[177Lu]Lu-NeoB + Ribociclib + Fulvestrant for Breast Cancer

Recruiting at 18 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Must not be taking: Warfarin, NEP inhibitors

Disqualifiers: CNS involvement, Cardiac disease, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 69

48 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this trial is to estimate the recommended dose (RD) of \[177Lu\]Lu-NeoB in combination with ribociclib and fulvestrant in participants with estrogen receptor (ER) positive (ER+), human epidermal growth factor receptor-2 (HER2) negative (HER2-) and gastrin releasing peptide receptor (GRPR) positive (GRPR+) advanced breast cancer experiencing early relapse from (neo)adjuvant endocrine therapy or who have progressed on endocrine therapy in combination with a CDK4/6 inhibitor for advanced disease.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as those that strongly affect liver enzymes (CYP3A4), medications with a narrow safety margin, and those that affect heart rhythm, at least 7 days before starting the study. If you are on warfarin or similar blood thinners, you will need to switch to alternatives like heparin. It's best to discuss your current medications with the trial team to see if any changes are needed.

What data supports the effectiveness of the drug combination Ribociclib and Fulvestrant for breast cancer?

Research from the MONALEESA trials shows that the combination of Ribociclib and Fulvestrant significantly improves progression-free survival (the time during which the cancer does not get worse) and overall survival in postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer. ^{1 2 3 4 5}

Is the combination of [177Lu]Lu-NeoB, Ribociclib, and Fulvestrant safe for humans?

Ribociclib, when used with fulvestrant, has been shown to be generally safe in both men and women with advanced breast cancer, with side effects similar across genders. However, there is no specific safety data available for [177Lu]Lu-NeoB in combination with these drugs. ^{1 2 4 6 7}

What makes the drug [177Lu]Lu-NeoB + Ribociclib + Fulvestrant unique for breast cancer treatment?

This drug combination is unique because it includes [177Lu]Lu-NeoB, a radiolabeled compound that targets cancer cells with radiation, potentially enhancing the effectiveness of traditional cancer drugs like Ribociclib and Fulvestrant. The use of a radiolabeled component is a novel approach in breast cancer treatment, aiming to improve outcomes by directly targeting and damaging cancer cells. ^{8 9 10 11 12}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

This trial is for adults with advanced breast cancer that's ER+, HER2-, and GRPR+. They should have had an early relapse after endocrine therapy or progressed on such therapy plus a CDK4/6 inhibitor. Participants need good heart rates, organ function, and performance status. Those who've relapsed within 12 months from endocrine therapy without subsequent progression on another line of treatment are excluded.

Inclusion Criteria

My breast cancer is confirmed to be estrogen-receptor positive.

Standard 12-lead ECG values within defined parameters

My breast cancer is HER2 negative.

Exclusion Criteria

I am currently using or have recently used corticosteroids.

My CNS is affected by my condition but meets certain criteria.

I have previously received fulvestrant treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Dose Escalation

Estimate the recommended dose of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant; four provisional dose levels are tested in cohorts of 3 to 6 participants.

Varies per cohort

Visits every 28 days, additional visits on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3, C5D3

Backfill

Enrollment to a previously cleared dose level to obtain additional safety, tolerability, and preliminary efficacy data.

Varies per cohort

Visits every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment. Tumor assessments every 8 weeks until month 18, every 12 weeks until month 36, and every 24 weeks thereafter until month 60.

5 years

Every 12 weeks until month 36, every 24 weeks thereafter

Treatment Details

Interventions

• [177Lu]Lu-NeoB
• Fulvestrant
• Ribociclib

Trial Overview [177Lu]Lu-NeoB combined with ribociclib and fulvestrant is being tested to find the best dose for treating certain advanced breast cancers. The study includes patients whose cancer has returned quickly after hormone treatments or worsened despite them.

Participant Groups

Group I: Arm 1 Experimental Treatment 5 Interventions

Participants will receive \[177Lu\]Lu- NeoB in combination with ribociclib and fulvestrant, in the dose escalation and the backfill parts of the study. Goserelin administration is only applicable for pre/peri-menopausal women and men.

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Findings from Research

Ribociclib, a CDK 4/6 inhibitor, significantly improves median progression-free survival (PFS) in women with HR+/HER2- metastatic breast cancer when used in combination with endocrine therapy, with PFS ranging from 8 to 13 months across three phase III trials.

The treatment is well tolerated, particularly in elderly patients, and while it has some dose-limiting toxicities like neutropenia and QTc prolongation, it maintains health-related quality of life and reduces pain scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. Rascon, K., Flajc, G., De Angelis, C., et al.[2020]

Ribociclib, when combined with letrozole, significantly improves progression-free survival in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer, as shown in the MONALEESA-2 trial.

Ongoing trials (MONALEESA-3 and MONALEESA-7) further support ribociclib's efficacy, demonstrating significant progression-free survival benefits in both treatment-naive and previously treated postmenopausal patients, as well as in pre/perimenopausal women with ovarian function suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. Yardley, DA.[2020]

Ribociclib plus fulvestrant (R+F) significantly improves quality-adjusted progression-free survival (QAPFS) by 0.45 years compared to placebo plus fulvestrant (P+F) in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, based on data from the MONALEESA-3 study.

Patients receiving R+F also experienced greater time without symptoms or toxicity (Q-TWiST) and showed a numerical improvement in quality-adjusted overall survival (QAOS), suggesting that R+F not only extends survival but also enhances the quality of life during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2- Advanced Breast Cancer in the MONALEESA-3 Trial. Jerusalem, G., Delea, TE., Martin, M., et al.[2022]

Ribociclib, when combined with endocrine therapy, significantly improves progression-free survival (PFS) and overall survival (OS) in both pre-menopausal and post-menopausal women with advanced breast cancer, as demonstrated in the phase III MONALEESA trials involving various patient subgroups.

Importantly, ribociclib does not negatively impact health-related quality of life, and it even helps delay deterioration in quality of life and improves pain scores, making it a valuable treatment option for patients with challenging conditions like endocrine resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib efficacy in special populations and analysis of patient-reported outcomes in the MONALEESA trials. Sanò, MV., Martorana, F., Lavenia, G., et al.[2022]

Ribociclib, a CDK 4/6 inhibitor, has been shown to significantly improve progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer when used in combination with letrozole, based on the results of the MONALEESA-2 phase 3 trial involving a randomized, double-blind design.

The study highlights ribociclib's effectiveness across various patient subgroups, including those with different ages and disease histories, establishing it as a valuable treatment option for managing advanced breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. Hortobagyi, GN.[2019]

Ribociclib is a selective CDK4/6 inhibitor approved for advanced breast cancer, showing moderate absorption in humans (about 59%) and extensive metabolism primarily through the CYP3A4 pathway.

In a study with healthy male volunteers, ribociclib was mostly eliminated through feces (69.1%) and urine (22.6%), indicating that hepatic metabolism is the main clearance pathway (approximately 84%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data. James, AD., Schiller, H., Marvalin, C., et al.[2021]

Ribociclib has been approved by the FDA for use in male patients with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, showing an overall response rate of 46.9% in a clinical trial with 39 male patients.

The safety profile of ribociclib in male patients is similar to that observed in female patients, indicating that its efficacy and safety are consistent across genders when used in combination with aromatase inhibitors or fulvestrant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. Gao, JJ., Osgood, CL., Feng, Z., et al.[2023]

The anti-CD37 antibody-radionuclide conjugate 177Lu-lilotomab (Betalutin®) significantly delayed tumor growth in preclinical models of B-cell non-Hodgkin lymphoma, particularly in transformed follicular lymphoma (DOHH2) cells, even at low doses (100 MBq/kg).

177Lu-lilotomab's effectiveness was enhanced when combined with inhibitors of G2/M cell cycle arrest, suggesting that it works best in tumors with lower levels of CDK1 phosphorylation, indicating a potential strategy for improving treatment outcomes in resistant lymphoma cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest. Pichard, A., Marcatili, S., Karam, J., et al.[2022]

The 177Lu-labeled immunoconjugate 177Lu-CC49 effectively delayed the growth of established human colon carcinomas in mice, demonstrating its potential as a therapeutic option for cancer treatment.

While higher doses of 177Lu-CC49 showed toxicity, a fractionated dose of 750 microCi was well tolerated and successfully eliminated tumors in 90% of treated mice, indicating a promising therapeutic window for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate. Schlom, J., Siler, K., Milenic, DE., et al.[2013]

The modified 10-kDa-PEG diabody targeting CD22 showed a favorable safety profile in mice, tolerating high doses of 16 MBq without long-term organ toxicity, making it a promising option for radioimmunotherapy in B-cell non-Hodgkin lymphoma.

Combining the PEGylated diabody with Rituximab demonstrated greater therapeutic efficacy in reducing disease burden compared to traditional IgG-based radioimmunoconjugates, suggesting it could enhance treatment strategies for patients with B-NHL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model. Weber, T., Bötticher, B., Arndt, MA., et al.[2017]

The study developed a new bispidine ligand that effectively binds to the radioactive ion 177Lu, allowing for quick and efficient radiolabeling of antibodies, achieving over 90% purity in the final product.

In vivo experiments showed that the radiolabeled antibody specifically targeted ovarian cancer cells, resulting in significantly higher tumor uptake compared to control, indicating its potential as an effective radioimmunotherapy option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiolabelled 177Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers. Cieslik, PA., Klingler, S., Nolff, M., et al.[2023]

177Lu is a promising radionuclide for targeted therapy due to its high purity and suitable decay characteristics, produced with 99.99% radionuclidic purity and moderate specific activity.

The study successfully created a novel estradiol-DOTA conjugate for radiolabelling with 177Lu, which showed potential biological activity in vitro with MCF-7 breast cancer cells that express estrogen receptors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An estradiol-conjugate for radiolabelling with 177Lu: an attempt to prepare a radiotherapeutic agent. Banerjee, S., Das, T., Chakraborty, S., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]

2. England pubmed.ncbi.nlm.nih.gov

MONALEESA clinical program: a review of ribociclib use in different clinical settings. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2- Advanced Breast Cancer in the MONALEESA-3 Trial. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Ribociclib efficacy in special populations and analysis of patient-reported outcomes in the MONALEESA trials. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate. [2013]

10. Ireland pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model. [2017]

11. Germany pubmed.ncbi.nlm.nih.gov

Radiolabelled 177Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers. [2023]

12. England pubmed.ncbi.nlm.nih.gov

An estradiol-conjugate for radiolabelling with 177Lu: an attempt to prepare a radiotherapeutic agent. [2013]