|
Writing committee :
| Martine VAN GLABBEKE | Assistant Director, EORTC Data Center | |
| Denis LACOMBE | Medical Supervisor, EORTC Data Center | |
| Patrick THERASSE | Deputy Director, EORTC Data Center |
Dates :
| First draft | January 27, 1995 | |
| Final version | February 2, 1996 | |
| PRC approval | January 24, 1996 |
EORTC DATA CENTER
Phase II Unit
© Copyright 1994
| Definition | |
| Investigational drug under study | |
| Tumour type to be studied | |
| Cycle duration (in weeks) | |
| Interval between disease evaluations (in week) | |
| Minimum delay (since treatment start) to qualify as "no change" (in weeks) | |
| Interval between follow-up examinations after treatment (in weeks) | |
| Maximum response rate of an inactive drug (%) | |
| Minimum response rate of an active drug (%) | |
| Maximum acceptable risk of accepting an inactive drug | |
| Maximum acceptable risk of rejecting an active drug | |
| Total sample size | |
| Sample size for the first stage | |
| Rejection level for the first stage | |
| Acceptance level for the first stage | |
| Rejection / acceptance level for the second stage |
1. BACKGROUND AND INTRODUCTION
Background on the disease to be studied, focusing
on the need for new drug development.
Inventory of the drugs known to be active.
Description of the type of drug (mechanism of action, if known), and rationale for developing this particular drug, if applicable
Results of pre clinical studies
Results of phase I trials, different schedules
that have been investigated (if applicable)
Conclusions on dose limiting toxicities and dose recommendations
for the schedule selected for the trial
Results of phase II trials already performed, focusing on previous trials justifying the present study
Description of pharmacokinetic parameters, if previously investigated (general profile, half life(s), assumed route(s) of excretion...)
Description of the expected safety profile, on the basis of experience accumulated in previous studies
The principal objective of the trial is to assess the therapeutic
activity of drug in patients with disease.
The principal end-point is the objective response to treatment,
as defined by the "WHO handbook for reporting results of
cancer trials, 1979".
For patients presenting with an objective response, the duration
of response will be assessed.
The secondary objective is to characterise the acute side effects
of drug in patients with disease.
Acute side effects will be graded according to the "Common
Toxicity Criteria" defined by the NCI (US) and as extended
by the NCIC (Canada).
A third objective of those trials may be to characterize the pharmacokinetic parameters of the drug, administered according to the protocol schedule. The "population pharmacokinetic" technique is applied to this objective.
Those are normally the only objectives and end-points of a phase II trial. Any other objective should be discussed with the statistician of the EORTC Data Center Phase II Unit, in order to decide if the study projected by the group does indeed correspond to the EORTC definition of a phase II trial, or if it is rather a "feasibility" or "pilot" study (as defined in the "Practical Guide to EORTC studies").
Survival, long term side effects and quality of life are generally not end-points in phase II trials.
In order to avoid confusion and repetition, it is recommended to express all selection criteria as inclusion criteria (exclusion criteria may be easily translated). This enable to classify them in a logical order.
The two following criteria are essential for all phase II studies, and must always be included as first selection criteria:
Some protocols also require a recent histological or cytological proof of malignancy for a solitary lesion
The following items are generally used in the definition of eligibility criteria:
The following two criteria are mandatory in all clinical trials. "Informed consent", which is a legal requirement, is generally included as the last selection criterion to underline its importance.
This is an open non randomised multicenter phase II trial.
The Simon design will be applied: n1 or n eligible patients will be registered, according to the number of responses observed in the n1 first patients (page 21).
Patients will be registered at the EORTC Data Center prior to the start of treatment, and after verification of the eligibility criteria and selection of the target lesions. Treatment will be given until progression of the disease, unacceptable toxicity or patient refusal.
The disease will be assessed every w2 weeks (page 14) until documented progression, and treatment side effects will be assessed separately for each cycle of therapy.
Formula, properties, non-proprietary and commercial names...
Drug ordering procedures, as well as name(s) and full address(es)(s) with phone and fax numbers of the persons from whom the drug should be ordered must be fully described in this section.
Description of the packaging and labelling of the vials, instructions for dilution, recommendations for storage....
