Phase I/II Open-Label Multi-Center Trial of Lutetium (177Lu)-NeoBomb1 and Capecitabine in GRPR+, ER+, HER2- Metastatic Breast Cancer Post-Endocrine Therapy
- Trial ID
- 2023-506717-21-00
- Protocol
- CAAA603D12101
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to determine the **Recommended Doses (RD)** and dosing regimens of [177Lu]Lu-NeoB in combination with capecitabine for patients with metastatic breast cancer that is gastrin-releasing peptide receptor positive, estrogen receptor-positive, and human epidermal growth receptor-2 negative. This is crucial for optimizing therapeutic efficacy and minimizing adverse effects in this patient population. Additionally, the study aims to evaluate the preliminary anti-tumor activity across two randomized cohorts with different doses/regimens of [177Lu]Lu-NeoB in combination with capecitabine, which is significant for assessing the potential clinical benefits of this treatment approach.
Secondary objectives include:
- Characterizing the pharmacokinetics (PK) and biodistribution (dosimetry) of [177Lu]Lu-NeoB in combination with capecitabine.
- Evaluating the safety and tolerability of [68Ga]Ga-NeoB.
- Assessing the agreement between [68Ga]Ga-NeoB PET and conventional imaging at the participant level.
- Determining the optimal [68Ga]Ga-NeoB radioactivity dose in Phase I.
- Evaluating preliminary anti-tumor activity of [177Lu]Lu-NeoB in combination with capecitabine in Phase I.
- Assessing the safety and tolerability of [177Lu]Lu-NeoB in combination with capecitabine in Phase II.
Participants
The clinical trial involves a total of **26 participants** diagnosed with **breast cancer**, specifically focusing on those with ER+ and HER2- subtypes. The study population includes both **female and male adults** aged 18 years and older, with a particular emphasis on postmenopausal women for certain phases of the trial. Participants were selected based on their documented diagnosis and progression of metastatic breast cancer, with measurable disease as per RECIST 1.1 criteria. The trial includes individuals who have undergone no more than three prior endocrine therapies in the metastatic setting. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Adequate bone marrow and organ function are also prerequisites for inclusion. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures a focus on individuals with a clear progression of disease and measurable lesions, providing a robust basis for evaluating the trial's objectives.
Plans and Procedures
The clinical trial is designed as a **Phase I/II**, open-label, multi-center study to evaluate the combination of **[177Lu]Lu-NeoB** and **capecitabine** in adult patients with **metastatic breast cancer** that is positive for gastrin-releasing peptide receptor, estrogen receptor-positive, and human epidermal growth factor receptor-2 negative. The trial aims to determine the recommended doses and dosing regimens in Phase I, and to evaluate preliminary anti-tumor activity across two randomized cohorts in Phase II. The study is not categorized as low intervention and is expected to conclude by June 2031, with recruitment starting in April 2024.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, menopausal status, and previous treatment history. The trial will include multiple follow-up visits to monitor safety, efficacy, and pharmacokinetics, with assessments including imaging and laboratory tests. The end-of-study visit will conclude the participant's involvement, which is expected to last until the study's completion unless early termination criteria are met. Conditions for early termination include adverse events, disease progression, or withdrawal of consent.
The trial employs a randomized, controlled design, with participants receiving either the investigational combination therapy or standard care. The study will assess primary endpoints such as the incidence and severity of adverse events, dose-limiting toxicities, and overall response rate. Secondary endpoints include pharmacokinetic parameters and imaging assessments. The trial's methodology ensures rigorous monitoring and data collection to evaluate the safety and efficacy of the investigational treatment in the specified patient population.
Treatment
The clinical trial involves the administration of several treatments, including **CAPECITABINE**, which is provided in tablet form. **Capecitabine** is a chemical active substance administered orally. The dosage and frequency of administration are determined based on the trial protocol, and participant compliance is monitored throughout the study. **Capecitabine** is used in combination with other investigational treatments to evaluate its efficacy in the study population.
Another investigational product used in the trial is **AAA503**, a kit for radiopharmaceutical preparation. The active substance in this product is **NEOB**, which is of chemical origin. **AAA503** is administered via intravenous use. The preparation and administration of this product are conducted according to the specific guidelines outlined in the trial protocol to ensure safety and efficacy.
The trial also includes the use of **[177Lu]-NeoB solution for infusion**, which contains the active substance **LUTETIUM (177LU)-NEOBOMB1**. This solution is administered intravenously. The dosing regimen is carefully controlled and monitored to assess the therapeutic potential of this radiopharmaceutical in combination with other treatments.
**LEUPRORELIN** is included as an auxiliary treatment in the trial. It is provided as a solution for injection and is administered subcutaneously. **Leuprorelin** is a protein-based medicinal product, and its role in the trial is to support the primary investigational treatments.
Additionally, **TRIPTORELIN** is used as a prolonged-release suspension for injection. This protein-based substance is administered intramuscularly. The administration schedule is designed to maintain consistent therapeutic levels in the participants.
Lastly, **GOSERELIN** is provided in implant form and is administered subcutaneously. As a protein-based treatment, **Goserelin** serves as an auxiliary therapy in the trial, complementing the primary investigational treatments.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Phase I include the incidence and severity of adverse events (AEs), including dose-limiting toxicities (DLTs), serious adverse events (SAEs), and changes in laboratory parameters, vital signs, and ECGs. Tolerability will be evaluated through dose interruptions, discontinuations, and reductions. For Phase II, the primary endpoints will focus on objective response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR), and progression-free survival (PFS) as per RECIST v1.1 by local investigator assessment, as well as overall survival (OS).
Secondary endpoints for both Phase I and II will include time activity curves (TACs) and absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions, concentration of [177Lu]Lu-NeoB in blood over time, and derived pharmacokinetic (PK) parameters. Additionally, the incidence and severity of adverse events following [68Ga]Ga-NeoB administration at screening will be monitored. Positive Percent Agreement (PPA) and Positive Predictive Agreement (PPrA) using conventional imaging as a reference by central assessment at screening will also be evaluated. Phase I will include a visual assessment of image quality by central assessment, and further efficacy measures such as ORR, CBR, TTR, DOR, PFS, and OS will be assessed. In Phase II, the incidence and severity of AEs, SAEs, changes in laboratory parameters, vital signs, and ECGs, as well as dose interruptions, discontinuations, and reductions, will be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is female or male adult ≥ 18 years old at the time of informed consent(s)
- Participant has a histologically and/or cytologically documented diagnosis of ER+ breast cancer (ER expression >10% of tumor cell nuclei stain (regardless of PgR expression) (based on the most recently analyzed tissue sample tested by a local laboratory).
- Participant has HER2- breast cancer defined as a negative in situ hybridization test (ISH) or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative ISH (e.g., FISH, CISH, or SISH) (based on the most recently analyzed tissue sample tested by a local laboratory) is required.
- Participant received no more than three prior endocrine therapy/ies (single agent or in combination with targeted therapy) regimen/s in the metastatic setting of which at least one included endocrine therapy in combination with a CDK4/6i. In addition: - In case of confirmed presence of deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, the participant may also have received a PARP inhibitor-based therapy. - In case of HER2-low breast cancer, the participant may also have received Enhertu®. Note: disease progression while on adjuvant ET (with or without CDK4/6i) or within 12 months of completing adjuvant endocrine therapy (with or without CDK4/6i), will be considered a line of therapy.
- Participant has metastatic breast cancer with radiologically confirmed progression of disease after the most recent therapy
- Participant must have measurable disease, i.e., at least one measurable lesion as per RECIST 1.1. (a lesion at a previously irradiated site may only be counted as a target lesion if there is a clear sign of progression since the irradiation) as per local assessment. Note: If only lytic bone lesions are present, they must have at least one lesion with a soft tissue component that can be evaluated by CT or MRI and meets the definition of measurability as per RECIST 1.1 criteria (participants with only one predominantly lytic bone lesion that has been previously irradiated are eligible if there is documented evidence of disease progression of the bone lesion after irradiation).
