Clinical trial NCT00927823: A Trial To Assess Safety And Tolerability Of PF-04691502 In Cancer Patients
Official title: A Phase 1, Open-Label, Dose-Escalation Study To Evaluate Safety, Pharmacokinetics, And Pharmacodynamics Of The PI3K/MTOR Inhibitor PF-04691502 In Adult Patients With Advanced Malignant Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cancer
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2009-06-25
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A phase 1 dose-escalation trial to assess the safety, tolerability, and pharmacodynamics of PF-04691502 in adult cancer patients with solid tumors.


Eligibility criteria: Inclusion Criteria:

* Patients with a histologically or cytologically confirmed malignant solid tumor for which there is no currently approved treatment or which is unresponsive to currently approved therapies.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
* Female patients of childbearing potential must have a negative serum or urine pregnancy test within 72 hours of the first dose of PF-04961502, These patients or their partners must be surgically sterile or be postmenopausal, or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. Male patients or their partners must be surgically sterile or must agree to use effective contraception while receiving trial treatment and for at least 3 months thereafter. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate
* Adequate Bone Marrow Function, including:

  1. Absolute neutrophil count (ANC) ≥1500 cells/mm3
  2. Platelets ≥75,000 cells/mm3
  3. Hemoglobin ≥9 mg/dL
* Adequate Renal Function, including:

SrCr \<1.5 x ULN (upper limit of normal). OR Estimated creatinine clearance ≥60 mL/min, as calculated using method standard for the institution

* Adequate Liver Function, including:

Bilirubin ≤1.5 x ULN AST (SGOT) ≤2.5 x ULN ALT (SGPT) ≤2.5 x ULN

* Adequate glucose control, including no previous diagnosis of diabetes mellitus and HbA1c \<7%.
* Adequate Cardiac Function, including:

  12-Lead electrocardiogram (ECG) with normal tracing or non clinically significant changes that do not require medical intervention. QTc interval ≤470 msec and no history of Torsades des Pointes or other symptomatic QTc abnormality

Exclusion Criteria:

* Patients with known active brain metastases. Patients with previously diagnosed brain metastases are eligible if they have completed their CNS treatment and have recovered from the acute effects of radiation therapy or surgery prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable
* Chemotherapy, radiotherapy (other than palliative radiotherapy to lesions that will not be followed for tumor assessment on this study, ie, non target lesions), biological or investigational agents within 2 weeks of Baseline disease assessments
* Any surgery (not including minor procedures such as lymph node biopsy) within 4 weeks of Baseline disease assessments; or not fully recovered from any side effects of previous procedures
* Prior therapy with an agent that is known or proposed to be active by action on PI3K and/or mTOR
* Prior high-dose chemotherapy requiring hematopoetic stem cell transplantation within 12 months of study treatment start
* Uncontrolled or significant cardiovascular disease:

A myocardial infarction within 12 months Uncontrolled angina within 6 months Congestive heart failure within 6 months. Diagnosed or suspected congenital long QT syndrome. Any history of ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Any history of second or third degree heart block (may be eligible if currently have a pacemaker) Heart rate \<50/minute on pre-entry electrocardiogram Uncontrolled hypertension.

* Current use or anticipated need for food or drugs that are known potent CYP3A4 inhibitors or inducers
* Current use or anticipated need for food or drugs that are known potent CYP1A2 inhibitors or inducers
* Concurrent administration of herbal preparations
* Breast feeding: No studies have been conducted in humans to assess the impact of PF-04691502 on milk production, its presence in breast milk and its effects on the breast-fed child. Because drugs are commonly excreted in human milk and because of the potential for serious adverse reactions in nursing infants, lactating female patients are excluded from this study.
* Any clinically significant gastrointestinal abnormalities, which may impair intake, transit or absorption of the study drug, such as the inability to take oral medication in tablet form and malabsorption syndrome.
* Any mental disorder that would limit the understanding or rendering of informed consent and/or compromise compliance with the requirements of this protocol

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)
timeFrame: Baseline up to 28 days after the last dose
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline up to Cycle 1 Day 21
measure: Recommended Phase-2 Dose (RP2D)
timeFrame: Baseline up to Cycle 1 Day 21
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on Cycle 1 Day 21 (C1D21)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hours post-dose on C1D21
measure: Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period
measure: Plasma Decay Half-Life (t1/2)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours (hrs) post-dose in Lead-in period; pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21
measure: Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)]
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, 48, 72, 96 hours post-dose in Lead-in period
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24 hrs post-dose on C1D21
measure: Number of Participants With Increase From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT
measure: Number of Participants With Maximum Post-dose QT Interval Corrected Using Fridericia's Formula (QTcF)
timeFrame: Pre-dose, 30 minutes, 1, 2, 4, 8, 24, 48, hrs post-dose in Lead-in period; 1 hour post-dose on C1D8, C1D15; 1, 2, 4, 8 hours post-dose on C1D21; 1 hour post-dose C2D1, C2D15, D1 of subsequent cycles up to C8; EOT
measure: Change From Baseline in Serum Glucose at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)
timeFrame: Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT
measure: Change From Baseline in Serum Insulin at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)
timeFrame: Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT
measure: Change From Baseline in Serum C-peptide at Cycle 1 Day 8 (C1D8), C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and End of Treatment (EOT)
timeFrame: Baseline, C1D8, C1D15, C2D1, C2D15, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1 and EOT
measure: Change From Baseline in Fresh Tumor Biopsy Biomarkers at Cycle 1 Day 21
timeFrame: Baseline; 4 hours post-dose on C1D21
measure: Change From Baseline in Hair Follicle Biopsy Biomarkers at Cycle 1 Day 21
timeFrame: Baseline; pre-dose, 2, 4, 24 hours post-dose on C1D21
measure: Number of Participants With Mutation, Deletion, Amplification in Phosphatidylinositol 3-kinase (PI3K) Pathway Signaling Related Genes and/or Proteins in Biopsied Tumor Tissue
timeFrame: Baseline; 4 hours post-dose on C1D21
measure: Number of Participants With Objective Response
timeFrame: Baseline, prior to Day 1 of Cycle every odd-numbered cycle or when progressive disease was suspected
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Los Angeles
country: United States
facility: Pfizer Investigational Site
state: California
city: Santa Monica
country: United States
facility: Pfizer Investigational Site
state: California
city: Detroit
country: United States
facility: Pfizer Investigational Site
state: Michigan
city: Amherst
country: United States
facility: Pfizer Investigational Site
state: New York
city: Buffalo
country: United States
facility: Pfizer Investigational Site
state: New York
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: