[177Lu]Lu-NeoB in Combination With Ribociclib and Fulvestrant in Participants With ER+, HER2- and GRPR+ Advanced Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT05870579
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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.
- Detailed Description
The study comprises of a dose escalation part and, a concurrent backfill part.
1. The dose escalation part will estimate the RD of \[177Lu\]Lu-NeoB in combination with ribociclib and fulvestrant; four provisional dose levels are planned to be tested: 100 millicurie (mCi) (initial dose), 150mCi, 200 mCi and 250mCi in cohorts of 3 to 6 participants. After inclusion of each cohort of 3 to 6 participants, the incidence rate of DLTs will be compared to the pre-defined toxicity rate boundaries to decide whether the next cohort will receive a lower, higher or same dose or whether the trial will be terminated.
2. The backfill part will allow enrollment to a previously cleared dose level (during escalation part) in order to obtain additional safety, tolerability as well as preliminary efficacy data. During the backfill part, the cumulative incidence rate of DLTs will also be compared to the pre-defined toxicity rate boundaries to determine if escalation should be restarted from a lower dose level.
3. The recommended dose (RD) will be determined considering all available data from the escalation and backfill part.
During screening, study participants will receive the investigational imaging agent \[68Ga\]Ga-NeoB. An additional administration of the \[68Ga\]Ga-NeoB will be performed potentially at Cycle 2 Day 15, and within 4-8 weeks from the last administration of \[177Lu\]Lu-NeoB for a positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI). Study treatment will include \[177Lu\]Lu-NeoB on day 1 of each 28-day cycle (+ =\< 3 days) for 6 cycles, ribociclib (once daily; days 1 to 21 in a 28-day cycle) and fulvestrant (C1D1, C1D15, C2D1 and every 28 days thereafter) until disease progression. Pre- and perimenopausal women and men will additionally receive goserelin on day 1 of every cycle.
During the treatment period participants will be required to attend a site visit approximately every 28 days, on the first day of each cycle (as well as on C1D2, C1D3, C1D8, C1D15, C2D15, C3D3 and C5D3), to undergo study treatment administration, dosimetry and safety assessments. Tumor assessments are performed every 8 weeks until month 18, every 12 weeks until month 36 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 every 12 weeks until month 36 and every 24 weeks thereafter until month 60 for a total of 5 years from the participant's enrollment in the study, or until death, lost to follow-up, or withdrawal of consent (WoC), whichever occurs first.
The end of study is defined as the date of the last visit, scheduled procedure or follow up (or date of death, WoC or lost to follow up, whichever occurs first) of the last participant in the study globally, or at 5 years from the date of the last participant enrolled, whichever occurs earlier.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 48
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Arm 1 [68Ga]Ga-NeoB 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. Arm 1 [177Lu]Lu-NeoB 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. Arm 1 Ribociclib 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. Arm 1 Fulvestrant 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. Arm 1 Goserelin 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.
- Primary Outcome Measures
Name Time Method Incidence and nature of DLTs during the DLT observation period 28 days after the first administration of [177Lu]Lu-NeoB 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, ribociclib and fulvestrant with or without goserelin. The National Cancer Institute (NCI) CTCAE version 5.0 will be used for all grading.
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 60 months The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Incidence of dose interruptions, discontinuation and dose reductions From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 60 months Dose interruptions, discontinuation and dose reductions will be assessed for tolerability.
- Secondary Outcome Measures
Name Time Method Time activity curves (TACs) of [177Lu]Lu-NeoB in organs and tumor lesions Cycles 1, 3 and 5: Day 1 (1-4 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) (1 cycle = 4 weeks) Time activity curves (TACs) for the various organs and lesions will be produced as percentage of injected dose in selected organs and lesions.
Concentration of [177Lu]Lu-NeoB in blood over time Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. Blood concentration of \[177Lu\]Lu-NeoB will be summarized with descriptive statistics.
Absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions Cycles 1, 3 and 5: Day 1 (1-4 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) (1 cycle = 4 weeks) The absorbed dose in target organs will be summarized with descriptive statistics.
Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. Tmax will be listed and summarized using descriptive statistics.
Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. Vz will be listed and summarized using descriptive statistics.
Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. AUClast will be listed and summarized using descriptive statistics.
Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. CL will be listed and summarized using descriptive statistics.
Observed maximum blood concentration (Cmax) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. Cmax will be listed and summarized using descriptive statistics.
Terminal elimination half-life (T^1/2) of [177Lu]Lu-NeoB Cycle 1: 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) Venous whole blood samples will be collected for activity-based pharmacokinetics characterization of \[177Lu\]Lu-NeoB. T\^1/2 will be listed and summarized using descriptive statistics.
Objective Response Rate (ORR) From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 60 months 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.
Duration of Response (DoR) 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 60 months 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.
Time to Response (TTR) From the date of first dose to the date of documented response (CR or PR), assessed up to approximately 60 months Time to response (TTR) is the time from the date of first dose of \[177Lu\]Lu-NeoB to the first documented response (CR or PR) according to RECIST 1.1.
Clinical Benefit Rate (CBR) From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 60 months 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.
Progression Free Survival (PFS) 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 60 months 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) From the date of first dose to date due to any cause, assessed up to approximately 60 months 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.
Incidence and severity of AEs following [68Ga]Ga-NeoB administration 3 days after [68Ga]Ga-NeoB administration Incidence and severity of AEs following \[68Ga\]Ga-NeoB administration at screening will be done via the analysis of frequencies for Adverse Event (AEs), Serious Adverse Event (SAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.
Trial Locations
- Locations (5)
Hoag Memorial Hospital Presbyterian
🇺🇸Newport Beach, California, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Utah Intermountain Medical Center
🇺🇸Murray, Utah, United States
Novartis Investigative Site
🇪🇸Madrid, Spain