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

Sponsor
NCIC Clinical Trials Group (Other)
Overall Status
Completed
CT.gov ID
NCT01000025
Collaborator
Pfizer (Industry)
720
89
2
74.7
8.1
0.1

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
720 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Sep 4, 2009
Actual Primary Completion Date :
Jan 15, 2014
Actual Study Completion Date :
Nov 27, 2015

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: PF-00299804

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

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

Placebo Comparator: Placebo

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

Drug: Placebo
Placebo 45 mg PO, daily

Outcome Measures

Primary Outcome Measures

  1. Overall Survival [42 Months]

    Median and 95% confidence intervals

Secondary Outcome Measures

  1. Overall Survival in KRAS-WT Patients [42 Months]

    Median and 95% confidence intervals of Overall survival in KRAS-WT patients

  2. Overall Survival in EGFR-mutant Patients [42 Months]

    Overall survival by EGFR-mutantion subgroups

  3. Progression-free Survival [42 Months]

    progression were evaluated using the revised international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee

  4. Objective Response Rate [42 months]

    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.

  5. Number of Participants With Toxicity as Measured by NCI CTCAE Version 4.0 [42 Months]

    Number of participants with Toxicities by treatment received according to NCI CTCAE version 4.0

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No

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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Shapiro, Stafford and Yee Arcadia California United States 91007
2 Clintell, Inc. Skokie Illinois United States 60077
3 CER - Instituto Medico Buenos Aires B1878dvb Bs. As. Argentina
4 COIBA Centro de Oncologia e Investigacion Berazategui Provincia De Buenos Aires Argentina 01884
5 Damic-Fundacion Rusculleda Cordoba Argentina
6 Centro Medico San Roque San Miguel de Tucuman Argentina T4000IAK
7 Royal Prince Alfred Hospital Camperdown New South Wales Australia 2050
8 Concord Repatriation General Hospital Concord New South Wales Australia 2139
9 St. George Hospital, Cancer Care Centre Kogarah New South Wales Australia 2217
10 Prince of Wales Hospital Randwick New South Wales Australia 2031
11 Royal North Shore Hospital St. Leonards New South Wales Australia 2065
12 Calvary Mater Newcastle Hospital Waratah New South Wales Australia 2298
13 Westmead Hospital Westmead New South Wales Australia 2145
14 The Prince Charles Hospital Chermside Queensland Australia 4032
15 Nambour General Hospital Nambour Queensland Australia 4560
16 Royal Adelaide Hospital Adelaide South Australia Australia 5000
17 Monash Medical Centre Clayton Victoria Australia 3168
18 Western Hospital Footscray Victoria Australia 3011
19 Frankston Hospital - Peninsula Oncology Centre Frankston Victoria Australia 3199
20 Geelong Hospital Geelong Victoria Australia 3220
21 Austin Hospital Heidelberg Victoria Australia 3084
22 Sir Charles Gairdner Hospital Perth Western Australia Australia 6009
23 Centro de Oncologia e Radioterapia (COR) Mae de Deus Porto Alegre Rio Grande Do Sul Brazil 90840-440
24 ESHO - Empresa de Servicos Hospitalares Ltda. Brasilia Sao Paulo Brazil 01321-001
25 Fundacao Pio XII - Hospital de Cancer de Barretos Barretos SP Brazil 14784-400
26 Centro de Pesquisa Clinica do Hospital Porto Alegre SP Brazil 17210-120
27 Oxion Hospital Dia Oncologia LTDA - Oxion Belo Horizonte Brazil 30150-270
28 Centro Brazil 98700-000
29 Nucleo de Oncologia da Bahia Salvador Brazil 40170-110
30 GRAM - Grupo de Assistencia Medica Sao Paulo Brazil 01224-010
31 Cross Cancer Institute Edmonton Alberta Canada T6G 1Z2
32 BCCA - Abbotsford Centre Abbotsford British Columbia Canada V2S 0C2
