Ignite Creation Date:
2024-05-05 @ 12:01 PM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00212043
Status:
COMPLETED
Last Update Posted:
2009-10-08
First Post:
2005-09-13
Brief Title:
Phase III Trial of Infusional Gemcitabine in Combination With Carboplatin in Chemonaive Non-small Cell Carcinoma
Sponsor:
National University Hospital Singapore
Organization:
National University Hospital Singapore
Study Overview
Official Title:
Phase III Trial of Infusional Gemcitabine in Combination With Carboplatin in Chemonaive Non-small Cell Carcinoma
Status:
COMPLETED
Status Verified Date:
2008-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Hypothesis - Infusional gemcitabine may give better intracellular pharmacologic activation and be more effective clinically in non-small cell lung cancer
Detailed Description:
Objectives of study
1 to compare the response rate of carboplatin and constant rate infusion gemcitabine to the response rate of gemcitabine given in the standard 30-minute infusion
2 to compare the toxicity experience in both arms
3 To compare the time to progression in both study arms and overall survival
4 To compare the quality of life on both study arms using the EORTC QLQ-C30 and QLQ-LC13
Inclusion criteria
Histologically or cytologically confirmed NSCLC
Stage IIIB unsuitable for radical radiation eg with cytologically proven malignant effusion or stage IV disease as defined by the AJCC criteria see appendix 1
Karnofsky performance status 70 or higher see appendix 2
Presence of at least one bidimensionally or unidimensionally measurable non-CNS indicator lesion defined by radiologic study or physical examination
No previous chemotherapy for advanced disease Prior neoadjuvant or adjuvant chemotherapy or chemotherapy given concurrently with radiotherapy for non-metastatic disease is allowed if the last dose was given 6 months or more before study entry
Patients with recurrent disease after primary surgery andor radiotherapy will be eligible
For patients with previous radiotherapy the indicator lesions must not be within previous radiation field The last dose of radiotherapy should be at least 3 weeks prior to study entry The total radiotherapy received should not be more than 30 of the bone marrow
Screening laboratory criteria
WBC count 3500microl Neutrophils 2000microl Platelet count 100000microl Hemoglobin 9 gdl transfusion allowed
Serum creatinine 133 micromoll or Creatinine clearance 30 mlmin based on the Cockcroft formula see section 511
Bilirubin 15 x upper limit of normal ALTAST 2 x upper limit of normal if liver metastases are absent 5 x upper limit of normal if liver metastases are present
Aged 18 years and above
Life expectancy 3 months
Written informed consent
42 Exclusion criteria
The following conditions will render patients ineligible to participate in this study
Patients with only evaluable disease
Active uncontrolled infection
Pregnant or lactating women
Females of childbearing potential who are unwilling to avoid pregnancy for the duration of the study
Presence of any underlying medical conditions which in the investigators opinion would make the patient unsuitable for treatment
Concomitant malignancies or previous malignancies other than NSCLC within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin carcinoma-in-situ of the cervix or stage A low grade prostate cancer
Patients with CNS andor leptomeningeal metastases unless asymptomatic and not receiving corticosteriod therapy
43 Inclusion and exclusion criteria for phase I patients
The exclusion criteria are the same as above
The inclusion criteria are the same as above except for the following groups of patients which are allowed in the phase I study
Patients with evaluable disease only with no measurable lesions
Patients with one and only one line of chemotherapy for advanced NSCLC excluding patients who had received prior platinium andor gemcitabine
Patients with indicator lesions in previous radiation field
Measurability of indicator lesions
Measurable The lesion can be measured accurately in at least one dimension longest diameter to be recorded as 20 mm with conventional techniques or as 10mm with spiral CT scan
Non-measurable All other lesions including small lesions longest diameter 20 mm with conventional techniques or 10 mm with spiral CT scan and truly non-measurable lesions Lesions considered to be truly non-measurable include the following bone lesions leptomeningeal disease ascites pleuralcutispulmonis abdominal masses that are not confirmed and followed by imaging techniques and cystic lesions
Target Lesions All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total representative of all involved organs should be identified as target lesions and be recorded and measured at baseline Target lesions should be selected on the basis of their size lesion with the longest diameter and their suitability for accurate measurements either by imaging techniques or clinically A sum of the longest diameter LD for all target lesions will be calculated and reported as the baseline sum LD The baseline sum LD is used as the reference by which to characterize the objective tumor response If there are 10 measurable lesions those not selected as target lesions will be considered together with non-measurable disease as non-target lesions
Non-target Lesions All non-measurable lesions or sites of disease plus any measurable lesions over and above the 10 listed as target lesions Measurements are not required but these lesions should be noted at baseline and should be followed as present or absent
Any tumour measurement relying solely on physical examination should be verified by a second physician
The same diagnostic imaging method must be used throughout the study to evaluate the lesions
5 TREATMENT PLAN
51 Phase I study
511 Carboplatin
The starting dose of carboplatin is given at a fixed dose at a target AUC of 5 over 1 hour on day 1 in both arms of the study Carboplatin will be given before gemcitabine in all patients The dose is repeated every 21 days and will be calculated using the Calvert formula
Dose of carboplatin mg calculated glomerular filtration rate GFR 25 x 5
The GFR will be calculated according to the Cockroft-Gault formula
GFR mlmin 140 - age x body weight in kg 081 x serum creatinine micromoll
For female the correction factor is 085 x calculated GFR
512 Infusional gemcitabine
Infusional gemcitabine is given at a constant rate of 10 mgm2 per minute in all patients on days 1 and 8 the cycle is repeated every 21 days Dose escalation is achieved by increasing the duration of infusion The total dose of gemcitabine is re-constituted in 500 ml of normal saline and infused through a peripheral or central venous line
521 Treatment courses
Prior to initiating treatment eligible patients will be randomised to receive gemcitabine given either in the standard short 30 minutes infusion or constant rate prolonged infusion over the duration determined in the phase I study All patients in both arms will receive carboplatin at a dose of AUC of 5 over 1 hour
Standard arm
Carboplatin AUC of 5 over 1 hour day 1 followed by Gemcitabine 1000 mgm2 over 30 min day 1 and 8 Cycle is repeated every 21 days
Study arm
Carboplatin AUC of 5 over 1 hour day 1 followed by Gemcitabine 10 mgm2min at MTD day 1 and 8 Cycle is repeated every 21 days
Supportive treatment
All patients should receive pre-medications to prevent nausea and vomiting according to local policy
No prophylactic growth factors are allowed
Growth factor is allowed only in the rescue setting eg prolonged grade 4 neutropenia for more than 7 days or for febrile neutropenia
522 Dosing in cycle 2 and subsequent cycles
The next treatment cycle will begin on schedule providing
There is no evidence of tumour progression
Neutrophils 2 x 109L
Platelets 100000 x 109l
Absence of grade 2 or above non-haematological toxicity
523 Dose modifications
5231 General rules
No intra-patient dose escalation is allowed
Any patient who requires a dose reduction will not be eligible for any dose escalation for the remainder of the study
Treatment may be delayed up to day 35 to allow a patient sufficient time for recovery from treatment related toxicity Any patient who cannot proceed to the next cycle by day 35 will be discontinued from the study
5232 Dose modifications based on haematologic toxicity
Adjustment based on day 8 count Platelets x 109l ANC x 109l Action 75 and 10 Proceed with day 8 dose 75 and 05 - 10 Proceed with reduced dose 50 - 75 and 05 Proceed with reduced dose 50 andor 05 Omit dose When day 8 dose is reduced the same reduced dose will be used for the following cycle
When day 8 dose is omitted the cycle is completed and the next cycle will be scheduled on day 22 with dose reduction
Dose adjustment based on nadir count Platelets x 109l ANC x 109l Action 25 with no bleeding and 05 or 05 for 7 days No change 25 or 50 with bleeding andor 05 for 7 days Dose reduction see below Any and 05 and fever Dose reduction Recurrence of any of the above after 2 dose reductions Off study
Adjustment based on day 22 count Platelets x 109l ANC x 109l Action
100 and 20 Proceed with next cycle 100 andor 20 Delay 1 week Maximum delay of 2 weeks next cycle must start by day 35 to remain on study
Dose reduction schema First Reduction Second reduction Third reduction Carboplatin AUC 45 AUC 40 Off study Gemcitabine standard arm 750 mgm2 1000 mgm2 x 75 500 mgm2 1000 mgm2 x 50 Off study Infusional Gemcitabine 75 of Phase II duration 50 of previous infusion duration Off study
5233 Dose modifications for non-haematologic toxicity
Any grade 3 or 4 non-haematologic toxicity except for nausea and vomiting and fatigue and reversible transaminitis will render patient off study
Non-haematologic toxicity must be less than grade 2 before proceeding to the next cycle If they are higher than grade 2 treatment is delayed for 1 week Treatment may be delayed for a maximum of 2 weeks
524 Treatment duration
Responding patients will receive up to six cycles of chemotherapy
After treatment completion or withdrawal patients may continue to receive further treatment at the discretion of their physician
Screening evaluations
The following screening investigations must be performed within 28 days of day 1 of cycle 1
Complete staging and documentation of tumour status - baseline chest x-ray CT thorax abdomen brain and bone scan if clinically indicated
The following screening evaluations and investigations must be performed within 14 days of the first dose of therapy and includes the following
Consent
Complete medical history include details of symptoms prior treatments any residual toxicity concomitant medical conditions and medications
Physical examinations including documentation of all palpable lesions vital signs body weight and height and KPS
Documentation of indicator lesions to include date of assessment description of lesion site dimensions and type of diagnostic study to follow lesion The same diagnostic method must be used throughout the study to evaluate a lesion
The following tests must be performed within 7 days of the first dose of therapy and includes the following
Full blood count
Serum electrolytes and liver enzymes total calcium and magnesium
Serum pregnancy test if applicable
Dipstick urinalysis - if dipstick is positive for protein or blood a complete microscopic examination is required
83 Evaluation during treatment
Prior to day 1 of each cycle
History and physical examination
Assess and record toxicities from prior course Assign appropriate toxicity grades see Appendix 4
Record all medications taken since the last cycle
