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Skin and Connective Tissue Diseases

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Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

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Docetaxel

Nirogacestat

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Gamma Secretase Inhibitors and Modulators

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PF 03084014 will be administered orally, continuously, twice daily at doses from 80 to 150 mg in combination with docetaxel given every 3 weeks at doses from 75 to 100 mg/m\^2

PF-03084014

Solution for IV infusion 75 mg/m\^2, every 3 weeks

Solution for IV infusion 100 mg/m\^2, every 3 weeks

Pfizer CT.gov Call Center

This study is aimed to determine the tolerability of the PF-03084014 plus docetaxel combination in patients with advanced breast cancer. Preliminary information about the efficacy of the combination will also be collected.

A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer

Phase 1b Study Of Docetaxel + Pf 03084014 In Metastatic Or Locally Recurrent/Advanced Triple Negative Breast Cancer

Any DLT event in Cycle 1: Grade 4 neutropenia lasting more than (\>)7 days; febrile neutropenia (Grade more than or equal to \[\>=\] 3 and body temperature \>=38.5 degrees Celsius); Grade \>=3 neutropenic infection; Grade \>=3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia without bleeding; Grade \>=3 toxicities (except those that had not been maximally treated); Grade 3 prolongation of time from electrocardiogram (ECG) Q wave to the end of the T wave corresponding to electrical systole (QT) corrected for heart rate (QTc) which persisted after correction of reversible causes; delay of 2 weeks in receiving next scheduled cycle due to persisting treatment-related toxicities; and failure to deliver at least 80% of planned dose during first cycle due to treatment-related toxicities.

The period from study entry until disease progression, death or date of last contact. Assessment of response was made using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-emergent AEs (TEAEs) are defined as newly occurring AEs or those worsening after first dose. AEs comprised both SAEs and non-SAEs. An 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. Causality assessment was made by the investigator. Grading was per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 3.0: Grade 1=mild, Grade 2=moderate, Grade 3=severe, Grade 4=life-threatening, Grade 5=death related to AE.

Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, coagulation, liver function, renal function, electrolytes, clinical chemistry, and urinalysis (dipstick).

OR was based on assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than \[\<\] 10 millimeters \[mm\]). No new lesions. PR was defined as more than or equal to (\>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions.

Serum PF-03084014 pharmacokinetic (PK) parameters were calculated following twice daily (BID) doses of PF-03084014 given alone (Cycle 1 Day 21) and in combination with docetaxel (Cycle 1 Day 2 and Cycle 2 Day 1).

Plasma docetaxel PK parameters were calculated following a 1-hr infusion of docetaxel given alone (Cycle 1 Day 1) and in combination with BID dosing of PF-03084014 (Cycle 2 Day 1)

Serum PF-03084014 PK parameters were calculated following BID doses of PF-03084014 given alone (Cycle 1 Day 21) and in combination with docetaxel (Cycle 1 Day 2 and Cycle 2 Day 1)

Duration of response (DR) defined as time from start of first documented objective tumor response \[Complete Response (CR) or Partial Response (PR)\] to first documented objective tumor progression or death due to any cause, whichever occurs first. DR = (the end date for DR minus first subsequent confirmed CR or PR plus 1) divided by 7.02. CR: disappearance of all target lesions. PR: at least 30% decrease in the sum of diameters of target lesions.

Criteria for categorical summarization of the time corresponding to the beginning of depolarization to repolarization of the ventricles (QT) corrected for heart rate (QTc) using Bazett's correction (QTcB) or Fridericia's correction (QTcF) included: maximum QTcB or QTcF less than or equal to (\<=) 450 milliseconds (msec), 450 to \<=480 msec, 480 to \<=500 msec, more than (\>) 500 msec; maximum QTcB or QTcF changes (increases/decreases) from baseline (BL) less than (\<) 30 msec, 30 to \<60 msec, more than or equal to (\>=) 60 msec.

As PF-03084014 acts on the Notch pathway as an inhibitor, it is of interest to investigate its effects, if any, on the Notch family of receptors, mainly Notch 1-4.

Pfizer

All treated participants were analyzed for AEs. The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant or one participant may have experienced both a serious and nonserious event during the study.

PF-03084014 100 milligrams (mg) was given orally via tablets twice daily (BID) in 21-day cycles. On Day 1 of each cycle, participants were administered docetaxel 75 mg/square meters (m\^2) intravenously.

PF-03084014 100 mg BID + Docetaxel 75 mg/m^2

PF-03084014 100 milligrams (mg) was given orally via tablets twice daily (BID) in 21-day cycles. On Day 1 of each cycle, participants were administered docetaxel 100 mg/square meters (m\^2) intravenously.

PF-03084014 100 mg BID + Docetaxel 100 mg/m^2

PF-03084014 150 milligrams (mg) was given orally via tablets twice daily (BID) in 21-day cycles. On Day 1 of each cycle, participants were administered docetaxel 75 mg/square meters (m\^2) intravenously.

PF-03084014 150 mg BID + Docetaxel 75 mg/m^2

Total

Age, Continuous

Sex: Female, Male

Pfizer ClinicalTrials.gov Call Center

All enrolled participants who were eligible, received study treatment, and who either experienced DLT during the first cycle, or completed the 1-cycle observation period.

Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1

The 6-month PFS was evaluated only for the participants in the expansion cohort (PF-03084014 100 mg BID + docetaxel 75 mg/m\^2). Due to early study termination, only 7 participants were treated in the expansion cohort.

Progression-free Survival (PFS) at 6 Months - Expansion Cohort

All causality TEAEs

Treatment-related (TR) TEAEs

All causality SAEs

TR SAEs

Grade 3 or 4 TEAEs, all causality

Grade 3 or 4 TEAEs, TR

Grade 5 TEAEs, all causality

Grade 5 TEAEs, TR

Permanent withdrawal due to all causality TEAE(s)

Permanent withdrawal due to TR TEAE(s)

All 29 participants who received study treatment were included in the AE summarization/analysis.

Number of Participants With All Causality and Treatment-related Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs

All 29 participants who received study treatment were included in the safety analyses.

Number of Participants With Laboratory Abnormalities

All 29 participants who received study treatment were included in this analysis.

Percentage of Participants With Objective Response (OR)

C1D2

C1D21

C2D1

All 22 participants treated in the dose escalation stage were included in the analysis. n=number of evaluable participants at the specified time point.

Area Under the Concentration-time Curve (AUC) From Time 0 to Time of Last Measured Concentration (AUClast) of PF-03084014 in Dose-finding Cohort

AUClast, C1D1

AUClast, C2D1

AUCinf, C1D1

AUCinf, C2D1

AUClast and AUC From Time 0 Extrapolated to Infinite Time (AUCinf) of Docetaxel in Dose-finding Cohort

Cmax, C1D2

Cmax, C1D21

Ctrough, C1D21

Cmax, C2D1

Ctrough, C2D1

Maximum Serum or Plasma Concentration (Cmax) and Predose Concentration (Ctrough) of PF-03084014 in Dose-finding Cohort

Cmax, C1D1

Cmax of Docetaxel in Dose-finding Cohort

Tmax, C1D2

Tmax, C1D21

Tmax, C2D1

Time to Cmax (Tmax) of PF-03084014 in Dose-finding Cohort

Tmax, C1D1

Tmax of Docetaxel in Dose-finding Cohort

CL, C1D1

CL, C2D1

Systemic Clearance (CL) of Docetaxel in Dose-finding Cohort

t1/2, C1D1

t1/2, C2D1

Terminal Half-life (t1/2) of Docetaxel in Dose-finding Cohort

Vss, C1D1

Vss, C2D1

Volume of Distribution (Vss) of Docetaxel in Dose-finding Cohort

AUClast, C1D21

All 7 participants who received treatment in the expansion cohort were included in the analysis. n=number of evaluable participants at the specified time point.

AUClast of PF-03084014 in the Expansion Cohort

Cmax of PF-03084014 in the Expansion Cohort

Tmax of PF-03084014 in the Expansion Cohort

All 7 participants who received treatment in the expansion cohort were included in the analysis. At Cycle 1 Day 21, only 5 participants had available data for Ctrough.

Ctrough of PF-03084014 in the Expansion Cohort

Only 4 participants had CR or PR, 2 each in the PF-03084014 100 mg BID + docetaxel 75 mg/m\^2 and PF-03084014 150 mg BID + docetaxel 75 mg/m\^2 groups.

Duration of Response (DR)

QTcB <=450 msec

QTcB 450 to <=480 msec

QTcB 480 to <=500 msec

QTcB >500 msec

QTcF <=450 msec

QTcF 450 to <=480 msec

QTcF 480 to <=500 msec

QTcF >500 msec

QTcB increase from BL <30 msec

QTcB increase from BL 30-<60 msec

QTcB increase from BL >=60 msec

QTcF increase from BL <30 msec

QTcF increase from BL 30-<60 msec

QTcF increase from BL >=60 msec

QTcB decrease from BL <30 msec

QTcB decrease from BL 30-<60 msec

QTcB decrease from BL >=60msec

QTcF decrease from BL <30 msec

QTcF decrease from BL 30-<60 msec

QTcF decrease from BL >=60 msec

All 29 participants who received study treatment were analyzed for safety.

Number of Participants With QTc Values Meeting Categorical Summarization Criteria

Notch 1 RNA, C1D1

Notch 1 RNA, C1D2

Notch 1 RNA, C1D8

Notch 1 RNA, C1D21

Notch 1 RNA, EOT

Notch 2 RNA, C1D1

Notch 2 RNA, C1D2

Notch 2 RNA, C1D8

Notch 2 RNA, C1D21

Notch 2 RNA, EOT

Notch 3 RNA, C1D1

Notch 3 RNA, C1D2

Notch 3 RNA, C1D8

Notch 3 RNA, C1D21

Notch 4 RNA, C1D1

Notch 4 RNA, C1D2

Notch 4 RNA, C1D8

Notch 4 RNA, C1D21

Notch 4 RNA, EOT

All treated participants who had at least 1 screening and post treatment biomarker assessment. n=number of evaluable participants for the specified biomarker at the specified time point.

Percentage Change From Baseline in Notch 1 to 4 Ribonucleic Acid (RNA) in Blood

Overall Study

Spots Global Cancer Trial Database for A Study Evaluating The PF-03084014 In Combination With Docetaxel In Patients With Advanced Breast Cancer

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Study Description

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