- Participant has at least one target lesion [as per RECIST 1.1 and based on the baseline contrast-enhanced CT (or MRI)] with [68Ga]Ga-NeoB uptake above the liver at PET/CT or PET/MRI, as per local reading. In addition: Participant with liver or lung disease involvement must show [68Ga]Ga-NeoB uptake above the liver as follows: If there is liver disease involvement (in the absence of lung involvement), in ≥ 50% of all CT measurable liver lesions (RECIST 1.1) If there is lung disease involvement (in the absence of liver involvement), in ≥ 50% of all CT measurable lung lesions (RECIST 1.1) Participants with both liver and lung disease involvement must show [68Ga]Ga-NeoB uptake above the liver in ≥ 50% of all CT measurable lesions either in liver or lung (RECIST 1.1) and in at least one measurable lesion in the remaining organ (lung or liver)
- Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Participant has adequate bone marrow and organ function as defined by laboratory values in section 5.1 (as assessed by local laboratory).
- For Phase I part and stand alone Japanese cohort only: Female participant must be in postmenopausal status at the time of starting study treatment, as defined in Section 5.1 Male participants, provided that they do not require continued GnRHas while on study treatment For Phase II part only Female participant is post-menopausal as per criteria above at the time of starting study treatment. Female participant is pre/peri-menopausal at the time of starting study treatment, as defined in Section 5.1 Male participants, regardless of their need of GnRHas while on study treatment.
Exclusion Criteria
- Participant with symptomatic visceral disease or any disease burden that are at risk of life-threatening complications as per the investigator’s judgment.
- Participant has received >1 prior treatment with chemotherapy and/or Antibody Drug Conjugate (ADCs) in the metastatic setting. Chemotherapy in neoadjuvant/ adjuvant setting is not considered a line of therapy, unless progression or recurrence occurred during or within 12 months after completion of adjuvant chemotherapy).
- Participant has received prior treatment with capecitabine
- Participant has inflammatory breast cancer at screening.
- Participant has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate participant participation in the clinical study or compromise compliance with the protocol
- History or current diagnosis of impaired cardiac function, clinically significant cardiac disease or ECG abnormalities
- Participant is currently receiving brivudine which cannot be discontinued at least 4-week prior to start of capecitabine therapy.
- Participant is currently receiving NEP inhibitors (i.e., Entresto®) and images for dosimetry assessments cannot be acquired for this participant as per Section 8.7.3 of the protocol.
- Participant with known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.
- Sexually active male participants unwilling to: remain abstinent (refrain from sexual intercourse) or use a condom, while taking study treatment and for at least 4 months after the last administration of [177Lu]Lu-NeoB, or 3 months after the last dose of capecitabine (or as per locally prescribing information) whichever is longer, in addition to the highly effective method used by the partner who is a female of child-bearing potential.
- For Phase II part only · Pregnant or breast-feeding women · Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) UNLESS they are using highly effective methods of contraception throughout the study and for up to 7 months after the last administration of [177Lu]Lu-NeoB or 6 months after the last dose of capecitabine (or as per locally prescribing information) whichever is longer.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 30 Apr 2024 | 8 |
 Germany | Not Recruiting | 30 Apr 2024 | 8 |
 Italy | Not Recruiting | 30 Apr 2024 | 5 |
 The Netherlands | Not Recruiting | 30 Apr 2024 | — |
 Portugal | Not Recruiting | 30 Apr 2024 | 3 |
 Spain | Not Recruiting | 30 Apr 2024 | 13 |
| Netherlands | — | — | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
CAPECITABINE | Test | — | ORAL | — | — | SUB12474MIG |
CAPECITABINE | Test | — | ORAL | — | — | SUB12474MIG |
TRIPTORELIN | Other | — | INTRAMUSCULAR | — | — | SUB11324MIG |
[177Lu]-NeoB solution for infusion | Test | SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD8268370 |
LEUPRORELIN | Other | — | SUBCUTANEOUS | — | — | SUB08449MIG |
AAA503 | Test | KIT FOR RADIOPHARMACEUTICAL PREPARATION | INTRAVENOUS USE | — | — | PRD10217940 |
GOSERELIN | Other | — | SUBCUTANEOUS | — | — | SUB07962MIG |