Weight measurement for re-calculation of body surface area and creatinine clearance
Assessment of symptoms of disease QoL questionnaire should be given and filled by patient before assessment by investigator
Assessment of performance status
Full blood count electrolytes and liver enzymes if day15 levels are abnormal
Urine dipstick analysis if the baseline result is abnormal
Clinical tumour measurements should be obtained prior to every cycle of treatment
Radiographic tumour measurements should be obtained after every 2 cycles of treatment
Modify dose of the next cycle if necessary see section 523
Day 8 assessment
Full blood count
Day 15 assessment
Full blood count electrolytes and liver enzymes
84 Evaluation of response
Patients will be evaluable for response after 2 cycles of therapy Clinical tumour measurements should be performed prior to every cycle of treatment Radiographic tumour measurements should be obtained after every 2 cycles of treatment
If a patient meets the response criteria see section 7 for CR PR or SD for the first time another clinical and radiographic tumour assessment will be performed 4 or more weeks later to document that the response has lasted at least 4 weeks
Clinical tumour assessment after every cycle and radiographic tumour response after every 2 cycles will continue until completion of treatment or patient withdrawal
85 Post-treatment follow-up
Responding patients will be reviewed every 2 monthly after completion of chemotherapy Clinical tumour assessment will be carried out 2 monthly Radiographic tumour assessment will be done every 4 monthly These will continue until disease progression is documented
Patients who never had a response and patients with disease progression after a previously documented response will be followed every 3 monthly for survival data
9 TREATMENT COMPLETION AND WITHDRAWAL
A patient will be considered as completing the treatment if
Patient has completed 6 cycles of therapy
Patient has a confirmed CR or confirmed PR and received at least 4 cycles of therapy and the investigator does not feel further therapy is indicated
Patient maintained a status SD for at least 8 weeks on treatment and received at least 2 cycles of treatment
Patient has PD after completing at least one full course of treatment
A patient is removed from the study due to unacceptable toxicity
Patients may be withdrawn from the treatment for the following reasons
Adverse experience including intercurrent illness or unacceptable toxicity
If attending physician thinks a change of therapy would be in the best interest of the patient
Protocol violation including non-compliance
Patient withdrawal at hisher request for reasons other than those above
Lost to follow-up
All patients will be followed for status of disease and survival until death 10 QUALITY OF LIFE QoL ASSESSMENT
It is essential to explain to the patient that the QoL assessment is an important part of the trial and that all sections should be answered even if the patient feels them to be irrelevant It should be emphasized that the completion of these forms helps doctors find out more about the effects of treatment on patients well-being
A named contact person other than the responsible clinician managing the patient in the context of the trial must be appointed to take responsibility for the administration collection and checking of the completed EORTC QLQ-C30 and QLQ-LC13 questionnaire The questionnaire must be taken before consultation with the clinician according to the EORTC guidelines for QoL assessment They should be checked to ensure that all questions have been answered if necessary go back to the patient immediately and ask him or her to fill in any missing items If an assessment is missed because of administrative failure the patient should be contacted by telephone or letter and an arrangement should be made for the questionnaire to be taken within a week of the scheduled assessment
The questionnaire may be filled in by the patient if heshe is able to read and understand the language of the questionnaire Otherwise the named person for administering the QoL should read out the questions as written in the language the patient understands and record the response to each question without prejudicing hisher answer The mode of delivery should be noted in the questionnaire
11 RANDOMISATION PROCEDURE
Study participants will be randomly assigned to receive either gemcitabine given in the conventional 30 minutes infusion or protracted infusion both in combination with carboplatin
111 Stratification
Stratified randomization will be carried out using the minimization method based on the following factors
i Centre National University Hospital Sydney Cancer Centre Johns Hopkins-NUH International Medical Centre ii Karnofsky performance status 90 - 100 vs 70 - 80 iii Stage of disease IIIB vs IV
112 Registration
Patients will be entered into the trial by a telephone call to the National Medical Research Council NMRC Clinical Trials Epidemiology Research Unit CTERU Singapore 65 220-1292 between 0830 to 1730 hours Monday to Friday and 0830 to 1230 hours Saturday Singapore time or by Fax 65 220-1485 stating that the patient is to be entered into the CTRG L08 or SQLU02 trial
Informed written consent for entry into the study should be obtained prior to randomization All eligibility criteria and consent form will be checked and the stratification factors stated before treatment is allocated The patient will be randomized to long infusional gemcitabine L or 30- minute short infusion gemcitabine S and allocated a trial number The design will involve equal allocation of patients to the two treatments Confirmation fax will be sent to the investigator
12 STATISTICAL CONSIDERATIONS
The sample size calculation is carried out based on the statistical selection theory criterion as detailed in Simon et al 62 and Gibbons et al 63 Assuming a 90 probability of correctly selecting the best treatment and anticipating a baseline response rate of 40 then to detect a 15 superiority of the best treatment over the other a trial size of 37 patients per treatment arm would be required The total accrual target would thus be 74 patients
13 STATISTICAL ANALYSES
Statistical analysis of all study endpoints will be carried out on an intention-to-treat basis In the event of lost to follow-up patients will still be included in the analysis for the duration that they are observed The inherent comparability of results in this randomized phase II design using the statistical selection theory assures that the two treatments can be reliably ranked when large differences are obtained
The best response will be used in the analysis of objective tumour response In the case of adverse event where multiple events of the same kind has occurred in a patient only the maximum grade will be documented for the analysis The tumour response rates and toxicities between treatment groups will be compared descriptively using estimates of proportions
The response duration and time to response for responding patients will be assessed using appropriate descriptive statistics The evaluation of progression-free and overall survival will be carried out using the Kaplan-Meier technique at 1-year follow-up In the case of progression-free survival patients whose disease has not progressed will be censored at the date last known to be alive Similarly the analysis of overall survival censors patients who are lost to follow-up or who remained alive at the date last known to be alive
For each QoL dimension changes in scores over time will be compared between treatment arms by means of appropriate graphical representation or descriptive statistics
No interim analysis is planned for this randomised phase II trial
14 ETHICAL CONSIDERATIONS
141 IRBEthics committee
Before study initiation the protocol will be submitted for review and approval by the hospital and Ministry of Health research and ethics committee or equivalent group Approval of the protocol and informed consent must be obtained
142 Patient information
The responsible physician will inform the patient about the background and current knowledge of the treatment under study with special reference to known activity and toxicity The patient will be told about the investigative nature of this treatment and in particular the randomization process involved in this study The patient will be told of his or her right to withdraw from the study at any time without any penalty with regards to the continuation of care at this institution and by the same physicians as he chooses Before accrual all patients will sign a written informed consent form
143 Informed consent
Informed consent should meet the requirement of the latest revision of the Declaration of Helsinki and any applicable regulations and guidelines such as the Good Clinical Practice Singapore
The study will be completely explained to each prospective candidate and the subject must give consent by signing and dating the consent form
Consent must be obtained before any protocol-required procedures are performed including any procedures not part of normal patient care
Plasma dFdC and dFdU levels
Ten millilitres of blood will be drawn at 0 hours baseline 10 minutes 30 minutes 10 minutes before the end of the infusion and 30 minutes 1 hour 2 hours after the end of the infusion The blood will be drawn into 10 ml tubes green topped containing heparin and 5 micromol tetrahydrouridine The tubes are then centrifuged at 3300 rpm for 15 minutes and the supernatant plasma is then transferred to plain tubes red topped for immediate storage at -80oC Samples will be labeled with the patients name ID number date exact time of sample and protocol number A pharmacokinetic form will accompany the plasma samples to the Pharmacology laboratory in the Department of Pharmacology National University of Singapore co Prof Lee How Sung
DFdC and dFdU levels in plasma will be measured using reverse phase HPLC as described by Grunewald 22 Briefly 20 microl to 50 microl of plasma is injected onto a C18 mBondapak analytical column Waters Associates Inc Components will be separated with a mobile phase consisting of a 30 minute linear gradient starting with 100 solution A 05M ammonium acetate pH 68 and ending with 60 solution B 50 methanol in deionised water Flow rate is at 15 mlmin Detection wavelengths are 275 nm and 262 nm for dFdC and dFdU respectively
162 Intracellular dFdCTP levels
Samples of blood will be collected to assay intracellular dFdCTP Only 3 samples per patient obtained 10 minutes after the start and 10 minutes before the end of the infusion of gemcitabine and one in the middle of infusion will be assayed for dFdCTP
Plasma is first separated from the blood by centrifugation at 3300 rpm for 20 minutes Mononuclear cells are then isolated by Ficoll-Hypaque density gradient centrifugation and deoxyribonucleoside triphosphates are extracted with 04 NHClO4 and the acid-insoluble material is removed by centrifugation The supernatant is then carefully neutralized to pH 7 with potassium hydroxide and the precipitated KClO4 is then removed by centrifugation An ion-exchange high performance liquid chromatography method is then used to separate and quantitate the dFdCTP
17 STUDY ADMINISTRATION
171 Drug accountability
Stocks of gemcitabine will be supplied by Eli Lilly for trial purposes and all these vials will be accounted for at the site pharmacy
172 Maintenance of patients records
