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 receptor-2 negative metastatic breast cancer after progression on previous endocrine therapy in combination with CDK4/6 inhibitor

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 Oct 2024 → ongoing

Decision date (initial)

2024-04-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Therapy, Others, Diagnosis, Efficacy, Dose response

Phase I: To determine the Recommended Doses (RD) and dosing regimens of [177Lu]Lu-NeoB in combination with capecitabine

Phase II: To evaluate preliminary anti-tumor activity across two randomized cohorts of two different doses/regimens of [177Lu]Lu-NeoB in combination with capecitabine

Secondary objectives 6

1. Phase I and Phase II: ● To characterize the PK and biodistribution (dosimetry) of [177Lu]Lu-NeoB in combination with capecitabine
2. Phase I and Phase II: ● To evaluate the safety and tolerability of the [68Ga]Ga-NeoB
3. Phase I and Phase II: ● To evaluate, at the participant level, agreement between [68Ga]Ga-NeoB PET and conventional imaging
4. Phase I only: ● To determine the optimal [68Ga]Ga-NeoB radioactivity dose
5. Phase I only: ● To evaluate preliminary anti-tumor activity of [177Lu]Lu-NeoB in combination with capecitabine
6. Phase II only: ● To evaluate the safety and tolerability of [177Lu]Lu-NeoB in combination with capecitabine

Conditions and MedDRA coding

Breast Cancer

Regulatory references

Scientific advice from competent authorities

Federal Institute For Drugs And Medical Devices

Plan to share IPD

Yes

IPD plan description

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

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Participant is female or male adult ≥ 18 years old at the time of informed consent(s)
2. 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).
3. 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.
4. 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.
5. Participant has metastatic breast cancer with radiologically confirmed progression of disease after the most recent therapy
6. 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).
7. 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)
8. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
9. Participant has adequate bone marrow and organ function as defined by laboratory values in section 5.1 (as assessed by local laboratory).
10. 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 11

1. Participant with symptomatic visceral disease or any disease burden that are at risk of life-threatening complications as per the investigator’s judgment.
2. 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).
3. Participant has received prior treatment with capecitabine
4. Participant has inflammatory breast cancer at screening.
5. 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
6. History or current diagnosis of impaired cardiac function, clinically significant cardiac disease or ECG abnormalities
7. Participant is currently receiving brivudine which cannot be discontinued at least 4-week prior to start of capecitabine therapy.
8. 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.
9. Participant with known deficiency or family history of deficiency of dihydropyrimidine dehydrogenase.
10. 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.
11. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase I: Incidence and severity of AEs including dose limiting toxicities (DLTs), serious Adverse Events (SAEs), changes in laboratory parameters, vital signs and ECGs Tolerability: Dose interruptions, discontinuations, and reductions Phase II: ORR, CBR, TTR, DOR, PFS as per RECIST v1.1 by local investigator assessment Overall Survival (OS)

Secondary endpoints 6

1. Phase I and II: ● 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 PK parameters
2. Phase I and II: ● Incidence and severity of adverse events following [68Ga]Ga-NeoB administration at screening
3. Phase I and II: ● Positive Percent Agreement (PPA) and Positive Predictive Agreement (PPrA) using conventional imaging as reference by central assessment, at screening
4. Phase I only: ● Visual assessment of image quality by central assessment
5. Phase I only: ● ORR, CBR, TTR, DOR, PFS as per RECIST v1.1 by local investigator assessment ● OS
6. Phase II only: ● Incidence and severity of AEs, SAEs, changes in laboratory parameters, vital signs and ECGs Dose interruptions, discontinuations, and reductions

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Auxiliary 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 20

Locations

6 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 2 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 105 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications