, or local steroid injections, physiologic replacement doses of glucocorticoids (i.e. for adrenal insufficiency) and mineralocorticoids (e.g. fludrocortisone) or steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) is allowed.
Administration of a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Active or prior documented autoimmune or inflammatory disorders including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis,or glomerulonephritis. The following are exceptions to this criterion: o Patients with vitiligo or alopecia o Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement therapy o Any chronic skin condition that does not require systemic therapy o Patients without active disease in the last 5 years may be included o Patients with celiac disease controlled by diet alone
History of idiopathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), druginduced pneumonitis, radiation pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia) requiring steroids, or evidence of active pneumonitis on screening chest CT scan.
Active infection requiring systemic therapy.
History of HIV infection
Known active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
Known history of active tuberculosis clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
Concurrent treatment with other experimental drugs or participation in another clinical trial with therapeutic intent within 28 days prior to randomisation
Pregnant and lactating female patients
Major surgical procedure within 4 weeks prior to randomisation or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis
Malignancies other than breast cancer within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent)
Severe infections within 28 days prior to randomisation in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia
Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria o Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician. o Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, situations that would limit compliance with study requirement, substantially increase risk of incurring AEs
History of leptomeningeal carcinomatosis
Has clinically significant corneal disease.
Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
History of active primary immunodeficiency
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
Patient with Brain metastases or neoplastic spinal cord compression. Patients whose brain metastases have been treated may participate provided they show radiographic stability (defined as 2 brain images, both of which are obtained after treatment to the brain metastases. These imaging scans should both be obtained at least four weeks apart and show no evidence of intracranial progression. In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of prednisone or its equivalent and anticonvulsants for at least 14 days prior to the start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
Patients who have received prior anti–PD-1, anti PD-L1 or anti CTLA-4: o Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy o All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study o Must not have experienced a ≥Grade 3 immune related AE or an immune related neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE: Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. o Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day