A Study Of Oral Palbociclib (PD-0332991), A CDK4/6 Inhibitor, As Single Agent In Japanese Patients With Advanced Solid Tumors Or In Combination With Letrozole For The First-Line Treatment Of Postmenopausal Japanese Patients With ER (+) HER2 (-) Advanced Breast Cancer

Phase 2

Completed

Conditions: Breast Neoplasms
Neoplasms

Interventions: Drug: PD-0332991
Drug: letrozole

Registration Number: NCT01684215

Lead Sponsor: Pfizer

Brief Summary: This study is comprised of two portions: a Phase 1 portion and a Phase 2 portion. The Phase 1 portion is a single-country, non-randomized, open label, clinical trial which will evaluate the safety, tolerability, preliminary efficacy, and PK profile of PD-0332991 as a single agent in Japanese patients with advanced solid tumors, and PD-0332991 in combination with letrozole in the first-line treatment of Japanese patients with ER(+) HER2(-) ABC. The Phase 2 portion is a single-country, non-randomized, open-label, single-cohort, multi-center clinical trial to evaluate the efficacy and safety of PD-0332991 in combination with letrozole for the first-line treatment of postmenopausal Japanese patients with ER(+) HER2(-) ABC.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 61

Inclusion Criteria

Phase 1

In Part 1, advanced solid tumor (except SCLC or retinoblastoma) proven histologically or cytologically at original diagnosis, that is refractory to standard therapy or for whom no standard of care therapy is available.
In Part 2 and Phase 2, post menopausal women with proven diagnosis of ER-positive, HER2-negative adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease (including bone only disease) not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 or 1.
Resolved acute effects of any prior therapy to baseline severity or Grade ≤1

Phase 2

Adult women (≥ 20 years of age) with proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent and for whom chemotherapy is not clinically indicated.
Documentation of histologically or cytologically confirmed diagnosis of ER(+) breast cancer based on local laboratory results.
Adequate blood cell counts, kidney function and liver function and and Eastern Cooperative Oncology Group [ECOG] score of 0 to 2.

Exclusion Criteria

Phase 1

Active uncontrolled or symptomatic CNS metastases.
Uncontrolled infection, unstable or sever intercurrent medical condition, or current drug or alcohol abuse
Active or unstable cardiac disease or history of heart attack within 6 months

Phase 2

HER2 positive tumor based on local laboratory results utilizing one of the sponsor approved assays.
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
Prior neoadjuvant or adjuvant treatment with a non steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
PD-0332991 with letrozole	PD-0332991	Phase 2
Single-agent PD-0332991	PD-0332991	Phase 1 Part 1
PD-0332991 in combination with letrozole	PD-0332991	Phase 1 Part 2
PD-0332991 in combination with letrozole	letrozole	Phase 1 Part 2
PD-0332991 with letrozole	letrozole	Phase 2

Primary Outcome Measures

Name	Time	Method
Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 1	Lead-in period (Day -7) up to Day 28 (Cycle 1)	DLT was classified as per common terminology criteria for adverse events (CTCAE) version 4.0 as any of the events occurring during 28 days of Cycle 1,attributed to study drug:grade 4 neutropenia(for a duration of greater than \[\>\]7 days); febrile neutropenia (grade greater than or equal to \[\>=\]3 neutropenia,body temperature \>=38.5 degree Celsius);grade \>=3 thrombocytopenia with bleeding episode;grade 4 thrombocytopenia;grade \>=3 non-hematologic toxicity except grade 3 or more nausea, vomiting,electrolyte abnormality(if controllable by therapy);grade 3 QTc prolongation(\>500 millisecond \[msec\])persist after correction of reversible cause such as electrolyte abnormalities or hypoxia. Lack of hematologic recovery (platelets less than \[\<\]50,000/microliter \[mcL\],absolute neutrophil count \<1,000/mcL,hemoglobin \<8.0 gram/deciliter \[g/dL\]) or prolonged non hematologic toxicities that delays initiation of next dose by \>7 days;receipt of \<75 percent of planned dose in first cycle due to toxicity.
Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2	From initiation of treatment up to 12 months	PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurred first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.1-year PFS was defined as the percentage of participants without PFS events (PD or death due to any cause) at 12 months based on the Kaplan-Meier estimate. Percentage of participants with 1-year PFS with 90% confidence interval (CI) were reported.
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1	Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)	A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1	Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)	AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in National Cancer Institute (NCI) CTCAE grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).

Secondary Outcome Measures

Name	Time	Method
Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)	AUC24 is area under the plasma concentration-time curve from 0 to time 24 hours which is calculated by log-linear trapezoidal method.
Number of Participants With Clinically Significant Laboratory Abnormalities	Part 1 Phase 1: Lead-in period (Day -7) up to 308 days; Part 2 Phase 1: Baseline (Day 1) up to 1673 days; Phase 2: Baseline (Day 1) up to 1526 days	Abnormality criteria: hemoglobin: \<0.8\lower limit of normal \[LLN\], platelets: \<0.5\LLN or \>1.75\upper limit of normal \[ULN\], leukocytes: \<0.6\LLN or \>1.5\ULN, lymphocytes, total neutrophils: \<0.8\LLN or \>1.2\ULN, basophils, eosinophil,monocytes: \>1.2\ULN); aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GT): \>0.3\ULN, total protein, albumin: \<0.8\LLN or \>1.2\ULN, total bilirubin, direct bilirubin: \>1.5\ULN; blood urea nitrogen, creatinine: \>1.3\ULN, uric acid: \>1.2\ULN; sodium: \<0.95\LLN or \>1.05\ULN, potassium, chloride, calcium, magnesium: \<0.9\LLN or \>1.1\ULN, phosphate: \<0.8\LLN or \>1.2\ULN; creatine kinase: \>2.0\ULN, glucose fasting: \<0.6\LLN or \>1.5\ULN, glycosylated haemoglobin: \>1.3\ULN;urinalysis dipstick (urine protein, urine blood \>=1); urine protein 24 hour: \>1.1\ULN; coagulation Activated partial thromboplastin time \[APTT\], Prothrombin, prothrombin international ratio: \>1.1\ULN.
AUC24 Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)	AUC24 Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time 24 hours dose normalized to 125 mg which is calculated by log-linear trapezoidal method.
Cmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1	Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Cmax Dose Normalized to 125 mg is maximum plasma concentration dose normalized to 125 mg which is observed directly from the actual time-concentration data.
Number of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2	Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)	AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment emergent if occurred for the first time after the start of study treatment or occurred prior to the start of treatment but increased in NCI CTCAE version 4.0 grade during study treatment period. AE severity was defined to be the maximum toxicity grade of the TEAEs experienced by the participants during the study. AE was assessed according to severity as: Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 (severe AE), Grade 4 (life-threatening consequences) and Grade 5 (death related to AE).
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1	Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.
AUCtau Dose Normalized to 125 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1	Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	AUCtau Dose Normalized to 125 mg is area under the plasma concentration-time curve over dosing interval dose normalized to 125 mg which is calculated by log-linear trapezoidal method.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)	AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.
AUCinf Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)	AUCinf Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to infinity dose normalized to 125 mg which is calculated by log-linear trapezoidal method.
Apparent Oral Clearance of PD-0332991: Part 1 Phase 1	Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCinf. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.
Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1	Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.
AUClast Dose Normalized to 125 mg of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)	AUClast Dose Normalized to 125 mg is area under the plasma concentration-time curve from 0 to time of last measurable concentration dose normalized to 125 mg which is calculated by log-linear trapezoidal method.
Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Phase 2	0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15	Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.
Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1	Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.
Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2	Part 1 Phase 1: Lead-in period (Day -7) up to 28 days after last dose of study drug (up to 308 days), Phase 2: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1526 days)	A treatment related AE is any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event had a causal relationship with the treatment or usage. A SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Relatedness was judged by investigator. AEs included both serious and non-serious adverse events.
Area Under the Plasma Concentration-Time Curve From 0 to Time of Last Measurable Concentration (AUClast) of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)	AUClast is area under the plasma concentration-time curve from 0 to time of last measurable concentration which is calculated by log-linear trapezoidal method.
Terminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1	Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	t1/2 is terminal elimination half-life which is calculated by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Phase 2	0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15	Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.
Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Rss is the ratio of AUCtau (after multiple doses) to AUCinf (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method. AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.
Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7)	Vz/F is apparent volume of distribution estimated from terminal phase, which is calculated as CL/F/kel. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method (AUCinf). kel is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.
Percentage of Participants With Objective Response: Phase 1	From initiation of treatment up to disease progression (up to 30 months)	Objective response (OR) was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]). PR was defined as a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.
Duration of Response (DOR): Phase 2	From initiation of treatment up to disease progression (up to 1526 days)	Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease, all target nodes reduced to normal size (short axis \<10 mm) or PR (a \>=30 % decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Change From Baseline in Functional Assessment of Cancer Therapy-General (FACT-G): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment	Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)	FACT is a modular approach to assess participant's health-related quality of life. FACT-G total score was derived from the sum of these 4 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-G total score range was of 0 (not at all good) to 108 (very well), where higher scores indicating better quality of life.
Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1	Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Rac is the ratio of AUCtau (after multiple doses) to AUCtau (after single dose). AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.
Percentage of Participants With Objective Response: Phase 2	From initiation of treatment up to disease progression (up to 1526 days)	Objective response was defined as a complete response (CR) or partial response (PR) according to the RECIST version 1.1 recorded from first dose of study treatment until disease progression or death due to any cause. PD was defined using RECIST v1.1, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. CR was defined as disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR was defined as a \>=30% decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. Percentage of participants with objective response (who achieved CR or PR) were reported.
Presence of Tumor Tissue Biomarker- Ki67: Phase 2	Baseline (Day 1)	Tumor tissue biomarker, Ki67 was analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and was selected based on its known relevance to mechanisms involved in cell cycle regulation. Number of participants with less than or equal to and greater than 20 percent of Ki67 tumor tissue biomarker were reported.
Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1	Single dose: 0 hour (pre-dose),1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120 hours post-dose in Lead-in period (Day -7), Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8	Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.
Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2	0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15	AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.
Apparent Oral Clearance of PD-0332991: Phase 2	0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. It was calculated by dividing the given oral dose by AUCtau. AUCtau is the area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.
Pre-dose Plasma Concentration (Ctrough) of PD-0332991: Phase 2	0 (pre-dose), 1, 2, 4, 6, 8, 10, 24 hours post dose on Cycle 1 Day 15	Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.
Percentage of Participants With Disease Control (DC): Phase 2	From initiation of treatment up to disease progression (up to 1526 days)	DC: CR, PR or stable disease (SD) for \>=24 weeks according to RECIST version (v)1.1 recorded in time period between first dose of study treatment and disease progression or death to any cause. CR: disappearance of all target lesions with exception of nodal disease. All target nodes reduced to normal size (short axis \<10 mm). PR: \>=30% decrease in sum of longest dimensions of target lesions taking as a reference baseline sum longest dimensions. SD was defined as not achieving an OR with confirmed CR or PR according to RECIST v1.1, as determined by investigators, relative to response evaluable population, but remained stable for at least 24 weeks after first dose, then best overall response for such a participant was considered as stable disease. PD was defined using RECIST v1.1 as a 20% increase in sum of longest diameter of target lesions, or a measurable increase in a non-target lesion, or appearance of new lesions.
Duration of Response (DOR): Part 2 Phase 1	baseline up to 1673 days	Duration of response was defined as the interval from the first documentation of objective tumor response in participants with CR (disappearance of all target lesions with the exception of nodal disease. All target nodes reduced to normal size (short axis \<10 millimeter \[mm\]) or PR (a \>=30 percent decrease in sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions) according to RECIST version 1.1 to the first documentation of objective tumor progression or to death due to any cause, whichever occurred first.
Change From Baseline in Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment	Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)	The functional assessment of cancer therapy (FACT) is a modular approach to assess participant's health-related quality of life. FACT-B total score was derived from the sum of these 5 sub-scale scores: physical well-being, social/family well-being and functional well-being (all 3 sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life), emotional well-being (consists of 6 items and ranging from 0 to 24, where higher scores indicating better quality of life, and a breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. FACT-B total score range was of 0 (not at all good) to 144 (very well), where higher scores indicating better quality of life.
Progression Free Survival (PFS): Part 2 Phase 1	baseline up to 1673 days	PFS was defined as the time from first dose of study treatment to the date of the first documentation of objective progression of disease (PD) or death due to any cause in the absence of documented PD, whichever occurs first. PD was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Overall Survival (OS): Phase 2	From initiation of treatment up to follow-up period (up to 1526 days)	Overall survival was defined as the time from first dose of study treatment to date of death due to any cause. In the absence of confirmation of death, survival time was censored to last date the participant was known to be alive. OS was estimated with Kaplan-Meier method.
Presence of Tumor Tissue Biomarkers- Estrogen Receptor (ER) H-Score, Retinoblastoma (Rb) H-Score, B-cell Lymphoma-1 (BCL-1) H-Score, P16 H-Score: Phase 2	Baseline (Day 1)	Tumor tissue biomarkers ER, Rb, BCL-1 and P16 were analyzed to investigate possible associations with resistance or sensitivity to treatment with study drugs and were selected based on their known relevance to mechanisms involved in cell cycle regulation. Number of participants with positive ER (H-Score), Rb (H-Score), BCL-1 (H-Score) and P16 (H-Score) tumor tissue biomarkers were reported. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors.
Change From Baseline in Trial Outcome Index (TOI): Phase 2 at Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49 and End of Treatment	Baseline (Day 1 of Cycle 1), Day 1 of Cycle 2, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, End of treatment (up to 1526 days)	FACT is a modular approach to assess participant's health-related quality of life. TOI total score was derived from the sum of the 3 sub-scale scores: physical well-being, functional well-being (both sub-scales consisting of 7 items ranging from 0 to 28, where higher scores indicating better quality of life) and breast cancer subscale (consists of 9 items and ranging from 0 to 36, where higher scores indicating better quality of life). Each individual item was rated on a 5-point Likert scale, ranging from 0 (not at all good) to 4 (very well), where higher scores indicating better quality of life. TOI total score range was of 0 (not at all good) to 92 (very well), where higher scores indicating better quality of life.

Trial Locations

Locations (16): Aichi Cancer Center Hospital
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Nagoya, Aichi, Japan
National Cancer Center Hospital East
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Kashiwa, Chiba, Japan
National Hospital Organization Hokkaido Cancer Center
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Sapporo, Hokkaido, Japan
Chiba Cancer Center
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Chiba, Japan
Iwate Medical University Hospital
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Iwate, Japan
National Hospital Organization Shikoku Cancer Center
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Ehime, Japan
Kumamoto City Hospital
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Kumamoto, Japan
Hakuaikai Medical Corporation Sagara Hospital
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Kagoshima, Japan
Kumamoto University Hospital
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Kumamoto, Japan
Kyoto University Hospital
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Kyoto, Japan
National Hospital Organization Osaka National Hospital
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Osaka, Japan
Kumamoto Shinto General Hospital
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Kumamoto-city, Kumamoto, Japan
Saitama Cancer Center
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Kita-adachi-gun, Saitama, Japan
National Cancer Center Hospital
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Chuo-Ku, Tokyo, Japan
National Hospital Organization Kyushu Cancer Center
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Fukuoka, Japan
Hiroshima City Hiroshima Citizens Hospital
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Hiroshima, Japan