A Trial In Patients With Advanced Cancer And Leukemia

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

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

Conditions
-----------------
Neoplasms by Histologic Type

Intervention / Treatment
-----------------
* Drug: PF-03084014


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: PF-03084014<br>* 10 mg, 50 mg or 100 mg tablets. Patients dosed from 20 mg - 500 mg, twice daily<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Phase 1 dose escalation study in advanced solid tumor malignancy and leukemia