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Also known as LEE011, Ribociclib (neoadjuvant)
Ribociclib · 14 trials · 22 indications
iBCFS is defined as the time from the date of first dose to the date of the first event of invasive ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, death (any cause), or contralateral invasive BC. iBCFS will be assessed using STEEP criteria version 2.0 (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator. The iBCFS rate at 3 years will be assessed.
Invasive Disease-Free Survival (iDFS) is defined as the time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). iDFS will be assessed locally using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
Clinical Benefit Rate (CBR) after 24 weeks of treatment as defined by RECIST 1.1 as percentage of patients with Complete Response (CR), Partial response (PR) or Stable disease (SD) lasting 24 weeks or longer as well as patients with Non-complete response, nonprogressive disease (NCRNPD).
PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via local radiology assessment according to RECIST 1.1. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. The distribution of PFS between the two arms was compared using a stratified log-rank test at a one-sided 2.5% level of significance. The PFS hazard ratio with two-sided 95% confidence interval was derived from the stratified Cox proportional hazards model.
PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. In cases where patients did not experience an event, the PFS was censored at the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via local radiology assessment according to RECIST 1.1. As per protocol, the final PFS analysis was conducted after approximately 392 PFS events were documented. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval
Estimate subsequent recurrence-free survival (RFS) at 3 years for ribociclib when administered with ET (AIs or fulvestrant). RFS is defined as interval from registration until invasive or DCIS recurrence in the ipsilateral breast or locoregionally, invasive recurrence at a distant site, or death from breast cancer or any other cause, whichever occurs first. The censoring time is the completion of study at 6 years (3 years of patient accrual and 3 years of follow up time). The RFS at 3 years will be also treated as the primary endpoint in the power and sample size calculation.
DMFS is defined as the time from date of surgery to date of first event of distant metastatic recurrence or death (any cause).
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Maximally tolerated dose (MTD) of ribociclib in combination with docetaxel and prednisone is based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants who received treatment in Phase Ib. If 1 of 3 participants in a cohort experiences a DLT, then the cohort will be expanded to treat an additional 3 participants. If only 1 of 6 participants experiences a DLT, the next cohort of participants will be treated at the next higher dose level. If 2 or more participants in a cohort experience a DLT, then MTD has been exceeded and the previous dose level will be considered the MTD. If more than 1 of 6 patients experience a DLT at dose level IA then the study will be terminated, as the MTD cannot be determined and de-escalation from dose level IA is not planned. Per Investigator discretion the Recommended Phase 2 Dose (RP2D) schedule of ribociclib and docetaxel may be established in the absence of reaching MTD.
The RP2D of docetaxel will be reported when used in combination with ribociclib and prednisone based upon evaluation of dose-limiting toxicities (DLTs) and adverse events for all participants in the Phase Ib group. Per Investigator discretion, the RP2D schedule of docetaxel and ribociclib may be established in the absence of reaching MTD, based on the cumulative safety data of the treatment regimen.
Radiographic progression-free survival will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The percent of participants has been estimated using the Kaplan-Meier product limit method. Duration will be measured from day 1 of study treatment to first date of radiographic progression or death, whichever occurs first, for all Phase 1b or Phase 2 participants receiving the RP2D. Participants who discontinue study therapy for toxicity, withdrawal from study, or prostate-specific antigen (PSA)-only progression, will be censored at the date of last radiographic tumor assessment for this analysis. Patients who discontinue therapy for evidence of clinical progression/clinical deterioration will be included in this analysis.
Blood samples obtained for Pharmacokinetic (PK) analysis will be used to describe how study drugs are distributed and metabolized by human subjects. Samples for PK analysis will be obtained during Cycle 1 of all Cohorts. Area under the concentration-time curve from time zero to 24 hours (AUC(0-24hr)) is a measure of a subject's exposure to study drugs.
Blood samples obtained for Pharmacokinetic (PK) analysis will be used to describe how study drugs are distributed and metabolized by human subjects. Samples for PK analysis will be obtained during Cycle 1 of all Cohorts. Maximum observed concentration (Cmax) will be determined from the plasma concentration data
Blood samples obtained for Pharmacokinetic (PK) analysis will be used to describe how study drugs are distributed and metabolized by human subjects. Samples for PK analysis will be obtained during Cycle 1 of all Cohorts. Time of first observation of Cmax (tmax) will be determined from the plasma concentration data
Toxicities experience by study subjects will be reported and graded for severity using CTCAE version 5. These data will contribute to determining the Maximum tolerated dose (MTD)
This dose, determined by review of toxicity data, will define the highest dose that is tolerable in this patient population.
Phase I: Maximum tolerated dose (MTD) for subjects receiving ribociclib and bicalutamide without experiencing dose-limiting toxicity(s) (DLT) per Common Terminology Criteria for Adverse Events (CTCAE) v4
Compare sum of confirmed complete plus partial responses plus stable disease per response evaluation criteria in solid tumors (RECIST) 1.1 criteria
Maximum Tolerated Dose(s) (MTD(s)) and/or recommended phase 2 dose (RP2D(s)) and schedule of LEE011 in combination with ceritinib in ALK-positive non-small cell lung cancer (NSCLC) patients. Cycle = 28 days
Preliminary anti-tumor activity of the LEE011 and ceritinib combination
Measurement of pharmacokinetics (PK) parameters (AUC0-24h at C1D15)
This is the Phase II portion, which assesses trough plasma concentrations of study drug on each clinical visit day, prior to administration of ribociclib on that day.
| Arm | Type | Description |
|---|---|---|
| Ribociclib + endocrine therapy | EXPERIMENTAL | Participants will receive ribociclib 400 mg orally once daily on days 1 to 21 of a 28-day cycle, in combination with daily endocrine therapy (ET) for 36 months (approximately 39 cycles). ET consists of: * For postmenopausal women: letrozole 2.5 mg orally once daily continuously, anastrozole 1 mg orally once daily continuously, or exemestane 25 mg once daily continuously. * For pre/perimenopausal women, and men: letrozole 2.5 mg orally once daily continuously, anastrozole 1 mg orally once daily continuously, or exemestane 25 mg once daily continuously, combined with goserelin subcutaneously (at 3.6 mg once every 4 weeks if the one-month depot formulation is used or at 10.8 mg once every 3 months if the three-month depot formulation is used) or leuprolide subcutaneously (at 3.75 mg once every 4 weeks if the one-month depot formulation is used or at 11.25 mg once every 3 months if the three-month depot formulation is used) |
| Ribociclib + Endocrine Therapy (ET) | EXPERIMENTAL | Eligible participants will receive Ribociclib 400 mg once daily on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28). And Endocrine Therapy (ET) consisting of: * For postmenopausal women: \- Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously. * For premenopausal women and men: * Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously, combined with: * Goserelin 3.6 mg subcutaneously once every 4 weeks. |
| Endocrine Therapy (ET) | ACTIVE_COMPARATOR | Eligible participants will receive Endocrine Therapy (ET) consisting of: * For postmenopausal women: \- Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously. * For premenopausal women and men: * Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously, combined with: * Goserelin 3.6 mg subcutaneously once every 4 weeks. |
| ribociclib + letrozole cohort A | EXPERIMENTAL | ribociclib + letrozole cohort A - postmenopausal women, or men; naïve. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. |
| ribociclib + letrozole cohort B1 | EXPERIMENTAL | ribociclib + letrozole cohort B1 - premenopausal women or perimenopausal women; naïve All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly |
| ribociclib + letrozole cohort B2 | EXPERIMENTAL | ribociclib + letrozole cohort B2 - premenopausal women or perimenopausal women or postmenopausal women, or men; pre-treated. All patients received ribociclib 600mg p.o. daily + Letrozole 2.5 mg p.o. daily. Premenopausal patients additionally received goserelin 3.6 mg i.m. monthly |
| Ribociclib + fulvestrant | EXPERIMENTAL | Ribociclib was administered orally at a daily dose of 600mg for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment. |
| Placebo + fulvestrant | PLACEBO_COMPARATOR | Placebo was administered orally for 21 consecutive days within a 28-day cycle. This treatment was combined with fulvestrant, which was administered via intramuscular injections of 500mg every 28 days starting on Day 1 of each cycle. Additionally, an extra dose of fulvestrant was given on Day 15 of Cycle 1. For participants who did not tolerate the protocol-specified dosing schedule, dose adjustments were permitted in order to allow the patient to continue the study treatment. Participants were unblinded after the implementation of protocol amendment 4 (29-Jan-20) and were given the option to crossover to treatment with ribociclib and fulvestrant. |
| Ribociclib + NSAI/tamoxifen + goserelin | EXPERIMENTAL | Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days) |
| Placebo + NSAI/tamoxifen + goserelin | PLACEBO_COMPARATOR | Placebo daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin. |
| Ribociclib+ letrozole | EXPERIMENTAL | Ribociclib 600 mg daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral |
| Placebo + letrozole | PLACEBO_COMPARATOR | Placebo daily oral (3 weeks on/ 1 week off) in combination with letrozole 2.5 mg daily oral. Participants were unblinded once the final OS analysis was completed and after the implementation of protocol amendment 10 (30-Apr-21) and were given the option to crossover to treatment with ribociclib + letrozole |
| Investigational Group | EXPERIMENTAL | The drug ribociclib will be taken orally at a dose of 400 mg daily for 21 days out of a 28-day cycle. Ribociclib will be used in combination with ET per physician choice. All new subjects enrolled under the 08JUL2024 protocol or after will receive ribociclib 400mg daily for 21 days out of a 28-day cycle. Subjects receiving 600mg ribociclib under a prior protocol version will be switched to 400mg. Physician's choice of endocrine therapy includes: * 500 mg of fulvestrant received intramuscularly. This will be taken on Day 1 and Day 15 of Cycle 1 and on Day 1 of Cycle 2 and beyond. * 1 mg of anastrozole taken orally daily of the 28 day cycle. * 2.5 mg of letrozole taken orally daily of the 28 day cycle. * 25 mg of exemestane taken orally daily of the 28 day cycle. * Concomitant use with tamoxifen is not allowed. Premenopausal subjects must also be treated with ovarian suppression according to institutional standards or have undergone bilateral oophorectomy. |
| Responder (ROR-low) | EXPERIMENTAL | Ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting for 33 cycles. Letrozole or other aromatase inhibitor treatment duration must be of at least 5 years |
| Non-responder (ROR-medium/high) | OTHER | Adjuvant chemotherapy. 3 regimens are permitted. Regimen 1: \- Doxorubicin 60 mg/m2 IV day 1 (or Epirubicin 75-100 mg/m2) and Cyclophosphamide 600-830 mg/m2 day 1 every 14/21 days for 4 cycles, followed by Paclitaxel 80 mg/m2 every week for 12 weeks or Docetaxel 75-100 mg/m2 every 3 weeks for 12 weeks. Regimen 2: \- Docetaxel 75-100 mg/m2 IV day 1 and Cyclophosphamide 600-830 mg/m2 day 1 every 21 days for 4-6 cycles. Regimen 3: \- Paclitaxel 80 mg/m2 every week for 12 weeks or Docetaxel 75-100 mg/m2 every 3 weeks for 12 weeks followed by Doxorubicin 60 mg/m2 IV day 1 (or Epirubicin 75-100 mg/m2) and Cyclophosphamide 600-830 mg/m2 day 1 every 14/21 days for 4 cycles. Then, patients will receive ribociclib (400 mg/day; 3 weeks ON and 1 week OFF) in the adjuvant setting for 33 cycles. Letrozole or other aromatase inhibitor treatment duration must be of at least 5 years |
| Treatment (ribociclib) | EXPERIMENTAL | Patients receive ribociclib PO QD on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| Treatment (Phase 1b) | EXPERIMENTAL | The starting cohort dose level (1) for docetaxel will be 75 mg/m2, administered on day 1 of each cycle. Prednisone will be fixed at 5 mg twice a day. The starting dose level and schedule for ribociclib will begin at 200 mg orally once daily, starting on day 1 of the 21-day cycle. If dose level 1 is not tolerated, then alternative dosing schedules of docetaxel will be evaluated, starting with dose level 1A of 60mg/m2 docetaxel. |
| Treatment (Phase 2) | EXPERIMENTAL | Participants in Phase 2 will receive the Recommended Phase 2 Dose for docetaxel and ribociclib |
| Ribociclib (RIBO) + Dexamethasone (DEX) | EXPERIMENTAL | * Ribociclib administered daily for 21 consecutive days * Dexamethasone administered intravenously on days 1-5 and again on days 11-15 |
| RIBO + Everolimus (EVE) + DEX | EXPERIMENTAL | * Ribociclib administered daily for 21 consecutive days * Dexamethasone administered intravenously on days 1-5 and again on days 11-15 * Everolimus administered daily for 21 consecutive days |
| RIBO + EVE+ DEX (dose expansion) | EXPERIMENTAL | * Ribociclib administered daily for 21 consecutive days. Dosing at RDE * Dexamethasone administered intravenously on days 1-5 and again on days 11-15 * Everolimus administered daily for 21 consecutive days. Dosing at RDE |
| Arm A - Phase I | EXPERIMENTAL | Dose Escalation Cohort 1 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-21 of a 28 day cycle. Cohort 2 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 400mg PO daily on days 1-28 of a 28 day cycle. Cohort 3 will consist of 3-6 patients who will receive bicalutamide 150mg PO daily on days 1-28 of a 28 day cycle and ribociclib 600mg PO daily on days 1-21 of a 28 day cycle. Experimental: Arm B - Phase II Investigational Treatment The maximum safe dose of ribociclib in combination with bicalutamide will be given to up to 25 patients. |
| Ribociclib 100 mg + Ceritinib 300 mg | EXPERIMENTAL | LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use |
| Ribociclib 100 mg + Ceritinib 450 mg | EXPERIMENTAL | LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use |
| Ribociclib 200 mg + Ceritinib 300 mg | EXPERIMENTAL | LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use |
| Ribociclib 200 mg + Ceritinib 450 mg | EXPERIMENTAL | LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use |
| Ribociclib 300 mg + Ceritinib 450 mg | EXPERIMENTAL | LEE011 capsule for oral use (ribociclib) and Ceritinib for oral use |
| Administration of ribociclib | EXPERIMENTAL | Subjects will be administered ribociclib prior to surgical resection of their tumor. All patients will be orally-administered 5 doses of LEE011 (900 mg/d) with the final dose occurring at one of 3 following intervals before brain tumor resection: Cohort 1: last ribociclib dose 2-4 hours prior to craniotomy for tumor resection Cohort 2: last ribociclib dose 6-8 hours prior to craniotomy for tumor resection Cohort 3: last ribociclib dose 23-25 hours prior to craniotomy for tumor resection |
| Name | Type | Description |
|---|---|---|
| Ribociclib | DRUG | Ribociclib 400 mg orally once daily on days 1-21 of a 28 day cycle followed by 7 days rest |
| Letrozole | DRUG | Letrozole 2.5 mg orally once daily continuously |
| Ansastrozole | DRUG | Anastrozole 1 mg orally once daily continuously. |
| Goserelin | DRUG | Goserelin administered subcutaneously at 3.6 mg once every 4 weeks if the one-month depot formulation is used or at 10.8 mg once every 3 months if the three-month depot formulation is used |
| Leuprolide | DRUG | Leuprolide administered subcutaneously at 3.75 mg once every 4 weeks if the one-month depot formulation is used or at 11.25 mg once every 3 months if the three-month depot formulation is used |
| Exemestane | DRUG | Exemestane 25 mg once daily continuously |
| Endocrine Therapy (ET) | OTHER | Endocrine Therapy (ET) will be administered according to the local clinical guidelines and current local prescribing information |
| Fulvestrant | DRUG | Fulvestrant was administered via intramuscular injections at a dose of 500mg every 28 days, starting on Day 1 of each cycle. In Cycle 1, an additional dose of Fulvestrant was given on Day 15. |
| Placebo | DRUG | Placebo capsules were administered orally for 21 consecutive days within a 28-day cycle. |
| Tamoxifen | DRUG | Tamoxifen (20 mg, tablets) was administered orally on a continuous daily schedule (days 1-28 of each 28-day cycle) |
| Anastrozole | DRUG | Anastrozole (1 mg, tablets) was administered orally once daily on a continuous daily schedule (days 1-28 of each 28-day cycle) |
| Ribociclib (neoadjuvant) | DRUG | Ribociclib 600 mg/day + letrozole during neoadjuvant phase. |
| Chemotherapy (adjuvant) | DRUG | Adjuvant chemotherapy. 3 regimens are permitted. |
| Ribociclib (adjuvant) | DRUG | Ribociclib 400 mg/day + letrozole (or other aromatase inhibitor) during adjuvant phase. |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Pharmacological Study | OTHER | Correlative studies |
| Docetaxel-PNP | DRUG | Given IV |
| Prednisone | DRUG | Given Orally |
| Filgrastim | DRUG | Given IV |
| Dexamethasone | DRUG | Corticosteroids are commonly used to treat ALL. |
| Everolimus | DRUG | Everolimus is an inhibitor of mTOR. mTOR inhibition blocks the translation of genes that regulate cancer cell proliferation |
| Bicalutamide | DRUG | 150mg PO |
| Ceritinib | DRUG | ALK inhibitor |
Key Inclusion criteria: * Participant is an adult, male or female ≥ 18 years of age at the time of informed consent form signature (IC). * Participant has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer (BC)...
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LEE011, also known as ribociclib, is an investigational small molecule being studied for multiple oncology indications, including early breast cancer, hormone receptor positive HER2-negative breast cancer, advanced breast cancer, and glioblastoma multiforme. It is currently in Phase 1 clinical development.
LEE011 (ribociclib) is a cyclin-dependent kinase (CDK) inhibitor, belonging to the -ciclib class of drugs that target CDK enzymes involved in cell cycle regulation. It is being evaluated for its role in treating various cancers, including breast cancer and glioblastoma multiforme.
LEE011 (ribociclib) is developed by Novartis AG, a global pharmaceutical company listed on the stock exchange under the ticker symbol NVS. The drug is being investigated in clinical trials for multiple cancer indications.
LEE011 (ribociclib) is currently in Phase 1 clinical development. It is an investigational drug and has not been approved by regulatory authorities. The drug has received a rare pediatric disease designation from the FDA.
LEE011 (ribociclib) has been studied in 12 clinical trials with a total enrollment of 6,501 participants. Notable trials include NCT03701334, a Phase 3 study in early breast cancer with 5,101 patients, and NCT05827081, a Phase 3b study in early breast cancer currently recruiting.
Yes, LEE011 is also known as ribociclib. The drug is referred to by both names in clinical research, and it is being developed by Novartis AG for the treatment of various cancers, including breast cancer and glioblastoma multiforme.