CTRG clinical report forms will be used to record data for this study All patient clinical report forms will be faxed to the CTRG Office 65 777-5545 A copy of each patients eligibility report form randomization report form for phase II study schedule consent forms laboratory and radiological reports and QoL assessment will be kept in the CTRG Office All records will be kept for a period of 6 years following the date of study closure according to Singapore GCP guidelines
1 to compare the response rate of carboplatin and constant rate infusion gemcitabine to the response rate of gemcitabine given in the standard 30-minute infusion
2 to compare the toxicity experience in both arms
3 To compare the time to progression in both study arms and overall survival
4 To compare the quality of life on both study arms using the EORTC QLQ-C30 and QLQ-LC13
Inclusion criteria
Histologically or cytologically confirmed NSCLC
Stage IIIB unsuitable for radical radiation eg with cytologically proven malignant effusion or stage IV disease as defined by the AJCC criteria see appendix 1
Karnofsky performance status 70 or higher see appendix 2
Presence of at least one bidimensionally or unidimensionally measurable non-CNS indicator lesion defined by radiologic study or physical examination
No previous chemotherapy for advanced disease Prior neoadjuvant or adjuvant chemotherapy or chemotherapy given concurrently with radiotherapy for non-metastatic disease is allowed if the last dose was given 6 months or more before study entry
Patients with recurrent disease after primary surgery andor radiotherapy will be eligible
For patients with previous radiotherapy the indicator lesions must not be within previous radiation field The last dose of radiotherapy should be at least 3 weeks prior to study entry The total radiotherapy received should not be more than 30 of the bone marrow
Screening laboratory criteria
WBC count 3500microl Neutrophils 2000microl Platelet count 100000microl Hemoglobin 9 gdl transfusion allowed
Serum creatinine 133 micromoll or Creatinine clearance 30 mlmin based on the Cockcroft formula see section 511
Bilirubin 15 x upper limit of normal ALTAST 2 x upper limit of normal if liver metastases are absent 5 x upper limit of normal if liver metastases are present
Aged 18 years and above
Life expectancy 3 months
Written informed consent
42 Exclusion criteria
The following conditions will render patients ineligible to participate in this study
Patients with only evaluable disease
Active uncontrolled infection
Pregnant or lactating women
Females of childbearing potential who are unwilling to avoid pregnancy for the duration of the study
Presence of any underlying medical conditions which in the investigators opinion would make the patient unsuitable for treatment
Concomitant malignancies or previous malignancies other than NSCLC within the last 5 years with the exception of adequately treated basal or squamous cell carcinoma of the skin carcinoma-in-situ of the cervix or stage A low grade prostate cancer
Patients with CNS andor leptomeningeal metastases unless asymptomatic and not receiving corticosteriod therapy
43 Inclusion and exclusion criteria for phase I patients
The exclusion criteria are the same as above
The inclusion criteria are the same as above except for the following groups of patients which are allowed in the phase I study
Patients with evaluable disease only with no measurable lesions
Patients with one and only one line of chemotherapy for advanced NSCLC excluding patients who had received prior platinium andor gemcitabine
Patients with indicator lesions in previous radiation field
Measurability of indicator lesions
Measurable The lesion can be measured accurately in at least one dimension longest diameter to be recorded as 20 mm with conventional techniques or as 10mm with spiral CT scan
Non-measurable All other lesions including small lesions longest diameter 20 mm with conventional techniques or 10 mm with spiral CT scan and truly non-measurable lesions Lesions considered to be truly non-measurable include the following bone lesions leptomeningeal disease ascites pleuralcutispulmonis abdominal masses that are not confirmed and followed by imaging techniques and cystic lesions
Target Lesions All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total representative of all involved organs should be identified as target lesions and be recorded and measured at baseline Target lesions should be selected on the basis of their size lesion with the longest diameter and their suitability for accurate measurements either by imaging techniques or clinically A sum of the longest diameter LD for all target lesions will be calculated and reported as the baseline sum LD The baseline sum LD is used as the reference by which to characterize the objective tumor response If there are 10 measurable lesions those not selected as target lesions will be considered together with non-measurable disease as non-target lesions
Non-target Lesions All non-measurable lesions or sites of disease plus any measurable lesions over and above the 10 listed as target lesions Measurements are not required but these lesions should be noted at baseline and should be followed as present or absent
Any tumour measurement relying solely on physical examination should be verified by a second physician
The same diagnostic imaging method must be used throughout the study to evaluate the lesions
5 TREATMENT PLAN
51 Phase I study
511 Carboplatin
The starting dose of carboplatin is given at a fixed dose at a target AUC of 5 over 1 hour on day 1 in both arms of the study Carboplatin will be given before gemcitabine in all patients The dose is repeated every 21 days and will be calculated using the Calvert formula
Dose of carboplatin mg calculated glomerular filtration rate GFR 25 x 5
The GFR will be calculated according to the Cockroft-Gault formula
GFR mlmin 140 - age x body weight in kg 081 x serum creatinine micromoll
For female the correction factor is 085 x calculated GFR
512 Infusional gemcitabine
Infusional gemcitabine is given at a constant rate of 10 mgm2 per minute in all patients on days 1 and 8 the cycle is repeated every 21 days Dose escalation is achieved by increasing the duration of infusion The total dose of gemcitabine is re-constituted in 500 ml of normal saline and infused through a peripheral or central venous line
521 Treatment courses
Prior to initiating treatment eligible patients will be randomised to receive gemcitabine given either in the standard short 30 minutes infusion or constant rate prolonged infusion over the duration determined in the phase I study All patients in both arms will receive carboplatin at a dose of AUC of 5 over 1 hour
Standard arm
Carboplatin AUC of 5 over 1 hour day 1 followed by Gemcitabine 1000 mgm2 over 30 min day 1 and 8 Cycle is repeated every 21 days
Study arm
Carboplatin AUC of 5 over 1 hour day 1 followed by Gemcitabine 10 mgm2min at MTD day 1 and 8 Cycle is repeated every 21 days
Supportive treatment
All patients should receive pre-medications to prevent nausea and vomiting according to local policy
No prophylactic growth factors are allowed
Growth factor is allowed only in the rescue setting eg prolonged grade 4 neutropenia for more than 7 days or for febrile neutropenia
522 Dosing in cycle 2 and subsequent cycles
The next treatment cycle will begin on schedule providing
There is no evidence of tumour progression
Neutrophils 2 x 109L
Platelets 100000 x 109l
Absence of grade 2 or above non-haematological toxicity
523 Dose modifications
5231 General rules
No intra-patient dose escalation is allowed
Any patient who requires a dose reduction will not be eligible for any dose escalation for the remainder of the study
Treatment may be delayed up to day 35 to allow a patient sufficient time for recovery from treatment related toxicity Any patient who cannot proceed to the next cycle by day 35 will be discontinued from the study
5232 Dose modifications based on haematologic toxicity
Adjustment based on day 8 count Platelets x 109l ANC x 109l Action 75 and 10 Proceed with day 8 dose 75 and 05 - 10 Proceed with reduced dose 50 - 75 and 05 Proceed with reduced dose 50 andor 05 Omit dose When day 8 dose is reduced the same reduced dose will be used for the following cycle
When day 8 dose is omitted the cycle is completed and the next cycle will be scheduled on day 22 with dose reduction
Dose adjustment based on nadir count Platelets x 109l ANC x 109l Action 25 with no bleeding and 05 or 05 for 7 days No change 25 or 50 with bleeding andor 05 for 7 days Dose reduction see below Any and 05 and fever Dose reduction Recurrence of any of the above after 2 dose reductions Off study
Adjustment based on day 22 count Platelets x 109l ANC x 109l Action
100 and 20 Proceed with next cycle 100 andor 20 Delay 1 week Maximum delay of 2 weeks next cycle must start by day 35 to remain on study
Dose reduction schema First Reduction Second reduction Third reduction Carboplatin AUC 45 AUC 40 Off study Gemcitabine standard arm 750 mgm2 1000 mgm2 x 75 500 mgm2 1000 mgm2 x 50 Off study Infusional Gemcitabine 75 of Phase II duration 50 of previous infusion duration Off study
5233 Dose modifications for non-haematologic toxicity
Any grade 3 or 4 non-haematologic toxicity except for nausea and vomiting and fatigue and reversible transaminitis will render patient off study
Non-haematologic toxicity must be less than grade 2 before proceeding to the next cycle If they are higher than grade 2 treatment is delayed for 1 week Treatment may be delayed for a maximum of 2 weeks
524 Treatment duration
Responding patients will receive up to six cycles of chemotherapy
After treatment completion or withdrawal patients may continue to receive further treatment at the discretion of their physician
Screening evaluations
The following screening investigations must be performed within 28 days of day 1 of cycle 1
Complete staging and documentation of tumour status - baseline chest x-ray CT thorax abdomen brain and bone scan if clinically indicated
The following screening evaluations and investigations must be performed within 14 days of the first dose of therapy and includes the following
Consent
Complete medical history include details of symptoms prior treatments any residual toxicity concomitant medical conditions and medications
Physical examinations including documentation of all palpable lesions vital signs body weight and height and KPS
Documentation of indicator lesions to include date of assessment description of lesion site dimensions and type of diagnostic study to follow lesion The same diagnostic method must be used throughout the study to evaluate a lesion
The following tests must be performed within 7 days of the first dose of therapy and includes the following
Full blood count
Serum electrolytes and liver enzymes total calcium and magnesium
Serum pregnancy test if applicable
Dipstick urinalysis - if dipstick is positive for protein or blood a complete microscopic examination is required
83 Evaluation during treatment
Prior to day 1 of each cycle
History and physical examination
Assess and record toxicities from prior course Assign appropriate toxicity grades see Appendix 4
Record all medications taken since the last cycle
Weight measurement for re-calculation of body surface area and creatinine clearance
Assessment of symptoms of disease QoL questionnaire should be given and filled by patient before assessment by investigator
Assessment of performance status
Full blood count electrolytes and liver enzymes if day15 levels are abnormal
Urine dipstick analysis if the baseline result is abnormal
Clinical tumour measurements should be obtained prior to every cycle of treatment
Radiographic tumour measurements should be obtained after every 2 cycles of treatment
Modify dose of the next cycle if necessary see section 523
Day 8 assessment
Full blood count
Day 15 assessment
Full blood count electrolytes and liver enzymes
84 Evaluation of response
Patients will be evaluable for response after 2 cycles of therapy Clinical tumour measurements should be performed prior to every cycle of treatment Radiographic tumour measurements should be obtained after every 2 cycles of treatment
If a patient meets the response criteria see section 7 for CR PR or SD for the first time another clinical and radiographic tumour assessment will be performed 4 or more weeks later to document that the response has lasted at least 4 weeks
Clinical tumour assessment after every cycle and radiographic tumour response after every 2 cycles will continue until completion of treatment or patient withdrawal
85 Post-treatment follow-up
Responding patients will be reviewed every 2 monthly after completion of chemotherapy Clinical tumour assessment will be carried out 2 monthly Radiographic tumour assessment will be done every 4 monthly These will continue until disease progression is documented
Patients who never had a response and patients with disease progression after a previously documented response will be followed every 3 monthly for survival data
9 TREATMENT COMPLETION AND WITHDRAWAL
A patient will be considered as completing the treatment if
Patient has completed 6 cycles of therapy
Patient has a confirmed CR or confirmed PR and received at least 4 cycles of therapy and the investigator does not feel further therapy is indicated
Patient maintained a status SD for at least 8 weeks on treatment and received at least 2 cycles of treatment
Patient has PD after completing at least one full course of treatment
A patient is removed from the study due to unacceptable toxicity
Patients may be withdrawn from the treatment for the following reasons
Adverse experience including intercurrent illness or unacceptable toxicity
If attending physician thinks a change of therapy would be in the best interest of the patient
Protocol violation including non-compliance
Patient withdrawal at hisher request for reasons other than those above
Lost to follow-up
All patients will be followed for status of disease and survival until death 10 QUALITY OF LIFE QoL ASSESSMENT
It is essential to explain to the patient that the QoL assessment is an important part of the trial and that all sections should be answered even if the patient feels them to be irrelevant It should be emphasized that the completion of these forms helps doctors find out more about the effects of treatment on patients well-being
A named contact person other than the responsible clinician managing the patient in the context of the trial must be appointed to take responsibility for the administration collection and checking of the completed EORTC QLQ-C30 and QLQ-LC13 questionnaire The questionnaire must be taken before consultation with the clinician according to the EORTC guidelines for QoL assessment They should be checked to ensure that all questions have been answered if necessary go back to the patient immediately and ask him or her to fill in any missing items If an assessment is missed because of administrative failure the patient should be contacted by telephone or letter and an arrangement should be made for the questionnaire to be taken within a week of the scheduled assessment
The questionnaire may be filled in by the patient if heshe is able to read and understand the language of the questionnaire Otherwise the named person for administering the QoL should read out the questions as written in the language the patient understands and record the response to each question without prejudicing hisher answer The mode of delivery should be noted in the questionnaire
11 RANDOMISATION PROCEDURE
Study participants will be randomly assigned to receive either gemcitabine given in the conventional 30 minutes infusion or protracted infusion both in combination with carboplatin
111 Stratification
Stratified randomization will be carried out using the minimization method based on the following factors
i Centre National University Hospital Sydney Cancer Centre Johns Hopkins-NUH International Medical Centre ii Karnofsky performance status 90 - 100 vs 70 - 80 iii Stage of disease IIIB vs IV
112 Registration
Patients will be entered into the trial by a telephone call to the National Medical Research Council NMRC Clinical Trials Epidemiology Research Unit CTERU Singapore 65 220-1292 between 0830 to 1730 hours Monday to Friday and 0830 to 1230 hours Saturday Singapore time or by Fax 65 220-1485 stating that the patient is to be entered into the CTRG L08 or SQLU02 trial
Informed written consent for entry into the study should be obtained prior to randomization All eligibility criteria and consent form will be checked and the stratification factors stated before treatment is allocated The patient will be randomized to long infusional gemcitabine L or 30- minute short infusion gemcitabine S and allocated a trial number The design will involve equal allocation of patients to the two treatments Confirmation fax will be sent to the investigator
12 STATISTICAL CONSIDERATIONS
The sample size calculation is carried out based on the statistical selection theory criterion as detailed in Simon et al 62 and Gibbons et al 63 Assuming a 90 probability of correctly selecting the best treatment and anticipating a baseline response rate of 40 then to detect a 15 superiority of the best treatment over the other a trial size of 37 patients per treatment arm would be required The total accrual target would thus be 74 patients
13 STATISTICAL ANALYSES
