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\[177Lu\]Lu-NeoB 150mCi q6w + Capecitabine 1000mg/ m2 BID Day1-14 in a 21-day schedule

\[177Lu\]Lu-NeoB 100mCi q3w+ Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule

\[177Lu\]Lu-NeoB 200mCi q6w + Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule

\[177Lu\]Lu-NeoB 100mCi q6w + Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule

68Ga\]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions.

[68Ga]Ga-NeoB

\[177Lu\]Lu-NeoB is a radioligand therapy drug.

[177Lu]Lu-NeoB

Novartis Pharmaceuticals

In the phase I part, to determine the recommended doses (RD) and dosing regimens of \[177Lu\]Lu-NeoB in combination with capecitabine in adult patients with gastrin releasing peptide receptor positive, estrogen receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer after progression on previous endocrine therapy in combination with a CDK4/6 inhibitor. In the phase II part, to evaluate the preliminary anti-tumor activity of two different doses/regimens of \[177Lu\]Lu-NeoB in combination with capecitabine (dose optimization).

Despite remarkable clinical results with the use of CDK4/6i, breast cancer patients will experience progression of disease requiring alternative treatment options. The optimal sequence of therapy after progression on CDK4/6i has not been established and it depends on multiple factors, including previous regimens, mutational profile, comorbidities, patient preference or disease burden (NCCN v4, 2023). Thus, new targeted treatment modalities are needed for treatment of patients with endocrine-resistant mBC.The purpose of this phase I/II study is to determine the recommended doses and regimens of \[177Lu\]Lu-NeoB in combination with capecitabine (and a gonadotropin releasing hormone agonist (GnRha) for pre/peri-menopausal women in the Phase II part only and men, if applicable) in adult participants with ER+/HER2-, gastrin releasing peptide receptor positive (GRPR+) mBC after progression on CDK4/6i-based therapy, and to evaluate preliminary efficacy across two different dose levels and regimens. The study comprises of two parts: the phase I, dose escalation part, followed by the phase II, dose optimization part.

During screening, study participants will receive the radioligand imaging agent \[68Ga\]Ga-NeoB for a positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI). An additional \[68Ga\]Ga-NeoB for PET/CT or PET/MRI will be administered after their last administration of \[177Lu\]Lu-NeoB for phase II participants only.

During the treatment period participants will be required to attend a site visit approximately every 3 weeks for the first 9 months and every 6 weeks thereafter, on the first day of every cycle (defined as a period of 3 weeks) or every other cycle, respectively, to undergo study treatment administration or dispensing, dosimetry and safety assessments. Tumor assessments are performed every 9 weeks until month 18, every 12 weeks until month 46 and as clinically indicated thereafter, until disease progression. After study treatment discontinuation, participants will be followed up for safety for 8 weeks after their last study treatment administration. Beyond the initial 8 weeks of safety follow-up, all participants will be followed up as per the Section 1.3 SoA, for a total of 5 years from their last \[177Lu\]Lu-NeoB administration, or until death, lost to follow-up, participant/guardian's or investigator's decision or withdrawal of consent (WoC).

The end of study is defined as the date of the last visit, scheduled procedure or follow up (or date of death, participant/guardian's or investigator's decision, WoC or lost to follow up, whichever occurs first) of the last participant in the study globally, or at 5 years from the last \[177Lu\]Lu-NeoB administration to the last study participant, whichever occurs last.

This study includes \[177Lu\]Lu-NeoB and capecitabine as study treatment and \[68Ga\]Ga-NeoB as an imaging agent. Participants will receive \[177Lu\]Lu-NeoB in combination with capecitabine (and a GnRHa, where applicable, as per local clinical practice for pre-/peri-menopausal women in the phase II part only, and in men). \[68Ga\]Ga-NeoB is a PET imaging agent investigated as a selection tool for \[177Lu\]Lu-NeoB treatment in patients with tumors overexpressing GRPR, including mBC patients. \[68Ga\]Ga-NeoB has shown favorable technical and diagnostic performance to identify GRPR-expressing malignancies, both in preclinical and in clinical studies, with good image quality that allows proper interpretation.

\[177Lu\]Lu-NeoB has shown high affinity to the GRPR and its ability to target the GRPR expressing tumor has been confirmed in in vivo imaging and biodistribution studies in tumor models. \[177Lu\]Lu-NeoB is rapidly cleared from the blood, quickly eliminated through the renal system, with no retention in kidneys. \[177Lu\]Lu-NeoB is currently being evaluated as a single agent in an ongoing phase I/IIa, open-label, multi-center study (EUDRACT no. 2018-004727-37 ) which evaluates the safety, tolerability, whole-body distribution, radiation dosimetry and anti-tumor activity of \[177Lu\]Lu-NeoB administered in patients with advanced solid tumors known to overexpress GRPR who have no therapeutic available options. Data show that \[177Lu\]Lu-NeoB has shown a good tolerability and safety profile and a favorable biodistribution with low uptake in organs considered to be at risk due to GRPR-expression, such as the pancreas, or due to radioligand therapy (RLT), such as the red marrow, and the route of excretion, such as the kidneys.

