Clinical trial NCT01000025: PF-00299804 in Stage IIIB or Stage IV Non-Small Cell Lung Cancer Not Responding to Standard Therapy for Advanced or Metastatic Cancer
Official title: A Double Blind Placebo Controlled Randomized Trial of PF-804 in Patients With Incurable Stage IIIB/IV Non-Small Cell Lung Cancer After Failure of Standard Therapy for Advanced or Metastatic Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lung Cancer
Keywords: stage IIIB non-small cell lung cancer
stage IV non-small cell lung cancer
recurrent non-small cell lung cancer
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: Pfizer
First posted: 2009-10-22
Enrollment: 720
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: PF-00299804 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether PF-00299804 is more effective than a placebo in treating patients with advanced non-small cell lung cancer.

PURPOSE: This randomized phase III trial is studying PF-00299804 to see how well it works compared with a placebo in treating patients with stage IIIB or stage IV non-small cell lung cancer that has not responded to standard therapy for advanced or metastatic cancer.

Detailed description: OBJECTIVES:

Primary

* To compare overall survival in patients with incurable stage III or IV non-small cell lung cancer receiving PF-00299804 versus placebo after failure of standard therapy for advanced metastatic disease.

Secondary

* To compare overall survival in KRAS-WT patients between the two arms.
* To compare overall survival in EGFR-mutant patients between the two arms.
* To compare progression-free survival between arms.
* To compare objective response rates between arms.
* To estimate time to response and response duration in these patients.
* To evaluate the nature, severity, and frequency of toxicities between arms.
* To compare quality of life between arms.
* To determine the incremental cost-effectiveness and cost-utility ratios for PF-00299804.
* To correlate the expression of tumor and blood markers (at diagnosis) with outcomes and response.

OUTLINE: This is a multicenter study. Patients are stratified according to center, performance status (0 or 1 vs 2 or 3), tobacco use (never vs past or present), best response to prior EGFR tyrosine kinase inhibitor (progressive disease vs other), weight loss (\< 5% vs ≥ 5% or unknown), and ethnicity (East Asian vs other). Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Blood, serum, plasma, and tissue samples are collected and examined for biomarkers and gene mutations, and may be banked for future studies.

Patients complete quality-of-life questionnaires EORTC QLQ-C30 and other questionnaires at baseline and then periodically during and after completion of study treatment.

Cost effectiveness and cost utility of PF-00299804 is assessed via the Health Utilities Index (EQ-5D) and the Resource Utilization Assessment periodically.

After completion of study treatment, patients are followed at 4 weeks and then every 12 weeks thereafter.

Eligibility criteria: Eligibility Criteria

* Histologically confirmed diagnosis of non-small cell carcinoma of the lung. Patients must have an adequate histopathology or cytology specimen must consent to release of all specimens for this protocol, and the centre/pathologist must have agreed to submission of the specimens.
* Patients must have evidence of disease, but measurable disease is not mandatory. To be considered evaluable for complete or partial response assessment, patients must have at least one measurable lesion as follows:

X-ray ≥ 20 mm Spiral CT scan or physical exam ≥ 10 mm (lymph nodes must be ≥ 15 mm in the short axis); Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented.

* Male or female, 18 years of age or older.
* ECOG performance status of 0, 1, 2 or 3. Patients with performance status of 3 are eligible providing that the investigator attests that the patient has a reasonable life expectancy (≥ 6 weeks).
* Adequate renal and hepatic functions as defined by the following required laboratory values obtained within 14 days prior to randomization. If anemic, patients should be asymptomatic and should not be decompensated.

Creatinine \<1.5 upper limit of normal Total bilirubin \< 1.5 upper limit of normal ALT (SGPT) \< 2.5 times the upper limit of normal. Note: If clearly attributable to liver metastasis, ALT (SGPT) values \< 5 times the upper limit of normal are permitted.

- Previous Therapy Failure of a treatment regimen is defined as the inability to continue a regimen for any reason including, but not limited to, progressive disease, toxicity, or patient request. Up to a maximum of three lines of chemotherapy for advanced/metastatic disease (defined below) and at least one of erlotinib or gefitinib for advanced/ metastatic disease (defined below) should have failed.

Exchange of one chemotherapy agent for another within a combination chemotherapy regimen is not considered a new regimen in the following circumstances

* carboplatin is substituted for cisplatin due to nephrotoxicity
* one agent in the combination regimen is changed due to hypersensitivity occurring in the first cycle.