Those procedures are generally required by the Sponsor.
The following points should be included:
Treatment should be administered until documented disease progression, unacceptable toxicity, or patient refusal.
In specific protocols, a maximum cumulative dose or a maximum number of treatment cycles may also be foreseen.
In case of clear cut progression occurring before the first disease evaluation (w2 weeks after treatment start), the treatment will be discontinued and the response to treatment will be assessed as "early progression".
In case of stabilisation of the disease, the patient will be treated for a minimum of w3 weeks, and his/her disease status evaluated at the end of those w3 weeks. Thereafter, the decision to continue the treatment until disease progression will be left to the responsible investigator.
In case of objective (complete or) partial response, the treatment will be continued until documented disease progression. The disease status will be regularly assessed (every w2 weeks) during this period to evaluate the duration of response.
(In case of objective complete response, the treatment will be administered for ... cycles after documentation of the complete response. The patient will then be followed until progression, in the absence of any further anticancer treatment.)
The policy to be adopted in the case of complete response may vary according to the disease and the drug: either the patient is treated until progression, or he receives a few consolidation cycles and stops therapy. The number of consolidation cycles after CR has to be clearly indicated in the protocol.
Whatever the disease status, the treatment will always be discontinued in case of
patient refusal
excessive toxicity precluding further therapy, according to the responsible physician
a maximum cumulative dose of ..... has been reached (if applicable)
Patients discontinuing therapy in the absence of progression should not receive any other cancer treatment before their disease progresses, unless this is clearly not in the interest of the patient.
Sentences like "patients should be treated for a minimum of ... weeks to be considered as evaluable for response" must be avoided, because they are incompatible with the "intent to treat" analysis policy imposed by the WHO and by regulatory authorities. Classification of patients for whom the disease has not been assessed according to the protocol must be foreseen in the section on "evaluation of response" (page 15).
A full description of all modifications foreseen by the protocol is given in the following way:
This section should clearly describe which concomitant treatments are 1) recommended and 2) allowed and not allowed. Those obviously depend both of the type of disease, and of the therapy under investigation, and should therefore be specifically written for each protocol.
For side effects specifically expected from the drug, supportive therapies may be recommended. Those therapies should be described (dose, schedule), and it should be indicated if those therapies have to be given prophylactically for the initial treatment administration, for subsequent cures in case of previous toxicity, or only symptomatically.
Any type of standard supportive therapy specifically forbidden by the protocol must also be mentioned here.
This section should discuss the use of colony stimulating factors, antiemetics, or any other relevant "protective" agent.
Concomitant therapies which are recommended or contra-indicated
should be discussed in this section.
If the studied drug is still investigational, concomitant treatment with any kind of other investigational therapy is generally not allowed. If this is applicable to the study, it should be clearly indicated in the present section.
This section should describe all investigations
(and schedule) needed for
1) evaluating patient eligibility
2) assessing the initial disease status and the response to treatment
3) assessing the side effects for each cycle of therapy.
This should include an exhaustive list and the required frequency of laboratory data.
This section should preferably be summarised as a table.
The relevant medical history of the patient will be recorded.
The initial clinical examination, evaluation of the disease and measurement of all disease parameters, as well as blood counts and serum chemistry should be performed less than 14 days before the start of treatment. All investigations performed before this date must be repeated.
The initial clinical examination should include .....
This paragraph should explain how preexisting adverse conditions should be investigated, in order to provide a baseline evaluation for the reporting of adverse events. For investigational drugs, it should be based on the "investigator brochure" available from the Sponsor.
A complete evaluation of the disease should include ....
This paragraph should explain how each possible site of disease should be investigated, and how target lesions should be measured at each site. The protocol should require reproductible methods of measurements for the targets, and, as far as possible, reassessable by external experts. It must also be feasible (practically and economically) to repeat those mesurements for each evaluation of the disease required by the protocol (generally every 2 cycles, and one month after the first documentation of response).
Complete blood counts and serum chemistry should include ....
A clinical examination should be performed at the end of each cycle of therapy, i.e. immediately before the administration of the next cycle, and w1 weeks after the last drug administration.
This examination should include ....
A serum chemistry, including .... should be performed at the same time.