Capecitabine is an oral fluoropyrimidine carbamate that is converted to 5-fluorouracil (5-FU) preferentially in tumor tissue through exploitation of high intratumoral concentrations of thymidine phosphorylase. It is one of the most frequent chemotherapy treatment choices for HR+/HER2- mBC patients post-CDK4/6i failure from 2nd line and beyond as reflected in real word data. It is also considered to be a potent radiosensitizer. The synergistic combination of chemotherapy and radionuclides has the potential to enhance efficacy.

This study will enroll a total of between 36 and 58 participants, depending on the applicable scenario. In the phase I part, about 18 participants will be either enrolled or randomized (as applicable). In the phase II part, between 28 and 40 participants will be randomized, depending on the applicable scenario.

* The screening period of 42 days is followed by the treatment period until disease progression, discontinuation of study treatment due to any other reason such as unacceptable toxicity, symptomatic deterioration, WoC, lost to follow up, investigator decision or death, whichever occurs first. The post treatment follow up period comprises the safety follow up for 8 weeks after treatment discontinuation and the long term safety and survival follow up for up to 5 years from the date of the participant's last dose of \[177Lu\]Lu-NeoB
* During screening, each participant will receive \[68Ga\]Ga-NeoB for PET/CT or PET/MRI imaging to confirm eligibility. Additionally, within 4-8 weeks from the last administration of \[177Lu\]Lu-NeoB, another administration of \[68Ga\]Ga-NeoB for PET/CT or PET/MRI will be performed, in the phase II part only.
* In the phase I part, participants will receive \[177Lu\]Lu-NeoB at a starting dose of 150mCi +/- 10% (iv infusion) Q6W in combination with capecitabine (tablet, 1000 mg/m2 twice daily for 14 consecutive days followed by 7 days off treatment). If dose escalation is supported, then two higher dose levels of \[177Lu\]Lu-NeoB in combination with capecitabine are planned to be explored, in a randomized way: 200mCi Q6W and 100mCi Q3W. These correspond to the same total dose given in a 6 weeks timeframe but exploring a different dose fractionation.
* If dose escalation from the starting dose is not supported, then lower dose levels will be explored (100mCi Q6W and if shown safe, 100mCi Q3W). If none of these are shown safe then the study will be terminated
* In the phase II part, there are four potential scenarios that may apply, depending on the outcome of the phase I part:
* Scenario 1 (if both higher dose levels in phase I were shown safe) participants will be randomized to either \[177Lu\]Lu-NeoB 200mCi Q6W or 100mCi Q3W, in combination with capecitabine
* Scenario 2 (if only one of the two higher dose levels in phase I were shown safe) participants will be randomized to either \[177Lu\]Lu-NeoB 200mCi Q6W / 100mCi Q3W (whichever was shown safe in phase I) or 150 mCi Q6W, in combination with capecitabine
* Scenario 3 (if none of the higher doses in phase I are shown safe): participants will be randomized to either \[177Lu\]Lu-NeoB 150mCi Q6W or 100mCi Q6W, in combination with capecitabine
* Scenario 4 (if dose escalation from the starting dose was no supported in phase I and lower investigational dose levels and regimens are shown safe in phase I part): participants will be randomized to either \[177Lu\]Lu-NeoB 100 mCi Q6W or 100 mCi Q3W, in combination with capecitabine.
* Treatment duration with \[177Lu\]Lu-NeoB is 6 administrations for Q6W regimens and 12 administrations for Q3W regimens. Additional \[177Lu\]Lu-NeoB administrations may be considered based on an individual benefit-risk assessment performed by the Investigator, participant and Sponsor

A Phase I/II, Dose Finding and Optimization Study of [177Lu]Lu-NeoB in Combination With Capecitabine in Patients With GRPR+, ER+, HER2- Metastatic Breast Cancer After Progression on Previous Endocrine Therapy in Combination With a CDK4/6 Inhibitor.

