Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as [^14C]-LY2835219, Abemaciclib, Abemaciclib Capsules (Reference Formulation), Abemaciclib Tablet (Test Formulation)
LY2835219 · 53 trials · 121 indications
The rPFS time is measured from the date of randomization to the earliest date of investigator determined radiographic disease progression (by objective radiographic disease assessment per response evaluation criteria in solid tumors (RECIST) version 1.1 for soft tissue AND/OR radionuclide bone scan using prostate cancer working group 3 -PCWG3 criteria for bone) or death from any cause, whichever occurs first.
PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
superiority in invasive disease-free survival (iDFS) of abemaciclib + endocrine therapy vs. standard-of-care endocrine therapy in patients with HR+/HER2- high risk breast cancer.
IDFS, as defined by the STEEP System, was measured from the date of randomization to the date of first occurrence of one of the following events: ipsilateral invasive breast tumor recurrence, regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, second primary non-breast invasive cancer, death attributable to any cause.
Progression-free survival time was measured from randomization until the date of objective progression as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1), or death from any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. Patients who have neither progressed nor died were censored at the day of their last radiographic tumor assessment, if available, or date of randomization if no post-baseline radiographic assessment is available.
PFS defined as the time from the first day of therapy to the first evidence of disease progression as defined by RECIST v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date.
OS defined as from randomization date to the date of death due to any cause. For each participant who is not known to have died as of the data-inclusion cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.
Complete response (CR) or partial response (PR), during the first 12 weeks of treatment as per blinded independent central review, using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
A threshold of the posterior probability rate of 75% will be utilized for declaring feasibility to support the analysis of the primary objective in this pilot.
Progression-free survival at 24 months (PFS24) will be analyzed using Kaplan-Meier methods.
Event free survival as determined by blinded independent review committee.
PFS is defined as the time from the date the participant was registered to the date of documented progressive disease (PD) by RECIST version 1.1 or death (regardless of cause) in the absence of progression, regardless of whether the participant withdraws from study drug or receives another anti-cancer therapy prior to progression. Participants alive without disease progression are censored at date of last disease evaluation. A participant who dies without progression, and the death is \>12 weeks after the last evaluable tumor assessment, is censored for PFS at the date of last disease evaluation. A participant who has no baseline or no post treatment tumor assessment is censored at 0 days for PFS, unless she dies \< 12 weeks from randomization, in which case the PFS event date is the death date. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum, taking as reference the smallest sum on study with at least 5 mm absolute increase.
Disease control rate at week 16 in all patients (cohorts A, B, C and D combined) treated at the selected dose level. DCR is defined as the proportion of patients that present with stable disease, partial response or complete response per RECIST 1.1 at 16 weeks after treatment initiation.
RECIST is a standard system to measure how cancer responds to different treatments, including chemotherapy, immunotherapy, and radiation therapy.
Ki-67 will be evaluated by ImmunoHistoChemistry (IHC) following consensus recommendations using imaging analysis methods.
RCB will be determined using data from each participating institution pathology department, and will be reviewed by the study team pathologist.
The composite endpoint is the number and proportion of participants with abemaciclib discontinuation for any reason and/or abemaciclib dose reductions and/or the inability of study participants to reach the target dose of abemaciclib (full dose 150 mg BID) at 3 months (12 weeks).
PFS was defined as the time from randomization until the first occurrence of documented disease progression per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria, or death from any cause in absence of progressive disease, whichever came first. Progressive disease (PD) was defined as at least 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 millimeter (mm), or unequivocal progression of non-target lesions, or 1 or more new lesions. An event was considered when tumor progression or death occurred, with event date being the earliest date of PD or death. Participants known to be alive and without tumor progression were censored at date of their last adequate tumor assessment per RECIST v1.1 criteria, or date of randomization (whichever was later). Results were obtained using Bayesian analysis and are reported as posterior mean along with its 80% credible interval.
PFS was defined as the time from randomization until the first occurrence of documented disease progression per RECIST v1.1 criteria, or death from any cause in absence of progressive disease, whichever came first. PD was defined as at least 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. An event was considered when tumor progression or death occurred, with the event date being the earliest date of PD or death. Participants known to be alive and without tumor progression were censored at the date of their last adequate tumor assessment per RECIST v1.1 criteria, or date of randomization (whichever was later). Results were obtained using frequentist analysis.
The percentage of participants alive and progression-free at 6 months, as assessed by RECIST 1.1 and PCWG3.
The percentage of evaluable patients who had radiographic response (complete response or partial response) by RECIST 1.1 criteria OR 50% decline in PSA from pretreatment baseline per PCWG3 criteria.
DLT was assessed by Bayesian Continuous Toxicity Monitoring in Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized) and CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized) arms.
ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) in soft tissue per response evaluation criteria in solid tumors (RECIST) version 1.1 and do not have concurrent bone progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), as assessed by the investigator. ORR = (participants with confirmed CR and no bone progression) + (participants with confirmed PR and no bone progression) x 100 / all treated participants.
Rate of Progression Free Survival at 6 months on the combination.
To evaluate the efficacy in terms of the probability of surviving progression free for at least 6 months (PFS at 6 mo)
Evaluation of the number of patients with a RCB 0-I index as a measure of efficacy. RCB is a continuous variable derived from the primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. It is estimated from routine pathological sections of the primary breast tumor site and the regional lymph nodes after the completion of Neoadjuvant therapy. The pathological variables include bidimensional diameters of the primary tumor bed, the proportion of primary tumor area containing invasive carcinoma, the number of positive lymph nodes, and the diameter of the largest nodal metastasis
Therapy success rate defined as: PERCIST 15%-assessed Metabolic Response at early FDG-PET/CT (D12-D16)
Therapy success rate defined as: RECISTv1.1-assessed Disease Control (DC) after 2 treatment cycles (CR or PR or SD)
Percentage of participants with severe diarrhea (≥ grade 3) during the first 3 cycles. Events were as assessed by the investigator and graded according to Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 was defined as an increase of ≥7 stools per day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living (ADL).
Percentage of participants with prolonged grade 2 diarrhea during first 3 cycles. Events were as assessed by the investigator and graded according to Common Terminology Criteria for Adverse Events (CTCAE). Prolonged Grade 2 diarrhea was any event lasting more than 7 days. Grade 2 was defined as Increase of 4-6 stools per day over baseline; moderate increase in ostomy output compared to baseline.
Percentage of participants with dose reductions due to diarrhea during first 3 cycles.
Percentage of participants with dose interruptions due to diarrhea during first 3 cycles.
Percentage of participants who discontinue treatment due to diarrhea
Percentage of participants who utilized anti diarrheals at least once during the first 3 cycles.
The rPFS time is measured from the date of randomization to the earliest date of investigator determined radiographic disease progression (by objective radiographic disease assessment per response evaluation criteria in solid tumors (RECIST) version 1.1 for soft tissue AND/OR radionuclide bone scan using prostate cancer working group 3 -PCWG3 criteria for bone) or death from any cause, whichever occurs first.
proportion of patients who are alive and progression-free at 4 months on both arms.
Intratumoral abemaciclib concentration defined as the mean tumor-to-plasma ratio in contrast enhancing tissue. Patients were treated with abemaciclib prior to surgery. Tissue and plasma for analysis of this endpoint were obtained at the time of surgery.
The primary endpoint for the nonsurgical cohort was six-month progression free survival (PFS6). Progression is defined by Response Assessment in Neuro-Oncology criteria for high-grade glioma (RANO-HGG) as \> 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over best response or baseline if no decrease) on stable or increasing doses of corticosteroids AND/OR one or more of the following: significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids steroids compared to baseline scan or best response following initiation of therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, infection, seizures, post-operative changes, or other treatment effects); any new lesion; clear clinical deterioration not attributable to other causes apart from the tumor; or failure to return for evaluation due to death or deteriorating condition.
Disease control rate (DCR) is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
PFS was defined as the time from the date of randomization until first observation of objective progressive disease as defined by RECIST v1.1 or death from any cause, whichever comes first. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a patient does not have a complete baseline disease assessment, then the PFS time will be censored at the randomization date, regardless of whether or not objectively determined disease progression or death has been observed for the patient; otherwise, if a patient is not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time will be censored at the last complete objective progression-free disease assessment date.
Tumor tissue collected through a core biopsy at baseline and at the end of cycle 1 was used to determine Ki67 expression. Ki67 expression is defined as the percent of cells staining positive by validated central assay.
OIRR is the percentage of participants with a (CR) or (PR) based on the Response Assessment in Neuro-Oncology Brain Metastasis (RANO-BM) response criteria. CR is measurable target lesions, the disappearance of all central nervous system (CNS) target lesions for at least 4 weeks; no new lesions; no corticosteroids; stable or improved clinically. PR is at least a 30% decrease in the sum longest duration (LD) of CNS target lesions, taking as reference the baseline sum LD for at least 4 weeks; no new lesions; stable to decreased corticosteroid dose; stable or improved clinically. Nontarget lesions requires disappearance CNS non-target lesions and no new CNS lesions. Stable disease (SD) is less than (\<)30% decrease relative to baseline but \<20% increase in sum LD relative to nadir. Progressive disease (PD) is greater than or equal to (≥) 20% increase in sum LD relative to nadir and a relative increase of 20%, ≥1 lesion must increase by absolute value of ≥5 millimeter (mm).
ORR was the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions.
The DCR was estimated based on the Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al. 1999). DCR was assessed from date of first dose until disease progression or death or start of new anticancer therapy. CR is defined as the disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms based on CT scan or bone marrow biopsy; CRu = the CR criteria is met and a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the product diameter (SPD). PR is \>= 50% decrease in SPD of the six largest nodal masses/no new sites of disease. Progressive Disease (PD) is defined as an increase by 25% in longest diameter, new lesion or assessable disease progression. SD=small changes not meeting the above criteria; DCR and its exact 95% confidence interval (CI) was estimated for treated participants using the Clopper-Pearson method.
Dose-limiting toxicities will specifically be reported for the DLT evaluation period using the MTD-evaluable population.
Adverse events will be tabulated by the Medical Dictionary for Regulatory Activities (MedDRA version 21.1) preferred term and system organ class and a preferred term. The severity of the AEs will be assessed by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Descriptive statistics using the safety evaluable population will be used to report on all on-study AEs, grade 3-4 AEs, treatment-related AEs, grade 3-4 treatment-related AEs, serious adverse events (SAEs), treatment-related SAEs, and AEs leading to discontinuation per CTCAE v5.0. Grade 3-4 laboratory abnormalities will be summarized using worst grade NCI CTCAE v 5.0 criteria.
The Maximum Tolerated Dose (MTD) for the study drug combination is defined as the maximum dose combination at which \<33% of patients experience a Dose limiting toxicity (DLT) during Cycle 1 (the DLT-evaluation period). If a DLT is observed in 1 of 3 patients, then 3 additional patients will be enrolled at that same dose level. Dose escalation will continue to a dose of abemaciclib 200mg bid, which is the maximal dose levels. If DLTs are seen in 0-1 of 6 patients at dose level +1 (darolutamide 600mg bid and abemaciclib 200mg bid), then this will be the RP2D; otherwise the maximally tolerated dose (MTD) will be the RP2D.
Dose Limiting Toxicity (DLT) for Phase 1 is defined as an adverse event that is related to Darolutamide and Abemaciclib with an attribution of possible, probable or definite and occurs during and/or begins during the first 28 days of the study treatment, using NCI CTCAE criteria version 5.0.
RP2D will be determined after an Maximum Tolerated Dose (MTD) is identified or the maximum planned dose is achieved. Recommended Phase 2 Dose (RP2D) is defined as no more than 0-1 patients with dose limiting toxicity out of 6 at maximal dose level. Otherwise, the maximally tolerated dose will be used.
Pathologic response is defined as achieving either a complete response (pCR) or minimal residual disease (MRD, defined as ≤5mm residual tumor) at Radical Prostatectomy (RP) in both arms
If two or more patients in a cohort experience a dose-limiting toxicity (DLT), then the maximum tolerated dose (MTD)has been exceeded. The previous dose level will be considered the MTD and the recommended phase 2 dose. Per Investigator discretion, the recommended phase 2 dose/schedule of abemaciclib followed by 177Lu-PSMA-617 may be established in the absence of reaching MTD, based on the cumulative safety data of the treatment regimen.
Any non-hematologic, treatment-related adverse event (TRAE) Grade 3+, except of Grade 3 nausea,vomiting,diarrhea,constipation,fever,fatigue,skin rash,alopecia or non-clinically significant laboratory that resolves to Grade \<3 within 72 hours;Grade 4 thrombocytopenia lasting \>7 days;Grade 3+ thrombocytopenia with bleeding/requirement for platelet transfusion;Grade 4 neutropenia lasting \>7 days; Grade 3+ neutropenic fever;Grade 4+ anemia;TRAE requiring treatment discontinuation/delay of \>42 days;Failure to receive at least 66% of abemaciclib doses due to toxicity;Death not clearly due to underlying disease/extraneous causes;Hy's law;Grade 3+ nausea/vomiting/diarrhea \>72 hours;Grade 3+ fatigue \>7 days;Grade 3+ electrolyte abnormality \>72 hours, unless patient has clinical symptoms;All AEs of specified grades should count as DLTs except those that are clearly due to progression/extraneous causes.
The uptake in the three lesions with the highest SUVmax on the initial scan will be compared to SUVmax measurements in the same lesions on the PSMA PET scan following 14 days of priming treatment with abemaciclib
The RP2D of abemaciclib was determined based on the totality of safety, tolerability, and pharmacokinetic results. RP2D of abemaciclib in combination with 50 mg/m²/day irinotecan and 100 mg/m²/day temozolomide on days 1-5 of 21-day cycles was reported.
