Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication KISQALI is a kinase inhibitor indicated: in combination with an aromatase inhibitor for the adjuvant treatment of adults with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative stage II and III early breast cancer at high risk of recurrence. FDA label
Also known as LEE011, Ribociclib (neoadjuvant), ribociclib (LEE011), Kisqali, LEE011 (ribociclib)
Ribociclib · 42 trials · 71 indications
PFS is defined as time from randomization to progression of disease or death of any cause, whichever comes first. It will be assessed by imaging until progressive disease or start of next-line therapy.
using RECIST 1.1 criteria, as assessed by local radiologists/investigators
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).
AEs were defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s). SAEs were defined as meeting at least 1 of the following criteria: is fatal or life-threatening, Results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, is medically significant, requires inpatient hospitalization or prolongation of existing hospitalization. A SAE which caused death of the participant was considered as fatal SAE. AEs were assessed and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Grade 1 to 5 were used to characterize the severity of the Adverse Event. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening and Grade 5: death related to AE. A participant with multiple severity grades for an AE is only counted under the maximum grade.
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
Progression free survival (PFS) is defined as the interval from the time of randomization until objective disease progression (local assessment) or death from any cause. Disease status will be assessed with comprehensive radiographic studies every three treatment cycles (approximately every 12 weeks (+/- 1 week)). Disease progression as assed by RECIST 1.1 defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with DIPG by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.
To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and everolimus given to patients with metastatic HGG who have received craniospinal irradiation CSI.
Identify the safe dose of ribociclib powder for oral solution (PfOS) formulation in combination with everolimus that is feasible in pediatric patients with newly-diagnosed HGG, including DIPG, with cell cycle and/or PI3K/mTOR pathway alterations. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0 in the first 6-12 patients enrolled
Establish RP2D of ribociclib and temozolomide (Phase 1 Run-In Stratum E) Description: To identify the Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and temozolomide given to patients with newly diagnosed localized DHG, H3G34-mutant who have received RT.
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).
ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1. CR: Disappearance of all lesions with lymph nodes measuring \< 10 mm. PR: At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.
ORR was defined as the percentage of participants in the analysis population who achieved a complete response or partial response, as assessed by RECIST 1.1.
The treatment feasibility will be evaluated as the proportion of patients not having experienced disease progression (PD), still on treatment with ribociclib plus NSAI 6 months after the first drug administration
Progression-free survival (PFS) was defined as the time from randomization to the first documented disease progression or death from any cause. PFS was assessed by local investigators based on tumor evaluations using RECIST version 1.1 criteria. Patients who had not experienced progression or death by the analysis cut-off date of 25 April 2022 were censored at the date of their last adequate tumor assessment prior to that cut-off.
These are the number of participants who had adverse events or serious adverse events regardless of whether is was suspected to be drug-related or not
These are the percentage of participants that had adverse events or serious adverse events regardless of whether is was suspected to be drug-related or not
Continued access to study treatment as a single agent or in combination with other investigational treatments until patients discontinue study
Assessed by duration in days from start of study treatment until study treatment discontinuation
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.
Clinical benefit (CB) for patients with solid tumors were assessed using RECIST 1.1 and included responses of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm. FAS
CBR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR + PR + SD for ≥ 16 weeks. CR and PR (for solid tumors) required a confirmation at least 4 weeks after the initial response observation. For hematologic tumors other appropriate hematological response criteria was applied. CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm, PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters, SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study, PD=At least a 20% increase in the sum of diameter of all measured target lesions and also demonstrate an absolute increase of at least 5 mm FAS
ORR was determined by local, Investigator assessment for each tumor assessment and defined as responses of CR+PR ≥ 16 weeks. FAS
Standard 3+3 phase-I design will be utilized in this trial. Briefly, a minimum of 3 evaluable patients will be entered at first dose level (=300 mg ribociclib) and T-DM1 (3.6 mg/kg IV). If 1 out of the first 3 patients enrolled experiences a dose-limiting toxicity (DLT), 3 additional patients will be enrolled to that dose level. If no more than 1 patient in 6 experiences a DLT, dose escalation of ribociclib will continue to next dose-level. If 2 or more patients at any given dose level experience a DLT, dose escalation will stop and the Recommended Phase2 Dose (RP2D) will be defined. Maximum dose-escalation of Ribociclib (LEE011) will be up to 600 mg.
CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.
CBR is defined as the proportion of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) at week 24 by RECIST 1.1 criteria. CBR will be reported with 90% confidence interval, adjusting for two-stage design using the method from Atkinson and Brown.
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.
Defined as the highest dose level that does not lead to unacceptable toxicity in two or more patients in a dosing level.
Defined as no invasive tumor in the breast or lymph nodes at the time of surgery. Response evaluable participants are defined as participants who are randomized and have receive at least one cycle of protocol therapy. The pCR rate is defined as percentage of randomized patients with a pCR in each of the treatment arms.The estimated pCR rate (and 95% confidence interval \[CIs\]) will be calculated for each experimental arm and compared to the corresponding control arm using the Cochran-Mantel-Haenszel x\^2 test, with a two-sided significance level of 5%. Absolute differences in pCR rate between study arms will be calculated, along with 95% exact confidence intervals. This will be stratified according to hormone receptor (HR) status Multivariate logistic regression will be used to control for important baseline characteristics and odds ratios with corresponding CIs will be calculated.
incidence of DLTs during the defined DLT period
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
Determine the Recommended Phase II dose (RP2D) of LEE011 (ribociclib) in the combination with everolimus in patients with mPAC refractory to 5-FU- and GEM-based chemotherapy based on DLTs within the first 4 weeks of treatment.
PFS at 8 weeks in a patient with refractory mPAC treated with LEE011 and everolimus, defined as positive if a patient does not have evidence of progressive disease at 8 weeks as measured by expert radiologists using RECIST v1.1 criteria
Determination of MTD and RP2D of ribociclib and capecitabine combination, PO in a 21 day schedule (2 weeks on/1 week off), in subjects eligible to a capecitabine treatment, with locally advanced/metastatic breast cancer who failed anthracycline and taxane treatment.
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as having a reasonably possible relationship to the study medication(s) and is unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days of treatment (cycle 1) and meets any of the criteria defined in the protocol. National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03 will be used for all grading.
Clinical Benefit Rate (CBR) is defined as the percentage of participants with a complete response (CR) or partial response (PR) or with stable disease (SD) as per Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 or Non-Complete Response or Non-Progressive Disease (NCRNPD) during first 24 weeks of first dose. CR=disappearance of all non-nodal target lesions, PR=at least a 30% decrease in the sum of diameter of all target lesions, SD=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease (PD), PD=at least a 20% increase in the sum of diameter of all target lesions. The hypothesis was to be rejected if the lower limit of the 95% Confidence Interval for Clinical Benefit Rate (CBR) was greater than 10%.
Complete response (CR) or partial response (PR), or stable disease (SD) at 24 weeks as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or Non-CR Non-PD (NCRNPD) at Week 24.
Primary composite PK parameters: Cmax, AUClast, AUCinf, and CL/F. To determine the impact of various degrees of renal impairment on primary PK parameters of LEE011 following a single 400mg oral dose
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)
PK profile includes the following parameters Tmax, Cmax, AUClast, AUCinf, T1/2, CL/F, Vz/F.
DLTs at each dose level associated with administration of LEE011 and letrozole
This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of AEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant
This will be defined by changes in hematology and chemistry values, vital signs and ECGs, frequency and duration of SAEs, lab abnormalities and other safety parameters. For LEE011 and letrozole or tamoxifen or fulvestrant
Dose Escalation Phase: Frequency of DLTs at each dose level associated with administration of LEE011, buparlisib, and letrozole in a 28 day cycle
Dose Expansion Phase: Incidence of AEs, SAEs (overal and severity), laboratory abnormalities, ECG, vital, dose interteruptions, dose reductions, and dose intensity as a measure of safety and tolerability.