All adverse events which have occurred during this cycle of therapy should be assessed.
Complete blood counts, including .... should be performed weekly.
The disease should be assessed every w2 weeks:
- the possible appearance of new lesions should be investigated
(chest X-ray, complete physical examination including...);
- all sites that were found to be involved at the initial assessment
should be re-investigated by the same method;
- all lesions chosen as target during the initial assessment must
be measured by the same method and, if possible, by the same person.
If the patient has not progressed, the disease should be assessed every w2 weeks, following the same procedure as during treatment.
This will be used to evaluate the duration of response and/or stabilisation of the disease.
A clinical examination should be simultaneously performed.
The patient should be followed every w4 weeks for survival.
prior trt start | q w1 wks | q w2 wks 4 wks aft.resp. | q w2 wks | q w4 wks | ||
in all cases only if initially abnormal
* haematology includes white blood cells, neutrophils, platelets, haemoglobin counts, ....
** serum chemistry includes creatinine, bilirubine, ....
Response to treatment is assessed on the basis of a set of "target lesions" chosen before the first treatment administration (the complete list of target lesions must be reported on the initial measurement form before the start of treatment). These lesions must initially be measured in their two perpendicular dimensions, and these measurement must be repeated at each evaluation of the disease by the same method. A maximum of 3 lesions will be chosen as target for the same organ site. A maximum of 5 target lesions will be chosen for a patient.
All other lesions, and, if applicable, markers, are assessed according to the same schedule. They are only taken into account in two situations:
Adequate investigations must be carried out at each evaluation of the disease to detect eventual new lesions. If any new lesion is found, the response will be evaluated as "progression".
Only the following lesions are eligible as target lesions:
Target lesions must be measurable in two perpendicular diameters.
Lesions in an irradiated area can be used as targets provided radiotherapy has ended three months prior to entry, and they have since either progressed, or appeared. They must satisfy the above criteria.
Whenever feasible, it is preferred to restrict phase II trials to patients with bidimensionally measurable disease. This criteria will probably affect the recruitment rate, but improve the quality of the study, and reduce the number of unevaluable patients. A phase II trial should be seen as a scientific study, where the number of patients submitted to the investigational therapy has to be minimised. Therefore, any factor increasing the potential risk of non evaluability should be considered as an exclusion criterion.
However, for particular tumour types, this restriction may be prohibitive for the recruitment, or lead to an unrepresentative patients selection (i.e. when patients generally present with locally advanced disease, and the primary tumour type is only measurable in one dimension). In those cases, the present section should specify which types of unidimensional lesions may be used as target, and the definition of "overall response" should explain how to combine the response of the different sites.
The use of ultrasounds to measure target lesions is presently debated, because the external review of responses is very difficult. It should be discussed on a protocol by protocol basis if those are acceptable.
The initial assessment of disease (including measurement of all target lesions) must be performed in the two weeks preceding the first treatment administration.
Follow-up assessments will be performed every w2 weeks until disease progression (even after treatment discontinuation), or until the start of another treatment.
In case of detection of a complete or partial response, a confirmation assessment must be performed 4 weeks after the first documentation of the response.
If measurable disease is present at different sites in a given patient, the response is separately assessed for each site. The results in the different sites are then combined to obtain the overall response.
Target lesions are measured in their two largest perpendicular diameters. Their area is conventionally calculated as the product of these diameters. The total tumour size in one site is calculated as the sum of the area of all target lesions in this site.
Response by site is defined as follows:
In case of CR of the target lesions, a PR or NC in a non target lesion will result in PR for the site. The evidence of progression of any lesion or appearance of a new lesion will result in PD for the site.
The overall response is evaluated at each assessment of the disease.
The poorest response designation by organ site shall prevail.
However, if, in the total of responses by organ site, there are
equal or greater numbers of complete plus partial responses than
of no change designations, then overall response will be partial.
If progressive disease exists in any lesion, or when a new lesion appears, then the overall result will be progressive disease.
Mixed responses with a progressive site are considered as progressive disease, but the response per site must also be documented.
Progression in non measurable lesions leading to definite deterioration of the patient due to tumour bulk should be taken to indicate progression, regardless of what happens in measurable disease.
Progression in disease markers is generally not a response parameter.
Best overall response is the best response designation recorded from the start of treatment until disease progression.
Complete and partial responses have to be confirmed by two evaluations of the disease, taken at least 4 weeks apart.
No change is only accepted if it is measured at least w3 weeks after treatment start.
The duration of response will be measured from the date of start of treatment to the date of objective progression, in the absence of other treatment (in case of response or stabilisation, response must be regularly assessed until progression, even if the treatment has been stopped, or until start of a new treatment).
For complete responders, a second parameter, called "duration of complete response" will be measured from the date of first documentation of a complete response to the date of objective progression (page 22)
All eligible patients, i.e. patients satisfying eligibility criteria (page 7), will be included in the table and analysis of responses. If response has not been assessed, they will be included in the following categories:
Unfortunately, it is not always possible to assess response for all patients who were eligible for the trial before the start of treatment. Reason may be related to the disease, to the choice of the target lesions, to the treatment... and is most often unclear.
There are no strict guide-lines explaining how to classify and report these cases and how to consider them in the different analyses. In order to remain consistent between the different EORTC co-operative groups and the different Study Co-ordinators, we would like to define a common EORTC policy, in cooperation with the different EORTC co-operative groups.
Therefore, to avoid all bias and misinterpretations, we recommend to always include all eligible patients in the table of response and in the response rates, and to specify this in the text of the publication, in accordance with the WHO guidelines.
All adverse events will be recorded on the case report forms; the investigator will decide if those events are drug related (unrelated, unlikely, possible, probable or almost definitly) and his decision will be recorded on the forms for all adverse events.
Adverse events definitely not drug related (i.e. reported as unrelated) will not be considered as side effects or toxicity, but reported separately.
Haematological toxicity will be assessed on the basis of at least weekly blood counts. The nadir count will be computed for each cycle of therapy, and graded according to the "Common Toxicity Criteria" defined by the NCI (US).
Non haematological acute side effects will be assessed and reported separately for each cycle of therapy, and graded according to the "Common Toxicity Criteria" defined by the NCI (US) and extended by the NCIC (Canada).
Serious adverse events are defined as any undesirable experience occurring to a patient, whether or not considered related to the investigational drug, that is fatal, life-threatening, permanently disabling, or which results in in-patients hospitalisation or prolongation of hospitalisation.
The definition of "serious" also includes the development of new cancers and congenital abnormalities, but those events are not likely to be recorded within the duration of the study.
Toxic death is defined as death due to toxicity. This must be reported on the summary form: the cause of death must be reported as "toxicity".
The evaluation of toxic deaths is independent of the evaluation of response (patients can die from toxicity after a complete assessment of the response to therapy)
All eligible patients who have started the treatment will be included in overall toxicity analyses.
For haematological toxicity, the Study Co-ordinator may decide that blood counts have not been performed and/or reported according to the protocol (page 10) and are therefore inadequate for the evaluation of one/several haematological parameters in those patients.
Patients who have discontinued treatment because of toxicity will always be included in the toxicity analyses.
Toxicity and adverse events occurring in ineligible patients will be reported separately.
A patient can be registered after verification of eligibility
directly on the EORTC Data Center computer, 24 hours a day, 7
days a week, through the EuroCODE or the INTERNET network.
Alternatively registration can be done by telephone to the EORTC
Data Center from 9.00 am to 6.00 p.m. Monday through Friday.
This must be done before the start of the treatment.
Telephone: (32 2) 774 16 00
EuroCODE (modem): (32 2) 772 04 26
EuroCODE (X25): (206) 221 01 42
Internet: ecvaxeortc.be
A patient who has not been registered before the first treatment administration will not be accepted for the study at a later date.
An exhaustive list of questions to be answered during the registration procedure is included in the registration check-list, which is part of the case report forms. This check-list should be completed by the responsible investigator before the patient is registered.
At the end of the registration procedure, a number will be allocated to the patient (patient sequential identification number). This number has to be recorded on the registration check-list, along with the date of registration. The completed check-list must be signed by the responsible investigator and returned to the data center with the initial data of the patient.
The sequential identification number attributed to the patient at the end of the registration procedure identifies the patient and must be reported on all case report forms.
