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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.

PHASE1PHASE2RECRUITING

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).

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Signed informed consent must be obtained prior to participation in the study.

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-negative (as per ASCO-CAP guidelines Wolff et al 2018) 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 (as per ASCO-CAP guidelines Wolff et al 2018), 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.

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)

Participants with central nervous system (CNS) involvement are eligible providing they meet ALL the following criteria: At least 2 weeks from prior therapy completion (including radiation and/or surgery) to initiation of the study treatment, Clinically stable CNS tumor at the time of screening, Participant is not receiving steroids and/or anti-epileptic medications for brain metastases at the time of initiation of the radioligand study treatment

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 the following laboratory values (as assessed by local laboratory): Absolute neutrophil count ≥ 1.5 × 109/L, Platelets ≥ 100 × 109/L, Hemoglobin ≥ 9.0 g/dL, International Normalized Ratio (INR) ≤1.5, Creatinine Clearance ≥60 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Total bilirubin (TBIL) < 1.5 × ULN (any elevated bilirubin should be asymptomatic at enrollment) except for participants with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN, In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN. If the participant has liver metastases, the participant will be eligible for the study if ALT and AST < 5 X ULN. Serum lipase ≤ 1.5 × ULN Note: no platelet transfusion, packed red blood cell transfusion, or G-CSF will be allowed during the screening phase after ICF signature, Participant must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication: Potassium, Magnesium, Total Calcium (corrected for serum albumin)

Participant must be able to swallow capecitabine tablets.

Participant must be able to communicate with the investigator and comply with the requirements of the study procedures.

For Phase I part only Female participant must be in postmenopausal status at the time of starting study treatment. Postmenopausal status is defined either by: Prior surgical bilateral oophorectomy (with or without hysterectomy), Age ≥60 years, Age <60 years and ≥ 12 months of natural (spontaneous) amenorrhea in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression with serum Follicle-Stimulating Hormone (FSH) and estradiol in the postmenopausal range per local normal range. Aged < 60 years: therapy-induced amenorrhea for > 12 months with serial measurements of FSH and estradiol in post-menopausal ranges (NCCN V4 2023). Aged < 60 years: on tamoxifen with serial measurements of FSH and estradiol in post-menopausal ranges Note: Ovarian radiation or treatment with a gonadotropin releasing hormone agonist (GnRHas e.g. goserelin acetate) is not permitted for induction of ovarian suppression in the Phase I part.

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

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 prior treatment with chemotherapy in the metastatic setting (allowed in neoadjuvant/ adjuvant setting, unless progression or recurrence occurred during or within 12 months after completion of adjuvant chemotherapy).

Participant has received prior treatment with capecitabine

History of hypersensitivity or contraindication to any of the study treatments or their excipients or to drugs of similar chemical classes.

Participant has inflammatory breast cancer at screening.

Participant has had major surgery within 14 days prior to starting study treatment or has not recovered from major side effects.

Participant has received any prior treatment with a therapeutic radiopharmaceutical

Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow.

Participant has a concurrent malignancy or malignancy within 3 years of start of study treatment, with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer, or curatively resected cervical cancer.

Participant has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel resection) based on investigator's discretion.

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 (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, interstitial lung disease (ILD)/ pneumonitis etc.).

Participant has a history of or ongoing acute pancreatitis within 1 year of screening.

History or current diagnosis of impaired cardiac function, clinically significant cardiac disease or ECG abnormalities indicating significant risk of safety for participants in the study such as: Documented myocardial infarction (MI), angina pectoris, cardiomyopathy, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry, Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block), Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for TdP including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, Inability to determine the Fridericia QT correction formula (QTcF) interval, Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening as per standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed locally, Left Ventricular Ejection Fraction (LVEF) < 50% as determined by echocardiogram (ECHO) or MUGA., Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mmHg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without anti-hypertensive medication.

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.

Participant with known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.

Use of other investigational drugs within 5 half-lives of the investigational drug or within 30 days prior to start of study treatment, whichever is longer; or as required by local regulations.

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. Note: A condom is required for all sexually active male participants to prevent them from fathering a child and to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.

Participants with legal incapacity to give informed consent, where required by local regulation (e.g. in EU).

For Phase II part only Pregnant or breast-feeding women, Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study 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. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female bilateral tubal ligation, female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or total hysterectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. Male partner sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant. Placement of an intrauterine device (IUD) and concurrent use of barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2024-08-14

Primary completion: 2031-09-09

Study completion finish: 2031-09-09

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT06247995

Intervention or treatment

DRUG: [68Ga]Ga-NeoB

DRUG: [177Lu]Lu-NeoB

DRUG: Capecitabine

Conditions

• Breast Cancer

Condition: Breast Cancer
DRUG: [68Ga]Ga-NeoB and other drugs
Darlinghurst, New South Wales, Australia and more
Sponsor: Novartis Pharmaceuticals

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Find a site

Closest Location:

Novartis Investigative Site

Research sites nearby

Select from list below to view details:

Novartis Investigative Site
Darlinghurst, New South Wales, Australia
Novartis Investigative Site
Malvern, Victoria, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Dose A: [177Lu]Lu-NeoB 150mCi q6w + capecitabine \[177Lu\]Lu-NeoB 150mCi q6w + Capecitabine 1000mg/ m2 BID Day1-14 in a 21-day schedule	DRUG: [68Ga]Ga-NeoB 68Ga\]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions.
EXPERIMENTAL: Dose B: [177Lu]Lu-NeoB 100mCi q3w + capecitabine \[177Lu\]Lu-NeoB 100mCi q3w+ Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule	DRUG: [68Ga]Ga-NeoB 68Ga\]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions.
EXPERIMENTAL: Dose C: [177Lu]Lu-NeoB 200mCi q6w + capecitabine \[177Lu\]Lu-NeoB 200mCi q6w + Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule	DRUG: [68Ga]Ga-NeoB 68Ga\]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions.
EXPERIMENTAL: Dose D: [177Lu]Lu-NeoB 100mCi q6w + capecitabine \[177Lu\]Lu-NeoB 100mCi q6w + Capecitabine 1000mg/m2 BID Day1-14 in a 21-day schedule	DRUG: [68Ga]Ga-NeoB 68Ga\]Ga-NeoB serves as a radioactive imaging compound to be used for PET imaging for localization of GRPR positive lesions.