Dose limiting toxicities
Progression Free Survival per RECIST v 1.1 by local investigator assessment
Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
To characterize PK profiles of LEE011 and Letrozole.
DLT is defined as treatment-related toxicity (classified according Common Toxicity Criteria for Adverse Events (CTCAE) Version 4) occurring during the first 28 treatment days and meeting specific protocol-predefined criteria.
Adverse events were collected for approximately 4.5 years for dose expansion including the 30 days safety follow-up period.
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 |
|---|---|---|
| Arm A | EXPERIMENTAL | Combination of ribociclib and aromatase inhibitor or fulvestrant |
| Arm B | ACTIVE_COMPARATOR | Capecitabine + bevacizumab OR Paclitaxel +/- bevacizumab |
| Ribociclib + Endocrine Therapy | EXPERIMENTAL | Ribociclib + Fulvestrant or Letrozole |
| Palbociclib + Endocrine Therapy | EXPERIMENTAL | Palbociclib + Fulvestrant or Letrozole |
| Paclitaxel +/- Tislelizumab - Exploratory cohort | EXPERIMENTAL | Additional experimental Cohort that includes patients with Basal-Like intrinsic subtype. |
| 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+goserelin/leuprolide | EXPERIMENTAL | Participants received ribociclib (orally taken, 3 weeks on/1 week off) in combination with letrozole (orally taken once daily). For men and premenopausal women, either goserelin was given as an injectable subcutaneous implant or leuprolide was given as an intramuscular injection. |
| 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 |
| Ribociclib (LEE-011)/Fulvestrant | EXPERIMENTAL | LEE-011 is administered orally, 600mg, daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks. |
| Placebo/Fulvestrant | PLACEBO_COMPARATOR | Placebo is administered orally, 600mg daily for 3 weeks and 1 week off. Fulvestrant is administered intramuscularly, 500mg, every 2 weeks x 3, then every 4 weeks. |
| Stratum A (n=40) | EXPERIMENTAL | Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata B, C, or D). |
| Stratum B (n=40) | EXPERIMENTAL | Patients with DIPG, defined as a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (e.g., diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma). |
| Stratum C (n=6-12) | EXPERIMENTAL | Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG. |
| Stratum D (n=6-12) | EXPERIMENTAL | Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation. |
| Stratum E (n=20) | EXPERIMENTAL | Patients with localized H3G34-mutant DHG |
| 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 |
| Ribociclib 400 mg | EXPERIMENTAL | Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) |
| Ribociclib 600 mg | ACTIVE_COMPARATOR | Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) |
| Ribociclib and letrozole | OTHER | Ribociclib 600mg oral daily for 3 weeks then 1 week off plus Letrozole 2.5 mg oral daily |
| single arm | EXPERIMENTAL | patients will receive anastrozole tablets (1 mg once daily) or letrozole tablets (2.5 mg once daily) + ribociclib tablets (600 mg day 1 to 21 in a 28 day cycle). Courses repeat every 28 days in the absence of disease progression, unacceptable toxicity, physician's decision, patient's refusal/consent withdrawal, or lost to follow-up. A LHRH agonist (triptorelin 3,75 mg or leuprolide 3,75 mg or goserelin 3,6 mg, as injectable intramuscular (i.m.) or subcutaneous (s.c.) implant every 28 days) will be used in men. |
| Ribociclib | EXPERIMENTAL | Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm. Premenopausal experimental arm: Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Ribociclib. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and \< 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history. Postmenopausal experimental arm: Letrozole + Ribociclib. Pharmacokinetic (PK) Cohort: Open-label treatment with Ribociclib + Letrozole combination. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent. |