Data will be reported on the STANDARD EORTC Phase II forms and send to:
Case report forms must be completed according to the following schedule:
A. Before the treatment starts:
the registration check-list (form 1)
the on-study form (form 2)
the initial measurement form (form 3)
a concomitant medication form (form 4)
a laboratory data form (form 5)
The optimal way to work is to complete the registration check-list and, if possible, the above set of forms first, and to register the patient through Eurocode as soon as data are complete; the date of registration and patient sequential identification number are then completed on the check-list, and the whole set can be sent to the Data Center. As soon as the patient has been registered, the first treatment may be administered.
B. At the end of each cycle of therapy:
Each cycle of therapy needs to be documented separately. One cycle of therapy consists of w1 weeks of treatment (... treatment administration). At the end of each cycle (i.e. the day of the beginning of the next cycle, or the day the investigator has decided to stop the treatment), a set of forms has to be sent to the Data Center, including
C. After each evaluation of the disease (every w2 weeks, cf. paragraph 7.1.3.)
D. As soon as the investigator has decided to stop the treatment
E. After treatment discontinuation
If the patient is responding, or presents stable disease, the disease will continue to be evaluated every w2 weeks, according to the schedule defined in this protocol (page 10) until disease progression, or start of another treatment.
F. Upon patient death
G. Upon occurrence of a serious adverse event (also see page 20)
The case report forms must be completed and signed by the investigator as soon as the requested information is available, according to the above described schedule. It is the responsibility of the investigator to check that original case report forms sent to the Data Center and that they are completely and correctly filled out.
The original copy must be immediately returned to the EORTC Data Center, and a copy must be kept by the investigator.
The EORTC Data Center will perform extensive consistency checks on the CRFs and issue Query Forms in case of inconsistent data. Those Query Forms must be immediately answered and signed by the investigator. The original must be returned to the EORTC Data Center, and a copy must be appended to the investigator's copy of the CRFs.
If modifications have to be brought to a CRF after the original copy has been returned to the EORTC Data Center, this should be recorded on a Query Form following the same procedure as those issued by the Data Center.
The investigator's copy of the CRFs may not be modified unless modifications are reported on a Query From, and the Query Form reference is indicated on the CRF.
All adverse events occurring during the treatment period, and until 30 days after the end of the last cycle of treatment, will be reported on the treatment forms regardless of their relation to the drug.
The period of follow-up for adverse events is not well defined; however, according to a widely accepted standard, patients should be followed for 30 days after the last drug administration. This follow-up period may be extended for specific drugs, according to foreseen side effects or pharmacokinetic considerations included in the investigators brochure.
The relation to the drug will be estimated by the principal investigator for each adverse event and reported on the forms.
Additionally, all serious (page 17) adverse events must be
reported within 48 hours to the Data Center, the Study Co-ordinator
and the Sponsor by phone, fax or electronic mail.
They should all be documented on a special "Serious Adverse
Event" form that must be returned to the Data Center within
10 working days. These forms are considered as part of the patient
file.
A quick and well defined procedure for reporting serious adverse events is imposed by the GCP guidelines. This procedure must be clearly described in all protocols.
Severe unexpected side effects should be reported through the same procedure.
This is not imposed by the GCP standards, but is generally included in phase II protocols. The Study Co-ordinator will decide if this should be done, and objectively describe in the protocol what is called a "severe" side effect.
The aim of this trial is to decide if drug should be further investigated in the disease, on the basis of the following criteria :
The trial will be conducted in two successive steps, to avoid treating too many patients with an inactive drug.
The Simon one sample two stage testing procedure will be used (optimal or minimax design)
The following hypothesis will be made:
As this is the most important risk for phase II
trial, must always be 0.1, and preferably= 0.05.
However, values of 0.1 or 0.2 are acceptable for .
Under those hypothesis, the total sample size for this trial will be n patients; the trial may however be discontinued after n1 patients according to the following rule.
A first test will be performed when the first n1 patients are evaluable for response:
A second test will be performed amongst those n patients:
The end-points of a phase II trial are
1) the response rate and the duration of response
2) the acute side-effects
Survival and quality of life are not generally end-points in phase II trials.
