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

Pfizer61 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Neoplasms Breast Neoplasms

Interventions

PD-0332991 (100 mg or 125 mg) will be orally administered once a day for 3 weeks followed by 1 week off treatment, in the morning on an empty stomach. Dose reduction of PD-0332991 by one (100 mg) or two (75 mg) dose level is permitted depending on treatment related toxicity.

PD-0332991DRUG

PD-0332991, 125 mg, will be orally administered with food once a day for 3 weeks followed by 1 week off treatment. PD-0332991 will be administered once a day together with letrozole. Dose reduction of PD-0332991 by one (100 mg) or two (75 mg) dose level is permitted depending on treatment related toxicity.

letrozoleDRUG

Letrozole, 2.5 mg, will be orally administered once a day in continuous daily dosing together with PD-0332991. Dose reduction of letrozole is not permitted, but dosing interruptions for letrozole-related toxicity are allowed as per investigator's medical judgement.

PD-0332991DRUG

letrozoleDRUG

Eligibility

Sex: ALLMin age: 20 Years

Medical Language ↔ Plain English

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.

Locations (16)

Aichi Cancer Center Hospital

Nagoya, Aichi-ken, Japan

National Cancer Center Hospital East

Kashiwa, Chiba, Japan

National Hospital Organization Hokkaido Cancer Center

Sapporo, Hokkaido, Japan

Kumamoto Shinto General Hospital

Kumamoto, Kumamoto, Japan

Saitama Cancer Center

Kita-adachi-gun, Saitama, Japan

National Cancer Center Hospital

Chuo-Ku, Tokyo, Japan

Chiba Cancer Center

Chiba, Japan

National Hospital Organization Shikoku Cancer Center

Ehime, Japan

National Hospital Organization Kyushu Cancer Center

Fukuoka, Japan

Hiroshima City Hiroshima Citizens Hospital

Hiroshima, Japan

...and 6 more locations

Outcomes

Primary Outcomes

Number of Participants With Dose Limiting Toxicities (DLT): Part 1 Phase 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.

Time frame: Lead-in period (Day -7) up to Day 28 (Cycle 1)

Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Part 2 Phase 1

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.

Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) By Severity: Part 2 Phase 1

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).

Time frame: Baseline (Day 1) up to 28 days after last dose of study drug (up to 1673 days)

Percentage of Participants With 1 Year Progression Free Survival (PFS): Phase 2

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.

Time frame: From initiation of treatment up to 12 months

Secondary Outcomes

Number of Participants With Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Phase 1 (Part 1) and Phase 2

Time frame: 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)

Number of Participants With Treatment-Emergent Adverse Events (AEs) By Severity: Phase 1 (Part 1) and Phase 2

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).

Number of Participants With Clinically Significant Laboratory Abnormalities

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.

Data from ClinicalTrials.gov

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Time frame: 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

Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.

Time frame: 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 Milligram (mg) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

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.

Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Area Under the Plasma Concentration-Time Curve From 0 to Time 24 Hours (AUC24) of PD-0332991 Following Single Dose: Part 1 Phase 1

AUC24 is area under the plasma concentration-time curve from 0 to time 24 hours which is calculated by log-linear trapezoidal method.

Time frame: 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 of PD-0332991 Following Single Dose: Part 1 Phase 1

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.

Time frame: Single dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12 and 24 hours post-dose in Lead-in period (Day -7)

Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of PD-0332991 Following Single Dose: Part 1 Phase 1

AUCinf is area under the plasma concentration-time curve from 0 to infinity which is calculated by log-linear trapezoidal method.

Time frame: 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 of PD-0332991 Following Single Dose: Part 1 Phase 1

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.

Time frame: 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)

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

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.

Time frame: 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 of PD-0332991 Following Single Dose: Part 1 Phase 1

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.

Time frame: 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)

Apparent Oral Clearance of PD-0332991: Part 1 Phase 1

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.

Time frame: 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

Maximum Observed Plasma Concentration (Cmax) Of PD-0332991: Part 1 Phase 1

Cmax is maximum plasma concentration which is observed directly from the actual time-concentration data.

Cmax Dose Normalized to 125 mg of PD-0332991: Part 1 Phase 1

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.

Pre-dose Plasma Concentration (Ctrough) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

Ctrough is pre-dose concentration during multiple dosing which is observed directly from the actual time-concentration data.

Time frame: Multiple dose: 0 hour (pre-dose), 1, 2, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 8

Accumulation Ratio (Rac) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

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.

Time frame: 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

Linearity (Rss) of PD-0332991 Following Multiple Dose: Part 1 Phase 1

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.

Time frame: 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

Time to Reach Maximum Observed Plasma Concentration (Tmax) of PD-0332991: Part 1 Phase 1

Tmax is time at which maximum plasma concentration (Cmax) was observed. It was observed directly from data as time of first occurrence.

Terminal Half-Life (t1/2) of PD-0332991: Part 1 Phase 1

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.

Volume of Distribution (Vz/F) of PD-0332991 Following Single Dose: Part 1 Phase 1

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.

Time frame: 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)

Area Under the Plasma Concentration Time Curve Over Dosing Interval (AUCtau) of PD-0332991: Phase 2

AUCtau is area under the plasma concentration-time curve over dosing interval which is calculated by log-linear trapezoidal method.