Chemotherapy for Advanced/Metastatic Disease:

Patients must have recovered from any reversible toxic effects and at least 21 days must have elapsed from the last dose and prior to randomization (14 days from the last dose for chemotherapy regimens administered on a weekly schedule). Further palliative cytotoxic chemotherapy must not be planned.

Patients \< 70 years:

• Must have received 1 and up to a maximum of 3prior chemotherapy regimens (at least one of the three must have been a combination regimen and at least one must have contained platinum).

Patients ≥ 70 years (generally accepted as being at the time of the administration of the first regimen of chemotherapy for advanced disease):

• Must have received 1 and up to a maximum of 3 prior chemotherapy regimens for their disease. These may have been single agent chemotherapy regimens and a platinum agent is not required in keeping with current standards of practice.

Adjuvant Chemotherapy: Patients may ALSO have had prior adjuvant therapy for completely resected disease, providing completed at least 12 months prior to randomization. Adjuvant regimens \< 12 months prior to randomization and combined chemotherapy/radiation regimens for irresectable locally advanced stage III disease (irrespective of timing), are considered to be for advanced/metastatic disease and constitute one of the 3 permissible regimens. Patients must have recovered from any reversible treatment related toxicities prior to randomization.

EGFR Inhibitor Therapy: Patients may only be enrolled after failure of prior gefitinib or erlotinib for advanced or metastatic disease. Patients who have received adjuvant gefitinib or erlotinib for completely resected NSCLC and who have recurred \< 12 months after discontinuing erlotinib or gefitinib are eligible. Patients who received gefitinib or erlotinib for neoadjuvant therapy only are not eligible. EGFR inhibitor therapy must have been discontinued at least 21 days prior to randomization. Patients who discontinued prior gefitinib or erlotinib therapy for severe or life threatening organ toxicity are not eligible. Patients may also have received other EGFR active agents (such as reversible oral agents or monoclonal antibodies or vaccines) in addition to erlotinib or gefitinib but may not have received ANY prior irreversible EGFR inhibitor such as BIBW2992, HKI-272 (neratinib).

Maintenance Therapy: The same chemotherapy or agent/s continued for longer than 4-6 cycles for the purposes of 'maintenance' is considered one regimen; if another chemotherapy agent is given with 'maintenance' intent, it is considered a second regimen providing that 'failure' is documented. Patients who received erlotinib or gefitinib with 'maintenance' intent after completion of 1st line chemotherapy are eligible providing that 'failure' is documented.

Radiation: Patients may have had prior radiation therapy provided that a minimum of 14 days has elapsed between the end of radiotherapy and randomization onto the study. (Exceptions may be made however, for low dose, non-myelosuppressive radiotherapy. Patients must have recovered from any acute toxic effects from radiation prior to randomization.

Previous Surgery: Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed (major surgery).

* Patient able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires. The baseline assessment must already have been completed. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
* Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
* Patients must be accessible for treatment and follow-up. All randomized patients must be followed and treated at participating centres. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
* In accordance with NCIC CTG policy, protocol treatment is to begin within 2 working days of patient randomization.

Ineligibility Criteria

Patients who fulfill any of the following criteria are not eligible for admission to the study:

* Patients receiving concurrent treatment with other experimental drugs or anti-cancer therapy.
* Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, should have a LVEF \> 50%.
* Patients with untreated brain or meningeal metastases are not eligible (CT scans are not required to rule this out unless there is a clinical suspicion of CNS disease). Patients with treated CNS disease who have radiologic or clinical evidence of stable brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion, are eligible providing that they are asymptomatic and do not require corticosteroids (must have discontinued steroids at least 1 week prior to randomization).
* Patients with active or uncontrolled infections, or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol, including

