A Trial In Patients With Advanced Cancer And Leukemia

A PHASE I TRIAL OF PF-03084014 IN PATIENTS WITH ADVANCED SOLID TUMOR MALIGNANCY AND T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOBLASTIC LYMPHOMA

This is a phase 1, dose escalating study to determine the safety of PF-03084014 in patients with advanced cancer and leukemia

Study Overview

• Status: Completed
• Conditions: Neoplasms by Histologic Type
• Intervention / Treatment: Drug: PF-03084014

• Study Type: Interventional
• Enrollment (Actual): 72
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy, 40138
    • Istituto di Ematologia Seragnoli
  • Bologna, Italy, 40138
    • DIPRTMNT CLIN Scienze RADIOL e Istocitopatologiche
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
    • Aurora, Colorado, United States, 80045
      • Anschutz Cancer Pavilion
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver CTRC
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Clinical Laboratory
    • Boston, Massachusetts, United States, 02215
      • Dana Ferber Cancer institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Center / Wayne State University
  • Texas
    • Houston, Texas, United States, 77030-4009
      • The University of Texas Md Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with advanced cancer that is resistant to standard therapy or for which no standard therapy is available
• Patients with acute T cell leukemia/lymphoblastic lymphoma that is resistant to standard therapy or for which no standard therapy is available
• Men and women >16 years old

Exclusion Criteria:

• Prior treatment with a gamma secretase inhibitor for treatment of cancer
• Patients taking Tamoxifen
• Patients with active graft versus host disease
• Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness
• Patients who are pregnant or breast feeding
• Patients with clinical evidence of central nervous system disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1	Drug: PF-03084014; 10 mg, 50 mg or 100 mg tablets. Patients dosed from 20 mg - 500 mg, twice daily; Other Names: gamma secretase inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Solid Tumor Participants With First-Cycle Dose-Limiting Toxicity (DLT)	Any DLT event attributable to PF-03084014 during Cycle 1: non-hematologic toxicities >= Grade 3 despite optimal care; treatment delay >=7 days or unable to deliver at least 80% of planned dose due to treatment-related toxicities; Grade 4 neutropenia >7 days; febrile neutropenia; neutropenic infection; Grade >=3 thrombocytopenia with bleeding	Baseline to the end of Cycle 1 (Week 4)
Number of T-ALL/LBL Participants With First-Cycle DLT	Any DLT attributable to PF-03084014 at 1st Cycle: non-hematologic toxicities >= Grade 3 despite optimal care; treatment delay >=7 days; unable to deliver at least 80% of planned dose; absolute neutrophil count (ANC) <1000/microliter (uL), or platelet count <30,000/uL, or hemoglobin <8 gram/deciliter (g/dL) in a bone marrow with <5% blasts and no evidence of leukemia or abnormal dysplasia for >42 days	Baseline to the end of Cycle 1 (Week 4)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality)	An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of casual relationship. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), and resulted in congenital anomaly/birth defect.	Baseline up to end of study (maximum of 84 months)
Number of Participants With TEAEs (Treatment-Related)	An AE was any untoward medical occurrence in a participant who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. An SAE was any untoward medical occurrence at any dose that: resulted in death, was life-threatening (immediate risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), and resulted in congenital anomaly/birth defect.	Baseline up to end of study (maximum of 84 months)
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality) by Severity (by Maximum Common Terminology Criteria for Adverse Events [CTCAE] Grade)	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE.	Baseline up to end of study (maximum of 84 months)
Number of Participants With TEAEs (Treatment-Related) by Severity (by Maximum CTCAE Grade)	An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Treatment-related events were those assessed by the investigator as related to study medication. CTCAE version 3.0 was used for AE grading: Grade 1 mild AE; Grade 2 moderate AE; Grade 3 severe AE; Grade 4 life-threatening or disabling AE; Grade 5 death related to AE.	Baseline up to end of study (maximum of 84 months)
Number of Participants With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval	Criteria for potentially important changes in ECG were defined as: maximum (max.) post-dose (post-baseline) time from electrocardiogram Q wave to the corresponding to electrical systole (QT interval) corrected for Fridericia's factor (QTcF), or QT interval corrected for Bazett's factor (QTcB): <450, 450 -<480, 480-<500, and >=500 msec. Maximum increase (inc.) from baseline in QTcF or QTcB: change (chg) <30, 30>=chg<60, and chg >=60 msec.	Baseline up to end of study (maximum of 84 months)
Number of Participants With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)	Parameters analyzed included: white blood cell (WBC) count plus differential, absolute (abs) neutrophil count, platelets, hemoglobin, sodium, potassium, bicarbonate, chloride, blood urea nitrogen, creatinine, glucose, uric acid, calcium, phosphate, magnesium, total protein, albumin, total bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), partial prothrombin time/international normalized ratio (PTT/INR). Urinalysis: pH, specific gravity, protein, glucose, ketones, blood, leukocyte esterase, and nitrites. Pregnancy test: Serum or urine pregnancy test for women of childbearing potential. There were no changes in urine protein among the solid tumor and T-ALL/LBL participants that were clinically significant. Clinical significance was judged by the investigator.	Baseline up to end of study (maximum of 84 months)
Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1	Cmax was the maximum observed serum concentration.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1	Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1	AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). CV is the coefficient of variation.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
Dose-normalized AUCtau [AUCtau (dn) ] After a Single Dose on Cycle 1 Day 1	AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. NE is not estimable.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1	Tmax was the time to reach maximum serum concentration (Cmax).	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
Cmax After Multiple Dose on Cycle 1 Day 21	Cmax was the maximum observed serum concentration. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant. CV is the coefficient of variation.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Time to Reach Cmax (Tmax) After Multiple Dose on Cycle 1 Day 21	Tmax was the time to reach maximum serum concentration (Cmax). Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
AUCtau After Multiple Dose on Cycle 1 Day 21	AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired concentration of a drug. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21	Serum decay half-life (t1/2) is the time measured for the serum concentration to decrease by one half. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Apparent Oral Clearance (CL/F) on Cycle 1 Day 21	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21	Cmin was the minimum serum concentration. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21	Cavg was the average serum concentration at steady state. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Accumulation Ratio (Rac) on Cycle 1 Day 21	Accumulation was calculated as AUCtau at steady state (Cycle 1 Day 21) divided by AUCtau after a single dose on Cycle 1 Day 1. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose), Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21	AUCtau (dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21	Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Cycle 1 Day 21 PK parameter summaries are presented only for participants who were considered to be dose compliant.	Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
AUCtau in the Fasted State for Solid Tumor Participants	AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval).	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
AUCtau in the Fed State for Solid Tumor Participants	AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval).	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Cmax in the Fasted State for Solid Tumor Participants	Cmax was the maximum observed serum concentration.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Cmax in the Fed State for Solid Tumor Participants	Cmax was the maximum observed serum concentration.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Participants	AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Participants	AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Participants	Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-Normalized Cmax [Cmax(dn)] in the Fed State for Solid Tumor Participants	Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.	Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose) or Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose).