33 BCCA - Fraser Valley Cancer Centre Surrey British Columbia Canada V3V 1Z2
34 BCCA - Vancouver Cancer Centre Vancouver British Columbia Canada V5Z 4E6
35 Atlantic Health Sciences Corporation Saint John New Brunswick Canada E2L 4L2
36 Dr. H. Bliss Murphy Cancer Centre St. John's Newfoundland and Labrador Canada A1B 3V6
37 QEII Health Sciences Centre Halifax Nova Scotia Canada B3H 1V7
38 Juravinski Cancer Centre at Hamilton Health Sciences Hamilton Ontario Canada L8V 5C2
39 Cancer Centre of Southeastern Ontario at Kingston Kingston Ontario Canada K7L 5P9
40 London Regional Cancer Program London Ontario Canada N6A 4L6
41 Lakeridge Health Oshawa Oshawa Ontario Canada L1G 2B9
42 Ottawa Health Research Institute - General Division Ottawa Ontario Canada K1H 8L6
43 Algoma District Cancer Program Sault Ste. Marie Ontario Canada P6B 0A8
44 Niagara Health System St. Catharines Ontario Canada L2S 0A9
45 Health Sciences North Sudbury Ontario Canada P3E 5J1
46 Univ. Health Network-Princess Margaret Hospital Toronto Ontario Canada M5G 2M9
47 Windsor Regional Cancer Centre Windsor Ontario Canada N8W 2X3
48 CHUM - Hopital Notre-Dame Montreal Quebec Canada H2L 4M1
49 McGill University - Dept. Oncology Montreal Quebec Canada H2W 1S6
50 Allan Blair Cancer Centre Regina Saskatchewan Canada S4T 7T1
51 Saskatoon Cancer Centre Saskatoon Saskatchewan Canada S7N 4H4
52 Centro di Riferimento Oncologico - CRO Aviano PN Italy 33081
53 A.O. Busto Arsizio - P.O. Saronno Saronno VA Italy 21047
54 U.O. di Oncologia Medica Azienda Ospedaliera G Rummo Benevento Italy 82100
55 Ospedale Santa Croce Fano Italy 61032
56 U.O. di Oncologia Ospedale Villa Scassi Genova Italy 16149
57 Intstituto Scientifico Romangnolo Meldola Italy 47014
58 U.O.C. Terapie Integrate in Oncologia, Messina Italy 98125
59 U.O.C. Oncologia Medica, Messina Italy 98158
60 Ospedale San Raffaele Milan Italy 20132
61 U.O.C. di Oncologia U.L.S.S. 13 Mirano Italy 30035
62 Dott. Fortunato Ciardiello,Cattedra Oncologia Medica Napoli Italy 80131
63 Unita Sperimentazioni Cliniche Istituto per lo Napoli Italy 80131
64 UOC Oncologia Medica II Instituto Oncologio Veneto Padova Italy 35128
65 La Maddalena, Dipartimento Oncologico Palermo Italy
66 Azienda USL di Piacenza, Ospedale Gugliemimo Salieto Piacenza Italy 29100
67 Azienda Ospedaliera S. Camillo-Forlanin Rome Italy 00152
68 Policlinico Umberto I, Universita Sapienza Rome Italy 00161
69 Ospedale Casa Sollievo della Sofferenza San Giovanni Rotondo Italy 71013
70 Ospedale E. Morelli-Sondalo Sondalo Italy 23039
71 Ajou University Hospital GyeongGi-Do Korea, Republic of 443-721
72 Chonnan National University Hwasun Hospital Jeongnam Korea, Republic of 519-763
73 Yonsei University College of Medicine Seoul Korea, Republic of 120-752
74 Seoul Veterans Hospital Seoul Korea, Republic of 134-791
75 The Catholic University of Korea, Seoul Korea, Republic of 137-701
76 Auckland City Hospital Auckland New Zealand 1023
77 Hospital Central De La Fuerza Aerea Del Peru Lima Peru 18
78 Hospital Nacional Luis N. Saenz Lima Peru
79 Instituto de Oncologia y Radioterapia de Lima Peru
80 Perpetual Succour Hospital Cebu City Philippines 6000
81 Makati Medical Center Makati City Philippines 1229
82 Phillippine General Hospital Manila Philippines 1000
83 China Medical University Hospital Taichung Taiwan 404
84 Chi-Mei Foundation Hospital Tainan Taiwan 736
85 Tri-Service General Hospital Taipei Taiwan 114
86 Chulalongkorn University Bangkok Thailand 10330
87 Ramathibodi Hospital Bangkok Thailand 10400
88 Siriraj Hospital, Oncology Unit Bangkok Thailand 10700
89 Maharaj Nakorn Chiangmai Hospital Chiangmai Thailand 50200

Sponsors and Collaborators

  • NCIC Clinical Trials Group
  • Pfizer

Investigators

  • Study Chair: Peter Ellis, MD, Margaret and Charles Juravinski Cancer Centre
  • Study Chair: Penny Bradbury, MD, NCIC Clinical Trials Group
  • Study Chair: Michael Millward, MD, Sir Charles Gairdner Hospital - Nedlands

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01000025
Other Study ID Numbers:
  • BR26
  • CAN-NCIC-BR26
  • PFIZER-CAN-NCIC-BR26
  • CDR0000657246
First Posted:
Oct 22, 2009
Last Update Posted:
Apr 22, 2020
Last Verified:
Apr 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
No
Keywords provided by NCIC Clinical Trials Group
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title PF-804 Placebo
Arm/Group Description Study treatment arm Control arm
Period Title: Overall Study
STARTED 480 240
COMPLETED 12 2
NOT COMPLETED 468 238

Baseline Characteristics

Arm/Group Title PF-00299804 Placebo Total
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily Total of all reporting groups
Overall Participants 480 240 720
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
63.5
65.5
64
Sex: Female, Male (Count of Participants)
Female
236
49.2%
120
50%
356
49.4%
Male
244
50.8%
120
50%
364
50.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
2
0.4%
0
0%
2
0.3%
Asian
172
35.8%
87
36.3%
259
36%
Native Hawaiian or Other Pacific Islander
1
0.2%
0
0%
1
0.1%
Black or African American
4
0.8%
1
0.4%
5
0.7%
White
288
60%
144
60%
432
60%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
13
2.7%
8
3.3%
21
2.9%
Region of Enrollment (participants) [Number]
United States
1
0.2%
1
0.4%
2
0.3%
Philippines
20
4.2%
11
4.6%
31
4.3%
Taiwan
11
2.3%
6
2.5%
17
2.4%
Canada
207
43.1%
101
42.1%
308
42.8%
Thailand
28
5.8%
14
5.8%
42
5.8%
Brazil
25
5.2%
14
5.8%
39
5.4%
Peru
0
0%
1
0.4%
1
0.1%
Australia
50
10.4%
27
11.3%
77
10.7%
New Zealand
7
1.5%
4
1.7%
11
1.5%
Italy
77
16%
34
14.2%
111
15.4%
Korea, Republic of
47
9.8%
24
10%
71
9.9%
Argentina
7
1.5%
3
1.3%
10
1.4%

Outcome Measures

1. Primary Outcome
Title Overall Survival
Description Median and 95% confidence intervals
Time Frame 42 Months

Outcome Measure Data

Analysis Population Description
ITT
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 480 240
Median (95% Confidence Interval) [Months]
6.83
6.31
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PF-00299804, Placebo
Comments The trial was designed to detect a 25% deduction in risk of death with PF-804 with 90% power using a 1-sided 2.5% level significance test. The sample size was estimated as 720 patients.
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.506
Comments Stratified by stratification factors at randomization except study center, but included K-Ras mutation status.1-sied p-value.
Method Log Rank
Comments Stratified by stratification factors at randomization except study center, but included K-Ras mutation status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.00
Confidence Interval (2-Sided) 95%
0.83 to 1.21
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Overall Survival in KRAS-WT Patients
Description Median and 95% confidence intervals of Overall survival in KRAS-WT patients
Time Frame 42 Months

Outcome Measure Data

Analysis Population Description
Patients with K-Ras mutation wild type
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 220 120
Median (95% Confidence Interval) [Months]
7.00
5.19
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PF-00299804, Placebo
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.043
Comments 1-sided p-value
Method Log Rank
Comments Stratified by stratification factors at randomization except study center.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.61 to 1.03
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Overall Survival in EGFR-mutant Patients
Description Overall survival by EGFR-mutantion subgroups
Time Frame 42 Months

Outcome Measure Data

Analysis Population Description
Patients with EGFR mutation
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 114 68
Median (95% Confidence Interval) [Months]
7.23
7.52
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PF-00299804, Placebo
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.46
Comments 1-sided pvalue
Method Log Rank
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.98
Confidence Interval (2-Sided) 95%
0.67 to 1.44
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Progression-free Survival
Description progression were evaluated using the revised international criteria (1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumours) committee
Time Frame 42 Months

Outcome Measure Data

Analysis Population Description
ITT
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 480 240
Median (95% Confidence Interval) [Months]
2.66
1.58
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PF-00299804, Placebo
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value < 0.0001
Comments
Method Log Rank
Comments Stratified by stratification factors at randomization except study center, but included K-Ras mutation status.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.66
Confidence Interval (2-Sided) 95%
0.55 to 0.79
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Objective Response Rate
Description 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.
Time Frame 42 months

Outcome Measure Data

Analysis Population Description
ITT
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 480 240
Mean (95% Confidence Interval) [percentage of participants]
7.1
1.5%
1.3
0.5%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection PF-00299804, Placebo
Comments
Type of Statistical Test Superiority or Other (legacy)
Comments
Statistical Test of Hypothesis p-Value 0.001
Comments
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 6.11
Confidence Interval (2-Sided) 95%
1.84 to 20.3
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Number of Participants With Toxicity as Measured by NCI CTCAE Version 4.0
Description Number of participants with Toxicities by treatment received according to NCI CTCAE version 4.0
Time Frame 42 Months

Outcome Measure Data

Analysis Population Description
As treated population
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
Measure Participants 477 239
Number [participants]
467
97.3%
223
92.9%

Adverse Events

Time Frame 42 Months
Adverse Event Reporting Description
Arm/Group Title PF-00299804 Placebo
Arm/Group Description Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PF-00299804: PF-804 45 mg PO, daily Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Placebo: Placebo 45 mg PO, daily
All Cause Mortality
PF-00299804 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
PF-00299804 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 191/477 (40%) 87/239 (36.4%)
Blood and lymphatic system disorders
Anemia 1/477 (0.2%) 0/239 (0%)
Febrile neutropenia 1/477 (0.2%) 1/239 (0.4%)
Cardiac disorders
Atrial fibrillation 0/477 (0%) 1/239 (0.4%)
Cardiac arrest 1/477 (0.2%) 0/239 (0%)
Myocardial infarction 1/477 (0.2%) 1/239 (0.4%)
Pericardial effusion 1/477 (0.2%) 2/239 (0.8%)
Pericardial tamponade 0/477 (0%) 1/239 (0.4%)
Pericarditis 1/477 (0.2%) 0/239 (0%)
Ear and labyrinth disorders
Hearing impaired 1/477 (0.2%) 0/239 (0%)
Endocrine disorders
Adrenal insufficiency 0/477 (0%) 1/239 (0.4%)
Eye disorders
Cataract 1/477 (0.2%) 0/239 (0%)
Corneal ulcer 1/477 (0.2%) 0/239 (0%)
Gastrointestinal disorders
Abdominal distension 1/477 (0.2%) 0/239 (0%)
Abdominal pain 4/477 (0.8%) 3/239 (1.3%)
Anal hemorrhage 1/477 (0.2%) 0/239 (0%)
Ascites 1/477 (0.2%) 0/239 (0%)
Colitis 1/477 (0.2%) 0/239 (0%)
Colonic obstruction 1/477 (0.2%) 0/239 (0%)
Constipation 3/477 (0.6%) 0/239 (0%)
Diarrhea 17/477 (3.6%) 1/239 (0.4%)
Dysphagia 0/477 (0%) 2/239 (0.8%)
Esophageal stenosis 0/477 (0%) 1/239 (0.4%)
Gastrointestinal pain 1/477 (0.2%) 0/239 (0%)
Ileus 0/477 (0%) 1/239 (0.4%)
Mucositis oral 5/477 (1%) 0/239 (0%)
Nausea 5/477 (1%) 0/239 (0%)
Obstruction gastric 0/477 (0%) 1/239 (0.4%)
Pancreatitis 1/477 (0.2%) 0/239 (0%)
Small intestinal obstruction 1/477 (0.2%) 0/239 (0%)
Upper gastrointestinal hemorrhage 0/477 (0%) 1/239 (0.4%)
Vomiting 8/477 (1.7%) 3/239 (1.3%)
General disorders
Chills 1/477 (0.2%) 0/239 (0%)
Death NOS 2/477 (0.4%) 0/239 (0%)
Fatigue 4/477 (0.8%) 2/239 (0.8%)
Fever 7/477 (1.5%) 1/239 (0.4%)
Gait disturbance 1/477 (0.2%) 0/239 (0%)
Infusion site extravasation 1/477 (0.2%) 0/239 (0%)
Non-cardiac chest pain 1/477 (0.2%) 0/239 (0%)
Pain 2/477 (0.4%) 1/239 (0.4%)
Sudden death NOS 1/477 (0.2%) 2/239 (0.8%)
Hepatobiliary disorders
Hepatic failure 1/477 (0.2%) 0/239 (0%)
Infections and infestations
Bronchial infection 1/477 (0.2%) 1/239 (0.4%)
Enterocolitis infectious 1/477 (0.2%) 0/239 (0%)
Lung infection 32/477 (6.7%) 12/239 (5%)
Lymph gland infection 1/477 (0.2%) 0/239 (0%)
Mucosal infection 1/477 (0.2%) 0/239 (0%)
Other infections and infestations 1/477 (0.2%) 0/239 (0%)
Scrotal infection 1/477 (0.2%) 0/239 (0%)
Sepsis 2/477 (0.4%) 3/239 (1.3%)
Skin infection 1/477 (0.2%) 0/239 (0%)
Urinary tract infection 2/477 (0.4%) 0/239 (0%)
Injury, poisoning and procedural complications
Fall 1/477 (0.2%) 0/239 (0%)
Fracture 3/477 (0.6%) 1/239 (0.4%)
Hip fracture 3/477 (0.6%) 0/239 (0%)
Investigations
Neutrophil count decreased 0/477 (0%) 1/239 (0.4%)
Weight loss 0/477 (0%) 1/239 (0.4%)
Metabolism and nutrition disorders
Anorexia 3/477 (0.6%) 1/239 (0.4%)
Dehydration 16/477 (3.4%) 0/239 (0%)
Hypercalcemia 0/477 (0%) 1/239 (0.4%)
Hyperglycemia 0/477 (0%) 1/239 (0.4%)
Hypokalemia 1/477 (0.2%) 0/239 (0%)
Hyponatremia 1/477 (0.2%) 0/239 (0%)
Musculoskeletal and connective tissue disorders
Back pain 2/477 (0.4%) 2/239 (0.8%)
Bone pain 1/477 (0.2%) 0/239 (0%)
Chest wall pain 1/477 (0.2%) 1/239 (0.4%)
Generalized muscle weakness 2/477 (0.4%) 0/239 (0%)
Pain in extremity 2/477 (0.4%) 0/239 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other neoplasms benign, malignant and unspecified 79/477 (16.6%) 43/239 (18%)
Tumor pain 2/477 (0.4%) 0/239 (0%)
Nervous system disorders
Cognitive disturbance 0/477 (0%) 1/239 (0.4%)
Depressed level of consciousness 4/477 (0.8%) 0/239 (0%)
Dizziness 2/477 (0.4%) 1/239 (0.4%)
Dysphasia 1/477 (0.2%) 0/239 (0%)
Encephalopathy 1/477 (0.2%) 0/239 (0%)
Intracranial hemorrhage 0/477 (0%) 1/239 (0.4%)
Ischemia cerebrovascular 1/477 (0.2%) 0/239 (0%)
Other nervous system disorders 1/477 (0.2%) 0/239 (0%)
Paresthesia 0/477 (0%) 1/239 (0.4%)
Seizure 1/477 (0.2%) 0/239 (0%)
Sinus pain 1/477 (0.2%) 0/239 (0%)
Stroke 2/477 (0.4%) 3/239 (1.3%)
Syncope 0/477 (0%) 1/239 (0.4%)
Transient ischemic attacks 0/477 (0%) 1/239 (0.4%)
Psychiatric disorders
Confusion 3/477 (0.6%) 1/239 (0.4%)
Personality change 0/477 (0%) 1/239 (0.4%)
Renal and urinary disorders
Acute kidney injury 6/477 (1.3%) 0/239 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration 0/477 (0%) 1/239 (0.4%)
Bronchopulmonary hemorrhage 6/477 (1.3%) 4/239 (1.7%)
Cough 0/477 (0%) 1/239 (0.4%)
Dyspnea 26/477 (5.5%) 14/239 (5.9%)
Epistaxis 2/477 (0.4%) 0/239 (0%)
Hoarseness 1/477 (0.2%) 0/239 (0%)
Hypoxia 4/477 (0.8%) 0/239 (0%)
Pleural effusion 7/477 (1.5%) 3/239 (1.3%)
Pleuritic pain 1/477 (0.2%) 0/239 (0%)
Pneumonitis 2/477 (0.4%) 0/239 (0%)
Pneumothorax 2/477 (0.4%) 1/239 (0.4%)
Productive cough 1/477 (0.2%) 0/239 (0%)
Pulmonary edema 1/477 (0.2%) 0/239 (0%)
Respiratory failure 6/477 (1.3%) 2/239 (0.8%)
Skin and subcutaneous tissue disorders
Other skin and subcutaneous tissue disorders 2/477 (0.4%) 1/239 (0.4%)
Rash acneiform 2/477 (0.4%) 0/239 (0%)
Stevens-Johnson syndrome 1/477 (0.2%) 0/239 (0%)
Vascular disorders
Hypotension 0/477 (0%) 1/239 (0.4%)
Other vascular disorders 0/477 (0%) 1/239 (0.4%)
Thromboembolic event 12/477 (2.5%) 3/239 (1.3%)
Other (Not Including Serious) Adverse Events
PF-00299804 Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 465/477 (97.5%) 219/239 (91.6%)
Eye disorders
Conjunctivitis 47/477 (9.9%) 0/239 (0%)
Dry eye 41/477 (8.6%) 5/239 (2.1%)
Gastrointestinal disorders
Abdominal pain 61/477 (12.8%) 18/239 (7.5%)
Constipation 120/477 (25.2%) 74/239 (31%)
Diarrhea 380/477 (79.7%) 47/239 (19.7%)
Dry mouth 50/477 (10.5%) 11/239 (4.6%)
Dyspepsia 39/477 (8.2%) 12/239 (5%)
Gastroesophageal reflux disease 30/477 (6.3%) 9/239 (3.8%)
Mucositis oral 206/477 (43.2%) 8/239 (3.3%)
Nausea 168/477 (35.2%) 59/239 (24.7%)
Vomiting 134/477 (28.1%) 37/239 (15.5%)
General disorders
Edema limbs 57/477 (11.9%) 28/239 (11.7%)
Fatigue 254/477 (53.2%) 115/239 (48.1%)
Fever 42/477 (8.8%) 15/239 (6.3%)
Non-cardiac chest pain 33/477 (6.9%) 21/239 (8.8%)
Pain 93/477 (19.5%) 50/239 (20.9%)
Infections and infestations
Lung infection 25/477 (5.2%) 6/239 (2.5%)
Paronychia 142/477 (29.8%) 0/239 (0%)
Investigations
Weight loss 73/477 (15.3%) 23/239 (9.6%)
Metabolism and nutrition disorders
Anorexia 222/477 (46.5%) 93/239 (38.9%)
Musculoskeletal and connective tissue disorders
Back pain 83/477 (17.4%) 47/239 (19.7%)
Bone pain 48/477 (10.1%) 20/239 (8.4%)
Chest wall pain 41/477 (8.6%) 27/239 (11.3%)
Pain in extremity 79/477 (16.6%) 35/239 (14.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain 31/477 (6.5%) 13/239 (5.4%)
Nervous system disorders
Dizziness 55/477 (11.5%) 25/239 (10.5%)
Dysgeusia 34/477 (7.1%) 4/239 (1.7%)
Headache 53/477 (11.1%) 29/239 (12.1%)
Peripheral sensory neuropathy 84/477 (17.6%) 32/239 (13.4%)
Psychiatric disorders
Anxiety 30/477 (6.3%) 20/239 (8.4%)
Insomnia 84/477 (17.6%) 45/239 (18.8%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage 25/477 (5.2%) 14/239 (5.9%)
Cough 233/477 (48.8%) 108/239 (45.2%)
Dyspnea 276/477 (57.9%) 132/239 (55.2%)
Epistaxis 72/477 (15.1%) 4/239 (1.7%)
Productive cough 58/477 (12.2%) 32/239 (13.4%)
Sore throat 26/477 (5.5%) 3/239 (1.3%)
Skin and subcutaneous tissue disorders
Alopecia 25/477 (5.2%) 11/239 (4.6%)
Dry skin 171/477 (35.8%) 27/239 (11.3%)
Other skin and subcutaneous tissue disorders 30/477 (6.3%) 5/239 (2.1%)
Palmar-plantar erythrodysesthesia syndrome 55/477 (11.5%) 2/239 (0.8%)
Pruritus 87/477 (18.2%) 28/239 (11.7%)
Rash acneiform 283/477 (59.3%) 24/239 (10%)
Rash maculo-papular 78/477 (16.4%) 16/239 (6.7%)

Limitations/Caveats

Despite the eligibility requirement for tumor samples, samples were not available or inadequate for translational studies in 30 - 40% of patients. This does limits the power of the secondary analyses examining biomarker driven outcomes.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Dr. Keyue Ding
Organization NCIC Clinical Trails Group
Phone 1-613-533-6000 ext 77705
Email kding@ctg.queensu.ca
Responsible Party:
NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT01000025
Other Study ID Numbers:
  • BR26
  • CAN-NCIC-BR26
  • PFIZER-CAN-NCIC-BR26
  • CDR0000657246
First Posted:
Oct 22, 2009
Last Update Posted:
Apr 22, 2020
Last Verified:
Apr 1, 2020