DLT was 1 of the following adverse events likely related to abemaciclib/combination and fulfils any 1 of the following criteria graded per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0: * Any non-hematologic Grade (G) ≥3 toxicity, except: * G3 diarrhea lasting \<72 hour (h) * Acute irinotecan-associated diarrhea lasting \<7 days * G≥3 nausea, vomiting, constipation that lasts \<72 h * G3 mucositis/stomatitis lasting \<72 h * G3 fever/infection * G≥3 electrolyte abnormality that lasts \<72 h, is not complicated, and resolves spontaneously or responds to conventional medication; * G≥3 amylase/lipase that is not associated with symptoms/clinical manifestations of pancreatitis; or * AST/ALT elevation resolving to eligibility criteria within 7 days; * Hematologic toxicities considered a DLT: * A \>14-day Cycle 2 delay due to neutropenia/thrombocytopenia * G≥3 thrombocytopenia with significant bleeding; or * G≥ 4 neutropenic fever
The MTD was defined as the highest dose level at which less than 33% of participants experienced a DLT.
PK: (AUC0-tlast) was reported.
PK: AUC0-tlast) was reported.
PK: AUC0-tlast was reported.
The RP2D of abemaciclib was determined based on the totality of safety, tolerability, and pharmacokinetic results. RP2D of abemaciclib in combination with 150 mg/m²/day temozolomide on days 1-5 of 21-day cycles was reported.
A DLT was 1 of the following adverse events likely related to abemaciclib/combination and fulfils any 1 of the following criteria graded as per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0: * Any non-hematologic Grade (G) ≥3 toxicity, except: * G3 diarrhea lasting \<72 hr * Acute irinotecan-associated diarrhea lasting \<7 days * G≥3 nausea, vomiting, constipation that lasts \<72 hr * G3 mucositis/stomatitis lasting \<72 hr * G3 fever/infection * G≥3 electrolyte abnormality that lasts \<72 hr, is not complicated, and resolves spontaneously or responds to conventional medication; * G≥3 amylase/lipase that is not associated with symptoms/clinical manifestations of pancreatitis; or * AST/ALT elevation resolving to eligibility criteria within 7 days; * Hematologic toxicities considered a DLT: * A \>14-day Cycle 2 delay due to neutropenia/thrombocytopenia * G≥3 thrombocytopenia with significant bleeding; or * G≥ 4 neutropenic fever
The MTD was defined as the highest dose level at which less than 33% of participants experienced a DLT.
PK: AUC0-tlast was reported.
PK: AUC0-tlast was reported.
ORR: Number of participants with best response of Complete Response (CR), Partial Response (PR), or Minor Response (MR) per International Neuroblastoma Response Criteria (INRC). * CR is defined as complete response in all response components: * Primary Tumor: \<10 mm residual soft tissue primary site and complete resolution of MIBG-avid tumors * Soft tissue and bone metastatic response: nonprimary target and nontarget lesions \<10 mm and nodes identified as targets decreased to short axis \<10mm and MIBG-avid update of nonprimary lesions completely resolved * Bone marrow response: no tumor infiltration on reassessment; disappearance of all target lesions; * PR is defined as PR in \>1component and all other components are either CR, minimal disease (MD) (bone marrow only), PR (soft tissue or bone), or not involved (NI) and no components with progressive disease (PD). * MR is defined PR or CR in \>1 component and SD in \>1 component and no component with PD
Number of Participants with DLTs
Number of participants with one or more drug related adverse events. Clinically significant events were defined as serious adverse events, regardless of causality. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Event module.
A DLT defined as adverse event(AE) occurring between Day 1 and Day 21 of Cycle 1 that was considered at least possibly related to either abemaciclib or the combination therapy and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 \[NCI-CTCAE v 4.0\] \[NCI 2009\]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr) and for Part D participants (pts): Gr3 hyperglycemia (fasting) of \<5 days, Gr3 hypertriglyceridemia or hyperlipidemia without optimal treatment.A DLT-equivalent defined as AE that would have met the criteria for DLT if it had occurred during Cycle 1 for pts enrolled in dose-escalation phase,but that occurs between 1)Day 1 and Day 21 of Cycle 2 and beyond for a participant enrolled in dose-escalation phase 2) at any time for a participant in dose-expansion phase.
Number of participants with one or more drug-related adverse events
DLT is defined as an adverse event between Day -3 and Day 29 of Cycle 1 that is possibly related to the study drug and fulfills any one of the following criteria using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
The number of participants with clinically significant findings in the study were reported in this outcome measure.
Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in enhancing and non-enhancing tumor tissue
Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in CSF
Total and Unbound LY3214996 and Abemaciclib (and related M2 and M20 metabolites) concentration in plasma
Phase 2: 6-month progression-free survival (PFS6) rate measured from time of surgery to date of recurrence
| Arm | Type | Description |
|---|---|---|
| Abemaciclib | EXPERIMENTAL | Participants received 200 milligram (mg) abemaciclib twice daily (BID) in combination with standard doses of 1000 mg abiraterone acetate once daily and 5mg prednisone BID administered orally on a continuous dosing schedule on days 1 through 28 of a 28-day cycle until radiographic and/or symptomatic progression or until another discontinuation criterion is met. |
| Placebo | ACTIVE_COMPARATOR | Participants received placebo BID in combination with standard doses of 1000 mg abiraterone acetate once daily and 5mg prednisone BID administered orally on a continuous dosing schedule on days 1 through 28 of a 28-day cycle until radiographic and/or symptomatic progression or until another discontinuation criterion is met. |
| Arm A: Abemaciclib plus Fulvestrant | EXPERIMENTAL | Abemaciclib 150 milligram (mg) administered orally twice daily (BID) on Days 1 to 28 of a 28-day cycle in combination with fulvestrant 500 mg administered intramuscularly (IM) on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond. Participants received treatment until discontinuation criteria were met. |
| Arm B: Placebo plus Fulvestrant | ACTIVE_COMPARATOR | Placebo administered orally BID on Days 1 to 28 of a 28-day cycle in combination with fulvestrant 500 mg administered IM on Days 1 and 15 of Cycle 1, then on Day 1 of Cycle 2 and beyond. Participants received treatment until discontinuation criteria were met. |
| Placebo Arm | PLACEBO_COMPARATOR | Patients will be randomized 1:1 and will receive placebo if they are randomized to the placebo arm of the study. Each cycle is 28 days. |
| Abemaciclib plus ET | EXPERIMENTAL | Abemaciclib 150 mg, 2 x daily, resulting in 300 mg/day, oral, 24 months plus endocrine treatment of physician´s choice |