AUCtau on Cycle 2 Day 1	AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). Data for this outcome measure was planned to be analyzed for two arms only.	Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-normalized AUCtau [AUCtau (dn)] on Cycle 2 Day 1	AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose. Data for this outcome measure was planned to be analyzed for two arms only.	Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Cmax on Cycle 2 Day 1	Cmax was the maximum observed serum concentration. Data for this outcome measure was planned to be analyzed for two arms only.	Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Dose-normalized Cmax [Cmax (dn)] on Cycle 2 Day 1	Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose. Data for this outcome measure was planned to be analyzed for two arms only.	Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Tmax on Cycle 2 Day 1	Tmax was the time to reach maximum serum concentration (Cmax). Data for this outcome measure was planned to be analyzed for two arms only.	Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
Percentage of Solid Tumor Participants With Objective Response (OR)	Objective response (OR) was defined as confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0). Confirmed CR defined as disappearance of all target lesions. Confirmed PR defined as >=30% decrease in sum of the longest dimensions (LD) of the target lesions taking as a reference the baseline sum LD according to RECIST. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (plus [+] or minus [-] 5 days) of every odd cycle or as clinically indicated, up to Cycle 9; afterwards assessed on Day 1 (+ or -5 days) every 4 cycles
Time to Tumor Progression (TTP) for Solid Tumor Participants	Time from Cycle 1 Day 1 to first documentation of disease progression. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, uneuivocal progression of non-target disease, or the appearance of new lesions. TTP (months) was calculated as (first event date minus the date of first dose of study medication plus 1) divided by 30.	Baseline until first documented objective progression (up to maximum of 84 months)
Duration of Response (DR) for Solid Tumor Participants	Time from the first documentation of OR to objective disease progression or death due to any cause. DR was only calculated for participants with an OR. DR (months) was calculated as (date of first documentation of objective progression or death minus date of first documentation of PR or CR plus 1) divided by 30.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or -5 days) of every odd cycle or as clinically indicated, up to Cycle 9. Afterwards, assessed on Day 1 (+ or -5 days) every 4 cycles (up to maximum of 84 months)
Progression-Free Survival (PFS) for Solid Tumor Participants	PFS was defined as the time from Cycle 1 Day 1 to date of first documentation of progression or death due to any cause. Progression was defined as per RECIST version 1.0, as a 20% increase in the sum of the longest diameter of target lesions, or target lesions over nadir, unequivocal progression of non-target disease, or the appearance of new lesions. PFS (months) was calculated as (the first event date minus the date of first dose of study medication plus 1) divided by 30.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9; afterwards assessed on Day 1 (+ or -5 days) every 4 cycles (up to maximum of 84 months)
Percentage of T-ALL/LBL Participants With OR	OR was adapted from International Working Group Response Criteria for Acute Myeloid Leukemia (AML). The response categories of interest were CR, complete response with incomplete hematopoietic recovery (CRi), and PR. CR: ANC >1500/microliter (uL), no circulating blasts. Platelets >100,000/uL, <5% marrow blast cells, no extramedullary disease, bone marrow cellularity >20% with tri-lineage hematopoiesis and <5% marrow blast cells, none of which were neoplastic; CRi: same as CR but ANC may be >1500/uL or platelet count >100,000/uL, no requirement on bone marrow cellularity; PR: same as CR but bone marrow with >= 50% reduction of leukemia blast cells and an absolute blast count between 5% and 25%.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9 (up to maximum of 84 months)
Relapse Free Survival (RFS) for T-ALL/LBL Participants	The RFS of CR was defined as the time from the date of first attaining CR to the date of relapse or death from any cause, whichever occurred first. Similarly, the RFS of CR + CRi (or RFS of CR + CRi + PR) was defined as the time from the date of first attaining CR + CRi (or CR + CRi + PR) to the date of relapse or death from any cause, whichever occurred first.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9 (up to maximum of 84 months)
Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Participants	PBR was the maximum percentage of peripheral blast count reduction for each participant who received at least one dose of study medication. PBR was derived by the Sponsor from percentage of peripheral blood Blast Count reported by sites.	Baseline, Cycle 2 Day 1, Cycle 3 Day 1 and then Day 1 (+ or - 5 days) of every odd cycle or as clinically indicated, up to Cycle 9 (up to maximum of 84 months)
Changes in Expression Levels of Notch 1 Target Genes in Tumor Biopsies for Solid Tumor Participants: Hairy and Enhancer of Split-4 (Hes4) Gene Expression Levels on Cycle 1 Day 21 Relative to That at Baseline	Gene expression analysis in tumor biopsies was done using cDNA prepared from RNA extracted from tumor biopsies. Gene expression was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Only Hes4 gene showed consistent down modulation across dosing cohorts (150 mg and 220 mg BID) and therefore results were reported for Hes4 only. Data for this outcome measure was planned to be analyzed for two arms only.	Baseline, Cycle 1 Day 21 (-5 days)
Changes From Baseline in Expression Levels of Notch 1 Target Genes in Peripheral Blood for T-ALL/LBL Participants: Hes4 Gene Expression Levels on Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 21 Relative to That at Baseline	Ribonucleic acid (RNA) was extracted from peripheral blood and used as a template to synthesize complementary deoxyribonucleic acid (cDNA). Gene expression in cDNA was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Results were reported Only for Hes4 as this was the only gene to show consistent down modulation across dosing cohorts (150 mg and 220 mg).	Baseline (morning), Cycle 1 Days 8, 15 and 21 (morning, matched with the first PK sample of the particular day), Cycle 1 Day 21 (24, 48, and 120 hr post-dose) and at end of treatment (EOT)
Changes in Expression Levels of Notch 1 Target Genes in Peripheral Blood for Solid Tumor Participants: Hes4 Gene Expression Level on Cycle 1 Day 8 and Cycle 1 Day 21 Relative to That at Baseline	Ribonucleic acid (RNA) was extracted from peripheral blood and used as a template to synthesize complementary deoxyribonucleic acid (cDNA). Gene expression in cDNA was measured by custom Taqman low density array (TLDA) cards run on Applied Biosystems 7900HT Fast Real-Time polymerase chain reaction (PCR) system. Changes from baseline were calculated as ratios to baseline. Results were reported Only for Hes4 as this was the only gene to show consistent down modulation across dosing cohorts (150 mg and 220 mg).	Baseline (morning), Cycle 1 Days 8 and 21 (pre-dose)
Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Participants	Notch intracellular domain (NICD) levels was measured in peripheral blood mononuclear cell (PBMC) pellets using a validated enzyme-linked immunosorbent assay (ELISA).	Baseline, Cycle 1 Days 8 and 15 (pre-dose AM), Cycle 1 Day 21 (pre-dose AM and 24, 48 and 120 hr post-dose) and end of treatment (EOT).
Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Bone Marrow for T-ALL/LBL Participants	Notch intracellular domain (NICD) was to be measured in bone marrow monoculear cell (BMMC) cell pellets using a validated ELISA.	Baseline, Cycle 1 Day 1 and Cycle 2 Day 1

