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A Trial In Patients With Advanced Cancer And Leukemia

Primary Purpose

Neoplasms by Histologic Type

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

PF-03084014

About this trial

This is an interventional treatment trial for Neoplasms by Histologic Type focused on measuring Phase 1 dose escalation study in advanced solid tumor malignancy and leukemia

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Arm Description

Outcomes

Primary Outcome Measures

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

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

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

Cmax was the maximum observed serum concentration.

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.

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.

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.

Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

Tmax was the time to reach maximum serum concentration (Cmax).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

Cmax in the Fasted State for Solid Tumor Participants

Cmax was the maximum observed serum concentration.

Cmax in the Fed State for Solid Tumor Participants

Cmax was the maximum observed serum concentration.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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%.

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.

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.

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.

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).

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

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).

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.

Full Information

NCT ID

NCT00878189

First Posted

April 6, 2009

Last Updated

October 21, 2019

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT00878189

Brief Title

A Trial 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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Completed

Study Start Date

June 25, 2009 (Actual)

Primary Completion Date

January 10, 2013 (Actual)

Study Completion Date

November 22, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms by Histologic Type

Keywords

Phase 1 dose escalation study in advanced solid tumor malignancy and leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

72 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

PF-03084014

Other Intervention Name(s)

gamma secretase inhibitor

Intervention Description

10 mg, 50 mg or 100 mg tablets. Patients dosed from 20 mg - 500 mg, twice daily

Primary Outcome Measure Information:

Title

Number of Solid Tumor Participants With First-Cycle Dose-Limiting Toxicity (DLT)

Description

Time Frame

Baseline to the end of Cycle 1 (Week 4)

Title

Number of T-ALL/LBL Participants With First-Cycle DLT

Description

Time Frame

Baseline to the end of Cycle 1 (Week 4)

Secondary Outcome Measure Information:

Title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality)

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Number of Participants With TEAEs (Treatment-Related)

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality) by Severity (by Maximum Common Terminology Criteria for Adverse Events [CTCAE] Grade)

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Number of Participants With TEAEs (Treatment-Related) by Severity (by Maximum CTCAE Grade)

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Number of Participants With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Number of Participants With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)

Description

Time Frame

Baseline up to end of study (maximum of 84 months)

Title

Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1

Description

Cmax was the maximum observed serum concentration.

Time Frame

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

Title

Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1

Description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.

Time Frame

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

Title

Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1

Description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval). CV is the coefficient of variation.

Time Frame

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

Title

Dose-normalized AUCtau [AUCtau (dn) ] After a Single Dose on Cycle 1 Day 1

Description

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.

Time Frame

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

Title

Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1

Description

Tmax was the time to reach maximum serum concentration (Cmax).

Time Frame

Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)

Title

Cmax After Multiple Dose on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Time to Reach Cmax (Tmax) After Multiple Dose on Cycle 1 Day 21

Description

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.

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

AUCtau After Multiple Dose on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Apparent Oral Clearance (CL/F) on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21

Description

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.

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21

Description

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.

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Accumulation Ratio (Rac) on Cycle 1 Day 21

Description

Time Frame

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)

Title

Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21

Description

Time Frame

Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)

Title

AUCtau in the Fasted State for Solid Tumor Participants

Description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval).

Time Frame

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)

Title

AUCtau in the Fed State for Solid Tumor Participants

Description

AUCtau was area under the serum concentration-time profile from time 0 to tau (dosing interval).

Time Frame

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)

Title

Cmax in the Fasted State for Solid Tumor Participants

Description

Cmax was the maximum observed serum concentration.

Time Frame

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)

Title

Cmax in the Fed State for Solid Tumor Participants

Description

Cmax was the maximum observed serum concentration.

Time Frame

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)

Title

Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Participants

Description

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose.

Time Frame

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)

Title

Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Participants

Description

AUCtau(dn) was calculated by area under the serum concentration-time profile from time 0 to tau (dosing interval) (AUCtau) divided by administered dose.

Time Frame

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)

Title

Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Participants

Description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.