  * Severe dry eye syndrome
  * Keratoconjunctivitis sicca
  * Sjogren's syndrome
  * Severe exposure keratopathy
  * Disorders that might increase the risk for epithelium-related complications (e.g., bullous keratopathy, aniridia, severe chemical burns, neutrophilic keratitis)
  * Uncontrolled inflammatory gastrointestinal diseases (Crohn's, ulcerative colitis etc.)
  * Prior pneumonitis/ILD secondary to EGFR inhibitors
* Mean QTc with Bazetts correction \> 470msec in screening ECG or history of familial long QT syndrome.
* Drugs that are highly dependent on CYP2D6 for metabolism are prohibited, since PF-804 is a potent CYP2D6 inhibitor in in vitro assays. These inhibitors or inducers are prohibited from 7 days prior to the first dose until the end of treatment with PF-804. These include: S-metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, flecainide, mexilletine, tamoxifen, venlafaxine. Lidocaine may be used with clinical monitoring (including telemetry). Opiates such as morphine, oxycodone, dihydrocodeine, hydrocodone, and tramadol can be used as substitutes to replace codeine. Use of these opiates should be monitored for altered analgesia during treatment with PF-804 as they may be partly metabolized by CYP2D6. If PF-804 is administered with drugs which are P-glycoprotein (P-gp) substrates and have a narrow therapeutic index, monitoring for exaggerated effect and/or toxicities is recommended.
* Pregnancy or inadequate contraception. Women must be post-menopausal, surgically sterile, or use two reliable forms of contraception. Women of child-bearing potential must have a pregnancy test taken and proven negative within 7 days prior to randomization. Men must be surgically sterile or use a barrier method of contraception.

