Clinical trial NCT00878189: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms by Histologic Type
Keywords: Phase 1 dose escalation study in advanced solid tumor malignancy and leukemia
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-04-08
Enrollment: 72
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Primary purpose: TREATMENT

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


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

Primary outcomes:
measure: Number of Solid Tumor Participants With First-Cycle Dose-Limiting Toxicity (DLT)
timeFrame: Baseline to the end of Cycle 1 (Week 4)
measure: Number of T-ALL/LBL Participants With First-Cycle DLT
timeFrame: Baseline to the end of Cycle 1 (Week 4)
Secondary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality)
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Number of Participants With TEAEs (Treatment-Related)
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (All Causality) by Severity (by Maximum Common Terminology Criteria for Adverse Events [CTCAE] Grade)
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Number of Participants With TEAEs (Treatment-Related) by Severity (by Maximum CTCAE Grade)
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Number of Participants With Potentially Clinical Significant Categorical Changes From Baseline in Electrocardiogram (ECG) Findings in QTc Interval
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Number of Participants With Laboratory Tests Abnormalities Meeting the Criteria of Potential Clinical Concern (Hematology and Chemistries, All Cycles)
timeFrame: Baseline up to end of study (maximum of 84 months)
measure: Maximum Observed Serum Concentration (Cmax) After a Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
measure: Dose-normalized Cmax [Cmax (dn)] After a Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
measure: Area Under the Time-Concentration Curve From Time 0 to the Dosing Interval (AUCtau) After a Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
measure: Dose-normalized AUCtau [AUCtau (dn) ] After a Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
measure: Time to Reach Cmax (Tmax) After a Single Dose on Cycle 1 Day 1
timeFrame: Cycle 1 Day 1 (pre-dose and 0.5, 1, 2, 4, and 10 hr post-dose)
measure: Cmax After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Time to Reach Cmax (Tmax) After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: AUCtau After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Apparent Volume of Distribution (Vz/F) on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Serum Decay Half-Life (t1/2) After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Apparent Oral Clearance (CL/F) on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Minimum Observed Serum Concentration (Cmin) After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Average Serum Concentration (Cavg) at Steady State on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Accumulation Ratio (Rac) on Cycle 1 Day 21
timeFrame: 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)
measure: Dose-normalized AUCtau [AUCtau (dn)] After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: Dose-normalized Cmax [Cmax (dn)] After Multiple Dose on Cycle 1 Day 21
timeFrame: Cycle 1 Day 21 (pre-dose and 0.5, 1, 2, 4, 10, 24, 48, 96 and 120 hr post-dose)
measure: AUCtau in the Fasted State for Solid Tumor Participants
timeFrame: 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)
measure: AUCtau in the Fed State for Solid Tumor Participants
timeFrame: 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)
measure: Cmax in the Fasted State for Solid Tumor Participants
timeFrame: 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)
measure: Cmax in the Fed State for Solid Tumor Participants
timeFrame: 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)
measure: Dose-normalized AUCtau [AUCtau(dn)] in the Fasted State for Solid Tumor Participants
timeFrame: 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)
measure: Dose-normalized AUCtau [AUCtau(dn)] in the Fed State for Solid Tumor Participants
timeFrame: 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)
measure: Dose-normalized Cmax [Cmax(dn)] in the Fasted State for Solid Tumor Participants
timeFrame: 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)
measure: Dose-Normalized Cmax [Cmax(dn)] in the Fed State for Solid Tumor Participants
timeFrame: 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).
measure: AUCtau on Cycle 2 Day 1
timeFrame: Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
measure: Dose-normalized AUCtau [AUCtau (dn)] on Cycle 2 Day 1
timeFrame: Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
measure: Cmax on Cycle 2 Day 1
timeFrame: Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
measure: Dose-normalized Cmax [Cmax (dn)] on Cycle 2 Day 1
timeFrame: Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
measure: Tmax on Cycle 2 Day 1
timeFrame: Cycle 2 Day 1 (pre-dose and 0.5, 1, 2, 4, 10 and 24 hr post-dose)
measure: Percentage of Solid Tumor Participants With Objective Response (OR)
timeFrame: 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
measure: Time to Tumor Progression (TTP) for Solid Tumor Participants
timeFrame: Baseline until first documented objective progression (up to maximum of 84 months)
measure: Duration of Response (DR) for Solid Tumor Participants
timeFrame: 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)
measure: Progression-Free Survival (PFS) for Solid Tumor Participants
timeFrame: 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)
measure: Percentage of T-ALL/LBL Participants With OR
timeFrame: 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)
measure: Relapse Free Survival (RFS) for T-ALL/LBL Participants
timeFrame: 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)
measure: Peripheral Blast Count Reduction (PBR) for T-ALL/LBL Participants
timeFrame: 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)
measure: 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
timeFrame: Baseline, Cycle 1 Day 21 (-5 days)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: Baseline (morning), Cycle 1 Days 8 and 21 (pre-dose)
measure: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Peripheral Blood for T-ALL/LBL Participants
timeFrame: 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).
measure: Changes From Baseline in Notch Intracellular Domain (NICD) Levels in Bone Marrow for T-ALL/LBL Participants
timeFrame: Baseline, Cycle 1 Day 1 and Cycle 2 Day 1
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Anschutz Cancer Pavilion
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver CTRC
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Boston
country: United States
facility: Massachusetts General Hospital Clinical Laboratory
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Ferber Cancer institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center / Wayne State University
state: Michigan
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Bologna
country: Italy
facility: DIPRTMNT CLIN Scienze RADIOL e Istocitopatologiche
city: Bologna
country: Italy
facility: Istituto di Ematologia Seragnoli
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
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.
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.