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Phase I: Incidence and severity of dose limiting toxicities (DLTs)	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.	42 days after the first administration of [177Lu]Lu-NeoB
Phase I: Incidence and severity of adverse events and serious adverse events for 177-Lu-NeoB in combination with capecitabine	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.	From start of study treatment until 56 days after the last dose of study treatment, assessed up to approximately 33 months
Phase I: Dose modifications for [177Lu]Lu-NeoB in combination with capecitabine	Dose modifications (dose interruptions, dose discontinuations and reductions) for \[177Lu\]Lu-NeoB in combination with capecitabine will be assessed and summarized using descriptive statistics.	From start of study treatment until the last dose of study treatment, assessed up to approximately 31 months
Phase II: Objective Response Rate (ORR)	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.	From date of randomization until date of progression, death or further antineoplastic therapy, whichever comes first, assessed up to approximately 88 months
Phase II: Clinical Benefit Rate (CBR)	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.	From date of randomization until date of progression, death or further antineoplastic therapy, whichever comes first, assessed up to approximately 88 months
Phase II: Time to Response (TTR)	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.	From date of randomization until first documented evidence of CR or PR (the response prior to confirmation), assessed up to approximately 88 months
Phase II: Duration of Response (DoR)	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.	From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 88 months
Phase II: Progression Free Survival (PFS)	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.	From the date of first dose to the date of confirmed progression or death due to any cause, whichever comes first, assessed up to approximately 88 months
Phase II: Overall Survival (OS)	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.	From the date of first dose until date of death from any cause, assessed up to approximately 88 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Phase I and II: Time activity curves (TACs) related to [177Lu]Lu-NeoB	Time-activity curves (TACs) for the various organs and lesions will be produced as percentage of injected dose in selected organs and lesions".	After First, Third and Fifth [177Lu]Lu-NeoB administrations: 1-4hrs, 24hrs, 48hrs and 168hrs after infusion.
Phase I and II: Absorbed radiation doses of [177Lu]Lu-NeoB in organs and target lesions	The absorbed dose in target organs will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.	After First, Third and Fifth [177Lu]Lu-NeoB administrations: 1-4hrs, 24hrs, 48hrs and 168hrs after infusion.
Phase I and II: Concentration of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Blood mass concentration data will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Maximum plasma concentration (Cmax) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Time of observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Area under the serum concentration-time cure from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Terminal elimination half-life (T1/2) of [177Lu]Lu-NeoB in blood over time	Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T1/2 will be listed and summarized using descriptive statistics.	First [177Lu]Lu-NeoB administration: Day 1 (Pre-dose (before start of infusion)), At end of infusion, 0.5, 1, 2, 4 and 6 hours post-dose/post-infusion (p.i.)), Day 2 (24 hours p.i), Day 3 (48 hours p.i), Day 8 (168 hours p.i)
Phase I and II: Positive Percent Agreement (PPA) and Positive Predictive Agreement (PPrA) of [68Ga]Ga-NeoB PET to conventional imaging as reference by central assessment	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))	Screening
Phase I: Visual assessment of [68Ga]Ga-NeoB PET/CT or PET/MRI image quality with different radioactivity dose ranges, by central assessment	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.	Screening
Phase I: Objective Response Rate (ORR)	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.	From date of randomization until date of progression, death or further antineoplastic therapy, whichever comes first, assessed up to approximately 88 months
Phase I: Clinical Benefit Rate (CBR)	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.	From date of randomization until date of progression, death or further antineoplastic therapy, whichever comes first, assessed up to approximately 88 months
Phase I: Time to Response (TTR)	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.	From date of randomization until first documented evidence of CR or PR (the response prior to confirmation), assessed up to approximately 88 months
Phase I: Duration of Response (DoR)	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.	From first documented evidence of CR or PR (the response prior to confirmation) until time of documented disease progression or death due to any cause, whichever comes first, assessed up to approximately 88 months
Phase I: Progression Free Survival (PFS)	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.	From the date of first dose to the date of confirmed progression or death due to any cause, whichever comes first, assessed up to approximately 88 months
Phase I: Overall Survival (OS)	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).	From the date of first dose until date of death from any cause, assessed up to approximately 88 months
Phase II: Incidence and severity of adverse events and serious adverse events for 177-Lu-NeoB in combination with capecitabine	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.	From start of study treatment until 56 days after the last dose of study treatment, assessed up to approximately 33 months
Phase II: Dose modifications for [177Lu]Lu-NeoB in combination with capecitabine	Dose modifications (dose interruptions, dose discontinuations and reductions) for \[177Lu\]Lu-NeoB in combination with capecitabine will be assessed and summarized using descriptive statistics.	From start of study treatment until the last dose of study treatment, assessed up to approximately 31 months

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References

Clinical Trials Gov: 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.