| Ribociclib Placebo | PLACEBO_COMPARATOR | Patients in premenopausal and postmenopausal cohorts were randomized in a 1:1 ratio to either the experimental arm or the control arm. Premenopausal control arm: Non-steroidal aromatase inhibitor (NSAI) + Goserelin + Placebo. For premenopausal patients only, the patient was an adult female who was ≥ 18 years old and \< 60 years old at the time of providing informed consent. The choice of non-steroidal aromatase inhibitor was based on the investigator's assessment of the patient's past medical history. Postmenopausal control arm: Letrozole + Placebo. For postmenopausal patients only, the patient was an adult female who was ≥ 18 years old at the time of providing informed consent. |
| Ribociclib + adjuvant endocrine therapy (ET) | EXPERIMENTAL | Patients in this arm took Ribociclib in combination with standard adjuvant endocrine therapy. ET was one of these 4: Letrozole, Anastrozole, Exemestane, Tamoxifen (Tamoxifen no longer permitted after protocol amendment 2) |
| Placebo + adjuvant endocrine therapy (ET) | PLACEBO_COMPARATOR | Patients in this arm took Placebo in combination with standard adjuvant endocrine therapy. ET was one of these 4: Letrozole, Anastrozole, Exemestane, Tamoxifen |
| LEE011 | EXPERIMENTAL | All patients in all combinations with LEE011 will be entered in one arm. |
| 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. |
| Placebo Arm | PLACEBO_COMPARATOR | 600 mg daily dosing days 1-21 of a 28 day cycle |
| Cohort A: Ribociclib + T-DM1 [3+3 Design] | EXPERIMENTAL | * Ribociclib will be given orally once day (day 5-18) at a pre-determine dose for two weeks of a 21 day cycle. During dose escalation, patients received doses of ribociclib of Period 1: 300 mg (n = 3), Period 2: 400 mg (n = 3), Period 3: 500 mg (n = 3), and Period 4: 600 mg (n = 3). Maximum dose-escalation of Ribociclib will be up to 600 mg. Dose-escalation will stop if DLT exceed limit. * T-DM1 will be given as IV infusions on Day 1 of a 3 week cycle at a pre-determined dose over pre-determined period of time. |
| Cohort B: Ribociclib + Trastuzumab [Phase 1b/2 Study] | EXPERIMENTAL | * Ribociclib will be given orally once day (400 mg per day on a continuous schedule) for a 21-day cycle of treatment. * Trastuzumab will be given as IV infusions over 6 mg/kg every 3 weeks. |
| Cohort C: Ribociclib + Trastuzumab + Fulvestrant [Phase 1b/2 Study] | EXPERIMENTAL | * Ribociclib will be given orally once a day continuously for a 28-day cycle of treatment (except at Dose Level -1, when Ribociclib is given Days 1-21 of a 28 day cycle). * Trastuzumab will be given as IV infusions over a pre-determined period of time and dose. Fulvestrant will be dosed approximately every 28 days as per standard of care. |
| 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 |
| Phase Ib (ribociclib, tucatinib, trastuzumab) | EXPERIMENTAL | Patients receive ribociclib PO QD on days 1-21, tucatinib PO BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. |
| Phase II, Arm C (ribociclib, tucatinib, trastuzumab) | EXPERIMENTAL | Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, and trastuzumab IV over 30-90 minutes every 7 days. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. |
| Phase II,Arm A(ribociclib,tucatinib, trastuzumab, fulvestrant) | EXPERIMENTAL | Patients receive ribociclib PO QD on days 1-21, tucatinib BID on days 1-28, trastuzumab IV over 30-90 minutes every 7 days and fulvestrant subcutaneously (SC) on days 1 and 15 of cycle 1 and day 1 of every subsequent cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. |
| Phase II,Arm B(docetaxel,carboplatin,trastuzumab,pertuzumab) | ACTIVE_COMPARATOR | Patients receive docetaxel IV over 1 hour on day 1, carboplatin IV on day 1, trastuzumab IV over 30-90 minutes on day 1, and pertuzumab IV over 1 hour on day 1. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. |
| Cohort 1: Dose Escalation Cohort | EXPERIMENTAL | Ribociclib and belinostat will be given at escalating doses and on multiple administration schedules throughout the dose escalation component of the study. The MTD identified in the dose escalation component will be used to define the dose and administration schedule used in the dose expansion. |
| Cohort 2: Dose expansion cohort | EXPERIMENTAL | Participant will be enrolled in dose expansion cohort at the identified Recommended Phase 2 Dose (RP2D). Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. However, dose expansion will only be open to the enrollment of patients diagnosed with triple-negative breast cancer |
| 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. |
| Phase I - Dose Level 1 | EXPERIMENTAL | Treatment cycles are 28 days long. LEE011 (taken orally) - 250mg Once daily on days 1-21 Everolimus (taken orally) - 2.5mg Once daily on days 1-28 |
| Phase I - Dose Level 2 | EXPERIMENTAL | Treatment cycles are 28 days long. LEE011 (taken orally) - 300mg Once daily on days 1-21 Everolimus (taken orally) - 2.5mg Once daily on days 1-28 |
| Phase I - Dose Level -1 | EXPERIMENTAL | Treatment cycles are 28 days long. LEE011 (taken orally) - 200mg Once daily on days 1-21 Everolimus (taken orally) - 2.5mg Once daily on days 1-28 |
| Phase I - Dose Level -2 | EXPERIMENTAL | Treatment cycles are 28 days long. LEE011 (taken orally) - 150mg Once daily on days 1-21 Everolimus (taken orally) - 2.5mg Once daily on days 1-28 |
| Phase II - Dose | EXPERIMENTAL | Treatment cycles are 28 days long. LEE011 (taken orally) - the recommended phase II dose Once daily on days 1-21 Everolimus (taken orally) - 2.5mg Once daily on days 1-28 |
| combination of ribociclib + capecitabine | EXPERIMENTAL | RIBOCICLIB from 200 to 600mg once daily + CAPECITABINE from 750 to 1000 mg/m² BID, cycles are defined in 21-day periods, 2 weeks on treatment, 1 week off treatment |
| Cohort A | EXPERIMENTAL | Ribociclib (250 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally for 28 days. If no DLTs occurred, progressed to Cohort B |
| Cohort B | EXPERIMENTAL | Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally |
| Cohort C | EXPERIMENTAL | Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally |
| Group 1 | EXPERIMENTAL | Ribociclib (300 mg daily), everolimus (2.5 mg daily) and exemestane (25 mg daily) taken orally |
| Group 2 | EXPERIMENTAL | Ribociclib (200 mg daily), everolimus (5 mg daily) and exemestane (25 mg daily) taken orally |
| Normal renal function | EXPERIMENTAL | Normal renal function; matched demography to renal impariment cohorts |
| Severe renal impairment | EXPERIMENTAL | Severe decrease in GFR (15-29 ml/min) |
| End Stage Renal Disease | EXPERIMENTAL | End stage renal disease not on dialysis; GFR \<15 ml/min |
| Mild renal impairment | EXPERIMENTAL | Mild decrease in GFR (60-89 ml/min) |
| Moderate renal impairment | EXPERIMENTAL | Moderate decrease in GFR (30-59 ml/min) |
| 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 |
| Normal Hepatic Function | EXPERIMENTAL | Normal hepatic function; matched demography to hepatic impairment cohorts |
| Mild Hepatic Impairment | EXPERIMENTAL | Child-Pugh Classification A (score 5-6) |
| Moderate Hepatic Impairment | EXPERIMENTAL | Child-Pugh Classification B (score 7-9) |
| Severe Hepatic Impairment | EXPERIMENTAL | Child-Pugh Classification C (score 10-15) |
| LEE011 +Letrozole | EXPERIMENTAL | LEE011 - 3 weeks on 1 week off Letrozole 2.5mg - Once daily |
| LEE011 + Tamoxifen | EXPERIMENTAL | LEE011 - 3 weeks on 1 week off Tamoxifen 20mg - Once daily |
| LEE011 + Fulvestrant | EXPERIMENTAL | LEE011 - 3 weeks on 1 week off Fulvestrant 500 mg - Dosed every 28 days (Day 1 for each cycle) with 1 additional dose on Day 15 of Cycle 1 |
| LEE011 + buparlisib + letrozole | EXPERIMENTAL | open label, dose escalation evaluating max tolerated dose of the triple combination |
| LEE011 + BKM120 + fulvestrant | EXPERIMENTAL | LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BKM120 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. |
| LEE011 + BYL719 + fulvestrant | EXPERIMENTAL | LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating) BYL719 - daily (dose escalating) fulvestrant - i.m. - 500 mg given on day 1 and day 15 of Cycle 1, then on Day 1 of each subsequent cycle. |
| LEE011 + letrozole Arm 1 | EXPERIMENTAL | LEE011 - 28 day cycles (21 days followed by a 7 day break - dose escalating), letrozole - 2.5 mg/day |
| BYL719 + letrozole Arm 2 | EXPERIMENTAL | BYL719 - daily (dose escalating) letrozole - 2.5 mg/day |
| LEE011 + BYL719 + letrozole Arm 3 | EXPERIMENTAL | LEE011 - 28 day cycles (21 days followed by a 7 day break -dose escalating), BYL719 - daily (dose escalating), letrozole 2.5 mg/day |
| LEE011+ BYL719+letrozole Arm 4 | EXPERIMENTAL | LEE011-daily (dose escalating), BYL719 -daily (dose escalating), letrozole 2.5 mg/day |
| L-R-E arm | EXPERIMENTAL | Participants who took ribociclib (LEE011), everolimus (RAD001) and exemestane triple combination |
| L-E arm | EXPERIMENTAL | Participants who ribociclib (LEE011) and exemestane double combination |
| 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 and aromatase inhibitor or fulvestrant | COMBINATION_PRODUCT | Combination of ribociclib and aromatase inhibitor or fulvestrant |
| Capecitabine + bevacizumab OR Paclitaxel +/- bevacizumab | COMBINATION_PRODUCT | Capecitabine with bevacizumab OR Paclitaxel with or without bevacizumab |
| Ribociclib + Letrozole OR Fulvestrant | DRUG | Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks |
| Palbociclib + Letrozole OR Fulvestrant | DRUG | Endocrine Therapy will be selected by the investigator. For premenopausal women and men: LHRH agonist once every 4 weeks |
| Paclitaxel +/- Tislelizumab | DRUG | Patients in this arm could receive as the first line of therapy |
| 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) |
| LEE-011 | DRUG | 600 mg capsule (3x 200 mg capsules) |
| Everolimus | DRUG | Everolimus PO qd on days 1-28 |
| Temozolomide (TMZ) | DRUG | Temozolomide PO qd on days 1-5 for the first 13 cycles |
| 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. |
| Aromatase Inhibitors, non steroideal | DRUG | letrozole 2.5 mg/day orally or anastrozole 1 mg/day orally |
| LHRH agonist | DRUG | Triptorelin 3,75 mg or Leuprolide 3,75 mg or goserelin 3,6 mg, as injectable. |
| Ribociclib Placebo | DRUG | Film-coated tablets for oral use (200 mg x 3) from days 1 to 21 of each 28 day cycle. |
| NSAI: Letrozole or Anastrazole | DRUG | Letrozole: Tablets for oral use, 2.5mg daily (all days of every cycle without interruption). Anastrazole: Tablets for oral use, 1mg daily (all days of every cycle without interruption) For Premenopausal cohort, it is the investigators choice for NSAI based on patients past history. For postmenopausal and PK cohorts, all patients will be on Letrozole. |
| Adjuvant endocrine therapy | DRUG | Letrozole 2.5 mg by mouth daily, or anastrozole 1 mg by mouth daily, exemestane 25 mg by mouth daily, tamoxifen 20 mg by mouth daily, for a total duration of at least 60 months. In premenopausal women, a GnRH agonist administered every 28 days. |
| LEE011 | DRUG | Single agent LEE011 or in combination with other treatments |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Pharmacological Study | OTHER | Correlative studies |
| LEE011 Placebo | DRUG | - |
| T-DM1 | DRUG | - |
| Trastuzumab | DRUG | - |
| Docetaxel-PNP | DRUG | Given IV |
| Prednisone | DRUG | Given Orally |
| Filgrastim | DRUG | Given IV |
| Carboplatin | DRUG | Given IV |
| Docetaxel | DRUG | Given IV |
| Pertuzumab | BIOLOGICAL | Given IV |
| Quality-of-Life Assessment | OTHER | Ancillary Studies |
| Tucatinib | DRUG | Given PO |
| Belinostat | DRUG | Belinostat Dose Level 0 (starting dose) 600mg/m2 daily for 5 days Dose Level 1A 600mg/m2 daily for 5 days Dose Level 1B 1000mg/m2 daily for 5 days Dose Level 2 1000mg/m2 daily for 5 days \*Administration on 5 consecutive days is preferred. Administration within 7 days allowed as needed to accommodate holidays and infusion schedules. |
| Dexamethasone | DRUG | Corticosteroids are commonly used to treat ALL. |
| Bicalutamide | DRUG | 150mg PO |
| Combination of ribociclib + capecitabine | DRUG | RIBOCICLIB from 200 to 600mg once daily + CAPECITABINE from 750 to 1000 mg/m² BID, cycles are defined in 21-day periods, 2 weeks on treatment, 1 week off treatment |
| Ceritinib | DRUG | ALK inhibitor |
| Buparlisib | DRUG | daily |
| BYL719 | DRUG | BYL719: supplied as tablets of dosage strength of 10 mg, 50 mg or 200 mg. Tablets will be differentiated through different sizes and/or colors. |
| BKM120 | DRUG | BKM120: supplied as 10 mg or 50 mg capsules. The capsules will be differentiated through different sizes. |
| ribociclib (LEE011) | DRUG | LEE011 is taken orally once per day for 21 days of each 28 day cycle. LEE011 comes in 50 mg and 200 mg capsules. |
| Everolimus (RAD001) | DRUG | Everolimus is taken orally once per day. Everolimus comes in 1 mg, 2.5 mg, 5mg, and 7.5 mg tablets |
Inclusion Criteria: * Age ≥ 18 years. * Any menopausal status. If pre-/perimenopausal, agreement to receive LHRH agonist (goserelin or leuprorelin) / ovarian ablation in case of randomization to arm A * Locally confirmed diagnosis of metastatic adenocarcinoma of the breast without prior systemic an...
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Ribociclib is a small-molecule oncology drug developed by Novartis AG. It is being studied in breast cancer, including early, advanced, and metastatic disease, as well as in acute lymphoblastic leukemia, advanced solid tumors, and advanced digestive system neuroendocrine neoplasms. It is also known as LEE011 or LEE-011.
Ribociclib targets CDK4 and CDK6, two cyclin-dependent kinases, and acts as an inhibitor of these enzymes. By inhibiting CDK4 and CDK6, ribociclib is designed to interfere with cell-cycle progression in cancer cells. It is a small molecule given in combination regimens such as ribociclib plus letrozole or fulvestrant.
Ribociclib is developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor behind the clinical trial program for ribociclib across breast cancer and other oncology indications.
Ribociclib is an investigational drug still in clinical development. Its trial program spans Phase 1 through Phase 3 studies, including a Phase 3b study in early breast cancer and Phase 1 and Phase 2 studies in other settings. It is not described here as approved.
Ribociclib trials include NCT05827081, a recruiting Phase 3b study in early breast cancer with 1,444 planned participants, and NCT05467891, a recruiting Phase 2 study in locoregional recurrent hormone receptor positive HER2 negative breast cancer. Other studies include NCT05843253 in high-grade glioma and NCT05319873 in HER2 positive breast cancer.
Yes, LEE011 and LEE-011 are alternative names for ribociclib. The drug is also referred to in combination regimens such as ribociclib plus letrozole, ribociclib plus fulvestrant, and ribociclib plus capecitabine, which describe study arms rather than separate products.