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A Study Of PF-06463922 An ALK/ROS1 Inhibitor In Patients With Advanced Non Small Cell Lung Cancer With Specific Molecular Alterations

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Pfizer
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT01970865
First received: October 16, 2013
Last updated: March 14, 2017
Last verified: March 2017
  Purpose
Phase 1 and 2 trial to study the safety, pharmacokinetics, pharmacodynamics, patient reported outcomes and efficacy of PF-06463922 in ALK + advanced non-small cell lung cancer patients and ROS1+ advanced non small cell lung cancer patients .

Condition Intervention Phase
ALK-positive Non Small Cell Lung Cancer (NSCLC) and ROS1-positive NSCLC
Drug: PF-06463922
Drug: Crizotinib
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase 1/2 Study Of Pf-06463922 (an Alk/ros1 Tyrosine Kinase Inhibitor) In Patients With Advanced Non-small Cell Lung Cancer Harboring Specific Molecular Alterations

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Percentage of Patients with Overall and Intracranial Objective Response (Phase 2) [ Time Frame: Every 6 weeks from the time of patient enrollment up to 4 years ]
    Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1.

  • Cycle 1 Dose Limiting Toxicities (DLTs). (Phase 1) [ Time Frame: One (1) cycle (21 days) ]
    Number of patients reporting DLTs during Cycle 1 of treatment.


Secondary Outcome Measures:
  • Adverse Events [ Time Frame: First dose of study drug through 28 days after the last dose of study drug ]
    Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.

  • Change from Baseline in Mini Mental State Examination (MMSE) across treatment cycles (Phase 1) [ Time Frame: Prior to dosing (Day -7 or Cycle 1 Day 1), Every 3 weeks from the time of enrollment up to 4 years ]
    MMSE measured general cognitive functioning: orientation, memory, attention, calculation, language, visuospatial functions. Total score derived from sub-scores; total ranges from 0 to 30, higher score indicates better cognitive state. Change: across treatment cycles

  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to first dose of treatment ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

  • Volume of Distribution at Steady State (Vz/F) (Phase 1 and first 10 patients in Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  • Maximum Observed Plasma Concentration (Cmax)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  • Area Under the Curve from Time Zero to end of dosing interval (AUCtau)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose of treatment ]
  • Apparent Volume of Distribution (Vz/F)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

  • Plasma Decay Half-Life (t1/2) (Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

  • Urine clearance of drug (Clr) for subjects in food effect and Midazolam substudy (Phase 1) [ Time Frame: Pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  • Urine Ae% for subjects in food effect and Midazolam substudy (Phase 1) [ Time Frame: Pre Cycle 1 Day 15 dose of treatment ]
  • Maximum Observed Plasma Concentration (Cmax) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  • Time to Reach Maximum Observed Plasma Concentration (Tmax) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to first dose and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast) after administration of MDZ

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)](Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).

  • Plasma Decay Half-Life (t1/2) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    Plasma decay half-life is the time measured for the plasma concentration to decrease by one half after administration of MDZ

  • Apparent Oral Clearance (CL/F) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood after administration of MDZ

  • Apparent Oral Clearance (CL/F) (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

  • Area Under the Curve From Time Zero to Last Quantifiable Concentration (AUClast)(Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment ]
    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast)

  • Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - 8)](Phase 1 and first 10 patients in Phase 2) [ Time Frame: 7 days prior to the first dose of treatment ]
    AUC (0 - 8)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - 8). It is obtained from AUC (0 - t) plus AUC (t - 8).

  • Selective molecular profiling of circulating nucleic acids (CNA) [ Time Frame: Within 28 days of first dose of treatment, at the end of Cycle 2 (Phase 2 only) and at 28 days after the last dose of treatment ]
    Selective molecular profiling of circulating nucleic acids (CNA) at the end of treatment visit defined as 28 days after the last treatment administration.

  • Selective molecular profiling of tumor tissue [ Time Frame: Within 28 days prior to first dose of treatment ]
    Blood specimen optimized for plasma preparation for nucleic acid analysis will be collected at screening and at end of treatment.

  • QTc interval [ Time Frame: Within 28 days prior to first dose of treatment, 7 days prior to the first dose of treatment and Day 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-5 and 28 days after the last dose of treatment ]
    ECGs performed to assess QTc (msec) at baseline and on study treatment and at the end of treatment visit defined as 28 days after the last treatment administration.

  • Patient reported Outcomes [ Time Frame: Prior to first dosing (Day -7 or Cycle 1 Day 1), Day 1 of every cycle, pre dose, up to 4 years and at 28 days after the last dose of treatment ]
    To assess impact of disease /treatment related symptoms of lung cancer and quality of life at D1 of every cycle and at the end of treatment visit defined as 28 days after the last treatment administration.

  • Duration of Response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
    DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first.

  • Progression-Free Survival (PFS) [ Time Frame: Every 6 weeks from the time of enrollment to the first documented progression or date of death from any cause, assessed up to 4 years ]
    The period from study entry until disease progression, death or date of last contact.

  • Overall Survival (OS) [ Time Frame: From the time of enrollment until the date of death from any causes at 18 months and 1 year. ]
    Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact.

  • Disease Control Rate (DCR) [ Time Frame: Every 12 weeks from the time of enrollment up to 4 years ]
    DCR is defined as the percent of patients with a confirmed complete response (CR), partial response (PR) or stable disease (SD) according to RECIST 1.1, at 6 weeks.

  • Objective tumor response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
    Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1.

  • Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Within 28 days prior to the first dose of treatment, pre dose on Day 1 of Cycle 2, pre dose on Day 1 of Cycle 3, pre dose on Day 1 of Cycle 5 and pre dose on Day 1 of every 2 Cycles thereafter; and at 28 days after the last dose of treatment ]
    Left Ventricular Ejection Fraction percentage change by echocardiogram or by multigated acquisition gated scan (MUGA)

  • Apparent Volume of Distribution (Vz/F) for subjects in Midazolam substudy (Phase 1) [ Time Frame: 7 days prior to the first dose of treatment and pre-dose, 0.5, 1, 2,3, 4, 6, 8, 9 and 24 hours post Cycle 1 Day 15 dose ]
    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

  • Time to Tumor Response [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
    TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). For patients whose OR proceeds from PR to CR, the onset of PR is taken as the onset of response. TTR will only be calculated for the subgroup of patients with a confirmed objective tumor response.

  • Time to Tumor Progression (Phase 2) [ Time Frame: From the time of enrollment up to 4 years ]
    TTP is defined as the time from first dose to first documentation of objective disease progression.

  • Time to Intracranial progression (Phase 2) [ Time Frame: From the time of enrollment up to 4 years. ]
    Time to Intracranial Progression is defined as the time from first dose to first documentation of objective intracranial disease progression.

  • Time to Extracranial Progression (Phase 2) [ Time Frame: From the time of enrollment up to 4 years. ]
    Time to Extracranial defined as the time from first dose to first documentation of objective extracranial disease progression.

  • Vital signs [ Time Frame: First dose of study medication through 28 days after the last dose of study medication. ]
    heart rate and blood pressure.

  • Cognitive Function Assessment (Phase 2) [ Time Frame: Within 28 days of first dose of study drug, Baseline (either Day -7 or Cycle 1 Day 1), Day 1 of Cycles 2-6 and then Day 1 of every other Cycle and at the end of treatment visit as defined by 28 days after the last dose of study drug. ]
    An assessment of cognitive function via a computerized cognitive test compromised of verbal learning, psychomotor function, attention and memory.

  • Adverse events for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Within 2 Weeks prior to first dose of crizotinib through 28 days of the last dose of crizotinib ]
    Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.03), seriousness and relationship to study therapy.

  • Laboratory abnormalities for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Within 2 Weeks of first dose of crizotinib through 28 days after the last dose of crizotinib ]
    Laboratory abnormalities as characterized by type, frequency, and severity (as graded by NCI CTCAE v.4.03).

  • Objective tumor response, as assessed by Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1 for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Every 6 weeks from the time of enrollment up to 4 years ]
    Percentage of patients with OR based assessment of intracranial and overall confirmed complete remission (CR) or confirmed partial remission (PR) according to a modified Response Evaluation Criteria in Solid Tumors (RECIST)v 1.1.

  • Progression Free Survival (PFS) for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Every 6 weeks from the time of enrollment to the first documented progression or date of death from any cause, assessed up to 4 years ]
    The period from study entry to disease progression of death due to any cause or until last contact

  • Duration of Response for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Every 6 weeks from time of enrollment up to 4 years ]
    DR is defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurs first

  • Time to Tumor Response in patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: Every 6 weeks from time of enrollment up to 4 years ]
    TTR is defined as the time from first dose to first documentation of objective tumor response (CR or PR). For patients whose OR proceeds from PR to CR, the onset of PR is taken as the onset of response. TTR will only be calculated for the subgroup of patients with a confirmed objective tumor response.

  • Overall Survival for patients receiving crizotinib following PF-06463922 (Phase 2) [ Time Frame: From the time of enrollment until the date of death from any causes ]
    Overall survival was the duration from enrollment to death. For participants who are alive, overall survival was censored at the last contact

  • Mood Assessment (Phase 2) [ Time Frame: Baseline (either Day -7 or Cycle 1 Day 1), Day 1 of Cycles 2-6 and then Day 1 of every other Cycle and at the end of treatment visit as defined by 28 days after the last dose of study drug. ]
    An assessment of mood via the Beck Depression Inventory-II (BDI-II) scale.

  • Suicidal Ideation and Behavior Assessment (Phase 2) [ Time Frame: Baseline (either Day -7 or Cycle 1 Day 1), Day 1 of Cycles 2-6 and then Day 1 of every other Cycle and at the end of treatment visit as defined by 28 days after the last dose of study drug ]
    An assessment of suicidal ideation and behavior via the Columbia Suicide Severity Rating Scale (C-SSRS).

  • Laboratory abnormalities [ Time Frame: First dose of study drug through 28 days after the last dose of study drug. ]
    Laboratory abnormalities as characterized by type, frequency, and severity (as graded by NCI CTCAE v.4.03).


Estimated Enrollment: 340
Actual Study Start Date: January 8, 2014
Estimated Study Completion Date: April 10, 2018
Estimated Primary Completion Date: March 15, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PF-06463922 Drug: PF-06463922
Oral, starting dose 10mg once a day, dose escalation in Phase 1 until recommended Phase 2 dose determined, continuous daily dosing, cycles lasting 21 days
Crizotinib
ALK+ NSCLC patients who are treatment naïve may be eligible to receive crizotinib following PF-06463922 as a substudy to the main study.
Drug: Crizotinib
Oral, starting dose of 250 mg BID continuous daily dosing every 21 days
Other Name: Xalkori

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Evidence of histologically or cytologically confirmed diagnosis of metastatic NSCLC (Stage IV, AJCC v7.0) that carries an ALK rearrangement, as determined by the Food and Drug Administration (FDA) approved FISH assay (Abbott Molecular Inc) or by Immunohistochemistry (IHC) (Ventana Inc), or a ROS1 rearrangement as determined by FISH or RT PCR or Next Generation Sequencing (NGS) via a local diagnostic test (LDT). All patients (ALK positive and ROS1 positive) must have archival tissue sample available and collected prior to enrollment.
  • Disease Status Requirements:

Phase 1: ALK-positive NSCLC and ROS1-positive patients must either be treatment naïve in the advanced setting or have had disease progression after at least 1 previous ALK/ROS1 inhibitor therapy(ies).

Phase 2:

ALK-positive NSCLC patients must either be or have had:

  • Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ALK inhibitor therapy allowed).
  • Disease progression after crizotinib only. No prior chemotherapy is allowed in the metastatic disease setting.
  • Disease progression after crizotinib and 1 or 2 prior regimens of chemotherapy in the metastatic disease setting.
  • Disease progression after 1 prior ALK inhibitor therapy other than crizotinib. Patients may have had any number of prior chemotherapy regimens in any disease setting.
  • Disease progression after 2 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.
  • Disease progression after 3 prior ALK inhibitor therapies. Patients may have had any number of prior chemotherapy regimens in any disease setting.

ROS1-positive NSCLC patients may be:

  • Treatment naïve (ie, no prior chemotherapy in the metastatic disease setting and no prior ROS inhibitor therapy).
  • Any number of prior therapies (ie, chemotherapy and/or ROS inhibitor therapies).

    • Tumor Requirements:

All Patients must have at least one measurable target extracranial lesion according to RECIST v1.1. In addition patients with asymptomatic CNS metastases (including patients asymptomatic by means of stable or decreasing doses of steroids within the last 2 weeks prior to study entry) will be eligible. Patients who have leptomeningeal disease (LM) or carcinomatous meningitis (CM) are eligible.

  • Adequate Bone Marrow, Pancreatic Function, Renal Function and Liver Function.
  • Negative Serum pregnancy test for females of childbearing potential Exclusion Criteria
  • Radiation therapy (except palliative to relieve bone pain) within 2 weeks of study entry. Whole brain radiation must have completed at least 4 weeks prior to study entry.
  • Systemic anti cancer therapy completed within a minimum of 5 half lives of study entry.
  • Prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including, but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody.
  • Active and clinically significant bacterial, fungal, or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness.
  • Clinically significant cardiovascular disease (that is, active or <3 months prior to enrollment): cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), second-degree or third-degree AV block (unless paced) or any AV block with PR >220 msec. Ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, uncontrolled atrial fibrillation of any grade, bradycardia defined as <50 bpm (unless patient is otherwise healthy such as long-distance runners, etc.), machine-read ECG with QTc >470 msec, or congenital long QT syndrome.
  • History of extensive, disseminated, bilateral or presence of Grade 3 or 4 interstitial fibrosis or interstitial lung disease including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, obliterative bronchiolitis and pulmonary fibrosis.
  • Current use or anticipated need for food or drugs that are known strong or moderate CYP3A4 inhibitors, inducers and substrates; drugs that are CYP2C9 substrates; drugs that are sensitive CYP2B6 substrates; drugs that are strong CYP2C19 inhibitors; drugs that are strong CYP2C8 inhibitors; and drugs that are P-gp substrates.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01970865

Contacts
Contact: Pfizer CT.gov Call Center 1-800-718-1021

  Show 77 Study Locations
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01970865     History of Changes
Other Study ID Numbers: B7461001
2013-002620-17 ( EudraCT Number )
Study First Received: October 16, 2013
Last Updated: March 14, 2017

Keywords provided by Pfizer:
Phase 1
Phase 2
safety
pharmacokinetic
pharmacodynamic
efficacy

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Crizotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 22, 2017