| Standard-of-care ET | NO_INTERVENTION | Standard-of-care ET according to clinical guidelines. Pre-/perimenopausal patients: * Either aromatase inhibitor + GnRH agonist * or Tamoxifen +/- GnRH-agonist (as per investigator´s decision) or Postmenopausal patients: * Either Aromatase inhibitor * or Tamoxifen OR |
| 150 mg Abemaciclib + Endocrine Therapy | EXPERIMENTAL | Participants received Abemaciclib orally at 150 milligrams (mg) twice daily with at least 6 hours between doses for up to 2 years or until evidence of disease recurrence or other discontinuation criteria were met, whichever occurs first. Endocrine therapy (physicians' choice) standard-of-care was administered according to package label until discontinuation criteria were met. |
| Endocrine Therapy | OTHER | Endocrine therapy (physicians' choice) standard-of-care was administered according to package label until discontinuation criteria were met. |
| Abemaciclib + Nonsteroidal Aromatase Inhibitor (NSAI) | EXPERIMENTAL | Abemaciclib given orally every 12 hours (Q12H) plus anastrozole or letrozole given orally every 24 hours (Q24H) on days 1 to 28 of a 28 day cycle. Participants receiving benefit may continue until disease progression. |
| Placebo + NSAI | EXPERIMENTAL | Placebo given orally Q12H plus anastrozole or letrozole given orally Q24H on days 1 to 28 of a 28 day cycle. Participants receiving benefit may continue until disease progression. |
| Abemaciclib + Fulvestrant | EXPERIMENTAL | Abemaciclib given orally Q12H on days 1 to 28 of a 28 day cycle plus fulvestrant intramuscularly (IM) on days 1 and 15 of cycle 1, then on day 1 of cycle 2 and beyond. Participants receiving benefit may continue until disease progression. |
| Placebo + Fulvestrant | EXPERIMENTAL | Placebo given orally Q12H on days 1 to 28 of a 28 day cycle plus fulvestrant IM on days 1 and 15 of cycle 1, then on day 1 of cycle 2 and beyond. Participants receiving benefit may continue until disease progression. |
| Abemaciclib + NSAI | EXPERIMENTAL | 150 milligrams (mg) Abemaciclib orally every 12 hours plus either 1 mg anastrozole or 2.5 mg letrozole orally once daily for 28 days (28 day cycles). |
| Erlotinib | ACTIVE_COMPARATOR | 150 mg erlotinib administered, orally, every 24 hours plus BSC on Days 1 to 28 (28 day cycles). |
| Interventional Arm (Arm A) | EXPERIMENTAL | Abemaciclib 150 mg orally twice daily (BID) during each 28 day cycle combined with ET (2.5 mg letrozole, orally administered and taken daily during each 28-day cycle, or 500 mg fulvestrant, by intramuscular \[IM\] administration on Days 1 and 15 (±3 days) of the first treatment cycle and Day 1 of each cycle thereafter. |
| Control Arm (Arm B) | ACTIVE_COMPARATOR | Paclitaxel 90 mg/m² infused over 1 hour on Days 1, 8, and 15 of the 28 day cycle, with at least a 6-day time span between separated doses. |
| Arm I (abemaciclib, gemcitabine) | EXPERIMENTAL | Patients receive abemaciclib PO BID on days 1-21 and gemcitabine IV over 30 minutes on days 1 and 8 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm II (abemaciclib, pemetrexed) | EXPERIMENTAL | Patients receive abemaciclib PO BID on days 1-21 and pemetrexed IV over 10 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm III (abemaciclib) | EXPERIMENTAL | Patients receive abemaciclib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm IV (abemaciclib, exemestane) | EXPERIMENTAL | Patients receive abemaciclib PO BID and exemestane PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm V (abemaciclib, letrozole) | EXPERIMENTAL | Patients receive abemaciclib PO BID and letrozole PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm VI (abemaciclib, tamoxifen) | EXPERIMENTAL | Patients receive abemaciclib PO BID and tamoxifen PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm VII (gefitinib, pemetrexed, carboplatin) | EXPERIMENTAL | Patients receive gefitinib PO QD on days 1-21, pemetrexed IV on day 1 of each cycle and carboplatin IV on day 1 of cycles 1-6. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm VIII (olaparib, temozolomide) | EXPERIMENTAL | Patients receive olaparib PO BID and temozolomide PO QD on days 1-7 of each cycle. Cycles repeat every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm IX (fulvestrant) | EXPERIMENTAL | Patients receive fulvestrant IM on days 1, 15 and 29 of cycle 1 and day 1 of subsequent cycles. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm X (gefitinib) | EXPERIMENTAL | Patients receive gefitinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm XI (olaparib) | EXPERIMENTAL | Patients receive olaparib PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm XII (olaparib, carboplatin, paclitaxel) | EXPERIMENTAL | Patients receive olaparib PO BID on days 1-3, 8-10, 15-17, 21-23 and carboplatin IV and paclitaxel IV on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection throughout the study. Patients also undergo tumor biopsy on study, as clinically indicated, and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm XIII (olaparib, liposomal doxorubicin) | EXPERIMENTAL | Patients receive olaparib PO BID on days 1-28 and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan and blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Arm XIV (osimertinib) | EXPERIMENTAL | Patients receive osimertinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography or MUGA scan and blood sample collection throughout the study. Patients also undergo tumor biopsy on study and optionally at the end of treatment. Additionally, prostate cancer patients undergo bone scan on study. |
| Active Treatment (Abemaciclib) | EXPERIMENTAL | Administered twice daily on days 1-28 of each 28-day cycle. |
| Abemaciclib + Temozolomide - Arm A | EXPERIMENTAL | Participants will receive abemaciclib administered orally in addition to temozolomide administered orally or intravenously (IV). |
| Temozolomide - Arm B | ACTIVE_COMPARATOR | Participants will receive temozolomide administered orally or IV. |
| Arm 1: Abemaciclib + Letrozole | EXPERIMENTAL | Participants will be stratified by Primary Stage IVb (4b) vs. Primary Measurable Stage III (3)/IVa (4a) vs. Recurrent Endometrial Cancer and will complete study procedures as follows: * Baseline visit with X-ray, CT, MRI, or PET scan. * Cycles 1 through 3: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * Cycle 4 and every 2 cycles thereafter: --Days 1 through 21 of 21 day cycle: Predetermined dose of Abemaciclib 2x per day. Predetermined dose of Letrozole 1x per day. * X-ray, CT, MRI, or PET scan every 9 weeks for first 9 months, then every 12 months. * End of Treatment visit with assessments and X-ray, CT, MRI, or PET scan. * Follow up for up to 3 years. |
| Abemaciclib and bicalutamide | EXPERIMENTAL | Participants receive Abemaciclib 150 mg tablet orally twice daily and Bicalutamide 150 mg orally once daily until disease progression or unacceptable toxicity. |
| Abemaciclib and letrozole | EXPERIMENTAL | Participants received abemaciclib 150 mg tablet orally twice daily and letrozole tablet 2.5 mg orally once daily until disease progression, unacceptable adverse event(s) or death. |
| Window Phase Arm A: Tamoxifen | EXPERIMENTAL | Participants will be randomly assigned to receive Tamoxifen 1x daily for 3 weeks (21days). |
| Window Phase Arm B: Anastrozole | EXPERIMENTAL | Participants will be randomly assigned to receive Anastrozole 1x daily for 3 weeks (21days). |
| Window Phase Arm C: Anastrozole + Degarelix | EXPERIMENTAL | Participants will be randomly assigned to receive Anastrozole 1x daily for 3 weeks (21days) and Degarelix on day 1 only. |
| Neoadjuvant Phase Arm D: Tamoxifen | EXPERIMENTAL | Participants will be randomly assigned to receive Tamoxifen 1x daily for 4 cycles (4 months); each study cycle is 28 days. |
| Neoadjuvant Phase Arm E: Tamoxifen + Abemaciclib | EXPERIMENTAL | Participants will be randomly assigned to receive Tamoxifen 1x daily and Abemaciclib 2x daily for 4 cycles (4 months); each study cycle is 28 days. |
| Neoadjuvant Phase Arm F: Anastrozole and Degarelix | EXPERIMENTAL | Participants will be randomly assigned to receive Anastrozole 1x daily and Degarelix on day 1 of each cycle for 4 cycles (4 months); each study cycle is 28 days. |
| Neoadjuvant Phase Arm G: Anastrozole + Degarelix + Abemaciclib | EXPERIMENTAL | Participants will be randomly assigned to receive Anastrozole 1x daily, Degarelix on day 1 of each cycle and Abemaciclib 2x daily for 4 cycles (4 months); each study cycle is 28 days. |
| Abemaciclib + Irinotecan +Temozolomide | EXPERIMENTAL | Participants received the following treatments in a 21-day cycle, continuing until disease progression, unacceptable toxicity, or a criterion for discontinuation was met. * Abemaciclib: 55 mg/m² (milligrams per square meter), administered orally twice daily (BID) for less than (\<18) years or 100 mg administered orally BID for greater than or equal to (≥)18 years. * Irinotecan: 50 mg/m²/day, administered intravenously (IV) on Days 1-5 of each cycle. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. |
| Irinotecan +Temozolomide | EXPERIMENTAL | Participants received the following treatments in a 21-day cycle, continuing until disease progression, unacceptable toxicity, or a criterion for discontinuation was met. * Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. |
| Biomarker-Unselected Abemaciclib Monotherapy (Randomized) | EXPERIMENTAL | Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Monotherapy : Participants will receive Abemaciclib orally 2x daily |
| Biomarker-Unselected Abemaciclib + Atezolizumab (Randomized) | EXPERIMENTAL | Participants in the Biomarker-Unselected Cohort, defined as those whose tumors are not known to have mutations in the CDK12 gene will be randomized to either receive Abemaciclib as monotherapy or in combination with Atezolizumab * Combination Therapy: Participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle |
| CDK12 Mutation Atezolizumab Monotherapy (Non-Randomized) | EXPERIMENTAL | Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Atezolizumab monotherapy will be given to participants 1-5, these participants will receive Atezolizumab intravenously Day 1 of each 21-Day cycle |
| CDK12 Mutation Abemaciclib + Atezolizumab (Non-Randomized) | EXPERIMENTAL | Participants in the CDK12 Mutation Cohort defined as those whose tumors are known to have mutations in the CDK12 gene are not randomized but are assigned to receive either Atezolizumab monotherapy or in combination with Abemaciclib based on how many participants in this cohort previously received study treatment. Combination Therapy will be given to participants 6-21, these participants will receive Abemaciclib orally 2x daily and Atezolizumab intravenously Day 1 of each 21-Day cycle |
| 200 milligram (mg) Abemaciclib Twice Daily | EXPERIMENTAL | Participants received 200 mg abemaciclib administered orally twice daily on a continuous dosing schedule (28-day cycle) until symptomatic and/or radiographic progression, unacceptable toxicity, or until another discontinuation criterion is met. |
| Single Arm, POC | EXPERIMENTAL | Single arm, POC Safety and Efficacy Osimertinib 80 mg QD Abemaciclib 150mg BID |
| Arm A: Doxorubicin plus cyclophosphamide and taxane | ACTIVE_COMPARATOR | Doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 21 days for 4 cycles followed by weekly paclitaxel 80mg/m2 for 12 weeks or 3-weekly docetaxel 100mg/m2 for 4 cycles. Approximately duration of 24 weeks (6 months). |
| Arm B: Letrozole plus abemaciclib +/- LHRH | EXPERIMENTAL | Letrozole 2.5mg orally daily + abemaciclib 150mg orally every 12 hours on a continuous dosing schedule, +/- luteinizing hormone-releasing hormone (LHRH) analogs in premenopausal women, up to 12 months, in 28-day cycles. |
| Treatment (abemaciclib) | EXPERIMENTAL | Patients receive abemaciclib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. |
| 200 mg Abemaciclib With a Meal | EXPERIMENTAL | 200 mg abemaciclib given twice a day (BID) orally with a meal. |
| 200 mg Abemaciclib Without a Meal | EXPERIMENTAL | 200 mg abemaciclib given twice a day (BID) orally without a meal, taken in the modified fasted condition. |
| 200 mg Abemaciclib Without Regard to Food | EXPERIMENTAL | 200 mg abemaciclib given twice a day (BID) orally without regard for food. |
| Participants with CCND1, CCND2, or CCND3 | EXPERIMENTAL | * Abemaciclib will be administered orally on a daily basis * Dosage will be determine by the PI |
| Participants with CDK4 or CDK6 | EXPERIMENTAL | * Abemaciclib will be administered orally on a daily basis * Dosage will be determine by the PI |
| Abemaciclib with Surgery | EXPERIMENTAL | * Abemaciclib will be administered on a continuous twice daily dosing schedule * Patients who require re-operation will receive a short preoperative course of Abemaciclib * Tissue will be used to investigate the ability of Abemaciclib to pass through the blood brain barrier. * After recovery from surgery, participants will resume Abemaciclib. Each cycle lasts 28 days. * NOTE: enrollment to this arm is complete |
| Abemaciclib without Surgery | EXPERIMENTAL | * Abemaciclib will be administered on a continuous twice daily dosing schedule. Each Cycle last 28 days. * NOTE: enrollment to this arm is complete |
| Cohort 1 Surgery Arm | EXPERIMENTAL | Participants who require reoperation will be treated with abemaciclib for 10-14 days prior to surgery. Tissue will be used to further investigate the abilities of Abemaciclib. After surgery participants will come off study and pursue standard of care treatments at their treating physician's discretion. |
| Abemaciclib + LY3023414 | EXPERIMENTAL | Abemaciclib given orally and LY3023414 given orally. |
| Standard of Care (Gemcitabine or Capecitabine) | EXPERIMENTAL | Gemcitabine given intravenously (IV) OR capecitabine given orally. |
| Abemaciclib + Tamoxifen | EXPERIMENTAL | Abemaciclib given orally every 12 hours (Q12H) in combination with tamoxifen given orally every day. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib + Prophylactic Loperamide | EXPERIMENTAL | Abemaciclib given orally Q12H in combination with prophylactic loperamide given orally. Participants may continue to receive treatment until discontinuation criteria are met. |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab + 500 mg Fulvestrant | EXPERIMENTAL | 150 milligram (mg) abemaciclib given orally every 12 hours (Q12H) of a 21-day cycle; plus 8 milligram per kilogram (mg/kg) trastuzumab intravenous (IV) infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle; plus 500 mg fulvestrant intramuscularly (IM) on day 1, 15 and 29 and then once every 4 weeks thereafter. |
| 150 mg Abemaciclib + 8 mg/kg Trastuzumab | EXPERIMENTAL | 150 mg abemaciclib given orally Q12H of a 21-day cycle; plus 8 mg/kg trastuzumab IV infusion on Day 1 of the cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle. |
| 8 mg/kg Trastuzumab + Standard of Care Chemotherapy | ACTIVE_COMPARATOR | 8 mg/kg trastuzumab IV infusion on Day 1 of a 21-day cycle then a 6 mg/kg maintenance dose IV infusion on Day 1 of each subsequent cycle plus standard of care single agent chemotherapy of physician's choice administered according to product label |
| Docetaxel | ACTIVE_COMPARATOR | 75 milligram per meter squared (mg/m²) docetaxel given intravenously (IV) on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib + Anastrozole | EXPERIMENTAL | Abemaciclib (150 milligrams \[mg\]) was given orally every 12 hours (Q12H) plus anastrozole (1 mg) orally once daily (QD) for 2 weeks. Loperamide was given as a prophylaxis for 4 weeks and then at physician discretion. All participants received abemaciclib (150 mg) orally Q12H plus anastrozole (1 mg) QD for an additional 14 weeks. Total treatment duration was 16 weeks. |
| Anastrozole | ACTIVE_COMPARATOR | Anastrozole (1 mg) is given orally QD for 2 weeks. All participants received abemaciclib (150 mg) orally Q12H plus anastrozole (1 mg) QD for an additional 14 weeks. Loperamide was given as a prophylaxis for the first 2 weeks of the combination treatment and then at physician discretion. Total treatment duration was 16 weeks. |
| Part A Abemaciclib: HR+, HER2+ Breast Cancer | EXPERIMENTAL | Abemaciclib 200 milligram (mg) was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or in combination with endocrine therapy (ET). Participants with hormone receptor positive (HR+), HER2+ breast cancer receiving concurrent trastuzumab, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Part B Abemaciclib: HR+, HER2- Breast Cancer | EXPERIMENTAL | Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants in combination with endocrine therapy (ET). Participants may continue to receive treatment until discontinuation criteria are met. |
| Part C Abemaciclib: Surgical Resection | EXPERIMENTAL | Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+, HER2+ breast cancer, NSCLC, or melanoma with intracranial lesions for which surgical resection is clinically indicated receiving concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours for 5-14 days prior to surgical resection. Dosing may resume following wound healing on a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Part D Abemaciclib: Non-Small Cell Lung Cancer (NSCLC) | EXPERIMENTAL | Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants with NSCLC receiving concurrent gemcitabine or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Part E Abemaciclib: Melanoma | EXPERIMENTAL | Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Part F Abemaciclib: HR+ Breast Cancer, NSCLC, or Melanoma | EXPERIMENTAL | Abemaciclib 200 mg was administered orally once every 12 hours on days 1-21 of a 21-day cycle when administered as a single agent or for participants with breast cancer in combination with endocrine therapy (ET). Participants with HR+ (either HER2+ or HER2-) breast cancer, NSCLC, or melanoma and leptomeningeal metastases received concurrent trastuzumab, gemcitabine, or pemetrexed, 150 mg abemaciclib was given orally once every 12 hours on days 1-21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Treatment (abemaciclib, niraparib) | EXPERIMENTAL | Patients receive abemaciclib PO BID and niraparib PO QD. Treatment repeats every 28 days for up to 2-4 cycles in the absence of disease progression or unacceptable toxicity. Patients who complete 4 cycles undergo standard of care mastectomy or lumpectomy. Patients demonstrating progressive disease after only 2 cycles are switched to receive standard of care chemotherapy prior to undergoing mastectomy or lumpectomy. |
| Treatment (abemaciclib, radiation therapy, surgery) | EXPERIMENTAL | Prior to surgery, patients receive abemaciclib orally PO BID on days 1-28. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy over 28 fractions starting on cycle 1 day 15 in the absence of disease progression or unacceptable toxicity. After completion of radiation therapy, patients may undergo surgery. Patients also undergo CT or MRI during screening and on study. |
| Phase 1 Lead In in CRPC | EXPERIMENTAL | Standard 3+3 dose escalation scheme with 3 dose levels of abemaciclib and a constant dose of darolutamide, per protocol, for 6, 28-day cycles |
| Phase 2 - Neoadjuvant Darolutamide and ADT prior to Radical Prostatectomy | EXPERIMENTAL | per protocol, for 6, 28-day cycles |
| Phase 2 - Neoadjuvant Darolutamide, Ademaciclib, and ADT prior to Radical Prostatectomy | EXPERIMENTAL | per protocol, for 6, 28-day cycles |
| Part A: Abemaciclib, 177Lu-PSMA-617 | EXPERIMENTAL | Patients receive abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. |
| Part B: Recommended Phase 2 dose of Abemaciclib, 177Lu-PSMA-617 | EXPERIMENTAL | Patients receive the recommended phase 2 dose of abemaciclib lead-in on days 1-14 and lutetium Lu 177 vipivotide tetraxetan IV over 30 minutes on day 15. Treatment repeats every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. |
| Part A Cohort A1 | EXPERIMENTAL | Participants received: * Abemaciclib: 70 mg/m², administered orally twice daily (BID). * Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part A Cohort A-1 | EXPERIMENTAL | Participants received: * Abemaciclib: 55 mg/m², administered orally BID. * Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part B Cohort B1 | EXPERIMENTAL | Participants received: * Abemaciclib: 70 mg/m², administered orally BID. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part B Cohort B2 | EXPERIMENTAL | Participants received: * Abemaciclib: 90 mg/m², administered orally BID. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part B Cohort B3 | EXPERIMENTAL | Participants received: * Abemaciclib: 115 mg/m², administered orally BID. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part B Cohort B5 | EXPERIMENTAL | Participants received: * Abemaciclib: 115 mg/m², administered orally BID. * Temozolomide: 150 mg/m²/day, administered orally on Days 1-5 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Part C Cohort C1 | EXPERIMENTAL | Participants received: * Abemaciclib: 55 mg/m², administered orally BID. * Irinotecan: 50 mg/m²/day, administered IV on Days 1-5 of each cycle. * Temozolomide: 100 mg/m²/day, administered orally on Days 1-5 of each cycle. * Dinutuximab: 17.5mg/m²/day, administered IV on Days 2-5 of each cycle. * Granulocyte-macrophage colony-stimulating factor (GM-CSF): 250 μg/m²/day, administered subcutaneously (SC) on Days 6-12 of each cycle. Treatment continued until progressive disease, a discontinuation criterion, or unacceptable toxicity. Each cycle lasted 21 days. |
| Abemaciclib + Abiraterone Acetate + Prednisolone | EXPERIMENTAL | Abemaciclib, abiraterone acetate and prednisolone given orally. |
| Abemaciclib Dose Level 1 | EXPERIMENTAL | Abemaciclib 150 milligram (mg) administered every 12 hours, orally, cycle 1 and then in cycle 2. Participants may continue to receive treatment until discontinuation criteria are met. One cycle is defined as 28 days. (Cycle 1: 32 days), with modifications during Cycle 1 to enable pharmacokinetic (PK) sampling following a single dose and repeated doses. |
| Abemaciclib Dose Level 2 | EXPERIMENTAL | Abemaciclib 200 mg administered every 12 hours, orally, cycle 1 and then in cycle 2. Participants may continue to receive treatment until discontinuation criteria are met. One cycle is defined as 28 days. (Cycle 1: 32 days), with modifications during Cycle 1 to enable PK sampling following a single dose and repeated doses. |
| NSCLC KRAS mt, PD-L1+ | EXPERIMENTAL | Abemaciclib given orally every 12 hours (Q12H) on days 1 to 21 of each 21 day cycle in combination with pembrolizumab given intravenously (IV) on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| NSCLC Squamous | EXPERIMENTAL | Abemaciclib given orally Q12H on days 1 to 21 of each 21 day cycle in combination with pembrolizumab given IV on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| HR+, HER2- Metastatic Breast Cancer | EXPERIMENTAL | Abemaciclib given orally Q12H on days 1 to 21 of each 21 day cycle in combination with pembrolizumab given IV on day 1 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| HR+, HER2- Locally Advanced or Metastatic Breast Cancer | EXPERIMENTAL | Abemaciclib given orally Q12H on days 1 to 21 of each 21 day cycle in combination with pembrolizumab given IV on day 1 of each 21 day cycle and anastrozole given orally Q24H on days 1 to 21 of each 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib: Normal Hepatic Function | EXPERIMENTAL | Single dose of Abemaciclib administered orally on Day 1 to participants with normal hepatic function. |
| Abemaciclib: Mild Hepatic Impairment | EXPERIMENTAL | Single dose of Abemaciclib administered orally on Day 1 to participants with mild hepatic impairment. |
| Abemaciclib: Moderate Hepatic Impairment | EXPERIMENTAL | Single dose of Abemaciclib administered orally on Day 1 to participants with moderate hepatic impairment. |
| Abemaciclib: Severe Hepatic Impairment | EXPERIMENTAL | Single dose of Abemaciclib administered orally on Day 1 to participants with severe hepatic impairment. |
| Abemaciclib Alone Period 1 | EXPERIMENTAL | 50 mg single oral dose of Abemaciclib was administered in Period 1 Day 1. |
| Abemaciclib + Clarithromycin Period 2 | EXPERIMENTAL | Clarithromycin 500 milligram (mg) orally twice daily for 12 days. Single oral dose of Abemaciclib 50 mg on Period 2 Day 5. Clarithromycin dosing continued for 7 days following the single dose of Abemaciclib. |
| Abemaciclib Safety Extension | EXPERIMENTAL | After completing Period 2, eligible participants continued to receive 200 mg Abemaciclib every 12 hours (Q12H) on a 28-day cycle in a safety-extension phase until discontinuation criteria were met. |
| Abemaciclib + Pemetrexed | EXPERIMENTAL | 150 milligram (mg) or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m\^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib + Gemcitabine | EXPERIMENTAL | 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 milligram/square meter (mg/m\^2) gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib + Ramucirumab | EXPERIMENTAL | 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| Abemaciclib + Pembrolizumab | EXPERIMENTAL | 100 mg or 150 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met. |
| LY2835219 + Letrozole | EXPERIMENTAL | LY2835219 administered orally. Letrozole administered orally. This arm is closed to enrollment. |
| LY2835219 + Anastrozole | EXPERIMENTAL | LY2835219 administered orally. Anastrozole administered orally. This arm is closed to enrollment. |
| LY2835219 + Tamoxifen | EXPERIMENTAL | LY2835219 administered orally. Tamoxifen administered orally. This arm is closed to enrollment. |
| LY2835219 + Exemestane | EXPERIMENTAL | LY2835219 administered orally. Exemestane administered orally. This arm is closed to enrollment. |
| LY2835219 + Exemestane + Everolimus Dose Escalation | EXPERIMENTAL | LY2835219 administered orally. Exemestane administered orally. Everolimus administered orally. This arm is closed to enrollment. |
| LY2835219 + Exemestane + Everolimus Dose Expansion | EXPERIMENTAL | LY2835219 administered orally. Exemestane administered orally. Everolimus administered orally. This arm is closed to enrollment. |
| LY2835219+ Trastuzumab Dose Escalation | EXPERIMENTAL | LY2835219 administered orally. Trastuzumab administered intravenously (IV) infusion. This arm is closed to enrollment. |
| LY2835219+ Trastuzumab Dose Expansion | EXPERIMENTAL | LY2835219 administered orally. Trastuzumab administered IV infusion. This arm is closed to enrollment. |
| LY3023414 + LY2835219 + Fulvestrant Dose Escalation | EXPERIMENTAL | LY3023414 administered orally. LY2835219 administered orally. Fulvestrant administered intramuscularly (IM). |
| LY3023414 + LY2835219 + Fulvestrant Dose Expansion | EXPERIMENTAL | LY3023414 administered orally. LY2835219 administered orally. Fulvestrant administered IM. |
| LY2835219 +Trastuzumab +Pertuzumab +Loperamide Dose Escalation | EXPERIMENTAL | LY2835219 administered orally. Loperamide administered orally. Trastuzumab administered IV infusion. Pertuzumab administered IV infusion. |
| LY2835219 +Trastuzumab + Pertuzumab +Loperamide Dose Expansion | EXPERIMENTAL | Hormone Receptor Negative (HR-): LY2835219 administered orally. Loperamide administered orally. Trastuzumab administered IV infusion. Pertuzumab administered IV infusion. Hormone Receptor Positive (HR+): LY2835219 administered orally. Loperamide administered orally. Trastuzumab administered IV infusion. Pertuzumab administered IV infusion. Endocrine therapy administered orally. |
| LY2835219 + Endocrine Therapy | EXPERIMENTAL | LY2835219 administered orally. Ongoing endocrine therapy administered orally. |
| Cohort 1 - 100 mg Abemaciclib | EXPERIMENTAL | 100 milligram (mg) abemaciclib administered orally every 12 hours (Q12H) in 28 day cycles. (Cycle 1 = 32 days.) Participants remained on treatment until discontinuation criteria were met. |
| Cohort 2 - 150 mg Abemaciclib | EXPERIMENTAL | 150 mg abemaciclib administered orally Q12H in 28 day cycles. (Cycle 1 = 32 days.) Participants remained on treatment until discontinuation criteria were met. |
| Cohort 3 - 200 mg Abemaciclib | EXPERIMENTAL | 200 mg abemaciclib administered orally Q12H in 28 day cycles. (Cycle 1 = 32 days.) Participants remained on treatment until discontinuation criteria were met. |
| Arm 1 | EXPERIMENTAL | 400 mg of LY3214996 QD for 6 doses and 100 mg of Abemaciclib BID for 11 doses over 5.5 days prior to surgical resection. On Day 6, participants will receive Abemaciclib + LY3214996 dose 7 to 9 hours prior to craniotomy for tumor resection. |