Primary outcomes:
measure: Overall Survival
timeFrame: 42 Months
Secondary outcomes:
measure: Overall Survival in KRAS-WT Patients
timeFrame: 42 Months
measure: Overall Survival in EGFR-mutant Patients
timeFrame: 42 Months
measure: Progression-free Survival
timeFrame: 42 Months
measure: Objective Response Rate
timeFrame: 42 months
measure: Number of Participants With Toxicity as Measured by NCI CTCAE Version 4.0
timeFrame: 42 Months
Other outcomes:
Locations:
city: Arcadia
country: United States
facility: Shapiro, Stafford and Yee
state: California
city: Skokie
country: United States
facility: Clintell, Inc.
state: Illinois
city: Buenos Aires
country: Argentina
facility: CER - Instituto Medico
state: B1878dvb Bs. As.
city: Berazategui
country: Argentina
facility: COIBA Centro de Oncologia e Investigacion
state: Provincia De Buenos Aires
city: Cordoba
country: Argentina
facility: Damic-Fundacion Rusculleda
city: San Miguel de Tucuman
country: Argentina
facility: Centro Medico San Roque
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Concord
country: Australia
facility: Concord Repatriation General Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St. George Hospital, Cancer Care Centre
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Nambour
country: Australia
facility: Nambour General Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital - Peninsula Oncology Centre
state: Victoria
city: Geelong
country: Australia
facility: Geelong Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Perth
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Porto Alegre
country: Brazil
facility: Centro de Oncologia e Radioterapia (COR) Mae de Deus
state: Rio Grande Do Sul
city: Brasilia
country: Brazil
facility: ESHO - Empresa de Servicos Hospitalares Ltda.
state: Sao Paulo
city: Barretos
country: Brazil
facility: Fundacao Pio XII - Hospital de Cancer de Barretos
state: SP
city: Porto Alegre
country: Brazil
facility: Centro de Pesquisa Clinica do Hospital
state: SP
city: Belo Horizonte
country: Brazil
facility: Oxion Hospital Dia Oncologia LTDA - Oxion
city: Centro
country: Brazil
city: Salvador
country: Brazil
facility: Nucleo de Oncologia da Bahia
city: Sao Paulo
country: Brazil
facility: GRAM - Grupo de Assistencia Medica
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Abbotsford
country: Canada
facility: BCCA - Abbotsford Centre
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Saint John
country: Canada
facility: Atlantic Health Sciences Corporation
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre at Hamilton Health Sciences
state: Ontario
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Oshawa
country: Canada
facility: Lakeridge Health Oshawa
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Health Research Institute - General Division
state: Ontario
city: Sault Ste. Marie
country: Canada
facility: Algoma District Cancer Program
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Cancer Centre
state: Ontario
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Regina
country: Canada
facility: Allan Blair Cancer Centre
state: Saskatchewan
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
state: Saskatchewan
city: Aviano
country: Italy
facility: Centro di Riferimento Oncologico - CRO
state: PN
city: Saronno
country: Italy
facility: A.O. Busto Arsizio - P.O. Saronno
state: VA
city: Benevento
country: Italy
facility: U.O. di Oncologia Medica Azienda Ospedaliera G Rummo
city: Fano
country: Italy
facility: Ospedale Santa Croce
city: Genova
country: Italy
facility: U.O. di Oncologia Ospedale Villa Scassi
city: Meldola
country: Italy
facility: Intstituto Scientifico Romangnolo
city: Messina
country: Italy
facility: U.O.C. Terapie Integrate in Oncologia,
city: Messina
country: Italy
facility: U.O.C. Oncologia Medica,
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Mirano
country: Italy
facility: U.O.C. di Oncologia U.L.S.S. 13
city: Napoli
country: Italy
facility: Dott. Fortunato Ciardiello,Cattedra Oncologia Medica
city: Napoli
country: Italy
facility: Unita Sperimentazioni Cliniche Istituto per lo
city: Padova
country: Italy
facility: UOC Oncologia Medica II Instituto Oncologio Veneto
city: Palermo
country: Italy
facility: La Maddalena, Dipartimento Oncologico
city: Piacenza
country: Italy
facility: Azienda USL di Piacenza, Ospedale Gugliemimo Salieto
city: Rome
country: Italy
facility: Azienda Ospedaliera S. Camillo-Forlanin
city: Rome
country: Italy
facility: Policlinico Umberto I, Universita Sapienza
city: San Giovanni Rotondo
country: Italy
facility: Ospedale Casa Sollievo della Sofferenza
city: Sondalo
country: Italy
facility: Ospedale E. Morelli-Sondalo
city: GyeongGi-Do
country: Korea, Republic of
facility: Ajou University Hospital
city: Jeongnam
country: Korea, Republic of
facility: Chonnan National University Hwasun Hospital
city: Seoul
country: Korea, Republic of
facility: Yonsei University College of Medicine
city: Seoul
country: Korea, Republic of
facility: Seoul Veterans Hospital
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea,
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Lima
country: Peru
facility: Hospital Central De La Fuerza Aerea Del Peru
city: Lima
country: Peru
facility: Hospital Nacional Luis N. Saenz
city: Lima
country: Peru
facility: Instituto de Oncologia y Radioterapia de
city: Cebu City
country: Philippines
facility: Perpetual Succour Hospital
city: Makati City
country: Philippines
facility: Makati Medical Center
city: Manila
country: Philippines
facility: Phillippine General Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: Chi-Mei Foundation Hospital
city: Taipei
country: Taiwan
facility: Tri-Service General Hospital
city: Bangkok
country: Thailand
facility: Chulalongkorn University
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital, Oncology Unit
city: Chiangmai
country: Thailand
facility: Maharaj Nakorn Chiangmai Hospital
Study officials:
affiliation: Margaret and Charles Juravinski Cancer Centre
name: Peter Ellis, MD
role: STUDY_CHAIR
affiliation: NCIC Clinical Trials Group
name: Penny Bradbury, MD
role: STUDY_CHAIR
affiliation: Sir Charles Gairdner Hospital - Nedlands
name: Michael Millward, MD
role: STUDY_CHAIR
References:
citation: Ellis PM, Shepherd FA, Millward M, Perrone F, Seymour L, Liu G, Sun S, Cho BC, Morabito A, Leighl NB, Stockler MR, Lee CW, Wierzbicki R, Cohen V, Blais N, Sangha RS, Favaretto AG, Kang JH, Tsao MS, Wilson CF, Goldberg Z, Ding K, Goss GD, Bradbury PA; NCIC CTG; Australasian Lung Cancer Trials Group; NCI Naples Clinical Trials Unit. Dacomitinib compared with placebo in pretreated patients with advanced or metastatic non-small-cell lung cancer (NCIC CTG BR.26): a double-blind, randomised, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1379-88. doi: 10.1016/S1470-2045(14)70472-3. Epub 2014 Oct 15.
citation: Martin P, Shiau CJ, Pasic M, Tsao M, Kamel-Reid S, Lin S, Tudor R, Cheng S, Higgins B, Burkes R, Ng M, Arif S, Ellis PM, Hubay S, Kuruvilla S, Laurie SA, Li J, Hwang D, Lau A, Shepherd FA, Le LW, Leighl NB. Clinical impact of mutation fraction in epidermal growth factor receptor mutation positive NSCLC patients. Br J Cancer. 2016 Mar 15;114(6):616-22. doi: 10.1038/bjc.2016.22. Epub 2016 Feb 18.