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

NCT ID: NCT01000025

Last Updated: 2023-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 720 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-12-23
• Study Completion Date: 2015-11-27

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.

Conditions

Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

PF-00299804

Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: ACTIVE_COMPARATOR

PF-00299804

Intervention Type: DRUG

PF-804 45 mg PO, daily

Placebo

Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo 45 mg PO, daily

Interventions

PF-00299804

PF-804 45 mg PO, daily

Intervention Type: DRUG

Placebo

Placebo 45 mg PO, daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Ellis, MD

Role: STUDY_CHAIR

Margaret and Charles Juravinski Cancer Centre

Penny Bradbury, MD

Role: STUDY_CHAIR

NCIC Clinical Trials Group

Michael Millward, MD

Role: STUDY_CHAIR

Sir Charles Gairdner Hospital - Nedlands

Locations

Shapiro, Stafford and Yee

Arcadia, California, United States

Clintell, Inc.

Skokie, Illinois, United States

CER - Instituto Medico

Buenos Aires, B1878dvb Bs. As., Argentina

COIBA Centro de Oncologia e Investigacion

Berazategui, Buenos Aires, Argentina

Damic-Fundacion Rusculleda

Córdoba, , Argentina

Centro Medico San Roque

San Miguel de Tucumán, , Argentina

Royal Prince Alfred Hospital

Camperdown, New South Wales, Australia

Concord Repatriation General Hospital

Concord, New South Wales, Australia

St. George Hospital, Cancer Care Centre

Kogarah, New South Wales, 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, Australia

The Prince Charles Hospital

Chermside, Queensland, Australia

Nambour General Hospital

Nambour, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Monash Medical Centre

Clayton, Victoria, Australia

Western Hospital

Footscray, Victoria, Australia

Frankston Hospital - Peninsula Oncology Centre

Frankston, Victoria, Australia

Geelong Hospital

Geelong, Victoria, Australia

Austin Hospital

Heidelberg, Victoria, Australia

Sir Charles Gairdner Hospital

Perth, Western Australia, Australia

Centro de Oncologia e Radioterapia (COR) Mae de Deus

Porto Alegre, Rio Grande do Sul, Brazil

Fundacao Pio XII - Hospital de Cancer de Barretos

Barretos, São Paulo, Brazil

ESHO - Empresa de Servicos Hospitalares Ltda.

Brasilia, São Paulo, Brazil

Centro de Pesquisa Clinica do Hospital

Porto Alegre, São Paulo, Brazil

Oxion Hospital Dia Oncologia LTDA - Oxion

Belo Horizonte, , Brazil

Centro, , Brazil

Nucleo de Oncologia da Bahia

Salvador, , Brazil

GRAM - Grupo de Assistencia Medica

São Paulo, , Brazil

Cross Cancer Institute

Edmonton, Alberta, Canada

BCCA - Abbotsford Centre

Abbotsford, British Columbia, Canada

BCCA - Fraser Valley Cancer Centre

Surrey, British Columbia, Canada

BCCA - Vancouver Cancer Centre

Vancouver, British Columbia, Canada

Atlantic Health Sciences Corporation

Saint John, New Brunswick, Canada

Dr. H. Bliss Murphy Cancer Centre

St. John's, Newfoundland and Labrador, Canada

QEII Health Sciences Centre

Halifax, Nova Scotia, Canada

Health Sciences North

Greater Sudbury, Ontario, 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

Lakeridge Health Oshawa

Oshawa, Ontario, Canada

Ottawa Health Research Institute - General Division

Ottawa, Ontario, Canada

Algoma District Cancer Program

Sault Ste. Marie, Ontario, Canada

Niagara Health System

St. Catharines, Ontario, Canada

Univ. Health Network-Princess Margaret Hospital

Toronto, Ontario, Canada

Windsor Regional Cancer Centre

Windsor, Ontario, Canada

CHUM - Hopital Notre-Dame

Montreal, Quebec, Canada

McGill University - Dept. Oncology

Montreal, Quebec, Canada

Allan Blair Cancer Centre

Regina, Saskatchewan, Canada

Saskatoon Cancer Centre

Saskatoon, Saskatchewan, Canada

Centro di Riferimento Oncologico - CRO

Aviano, PN, Italy

A.O. Busto Arsizio - P.O. Saronno

Saronno, VA, 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. Terapie Integrate in Oncologia,

Messina, , Italy

U.O.C. Oncologia Medica,

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

Padua, , 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

Ospedale E. Morelli-Sondalo

Sondalo, , Italy

Auckland City Hospital

Auckland, , New Zealand

Hospital Central De La Fuerza Aerea Del Peru

Lima, , Peru

Hospital Nacional Luis N. Saenz

Lima, , Peru

Instituto de Oncologia y Radioterapia de

Lima, , Peru

Perpetual Succour Hospital

Cebu City, , Philippines

Makati Medical Center

Makati City, , Philippines

Phillippine General Hospital

Manila, , Philippines

Ajou University Hospital

Gyeonggi-do, , South Korea

Chonnan National University Hwasun Hospital

Jeongnam, , South Korea

Yonsei University College of Medicine

Seoul, , South Korea

Seoul Veterans Hospital

Seoul, , South Korea

The Catholic University of Korea,

Seoul, , South Korea

China Medical University Hospital

Taichung, , Taiwan

Chi-Mei Foundation Hospital

Tainan City, , Taiwan

Tri-Service General Hospital

Taipei, , Taiwan

Chulalongkorn University

Bangkok, , Thailand

Ramathibodi Hospital

Bangkok, , Thailand

Siriraj Hospital, Oncology Unit

Bangkok, , Thailand

Maharaj Nakorn Chiangmai Hospital

Chiang Mai, , Thailand

Countries

United States; Argentina; Australia; Brazil; Canada; Italy; New Zealand; Peru; Philippines; South Korea; Taiwan; Thailand

References

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.

Reference Type: RESULT

PMID: 25439692 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26889973 (View on PubMed)

Other Identifiers

CAN-NCIC-BR26

Identifier Type: OTHER

Identifier Source: secondary_id

PFIZER-CAN-NCIC-BR26

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000657246

Identifier Type: OTHER

Identifier Source: secondary_id

BR26

Identifier Type: -

Identifier Source: org_study_id