Breast Cancer Clinical Trial
Official title:
A Phase Ib Dose Finding Study Assessing Safety and Activity of [177Lu]Lu-NeoB in Combination With Ribociclib and Fulvestrant in Participants With Estrogen Receptor Positive, Human Epidermal Growth Factor Receptor-2 Negative and Gastrin Releasing Peptide Receptor Positive Breast Cancer Experiencing Early Relapse From (Neo)Adjuvant Endocrine Therapy
The purpose of this phase 1b, single arm, multicenter, open label, dose finding study is to estimate the RD of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in adult female participants with ER+, HER2-, GRPR+, advanced or metastatic breast cancer who have relapsed during or within 12 months from completion of prior (neo)adjuvant ET (escalation part). Additionally this study aims to characterize the safety and tolerability of [177Lu]Lu-NeoB in combination with ribociclib and fulvestrant in post-menopausal participants and in combination with ribociclib, fulvestrant and goserelin in pre/peri-menopausal participants (expansion part) in the same indications.
| Status | Recruiting |
| Enrollment | 42 |
| Est. completion date | October 26, 2029 |
| Est. primary completion date | October 26, 2029 |
| Accepts healthy volunteers | No |
| Gender | Female |
| Age group | 18 Years and older |
| Eligibility | Inclusion Criteria: 1. Signed informed consent must be obtained prior to participation in the study 2. Adult female >= 18 years of age at the time of informed consent 3. Histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive with ER >10% (regardless of PgR expression) breast cancer by local laboratory testing (based on the most recently analyzed tissue sample) 4. HER2 negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (e.g. FISH, CISH, or SISH) test is required by local laboratory testing (based on the most recently analyzed tissue sample) 5. Disease relapse during (neo)adjuvant ET or =<12 months from completion of (neo)adjuvant ET (which may have included a CDK4/6 inhibitor) 6. Advanced [loco regionally recurrent not amenable to curative therapy (e.g. surgery and/or RT)] or metastatic disease 7. Dose escalation part only: Participant is post-menopausal at the time of starting study treatment. Post-menopausal status is defined by any of the following (NCCN Guideline Breast Cancer Version 4.2022): - Prior surgical bilateral oophorectomy - Age >= 60 - Age <60 and amenorrhoeic for >= 12 months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression, and FSH and estradiol in the postmenopausal range per local normal range - Age <60 years: chemotherapy-induced amenorrhea for >= 12 months with FSH and estradiol in post-menopausal range on serial assessments - Age <60 years: on tamoxifen with FSH and estradiol level in post-menopausal range Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone agonist (LHRHa) (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression for the purpose of the escalation part. Dose expansion part only 1. Participant is post-menopausal at the time of starting study treatment. 2. Participant is pre/peri-menopausal at the time of starting study treatment Pre-menopausal status is defined as either: - Patient had last menstrual period within the last 12 months OR - If on tamoxifen or toremifene within the past 14 days, plasma estradiol and FSH must be in the pre-menopausal range per local normal range OR - In case of therapy induced amenorrhea, plasma estradiol and/or FSH must be in the pre-menopausal range per local normal range. Peri-menopausal status is defined as neither pre-menopausal nor post-menopausal (see definition above) 8. A confirmed negative serum pregnancy test (ß-hCG) within 24 hours before starting study treatment in all pre/peri-menopausal participants in the expansion part (unless the participant has had a hysterectomy). 9. 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) OR If only lytic bone lesions are present, at least one lesion must have a soft tissue component that can be evaluated by CT or MRI and meets the definition of measurability as per RECIST criteria 1.1 (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). 10. Participant has at least one target lesion (RECIST 1.1, based on the baseline stand-alone CT/MRI) with [68Ga]Ga-NeoB uptake at PET/CT or PET/MRI The same identified measurable lesion shows the following [68Ga]Ga-NeoB uptake on PET/CT or PET/MRI based on the Visual Scoring Scale, see Section 8.5.2 - Escalation part: at least 1 target lesion (RECIST 1.1) scoring 1 or above - Expansion part: at least 1 target lesion (RECIST 1.1) scoring 2 or above 11. Adequate bone marrow and organ function as defined by the following laboratory values: - Absolute neutrophil count (ANC) >= 1.5 × 109/L - Platelets (PLT) >= 100 × 109/L - Hemoglobin (Hb) >= 9.0 g/dL - International Normalized Ratio (INR) =< 1.5 - Estimated glomerular filtration rate (eGFR) >= 60 ml/min/1.73m2 measured or calculated by the Cockcroft Gault method. - Total bilirubin < upper limit of normal (ULN) 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. - AST < 2.5 × ULN, except for participants with liver metastasis, who are only included if the AST is < 5 × ULN - ALT < 2.5 × ULN, except for participants with liver metastasis, who are only included if the ALT is < 5 × ULN 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) 12. Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed locally: - QTcF interval at screening < 450 msec - Mean resting heart rate 50-90 bpm (determined from the ECG) 13. ECOG performance status 0 or 1 14. Be able to communicate with the investigator and comply with the requirements of the study procedures 15. Willing to remain at the clinical site as required by the protocol Exclusion Criteria: 1. Prior treatment in the advanced/metastatic setting 2. Symptomatic visceral disease or any disease burden that makes the patient ineligible for ribociclib plus endocrine treatment per the Investigator's best judgment. 3. Presence of CNS involvement unless meeting BOTH of the following criteria: - At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment. - Clinically stable CNS tumor at the time of screening and not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases. 4. Currently receiving warfarin or other Coumadin derived anti-coagulant, for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin, or fondaparinux is allowed 5. Diagnosis of inflammatory breast cancer at screening 6. Child Pugh score B or C 7. 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: - History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment - Documented cardiomyopathy - Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) - 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 QTcF interval - 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) - Systolic Blood Pressure (SBP) >160 or <90 mmHg 8. Major surgery within 14 days prior to [68Ga]Ga-NeoB administration at screening or has not recovered from major side effects. 9. Use of tamoxifene or toremifene within a washout a period of 5 half-lives or goserelin =< 28 days from C1D1 10. Participant is concurrently using hormone replacement therapy. 11. Known or expected hypersensitivity to any of the study drugs or any of their excipients 12. Concurrent bladder outflow obstruction or unmanageable urinary incontinence 13. Prior administration of a radiopharmaceutical unless 10 or more half-lives have elapsed before injection of [68Ga]Ga-NeoB 14. Participant has received extended-field RT =< 4 weeks or limited field RT =< 2 weeks prior to start of treatment and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the participant at Investigator's discretion) and/or prior EBRT to more than 25% of the bone marrow. 15. Presence of concurrent malignancy or malignancy within 3 years of starting study treatment, with the exception of adequately treated, basal or squamous cell skin carcinoma or curatively resected cervical cancer. 16. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 17. Patient is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study treatment, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: single doses, topical applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intra-articular) 18. Participant has a history of ongoing acute pancreatitis within 1 year from screening 19. Presence of any other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, cause unacceptable safety risks, contraindicate patient 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, etc.) 20. Patient is currently receiving any of the following substances and cannot be discontinued 7 days prior to starting study treatment: - Concomitant medications, herbal supplements, and/or fruits (e.g., grapefruit, pummelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5, - Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5. - Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study treatment) 21. Participation in a prior investigational study within 30 days prior to start of treatment or within 5-half lives of the investigational product, whichever is shorter. If the participant is enrolled or planned to be enrolled in another study that does not involve an investigational product, the agreement of the Novartis study medical lead is required to establish eligibility. 22. For expansion part - 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 dose of [177Lu]Lu-NeoB or 2 years after the last dose of fulvestrant, 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). The vasectomized male partner should be the sole partner for the study 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. If local regulations deviate from the recommendations provided above, local regulations apply and will be described in the ICF. Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential. Note: Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or intrauterine system (IUS) or any other form of hormonal contraception for example hormone vaginal ring, IUD or transdermal hormone contraception is not allowed in this study. |
| Country | Name | City | State |
|---|---|---|---|
| France | Novartis Investigative Site | Saint Herblain | |
| Portugal | Novartis Investigative Site | Porto | |
| Spain | Novartis Investigative Site | Barcelona | Catalunya |
| Spain | Novartis Investigative Site | Madrid | |
| Spain | Novartis Investigative Site | Madrid |
| Lead Sponsor | Collaborator |
|---|---|
| Novartis Pharmaceuticals |
France, Portugal, Spain,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | Dose escalation part: Incidence and nature of DLTs during the DLT observation period | 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. The National Cancer Institute (NCI) CTCAE version 5.0 will be used for all grading. | 28 days after the first administration of [177Lu]Lu-NeoB | |
| Primary | Dose expansion part: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | 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. | From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 70 months | |
| Secondary | Dose escalation part: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) | 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. | From date of enrollment till 8 weeks after end of Treatment, assessed up to approximately 70 months | |
| Secondary | Dose escalation and expansion part: 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 radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 110 months | |
| Secondary | Dose escalation and expansion part: 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 110 months | |
| Secondary | Dose escalation and expansion part: 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 radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 110 months | |
| Secondary | Dose expansion part: 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 70 months | |
| Secondary | Dose escalation and expansion part: Time activity curves (TACs) of [177Lu]Lu-NeoB in organs and tumor lesions | Time activity curves (TACs) for the various organs and lesions will be produced as percentage of injected dose in selected organs and 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) | |
| Secondary | Dose escalation and expansion part: Absorbed radiation doses of [177Lu]Lu-NeoB in organs and tumor lesions | The absorbed dose in target organs will be summarized with descriptive statistics. | 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) | |
| Secondary | Dose escalation and expansion part: Concentration of [177Lu]Lu-NeoB in blood over time | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Observed maximum blood concentration (Cmax) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Time of maximum observed drug concentration occurrence (Tmax) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part:Area under the blood concentration-time curve from time zero to the time of last quantifiable concentration (AUClast) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Total systemic clearance for intravenous administration (CL) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Volume of distribution during the terminal phase following intravenous elimination (Vz) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Terminal elimination half-life (T^1/2) of [177Lu]Lu-NeoB | 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. | 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) | |
| Secondary | Dose escalation and expansion part: Incidence and severity of AEs following [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. | 3 days after [68Ga]Ga-NeoB administration |
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