A Phase I/II, Open-label, Multi-center Trial of [177Lu]Lu-NeoB in Combination With Capecitabine in Adult Patients With Gastrin Releasing Peptide Receptor Positive, Estrogen Receptor-positive, Human Epidermal Growth Factor Receptor-2 Negative Metastatic Breast Cancer After Progression on Previous Endocrine Therapy in Combination With a CDK4/6 Inhibitor.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the DLT period from C1D1 of treatment with \[177Lu\]Lu-NeoB and capecitabine. The National Cancer Institute (NCI) CTCAE version 5.0 will be used for all grading.

The distribution of adverse events for 177-Lu-NeoB in combination with capecitabine will be done via the analysis of frequencies for Adverse Event (AEs) and Serious Adverse Event (SAEs) through the monitoring of relevant clinical and laboratory safety parameters.

Dose modifications (dose interruptions, dose discontinuations and reductions) for \[177Lu\]Lu-NeoB in combination with capecitabine will be assessed and summarized using descriptive statistics.

Objective Response Rate (ORR) with confirmed response is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), as per local review and according to RECIST 1.1.

Clinical Benefit Rate (CBR) with confirmed response is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), or maintaining an overall response of Stable Disease (SD) for at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1.

Time to response is the time from the date of randomization to the first documented response (Complete Response (CR) or Partial Response (PR), which must be confirmed subsequently) as per local review and according to RECIST 1.1.

Duration of Overall Response (DoR) applies only to participants whose best overall response is confirmed CR or confirmed PR according to RECIST 1.1. The start date is the date of first documented confirmed response (CR or PR) and the end date is the date defined as first documented progression or death due to underlying cancer.

Progression Free Survival (PFS) is defined as the time from the date of first dose of \[177Lu\]Lu-NeoB to the date of confirmed progression or death due to any cause. PFS will be assessed via local review according to RECIST 1.1.

Overall Survival (OS) is defined as the time from date of first dose of \[177Lu\]Lu-NeoB to date of death due to any cause.

Time-activity curves (TACs) for the various organs and lesions will be produced as percentage of injected dose in selected organs and lesions".

The absorbed dose in target organs will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Blood mass concentration data will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.

Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T1/2 will be listed and summarized using descriptive statistics.

The participant level agreement between \[68Ga\]Ga-NeoB PET and conventional imaging (CI) will be assessed as per central assessment for all screening PET scans (including screen failed participants, if available). Findings from \[68Ga\]Ga-NeoB PET compared to CI will be used to calculate the Positive Percent Agreement (PPA), as an analog of sensitivity, and the Positive Predictive Agreement (PPrA), as an analog of the positive predictive value:

* Positive Percent Agreement (PPA) - Analog of Sensitivity: True Positive (TP) / (TP + False Negative (FN))
* Positive Predictive Agreement (PPrA) - Analog of Positive Predictive Value: True Positive (TP) / (TP + False Positive (FP))

Dose optimization study for \[68Ga\]Ga-NeoB will be performed. Three different \[68Ga\]Ga-NeoB dose ranges will be tested in a total of 6-9 of participants (at least 2-3 per dose range). The lowest dose range providing the best image quality will be selected as the optimal one to proceed with.

Objective Response Rate (ORR) is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), as per local review and according to RECIST 1.1.

Clinical Benefit Rate (CBR) is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR), or maintaining an overall response of Stable Disease (SD) for at least 24 weeks. CR, PR, and SD are defined as per local review according to RECIST 1.1.

Duration of Response (DOR) was defined as the duration between the date of first documented Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) and the date of first documented radiographic progression or death due to any cause as per local review and according to RECIST 1.1.

Overall Survival (OS) is defined as the time from date of first dose of \[177Lu\]Lu-NeoB to date of death due to any cause. If a participant is not known to have died, then OS will be censored at the latest date the participant was known to be alive (on or before the cut-off date).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I/II, Dose Finding and Optimization Study of [177Lu]Lu-NeoB in Combination With Capecitabine in Patients With GRPR+, ER+, HER2- Metastatic Breast Cancer After Progression on Previous Endocrine Therapy in Combination With a CDK4/6 Inhibitor.	NCT06247995	Breast Cancer	[68Ga]Ga-NeoB [177Lu]Lu-NeoB Capecitabine	18 Years -	Novartis
A Phase I/II, Dose Finding and Optimization Study of [177Lu]Lu-NeoB in Combination With Capecitabine in Patients With GRPR+, ER+, HER2- Metastatic Breast Cancer After Progression on Previous Endocrine Therapy in Combination With a CDK4/6 Inhibitor.	NCT06247995	Breast Cancer	[68Ga]Ga-NeoB [177Lu]Lu-NeoB Capecitabine	18 Years -	Novartis

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