Ineligible patients are those who did not satisfy the eligibility criteria specified in the protocol (page 7). They will be excluded from all analyses.
All other patients will be included in the response analysis and
in the final table of results.
Cases not assessed because of withdrawal or for other reasons
(treatment discontinued because of ...., early death because
of ..., target lesions not measured according to the protocol,
protocol violations, treatment or examinations refused, lost to
follow-up....) will be clearly reported in this table (page 15)
The objective response rate, and its 95% confidence interval (exact,
if applicable), will be reported based on ALL ELIGIBLE patients.
If appropriate, a separate analysis of duration of complete responses may be performed: in this analysis, the duration of complete response will be measured from the date of first CR assessment to the date of progression.
All eligible patients will be included in the analysis of side effects unless they have not received any treatment.
The occurrence and grade of haematological side-effects will be reported separately for the first cycle of therapy, and for the overall duration of therapy.
The occurrence and grade of non haematological side effects will generally be reported for the whole duration of treatment. Adverse events reported as non drug related by the responsible investigator will be separately reported.
Quality of life is generally not assessed in phase II trials, because it is not an end-point for those trials.
Cost evaluation is generally not performed in phase II trials.
Phase II trials do generally not require any independant data monitoring committee.
All side effects will be regularly reported to the Study Co-ordinator, and discussed with all responsible investigators, in order to identify and quantify all possible side effects, and eventually find appropriate therapies to prevent those events.
At the end of the first stage of the statistical design (page 8) the number of objective responses will be assessed, and the Study Co-ordinator will decide with the data center whether the trial should be discontinued.
Data forms will be entered in the database of the EORTC Data Center by a double data entry procedure.
Computerised and manual consistency checks will be performed on newly entered forms; Query Forms will be issued in case of inconsistencies.
Consistent forms will be validated by the Data Manager to be entered on the master database. Inconsistent forms will be kept "on-hold" until full resolution of inconsistencies.
All objective responses must be reviewed and confirmed by external experts.
Description of the exact procedure foreseen for
the external review of responses
(this may be different from one group to the other).
On-site quality control will be performed.
The aim of these site visits will be:
This quality control will be carried out retrospectively, based on data already available at the Data Center. All modifications, amendments and/or additions will be reported on query forms. This will enable a complete documentation of the modifications brought to the original case report forms, in accordance with the GCP standards and the EORTC policy.
All participating centres will be visited at least once.
The on-site quality control is mandatory for investigational drugs. This section should explain who will do the monitoring (the data center or the sponsor), how frequently (initiation visit, data review visits and closing visits), and which percentage of data that will be checked. Drug reconciliation procedures should also be addressed in this section.
For non investigational drugs, the monitoring is not mandatory. This issue should be discussed before the final version of the protocol is approved.
The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (Tokyo, Venice and Hong Kong amendments), or the laws and regulations of the country, whichever provides the greatest protection of the patient.
The protocol has been written, and the study will be conducted according to the guidelines for Good Clinical Practice issued by the European Union.
The protocol will by approved by the EORTC Protocol Review Committee and by the Local, Regional or National Review Boards.
A sequential identification number will be automatically attributed to each patient registered in the trial. This number will identify the patient. However, in order to avoid identification errors, patients initials (maximum of 4 letters), date of birth and local chart number will be reported on the case report forms.
All patients will be informed of the nature of the study drug, the aims of the study, the possible adverse experiences, the procedures and possible hazards to which he/she will be exposed. An example of patient information is given as an appendix to this protocol.
An example of "patient information sheet" should be prepared for each protocol, according to the "guidelines for informed consent for EORTC studies", appended to the present document.
It will be emphasised that the participation is voluntary and that the patient is allowed to refuse further participation in the protocol whenever he wants. This will not have any consequences for the patient's subsequent care.
Documented informed consent must be obtained for all patients included in the study before they are registered at the EORTC Data Center. This must be done in accordance with the national and local regulatory requirements and the local rules followed in the institution
Investigators will only be authorised to register patients in this trial when they have returned to the Data Center:
and, if those documents are not yet available at the Data Center:
As soon as all the documents have been received at the Data Center, the new investigator will be added to the "authorisation list", and will be allowed to register patients in the trial.
Patients registrations from centers not (yet) included on the authorisation list will not be accepted.
All administrative responsibilities related to the protocol should be discussed before the start of the study and described in the final protocol. Items like management of the authorisation list, on-site quality control, reporting of adverse events to the authorities... must be addressed in this chapter.
The Study Co-ordinator (in cooperation with the Data Center) will
be responsible for writing the protocol, reviewing all case report
forms and documenting his/her review on evaluation forms, discussing
the contents of the reports with the Data Manager and/or the Statistician,
and publishing the study results.
He will also be generally responsible for answering all clinical
questions concerning eligibility, treatment, and evaluation of
the patients.
STUDY CO-ORDINATOR: DR. ...
address
Tel: - ....
Fax: - ...
The EORTC Data Center will be responsible for reviewing the protocol,
collecting case report forms, controlling the quality of the reported
data, and generating reports and analyses in cooperation with
the Study Co-ordinator.
All methodological questions should be addressed to the EORTC
Data Center.
EORTC DATA CENTER
83, avenue Emmanuel Mounier, bte 11
B - 1200 BRUSSELS , BELGIUM
Fax: 32-2-772.35.45
Registration of patients:
Tel.: 32-2-774.16.00
or use Eurocode
or Internet (telnbet to ecvaxeortc.be
Statistician: M.VAN GLABBEKE
Tel.: 32-2-774.16.25
Eurocode: VANGLABBEKE
Internet: mvgeortc.be
Data Manager: M.A.LENTZ / C. HERMAN / S. DAAMEN
Tel.: 32-2-774.16.26 / 27
Eurocode: LENTZ / HERMANS / DAAMEN
Internet: maleortc.be / cheeortc.be / sdaeortc.be
The sponsor will be responsible for drug distribution.....
SPONSOR
Drug supply:
Reporting of adverse events:
All questions concerning membership in the cooperative group should be addressed to the chairman and/or secretary of the group.
CHAIRMAN and SECRETARY of the CO-OPERATIVE GROUP (if needed)
The Promotor of the study is the EORTC.
The Director General of the EORTC is:
Professor Françoise Meunier
EORTC Central Office/Data Center
Avenue Mounier 83, bte.11
B 1200 - Brussels (Belgium)
Tel: + 32 2 - 774 16 30
Fax: + 32 2 - 771 20 04
For studies financially supported by the industry:
- The pharmaceutical company will be the Sponsor.
- the name of the Sponsor, as well as the name, address, telephone
and fax number of the contact person must be included in the protocol.
- the financial aspects of this protocol covered by contracts
or agreements should be mentionned in the protocol.
For protocols not supported by the industry, the EORTC is the Promotor/Sponsor.
All EORTC trials must be covered by an adequate insurance. The reference of the insurance policy must be included in the protocol, and a copy of the policy must be made available to the Data Center.
The final publication of the trial results will be written by the Study Co-ordinator on the basis of the statistical analysis performed at the EORTC Data Center. A draft manuscript will be completed no later than 6 months after the last patient has discontinued therapy. After revision by the co-authors and the Sponsor, this manuscript will be sent to a major scientific journal.
Authors of the manuscript will include the Study Co-ordinator, the investigators who have included more than 5% of the eligible patients in the trial (by order of inclusion), the reference pathologist (if a central pathology review has been performed), and the Data Center data manager and statistician in charge of the trial.
The chapter on authorship should be amended as a function of the co-operative group statutes..
Interim publication or presentation of the study may include demographic and toxicity data, but no data on activity may be made publicly available before the recruitment is discontinued and all responses have been externally reviewed.
All publications, abstracts or presentations including data from the present trial will be submitted for review to the EORTC Data Center at least two weeks prior to submission for abstracts, and four weeks prior to submission for manuscripts and slides for presentation.
All publications, abstracts or presentations including data from the present trial will be submitted for review to the SPONSOR (if applicable) at least two weeks prior to submission for abstracts, and four weeks prior to submission for manuscripts and slides for presentation. However, the Sponsor will NOT be able to VETO any publication.
The protocol must be signed by the Responsible Investigator and the Sponsor.
The list of potential responsible investigators must be included in the protocol (name, address, telephone number, expected accrual). They will however only be authorised to enter patients when they have returned to the Data Center all documents indicated in the chapter on "Investigator commitment" (page 25).
A list of relevant references should be included in the protocol
The following appendices should be included in the protocol, if appropriate:
In case of combination chemotherapy, a phase II trial will generally be used to assess the activity of an investigational drug associated with other agents, already known to be active in the studied disease.
2 OBJECTIVES OF THE TRIAL
The definition of the objectives becomes:
Activity: The principal objective is to assess the therapeutic activity of the investigation agent "drug" associated with "...."
Side effects: The secondary objective is to characterise the acute side effects of the combination of "drug" with "...."
This uncontrolled study does not aim at providing any scientific evidence of a possible therapeutic benefit brought by the combination, but only to decide is "drug" should be further studied in association with "....."
2 OBJECTIVES OF THE TRIAL
In case of a randomised phase II trial testing two investigational agents, the definition of the objectives becomes:
Activity: The principal objective is to simultaneously assess the therapeutic activity of "drug1" and "drug2" in ...
Side effects: The secondary objective is to characterise the acute side effects of "drug1" and "drug2" .....
The aim is NOT to compare the two agents.
4.1 TRIAL DESIGN
The first sentence will be replaced by:
This is a randomised multicentric phase II trial, aiming at simultaneously testing two investigational agents in the same patient population.
8 PATIENT REGISTRATION PROCEDURE
This section should be entitled "Patient registration and randomisation procedure".
The two last paragraphs should be replaced with:
At the end of the registration procedure, the patient will be
randomly allocated to one of the therapeutic arms. The Pocock
minimisation technique will be used for randomisation.
A number will also be allocated to the patient (patient sequential
identification number).
The allocated treatment, sequential identification number and
date of randomisation have to be recorded on the registration
check-list. The completed check list must be signed by the responsible
investigator and returned to the data center with the initial
data of the patient.
The sequential identification number attributed to the patient at the end of the registration procedure identifies the patient, and must be reported on all case report forms.
11.1 SAMPLE SIZE
The first sentence will be replaced by
The total sample size will be determined for each therapeutic arm by the Simon one sample two stage testing procedure. Patients will be randomised between the two therapeutic arms until the sample size is achieved for one of the arms. Thereafter, all patients will be allocated to the other arm, until recruitment is also completed in this arm.
2 OBJECTIVES OF THE TRIAL
In case of a randomised phase II trial testing an investigational agent and its parent compound, the objectives of the study remain similar, but the following sentence should be added to the paragraph:
In order to control the study population, the investigational agent "drug1" or its parent compound "drug2" will be randomly allocated to patients registered in this trial.
The aim of the randomisation is NOT to compare the two agents, but to control for possible selection bias.
4.1 TRIAL DESIGN
The first sentence will be replaced by:
This is a randomised multicenter phase II trial, aiming at testing an investigational analogue of ...., and controlling the patient population by randomly assigning treatment with the parent compound to half of the patients.
8 PATIENT REGISTRATION PROCEDURE
This section should be entitled " Patient registration and randomisation procedure".
The two last paragraphs should be replaced with:
At the end of the registration procedure, the patient will be
randomly allocated to one of the therapeutic arms. The Pocock
minimisation technique will be used for randomisation.
A number will also be allocated to the patient (patient sequential
identification number).
The allocated treatment, sequential identification number and
date of randomisation have to be recorded on the registration
check-list. The completed check list must be signed by the responsible
investigator and returned to the data center with the initial
data of the patient.
The sequential identification number attributed to the patient at the end of the registration procedure identifies the patient, and must be reported on all case report forms.
11.1 SAMPLE SIZE
The first sentence will be replaced by
The sample size of the arm with the investigational drug will be determined by the Simon one sample two stage testing procedure. Patients will be randomised between the two therapeutic arms until this sample size is reached in the investigational arm.
However, if the conclusion that the parent compound should not
be further investigated is reached after the first stage of the
statistical design (because the response rate in the patient population
under study is too low), the Study Co-ordinator will discuss the
closure of the control arm or of the whole study with the cooperative
group.