Statistical analysis of all study endpoints will be carried out on an intention-to-treat basis In the event of lost to follow-up patients will still be included in the analysis for the duration that they are observed The inherent comparability of results in this randomized phase II design using the statistical selection theory assures that the two treatments can be reliably ranked when large differences are obtained
The best response will be used in the analysis of objective tumour response In the case of adverse event where multiple events of the same kind has occurred in a patient only the maximum grade will be documented for the analysis The tumour response rates and toxicities between treatment groups will be compared descriptively using estimates of proportions
The response duration and time to response for responding patients will be assessed using appropriate descriptive statistics The evaluation of progression-free and overall survival will be carried out using the Kaplan-Meier technique at 1-year follow-up In the case of progression-free survival patients whose disease has not progressed will be censored at the date last known to be alive Similarly the analysis of overall survival censors patients who are lost to follow-up or who remained alive at the date last known to be alive
For each QoL dimension changes in scores over time will be compared between treatment arms by means of appropriate graphical representation or descriptive statistics
No interim analysis is planned for this randomised phase II trial
14 ETHICAL CONSIDERATIONS
141 IRBEthics committee
Before study initiation the protocol will be submitted for review and approval by the hospital and Ministry of Health research and ethics committee or equivalent group Approval of the protocol and informed consent must be obtained
142 Patient information
The responsible physician will inform the patient about the background and current knowledge of the treatment under study with special reference to known activity and toxicity The patient will be told about the investigative nature of this treatment and in particular the randomization process involved in this study The patient will be told of his or her right to withdraw from the study at any time without any penalty with regards to the continuation of care at this institution and by the same physicians as he chooses Before accrual all patients will sign a written informed consent form
143 Informed consent
Informed consent should meet the requirement of the latest revision of the Declaration of Helsinki and any applicable regulations and guidelines such as the Good Clinical Practice Singapore
The study will be completely explained to each prospective candidate and the subject must give consent by signing and dating the consent form
Consent must be obtained before any protocol-required procedures are performed including any procedures not part of normal patient care
Plasma dFdC and dFdU levels
Ten millilitres of blood will be drawn at 0 hours baseline 10 minutes 30 minutes 10 minutes before the end of the infusion and 30 minutes 1 hour 2 hours after the end of the infusion The blood will be drawn into 10 ml tubes green topped containing heparin and 5 micromol tetrahydrouridine The tubes are then centrifuged at 3300 rpm for 15 minutes and the supernatant plasma is then transferred to plain tubes red topped for immediate storage at -80oC Samples will be labeled with the patients name ID number date exact time of sample and protocol number A pharmacokinetic form will accompany the plasma samples to the Pharmacology laboratory in the Department of Pharmacology National University of Singapore co Prof Lee How Sung
DFdC and dFdU levels in plasma will be measured using reverse phase HPLC as described by Grunewald 22 Briefly 20 microl to 50 microl of plasma is injected onto a C18 mBondapak analytical column Waters Associates Inc Components will be separated with a mobile phase consisting of a 30 minute linear gradient starting with 100 solution A 05M ammonium acetate pH 68 and ending with 60 solution B 50 methanol in deionised water Flow rate is at 15 mlmin Detection wavelengths are 275 nm and 262 nm for dFdC and dFdU respectively
162 Intracellular dFdCTP levels
Samples of blood will be collected to assay intracellular dFdCTP Only 3 samples per patient obtained 10 minutes after the start and 10 minutes before the end of the infusion of gemcitabine and one in the middle of infusion will be assayed for dFdCTP
Plasma is first separated from the blood by centrifugation at 3300 rpm for 20 minutes Mononuclear cells are then isolated by Ficoll-Hypaque density gradient centrifugation and deoxyribonucleoside triphosphates are extracted with 04 NHClO4 and the acid-insoluble material is removed by centrifugation The supernatant is then carefully neutralized to pH 7 with potassium hydroxide and the precipitated KClO4 is then removed by centrifugation An ion-exchange high performance liquid chromatography method is then used to separate and quantitate the dFdCTP
17 STUDY ADMINISTRATION
171 Drug accountability
Stocks of gemcitabine will be supplied by Eli Lilly for trial purposes and all these vials will be accounted for at the site pharmacy
172 Maintenance of patients records
CTRG clinical report forms will be used to record data for this study All patient clinical report forms will be faxed to the CTRG Office 65 777-5545 A copy of each patients eligibility report form randomization report form for phase II study schedule consent forms laboratory and radiological reports and QoL assessment will be kept in the CTRG Office All records will be kept for a period of 6 years following the date of study closure according to Singapore GCP guidelines
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None