| Name | Type | Description |
|---|---|---|
| Abemaciclib | DRUG | Administered orally. |
| Abiraterone | DRUG | Administered orally. |
| Prednisone or Prednisolone | DRUG | Administered orally. |
| Placebo for Abemaciclib | DRUG | Administered orally. |
| Fulvestrant | DRUG | Administered IM. |
| Placebo | DRUG | Administered orally. |
| Abemaciclib 50 MG; 150mg 1-0-1 per os | DRUG | Experimental: Abemaciclib plus ET Abemaciclib 150 mg, 2 x daily, resulting in 300 mg/day, oral, 24 months plus endocrine treatment of physician´s choice |
| Standard Adjuvant Endocrine Therapy | DRUG | Administered according to label instructions. |
| Anastrozole | DRUG | Administered orally |
| Letrozole | DRUG | Administered orally |
| Erlotinib | DRUG | Administered orally |
| Paclitaxel | DRUG | Paclitaxel 90 mg/m² infused over 1 hour on Days 1, 8, and 15 of the 28 day cycle, with at least a 6-day time span between separated doses. |
| Biopsy | PROCEDURE | Undergo tumor biopsy |
| Bone Scan | PROCEDURE | Undergo bone scan |
| Carboplatin | DRUG | Given IV |
| Echocardiography | PROCEDURE | Undergo echocardiography |
| Exemestane | DRUG | Given PO |
| Gefitinib | DRUG | Given PO |
| Gemcitabine | DRUG | Given IV |
| Multigated Acquisition Scan | PROCEDURE | Undergo MUGA |
| Olaparib | DRUG | Given PO |
| Osimertinib | DRUG | Given PO |
| Pegylated Liposomal Doxorubicin Hydrochloride | DRUG | Given IV |
| Pemetrexed | DRUG | Given IV |
| Survey Administration | OTHER | Ancillary studies |
| Tamoxifen | DRUG | Given PO |
| Temozolomide | DRUG | Given PO |
| Biospecimen Collection | PROCEDURE | Biological Sample Collection, Biological Sample Collection, Biospecimen Collected, Biospecimen Collection, Specimen Collection |
| Pembrolizumab | DRUG | Humanized immunoglobulin G4 monoclonal antibody, 4mL (milliliter) single-dose vial, via intravenous (into the vein) infusion per institutional standard of care. |
| Bicalutamide | DRUG | 150 mg tablet orally once daily |
| Degarelix | DRUG | Subcutaneous (under the skin) injection |
| LHRH Agonist | DRUG | Luteinizing hormone-releasing hormone agonist), taken orally per institutional standard of care |
| Irinotecan | DRUG | IV |
| Atezolizumab | DRUG | Intravenously Day 1 of 21 day cycle |
| Doxorubicin | DRUG | Doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 21 days for 4 cycles followed by weekly paclitaxel 80mg/m2 for 12 weeks or 3-weekly docetaxel 100mg/m2 for 4 cycles. |
| Cyclophosphamide | DRUG | Doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 21 days for 4 cycles followed by weekly paclitaxel 80mg/m2 for 12 weeks or 3-weekly docetaxel 100mg/m2 for 4 cycles. |
| Taxane | DRUG | Doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 (AC) every 21 days for 4 cycles followed by weekly paclitaxel 80mg/m2 for 12 weeks or 3-weekly docetaxel 100mg/m2 for 4 cycles. |
| LHRH Analogue | DRUG | Letrozole 2.5mg orally daily + abemaciclib 150mg orally every 12 hours on a continuous dosing schedule, +/- LHRH analogs in premenopausal women, up to 12 months, in 28-day cycles |
| Abiraterone acetate | DRUG | Administered orally. |
| Prednisone | DRUG | Administered orally. |
| Surgery | PROCEDURE | Surgery |
| LY3023414 | DRUG | Administered orally |
| Capecitabine | DRUG | Administered orally |
| Prophylactic Loperamide | DRUG | Administered orally |
| Trastuzumab | DRUG | Administered IV |
| Standard of Care Single Agent Chemotherapy | DRUG | Standard-of-care single-agent chemotherapy of physician's choice administered according to product label |
| Docetaxel | DRUG | Administered IV |
| Loperamide | DRUG | Administered orally |
| Niraparib Tosylate Monohydrate | DRUG | Given PO |
| Computed Tomography | PROCEDURE | Undergo CT |
| Magnetic Resonance Imaging | PROCEDURE | Undergo MRI |
| Radiation Therapy | RADIATION | Undergo radiation therapy |
| Therapeutic Surgical Procedure | PROCEDURE | Undergo surgery |
| Darolutamide | DRUG | Tablet administered orally, per protocol, 2 x daily. Darolutamide is an orally administered molecular drug therapy that blocks the action of testosterone, the male sex hormone which can stimulate growth of prostate cancer. |
| GNRH-A Leuprolide Acetate | DRUG | Administered via intramuscular injection, per standard of care. GnRH agonist is a hormonal therapy drug. |
| GNRH-A Goserelin | DRUG | Administered via subcutaneous injection, per standard of care. GnRH agonist is a hormonal therapy drug. |
| Lutetium Lu 177-PSMA-617 | DRUG | Given IV |
| Dinutuximab | DRUG | Administered IV |
| GM-CSF | DRUG | Administered SC |
| Prednisolone | DRUG | Administered orally |
| Clarithromycin | DRUG | Administered orally |
| Ramucirumab | DRUG | Administered IV |
| LY2835219 | DRUG | Administered orally. |
| Everolimus | DRUG | Administered orally. |
| Pertuzumab | DRUG | Administered IV infusion. |
| Endocrine therapy | DRUG | Endocrine therapy administered orally. |
| LY3214996 | DRUG | 400 mg of LY3214996 daily for 6 doses over 5.5 days prior to surgical resection. Participants with tumors demonstrating PK-response in Phase 0 will continue treatment with recommended Phase 2 dose (RP2D) continuously in 21d cycles after surgery. |
Inclusion Criteria: * Adenocarcinoma of the prostate (as the predominant histology) * High-risk metastatic hormone-sensitive prostate cancer. High risk is defined as: * Greater than or equal to (≥)4 bone metastases by bone scan and/or * ≥1 visceral metastases by computed tomography or magnetic...
LY2835219 is an investigational small molecule developed by Eli Lilly and Company for the treatment of breast neoplasms and neoplasm metastasis. It is being studied in Phase 1 clinical development in oncology. LY2835219 is also known as [^14C]-LY2835219.
LY2835219 is being studied for breast neoplasms and neoplasm metastasis. The Phase 1 trial NCT02057133 evaluates LY2835219 in combination with other therapies for breast cancer that has spread, and a separate Phase 1 study, NCT02014129, evaluated it in Japanese participants with advanced cancer.
LY2835219 targets CDK4/6, a pair of cyclin-dependent kinases involved in cell cycle regulation. By targeting CDK4/6, the small molecule is designed to interfere with cancer cell proliferation. This mechanism supports its investigation in breast neoplasms and metastatic disease.
LY2835219 is developed by Eli Lilly and Company, which trades under the ticker LLY. Lilly is running the clinical program for the drug in oncology, including the Phase 1 breast cancer combination study NCT02057133 and the Phase 1 advanced cancer study NCT02014129 in Japan.
LY2835219 is in Phase 1 clinical development. It is investigational and has not been approved. The program includes NCT02057133, an active Phase 1 study in breast cancer that has spread, and NCT02014129, a completed Phase 1 study in Japanese participants with advanced cancer.
LY2835219 has been studied in two Phase 1 trials. NCT02057133 is an active, not recruiting study of LY2835219 in combination with therapies for breast cancer that has spread, enrolling 198 female participants in the United States. NCT02014129 was a completed Phase 1 study in 12 Japanese participants with advanced cancer.