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General Publications

• Tabares-Seisdedos R, Rubenstein JL. Inverse cancer comorbidity: a serendipitous opportunity to gain insight into CNS disorders. Nat Rev Neurosci. 2013 Apr;14(4):293-304. doi: 10.1038/nrn3464.
• Papayannidis C, DeAngelo DJ, Stock W, Huang B, Shaik MN, Cesari R, Zheng X, Reynolds JM, English PA, Ozeck M, Aster JC, Kuo F, Huang D, Lira PD, McLachlan KR, Kern KA, Garcia-Manero G, Martinelli G. A Phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J. 2015 Sep 25;5(9):e350. doi: 10.1038/bcj.2015.80. No abstract available.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2009
• Primary Completion (Actual): January 10, 2013
• Study Completion (Actual): November 22, 2016

Study Registration Dates

• First Submitted: April 6, 2009
• First Submitted That Met QC Criteria: April 6, 2009
• First Posted (Estimate): April 8, 2009

Study Record Updates

• Last Update Posted (Actual): November 12, 2019
• Last Update Submitted That Met QC Criteria: October 21, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Phase 1 dose escalation study in advanced solid tumor malignancy and leukemia
• Additional Relevant MeSH Terms: Neoplasms; Leukemia; Neoplasms by Histologic Type
• Other Study ID Numbers: A8641014; 2010-022036-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.