Time Frame

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)

Title

Dose-Normalized Cmax [Cmax(dn)] in the Fed State for Solid Tumor Participants

Description

Cmax(dn) was calculated by maximum observed serum concentration (Cmax) divided by administered dose.

Time Frame

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).

Title

AUCtau on Cycle 2 Day 1

Description

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.

Time Frame

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Title

Dose-normalized AUCtau [AUCtau (dn)] on Cycle 2 Day 1

Description

Time Frame

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Title

Cmax on Cycle 2 Day 1

Description

Cmax was the maximum observed serum concentration. Data for this outcome measure was planned to be analyzed for two arms only.

Time Frame

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Title

Dose-normalized Cmax [Cmax (dn)] on Cycle 2 Day 1

Description

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.

Time Frame

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Title

Tmax on Cycle 2 Day 1

Description

Tmax was the time to reach maximum serum concentration (Cmax). Data for this outcome measure was planned to be analyzed for two arms only.

Time Frame

Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)

Title

Percentage of Solid Tumor Participants With Objective Response (OR)

Description

Time Frame

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

Title

Time to Tumor Progression (TTP) for Solid Tumor Participants

Description

Time Frame

Baseline until first documented objective progression (up to maximum of 84 months)

Title

Duration of Response (DR) for Solid Tumor Participants

Description

Time Frame

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)

Title

Progression-Free Survival (PFS) for Solid Tumor Participants

Description

Time Frame

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)

Title

Percentage of T-ALL/LBL Participants With OR

Description

Time Frame

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)

Title

Relapse Free Survival (RFS) for T-ALL/LBL Participants

Description

Time Frame

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)

Title

Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Participants

Description

Time Frame

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)

Title

Description

Time Frame

Baseline, Cycle 1 Day 21 (-5 days)

Title

Description

Time Frame

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)

Title

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

Description

Time Frame

Baseline (morning), Cycle 1 Days 8 and 21 (pre-dose)

Title

Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Participants

Description

Notch intracellular domain (NICD) levels was measured in peripheral blood mononuclear cell (PBMC) pellets using a validated enzyme-linked immunosorbent assay (ELISA).

Time Frame

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).

Title

Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Bone Marrow for T-ALL/LBL Participants

Description

Notch intracellular domain (NICD) was to be measured in bone marrow monoculear cell (BMMC) cell pellets using a validated ELISA.

Time Frame

Baseline, Cycle 1 Day 1 and Cycle 2 Day 1

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Pfizer CT.gov Call Center

Organizational Affiliation

Pfizer

Official's Role

Study Director

Facility Information:

Facility Name

Anschutz Cancer Pavilion

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Denver CTRC

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

University of Colorado Hospital

City

Aurora

State/Province

Colorado

ZIP/Postal Code

80045

Country

United States

Facility Name

Massachusetts General Hospital Clinical Laboratory

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

Beth Israel Deaconess Medical Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02115

Country

United States

Facility Name

Dana Ferber Cancer institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Karmanos Cancer Center / Wayne State University

City

Detroit

State/Province

Michigan

ZIP/Postal Code

48201

Country

United States

Facility Name

The University of Texas MD Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030-4009

Country

United States

Facility Name

DIPRTMNT CLIN Scienze RADIOL e Istocitopatologiche

City

Bologna

ZIP/Postal Code

40138

Country

Italy

Facility Name

Istituto di Ematologia Seragnoli

City

Bologna

ZIP/Postal Code

40138

Country

Italy

12. IPD Sharing Statement

Plan to Share IPD

IPD Sharing 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.

Citations:

PubMed Identifier

26407235

Citation

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.

Results Reference

derived

PubMed Identifier

23511909

Citation

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.

Results Reference

derived

Links:

URL

https://trialinfoemail.pfizer.com/pages/landing.aspx?StudyID=A8641014&StudyName=A%20Trial%20In%20Patients%20With%20Advanced%20Cancer%20And%20Leukemia

Description

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A Trial In Patients With Advanced Cancer And Leukemia

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A Trial In Patients With Advanced Cancer And Leukemia

Neoplasms by Histologic Type

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial