[177Lu]Lu-NeoB + Ribociclib + Fulvestrant for Breast Cancer
Recruiting in Palo Alto (17 mi)
+15 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Novartis Pharmaceuticals
Must not be taking: Warfarin, NEP inhibitors
Disqualifiers: CNS involvement, Cardiac disease, others
Stay on Your Current Meds
No Placebo Group
Breakthrough Therapy
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.
12345Is 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.
12467What 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.
89101112Eligibility 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.
+6 more
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.
+13 more
Trial 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
Participant Groups
[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.
1Treatment groups
Experimental Treatment
Group I: Arm 1Experimental Treatment5 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Hoag Memorial Hospital PresbyterianNewport Beach, CA
University of PennsylvaniaPhiladelphia, PA
MD Anderson Cancer CenterHouston, TX
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Who Is Running the Clinical Trial?
Novartis PharmaceuticalsLead Sponsor
References
Ribociclib in HR+/HER2- Advanced or Metastatic Breast Cancer Patients. [2020]To review the chemistry, pharmacology, pharmacokinetics, safety, and efficacy of ribociclib (LEE011, Kisqali) in hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) metastatic breast cancer.
MONALEESA clinical program: a review of ribociclib use in different clinical settings. [2020]Ribociclib has received approval in the pre/peri- and postmenopausal disease settings on the basis of the MONALEESA trials. MONALEESA-2 demonstrated that ribociclib plus letrozole significantly improved progression-free survival compared with placebo plus letrozole as first-line therapy in postmenopausal patients with HR-positive, HER2-negative advanced breast cancer. Subsequently, ongoing trials reported significant progression-free survival improvements with ribociclib in combination with either fulvestrant in postmenopausal patients with advanced breast cancer who were either treatment naive or received ≤1 line of prior endocrine therapy in the advanced disease setting (MONALEESA-3) or tamoxifen/nonsteroidal aromatase inhibitor with ovarian function suppression in pre/perimenopausal women (MONALEESA-7). This review summarizes the MONALEESA clinical program. ClinicalTrials.gov identifiers: NCT01958021 (MONALEESA-2), NCT02422615 (MONALEESA-3), NCT02278120 (MONALEESA-7).
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]MONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3.
Ribociclib efficacy in special populations and analysis of patient-reported outcomes in the MONALEESA trials. [2022]Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors abemaciclib, palbociclib, and ribociclib radically modified the treatment of hormone receptor-positive/human epidermal growth factor 2-negative advanced breast cancer. Ribociclib efficacy was proved in the phase III MONALEESA-2, -3, and -7 trials. In the first-line setting, ribociclib plus endocrine therapy determined statistically significant improvements in progression-free (PFS) and overall survival (OS) in pre-menopausal (MONALEESA-7) and post-menopausal (MONALEESA-2) women. Likewise, ribociclib and fulvestrant induced a significant PFS and OS benefit in post-menopausal women previously treated with endocrine therapy (MONALEESA-3). Additionally, ribociclib did not affect patients health-related quality of life in all the MONALEESA trials.
Ribociclib for the first-line treatment of advanced hormone receptor-positive breast cancer: a review of subgroup analyses from the MONALEESA-2 trial. [2019]Endocrine therapy is recommended for patients with hormone receptor-positive (HR+) advanced and metastatic breast cancer without visceral crisis (symptomatic visceral disease). However, many patients experience disease progression during treatment, and most patients eventually develop endocrine resistance. Therefore, it is important to identify treatment options that prolong the effectiveness of first-line endocrine therapies. Ribociclib is an orally bioavailable cyclin-dependent kinase (CDK) 4/6 inhibitor that has been approved for use in combination with an aromatase inhibitor for the treatment of HR+, human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. This approval is based on findings from the MONALEESA-2 study, a double-blind, placebo-controlled, randomized phase 3 trial (NCT01958021) in which first-line therapy with ribociclib + letrozole significantly improved progression-free survival (PFS) compared with placebo + letrozole in patients with HR+/HER2- advanced breast cancer. This review will discuss the overall findings from the MONALEESA-2 study and will provide a summarized analysis of results from the available subgroups in the study by age, visceral metastases, bone-only disease, de novo disease, and prior therapy. On the basis of these data, ribociclib has established itself as a beneficial treatment option for these different populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01958021 . Registered on 8 October 2013.
An integrated assessment of the ADME properties of the CDK4/6 Inhibitor ribociclib utilizing preclinical in vitro, in vivo, and human ADME data. [2021]Ribociclib (LEE011, Kisqali ®) is a highly selective small molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), which has been approved for the treatment of advanced or metastatic breast cancer. A human ADME study was conducted in healthy male volunteers following a single oral dose of 600 mg [14 C]-ribociclib. Mass balance, blood and plasma radioactivity, and plasma ribociclib concentrations were measured. Metabolite profiling and identification was conducted in plasma, urine, and feces. An assessment integrating the human ADME results with relevant in vitro and in vivo non-clinical data was conducted to provide an estimate of the relative contributions of various clearance pathways of the compound. Ribociclib is moderately to highly absorbed across species (approx. 59% in human), and is extensively metabolized in vivo, predominantly by oxidative pathways mediated by CYP3A4 (ultimately forming N-demethylated metabolite M4) and, to a lesser extent, by FMO3 (N-hydroxylated metabolite M13). It is extensively distributed in rats, based on QWBA data, and is eliminated rapidly from most tissues with the exception of melanin-containing structures. Ribociclib passed the placental barrier in rats and rabbits and into milk of lactating rats. In human, 69.1% and 22.6% of the radiolabeled dose were excreted in feces and urine, respectively, with 17.3% and 6.75% of the 14 C dose attributable to ribociclib, respectively. The remainder was attributed to numerous metabolites. Taking into account all available data, ribociclib is estimated to be eliminated by hepatic metabolism (approx. 84% of total), renal excretion (7%), intestinal excretion (8%), and biliary elimination (1%).
FDA Approval Summary: Ribociclib Indicated for Male Patients with Hormone Receptor-Positive, HER2-Negative Advanced or Metastatic Breast Cancer. [2023]On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib+AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single arm, multicenter clinical trial, in which 39 male patients (n=3,246 total patients) received ribociclib+letrozole+goserelin/leuprolide. The ORR based on confirmed responses in male patients with measurable disease at baseline was 46.9% (95% CI: 29.1, 65.3), consistent with an ORR 43.6% (95% CI: 41.5, 45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib+ET. The efficacy of ribociclib+fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib+fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib+AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.
The therapeutic effectiveness of 177Lu-lilotomab in B-cell non-Hodgkin lymphoma involves modulation of G2/M cell cycle arrest. [2022]Some patients with B-cell non-Hodkin lymphoma Lymphoma (NHL) become refractory to rituximab (anti-CD20 antibody) therapy associated with chemotherapy. Here, the effect of the anti-CD37 antibody-radionuclide conjugate lutetium-177 (177Lu)-lilotomab (Betalutin®) was investigated in preclinical models of NHL. In SCID mice bearing DOHH2 (transformed follicular lymphoma, FL) cell xenografts, 177Lu-lilotomab significantly delayed tumor growth, even at low activity (100 MBq/kg). In athymic mice bearing OCI-Ly8 (diffuse large B-cell lymphoma, DLBCL) or Ramos (Burkitt's lymphoma) cell xenografts, 177Lu-lilotomab activity had to be increased to 500 MBq/kg to show a significant tumor growth delay. Clonogenic and proliferation assays showed that DOHH2 cells were highly sensitive to 177Lu-lilotomab, while Ramos cells were the least sensitive, and U2932 (DLBCL), OCI-Ly8, and Rec-1 (mantle cell lymphoma) cells displayed intermediate sensitivity. The strong 177Lu-lilotomab cytotoxicity observed in DOHH2 cells correlated with reduced G2/M cell cycle arrest, lower WEE-1- and MYT-1-mediated phosphorylation of cyclin-dependent kinase-1 (CDK1), and higher apoptosis. In agreement, 177Lu-lilotomab efficacy in vitro, in vivo, and in patient samples was increased when combined with G2/M cell cycle arrest inhibitors (MK-1775 and PD-166285). These results indicate that 177Lu-lilotomab is particularly efficient in treating tumors with reduced inhibitory CDK1 phosphorylation, such as transformed FL.
Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate. [2013]177Lutetium (177Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a 177Lu-labeled immunoconjugate, 177Lu-CC49, in an experimental therapy model for human carcinoma. 177Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of 177Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of 177Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of 177Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, 177Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the 177Lu-CC49 versus that of the 177Lu-control MAb. The merits and limitations of the use of 177Lu-labeled immunoconjugates (in particular, 177Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.
Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model. [2017]Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.
Radiolabelled 177Lu-Bispidine-Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers. [2023]Radioimmunotherapy (TRIT) is a promising alternative to conventional treatment options. Here, we present experimental work on the synthesis, radiochemistry, and in vivo performance of a lanthanide-selective nonadentate bispidine ligand suitable for 177Lu3+ ion complexation. The ligand (bisp,1) was derivatised with a photoactivatable aryl azide (ArN3) group as a bioconjugation handle for light-induced labelling of proteins. Quantitative radiosynthesis of [177Lu]Lu-1+ was accomplished in 10 minutes at 40oC. Subsequent incubation [177Lu]Lu-1+ with trastuzumab, followed by irradiation with light at 365 nm for 15 min, at room temperature and pH8.0-8.3, gave the radiolabelled mAb, [177Lu]Lu-1-azepin-trastuzumab ([177Lu]Lu-1-mAb) in a decay-corrected radiochemical yield of 14%, and radiochemical purity (RCP)>90%. Stability studies and cellular binding assays in vitro using the SK-OV-3 human ovarian cancer cells confirmed that [177Lu]Lu-1-mAb remained biological active and displayed specific binding to HER2/neu. Experiments in immunocompromised female athymic nude mice bearing subcutaneous xenograft models of SK-OV-3 tumours revealed significantly higher tumour uptake in the normal group compared with the control block group (29.8±11.4%ID g-1 vs. 14.8±6.1%ID g-1, respectively; P-value=0.037). The data indicate that bispidine-based ligand systems are suitable starting points for constructing novel, high-denticity chelators for specific complexation of larger radiotheranostic metal ion nuclides.
An estradiol-conjugate for radiolabelling with 177Lu: an attempt to prepare a radiotherapeutic agent. [2013]177Lu is presently being considered as one of the most promising radionuclide for targeted therapy owing to its suitable decay characteristics. 177Lu in high radionuclidic purity (99.99%) and moderate specific activity (100-110 TBq/g) was produced using enriched (60.6% 176Lu) Lu2O3 target. The macrocycle 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) is known to form stable complexes with lanthanides. Herein, we describe a novel attempt to introduce 177Lu in the estradiol moiety through a steroidal-BFCA (Bifunctional Chelating Agent) conjugate. The preparation of a steroid conjugate via coupling of 6alpha-amino-17beta-estradiol with a C-functionalized DOTA derivative viz. p-NCS-benzyl-DOTA as a BFCA and thereafter the radiolabelling of the conjugate with 177Lu is reported. Biological activity of the resultant estradiol-DOTA conjugate after radiolabelling was studied by carrying out preliminary in vitro cell uptake studies with MCF-7, human breast carcinoma cell line expressing estrogen receptors as well as binding studies with anti-estradiol antibodies.