PF-00299804 in Stage IIIB or Stage IV Non-Small Cell Lung Cancer Not Responding to Standard Therapy for Advanced or Metastatic Cancer

Lung Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01000025
• Other study ID #: BR26
• Secondary ID: CAN-NCIC-BR26PFI
• Status: Completed
• Phase: Phase 3
• Start date: December 23, 2009
• Est. completion date: November 27, 2015

Study information

• Verified date: April 2020
• Source: Canadian Cancer Trials Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 720
• Est. completion date: November 27, 2015
• Est. primary completion date: January 15, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Cancer
• Lung Neoplasms

Intervention

Drug:
• PF-00299804
PF-804 45 mg PO, daily
• Placebo
Placebo 45 mg PO, daily

Locations

Country	Name	City	State
Argentina	COIBA Centro de Oncologia e Investigacion	Berazategui	Provincia De Buenos Aires
Argentina	CER - Instituto Medico	Buenos Aires	B1878dvb Bs. As.
Argentina	Damic-Fundacion Rusculleda	Cordoba
Argentina	Centro Medico San Roque	San Miguel de Tucuman
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Repatriation General Hospital	Concord	New South Wales
Australia	Western Hospital	Footscray	Victoria
Australia	Frankston Hospital - Peninsula Oncology Centre	Frankston	Victoria
Australia	Geelong Hospital	Geelong	Victoria
Australia	Austin Hospital	Heidelberg	Victoria
Australia	St. George Hospital, Cancer Care Centre	Kogarah	New South Wales
Australia	Nambour General Hospital	Nambour	Queensland
Australia	Sir Charles Gairdner Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	Calvary Mater Newcastle Hospital	Waratah	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Brazil	Fundacao Pio XII - Hospital de Cancer de Barretos	Barretos	SP
Brazil	Oxion Hospital Dia Oncologia LTDA - Oxion	Belo Horizonte
Brazil	ESHO - Empresa de Servicos Hospitalares Ltda.	Brasilia	Sao Paulo
Brazil	Centro de Oncologia e Radioterapia (COR) Mae de Deus	Porto Alegre	Rio Grande Do Sul
Brazil	Centro de Pesquisa Clinica do Hospital	Porto Alegre	SP
Brazil	Nucleo de Oncologia da Bahia	Salvador
Brazil	GRAM - Grupo de Assistencia Medica	Sao Paulo
Canada	BCCA - Abbotsford Centre	Abbotsford	British Columbia
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	Cancer Centre of Southeastern Ontario at Kingston	Kingston	Ontario
Canada	London Regional Cancer Program	London	Ontario
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	McGill University - Dept. Oncology	Montreal	Quebec
Canada	Lakeridge Health Oshawa	Oshawa	Ontario
Canada	Ottawa Health Research Institute - General Division	Ottawa	Ontario
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Atlantic Health Sciences Corporation	Saint John	New Brunswick
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Algoma District Cancer Program	Sault Ste. Marie	Ontario
Canada	Niagara Health System	St. Catharines	Ontario
Canada	Dr. H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador
Canada	Health Sciences North	Sudbury	Ontario
Canada	BCCA - Fraser Valley Cancer Centre	Surrey	British Columbia
Canada	Univ. Health Network-Princess Margaret Hospital	Toronto	Ontario
Canada	BCCA - Vancouver Cancer Centre	Vancouver	British Columbia
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Italy	Centro di Riferimento Oncologico - CRO	Aviano	PN
Italy	U.O. di Oncologia Medica Azienda Ospedaliera G Rummo	Benevento
Italy	Ospedale Santa Croce	Fano
Italy	U.O. di Oncologia Ospedale Villa Scassi	Genova
Italy	Intstituto Scientifico Romangnolo	Meldola
Italy	U.O.C. Oncologia Medica,	Messina
Italy	U.O.C. Terapie Integrate in Oncologia,	Messina
Italy	Ospedale San Raffaele	Milan
Italy	U.O.C. di Oncologia U.L.S.S. 13	Mirano
Italy	Dott. Fortunato Ciardiello,Cattedra Oncologia Medica	Napoli
Italy	Unita Sperimentazioni Cliniche Istituto per lo	Napoli
Italy	UOC Oncologia Medica II Instituto Oncologio Veneto	Padova
Italy	La Maddalena, Dipartimento Oncologico	Palermo
Italy	Azienda USL di Piacenza, Ospedale Gugliemimo Salieto	Piacenza
Italy	Azienda Ospedaliera S. Camillo-Forlanin	Rome
Italy	Policlinico Umberto I, Universita Sapienza	Rome
Italy	Ospedale Casa Sollievo della Sofferenza	San Giovanni Rotondo
Italy	A.O. Busto Arsizio - P.O. Saronno	Saronno	VA
Italy	Ospedale E. Morelli-Sondalo	Sondalo
Korea, Republic of	Ajou University Hospital	GyeongGi-Do
Korea, Republic of	Chonnan National University Hwasun Hospital	Jeongnam
Korea, Republic of	Seoul Veterans Hospital	Seoul
Korea, Republic of	The Catholic University of Korea,	Seoul
Korea, Republic of	Yonsei University College of Medicine	Seoul
New Zealand	Auckland City Hospital	Auckland
Peru	Hospital Central De La Fuerza Aerea Del Peru	Lima
Peru	Hospital Nacional Luis N. Saenz	Lima
Peru	Instituto de Oncologia y Radioterapia de	Lima
Philippines	Perpetual Succour Hospital	Cebu City
Philippines	Makati Medical Center	Makati City
Philippines	Phillippine General Hospital	Manila
Taiwan	China Medical University Hospital	Taichung
Taiwan	Chi-Mei Foundation Hospital	Tainan
Taiwan	Tri-Service General Hospital	Taipei
Thailand	Chulalongkorn University	Bangkok
Thailand	Ramathibodi Hospital	Bangkok
Thailand	Siriraj Hospital, Oncology Unit	Bangkok
Thailand	Maharaj Nakorn Chiangmai Hospital	Chiangmai
United States	Shapiro, Stafford and Yee	Arcadia	California
United States	Clintell, Inc.	Skokie	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
NCIC Clinical Trials Group	Pfizer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Italy,  Korea, Republic of,  New Zealand,  Peru,  Philippines,  Taiwan,  Thailand, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	Median and 95% confidence intervals	42 Months
Secondary	Overall Survival in KRAS-WT Patients	Median and 95% confidence intervals of Overall survival in KRAS-WT patients	42 Months
Secondary	Overall Survival in EGFR-mutant Patients	Overall survival by EGFR-mutantion subgroups	42 Months
Secondary	Progression-free Survival	progression were evaluated using the revised international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee	42 Months
Secondary	Objective Response Rate	Response were evaluated in this study using the revised international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee. BEST RESPONSE from the start of study treatment until the end of treatment were reported.Objective response rate is the sum of CR + PR divided by the total number of patients in each group.	42 months
Secondary	Number of Participants With Toxicity as Measured by NCI CTCAE Version 4.0	Number of participants with Toxicities by treatment received according to NCI CTCAE version 4.0	42 Months