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LMS Study (GOG 0277)A Phase III randomised trial of gemcitabine plus docetaxel followed
by doxorubicin versus observation for uterus limited, high grade uterine leiomyosarcoma
EudraCT Number: 2012-002852-17
Initiation Slides – Version 1, 30th December 2013
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Study Organisation
• This trial is an Intergroup Trial jointly conducted by Gynecologic Oncology Group (GOG) from USA, the EORTC Gynaecology Group, EORTC Soft Tissue Bone Sarcoma Group and National Cancer Research Network [NCRN] United Kingdom.
• In the UK the trial is being run under the auspices of the NCRN/NCRI Sarcoma and Gynaecology Clinical Study Groups with funding from Cancer Research UK.
• The Cancer Research UK Clinical Trials Unit, Glasgow (CTU) is co-ordinating the UK participation in the trial on behalf of NCRI/NCRN and NHS Greater Glasgow & Clyde (NHS GG&C).
• The EORTC is the sole legal Sponsor for participants in the European Union.
• UK Chief Investigator is Dr Helen Hatcher
• Trial co-ordination costs for UK participation in the trial are supported by a grant from Cancer Research UK. This is an academic trial and is part of the NCRN portfolio.
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Study Team in UK
- UK Chief Investigator: Dr Helen Hatcher
- Lead Pathologist UK: Professor Cyril Fisher
- Project Manager: Karen Carty
- Pharmacovigilance: Via EORTC
- UK Study Pharmacist: Dr Samantha Carmichael
- Quality Assurance Manager: Michaela Rodger
- Clinical Trial Co-ordinator: To be confirmed
- Clinical Trial Monitor: Jan Graham
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Design and Study Objectives
• Design:Study is designed as a two arm, open label randomised phase III with an observation only control arm and experimental arm of multi-agent chemotherapy.
• Study Objectives
Primary Objective:- To determine whether overall survival of patients with uterus-limited high grade leiomyosarcoma is superior among patients assigned to treatment with adjuvant gemcitabine plus docetaxel followed by doxurubicin compared to patients assigned to observation
Secondary Objectives:- To determine whether treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin improves recurrence free survival of patients with uterus-limited high grade leiomyosarcoma compared to observation- To explore the impact of potential predictors of recurrence or death such as patient age, and institution reported tumour size, cervix involvement (yes or no) and mitotic rate
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Statistical Design
• The study is designed as a two arm, open label, randomised phase III superiority trial with an observation only control arm and experimental arm of multi-agent chemotherapy (4 cycles of gemcitabine and docetaxel followed by 4 cycles of doxorubicin)
• The design will provide a direct assessment of the null hypothesis that multi-agent adjuvant chemotherapy offers no increase in survival when compared with observation until recurrence.
• Study duration: With an average accrual rate of 36 patients per year, the study accrual time will be approx 72 months to enrol 216 patients
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Outcome Measures (Primary End Point)
Outcome Measures
• Overall survival (primary outcome measure).
• Also recurrence free survival, frequency and severity of adverse events
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Study Population
Study Population:
- Patients with high risk uterine leiomyosarcoma
- FIGO stage I (confined to corpus +/- cervix)
- Patients require to have had at least a complete hysterectomy (including removal of cervix)
- All patients must have no evidence of persistent or metastatic disease as documented by a
post-resection CT of the chest/abdomen/pelvis or by CT chest + MRI abdomen/pelvis
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Inclusion Criteria (1)
Patients will be eligible for the study if the following criteria are met:
• Patients with high risk uterine leiomyosarcoma, FIGO stage I (confined to corpus +/- cervix). Patients with known uterine serosa involvement are not eligible. Patients should have had, at least, a complete hysterectomy (including removal of the cervix). Bilateral salpingo-oophorectomy is not required.
- Institutional pathology review calls the uterine leiomyosarcoma “high grade”.
- Additionally, if the pathology report indicates a mitotic rate, the mitotic rate should be greater than or equal to 5 mitoses/10 high power field.
All patients must be no longer than 12 weeks (3 months) from surgical resection of cancer at the time of the enrollment on study. If a patient requires a second operation to complete her surgery, i.e. trachelectomy to remove the cervix and/or BSO, the 12 weeks may be counted from the time of the second operation.
• All patients must have no evidence of persistent or metastatic disease as documented by a post resection CT scan of the chest, abdomen and pelvis or by CT scan of chest + MRI of abdomen and pelvis. The post resection imaging should be performed within 4 weeks of registration/randomisation on study.
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Inclusion Criteria (2)
• Patients must have adequate:- Bone Marrow Function:
Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (ANC 1.5 x 109/l)
Platelets greater than or equal to 100,000mcl (Platelets 100 x 109/l)
Haemoglobin greater than 8.0g/dl (=80g/L; or 4.9mmol/L)- Renal Function:
Creatinine less than or equal to 1.5 x ULN- Hepatic Function:
Bilirubin within normal range. SGOT (AST), SGPT(ALT) and alkaline phosphatase less than or equal to 2.5 x ULN. Patients with a history of Gilbert‘s syndrome may be eligible provided total bilirubin is less than or equal to 1.5 x ULN and the AST, ALT, Alkaline phosphatase meet the criteria detailed.- Neurologic Function:
Neuropathy (sensory and motor) less than or equal to CTCAE grade 1
• Patients with GOG performance status of 0 or 1; ECOG performance status of 0 or 1; or KPS > 80%
• Patients who have met the pre-entry requirements specified in section 7.0 of protocol
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Inclusion Criteria (3)
• Patients must have signed an approved informed consent.
• Patients must be a minimum of 18 years of age.
• Patients should be free of active infection requiring antibiotics (with the exception of an uncomplicated Urinary Tract Infection [UTI])
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Exclusion Criteria (1)
Patients will be excluded from the study in the following circumstances:
• Patients who have had prior therapy with docetaxel or gemcitabine or doxorubicin at any time in their history.
• Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are ineligible if there is any evidence of other malignancy being present within the last five years. Patients are also ineligible if their previous cancer treatment contraindicates this protocol therapy.
• Patients with a history of severe hypersensitivity reaction to taxotere (docetaxel) or other drugs formulated with polysorbate 80.
• Patients with GOG performance status of 2,3 or 4; or ECOG performance status of 2,3 or 4.
• Patients who are breast feeding
• Patients with a know history of congestive heart failure or cardiac ejection fraction <50% (or less than institutional normal limits). ECHO or MUGA is not required prior to enrollment. For patients assigned to the chemotherapy arm, an ECHO or MUGA should be done within 6 months of starting treatment.
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Exclusion Criteria (2)
• Patients with a history of prior whole pelvic radiation.
• Concurrent treatment with hormone replacement therapy is permitted at the discretion of the treating physician. Patients who have been taking hormonal/hormone blocking agents for breast cancer or breast cancer prevention or other indication are eligible. Use of anti-hormonal agents (tamoxifen, medroxyprogesterone, aromatase inhibitors) is permitted at the discretion of the treating physician. Documentation of concurrent medications is required.
• Patients with recurrent uterine LMS
• Patients who are know to be HIV (human immunodeficiency virus) positive are not eligible due to the high risk for infectious complications of the mylesuppressive therapy used in the experimental arm of this study.
• Patients with gross residual or metastatic tumour findings following complete surgical treatment for uterine LMS
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Pre-randomisation/ Baseline Assessments
. Baseline scanning assessments to be performed within 28 days prior to initiating protocol therapy- Medical history and physical examination- Review and documentation of concurrent medications- Serum pregnancy test (for patients of childbearing potential)- ECG- CT chest/abdomen/pelvis or CT chest + MRI abdomen/pelvis
Baseline assessments to be performed within 14 days prior to initiating protocol therapy - Full blood count (including haemoglobin, neutrophils, platelets, WBC)- Biochemistry (Albumin, Total Bilirubin, AST, ALT, Alkaline Phosphatase, Electrolytes, BUN, creatinine)- Toxicity Assessment
*Note for patients which are randomised to REGIMEN I an ECHO or MUGA scan must be done to document normal cardiac ejection within 6 months of day 1 of gemcitabine-docetaxel treatment
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Reporting to RECIST
• All radiological investigations must be reported as per protocol / RECIST version 1.1.
• Source documentation of this must be available for review if the original report has had to be supplemented to bring it in line with protocol requirements.
• CR-UK have produced a worksheet to assist with the documentation of study specific reporting and will make this available to any participating site upon request to the study monitor
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Registration/Randomisation Process
• UK Investigators/sites will randomise patients through the NCI Cancer Trials Support Unit (CTSU) online registration system “OPEN”. *Note after sites have been activated to recruitment, the CR-UK Clinical Trial Unit, Glasgow will take the necessary steps to request a username and password for each site and communicate this information to sites.
• Prior to accessing the OPEN registration system to randomise the patient the following requires to be done:
• Once the above has been confirmed/done, the OPEN registration system can be accessed at https://open.ctsu.org
• Each patient randomised will be allocated a unique study identifier XXX-0277-XXX (The first set [xxx] is the institution number, and the last set [xxx] is the sequential on study number, assigned at registration along with treatment allocation.
• The OPEN system will provide a printable confirmation of registration and treatment information, which sites require to print.
Check patient has given written informed consent
Check patient fulfils eligibility criteria per study protocol and within protocol stated timeframes
Complete Registration/Randomisation Form
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Treatment
Treatment:
REGIMEN I:- Gemcitabine 900mg/m2 IV on days 1 and 8- Docetaxel 75mg/m2 IV on day 8- Filgrastim (GCSF) 5 micrograms/kg SC on days 9 to 15 or Pegfilgrastim 6mg SC day 9 or 10
Every 21 days for 4 cycles followed by:
- Doxorubicin 60mg/m2 IV- Filgrastim (GCSF) 5 micrograms/kg SC on days 2 to 8 or Pegfilgrastim 6mg SC on day 2 or 3
optionalEvery 21 days for 4 cycles
REGIMEN II:- Observation only
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Duration of Study/ Study Visits
• Patients on REGIMEN 1 will receive therapy for a maximum of 8 cycles (4 cycles of gemcitabine + docetaxel, followed by 4 cycles of doxorubicin) or until disease recurrence or toxicity intervenes
• A patient is considered off study treatment when the patient has recurred or died, a non-protocol drug or therapy (directed at the disease) is initiated or all study therapy is totally discontinued
• Patients on the observation arm (REGIMEN II) are considered off study treatment at the end of 24 weeks from study entry.
• Patients who are considered off study treatment in both arms remain on study in terms of follow-up for evidence of recurrence and for survival status.
• Patients will be followed for recurrence with physical examination, history and imaging until recurrence, death or five years of follow-up is reached. If there is evidence of disease recurrence, patients will continue to be followed for survival for at least 5 years from study entry.
• Please refer to study protocol investigations tables for each arm of the study to ensure the correct observations and tests are performed at protocol specified time points.
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Treatment Modifications (REGIMEN 1) - 1
• Please refer to section 6.0 of the protocol for full details of treatment modifications/dose reductions/delays for haematological and non haematological toxicities for regimen 1 (Brief details in relation to treatment modifications are provided on these slides)
• Gemcitabine and Docetaxel Dose Level Definitions:
• Doxorubicin Dose Level Definitions:
• Patients who require a dose reduction because of a toxicity meeting criteria specified in protocol are permitted ONE dose reduction. If toxicity recurs of a severity that would require another dose reduction, a second dose reduction is NOT permitted. Instead, treatment with the regimen that caused the additional toxicity should be discontinued.
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Treatment Modifications (REGIMEN 1) - 2
• Haematologic Toxicity during EITHER gemcitabine + docetaxel OR doxorubicin
• Initial treatment modifications will consist of cycle delay and/or dose reduction as indicated below. The use of hematopoietic cytokines and protective reagents are restricted as noted:
• Patients will receive prophylactic growth factors [filgrastim (G-CSF), or pegfilgrastim (Neulasta)] on day 9 of each cycle of treatment with gemcitabine + docetaxel as detailed in section 5.2 of protocol. Use of [filgrastim (G-CSF), or pegfilgrastim (Neulasta)] on day 2 of treatment with doxorubicin is optional.
• Patients will NOT receive prophylactic thrombopoietic agents unless they experience recurrent grade 4 thrombocytopenia after treatment modifications as specified below.
• Patients may receive erythropoietin (EPO), iron supplements, and/or transfusions as clinically indicated for management of anaemia management of anemia. Treating physicians should be aware of the recent changes in prescribing information for the erythropoiesis stimulating agents (including Aranesp, Epogen and Procrit); this information notes a potential risk of shortening the time to tumor progression or disease-free survival and recommends that these agents be administered only to avoid red blood cell transfusions. They do not alleviate fatigue or increase energy. They should not be used in patients with uncontrolled hypertension. They can cause an increased incidence of thrombotic events in cancer patients on chemotherapy. The updated package inserts should be consulted.
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Treatment Modifications (REGIMEN 1) - 3
• Haematologic Toxicity during EITHER gemcitabine + docetaxel OR doxorubicin
• Patients may NOT receive amifostine or other protective reagents, as this would be considered a protocol violation.
• Treatment decisions will be based on the absolute neutrophil count (ANC) rather than the total white cell count (WBC).
• Subsequent cycles of therapy will not begin until the ANC is 1000 /mcl (ANC 1.0 x 109/liter (L). and the platelet count is 100,000/mcl (100 x 109/L) Gemcitabine and docetaxel, or doxorubicin (whichever is applicable) will be delayed for a maximum of two weeks until these values are achieved.
• Patients whose counts fail to recover adequately within a two week delay will not receive further study treatment with that regimen. If the patient was on the gemcitabine + docetaxel section of the adjuvant treatment, and the ANC and platelets recover after no longer than a 3 week delay, the patient may proceed on to the doxorubicin portion of the study. If again there is a failure to recover ANC and platelets within a 2 weeks delay during treatment with doxorubicin, then study treatment will be discontinued.
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Treatment Modifications (REGIMEN 1) - 4
• Haematologic Toxicity during EITHER gemcitabine + docetaxel OR doxorubicin
• For first occurrence of febrile neutropenia (ANC < 1,000/mcl and fever > 38.5 C), and/or documented Grade 4 neutropenia persisting 7 days, OR Grade 3 thrombocytopenia (platelet count 25,000 to < 50,000/mcl) that is associated with bleeding or need for transfusion, OR Grade 4 thrombocytopenia (platelet count < 25,000/mcl), reduce the doses of both gemcitabine and docetaxel, or doxorubicin (whichever is applicable), by one dose level on all subsequent cycles.
• For a second episode of febrile neutropenia occurring despite dose reduction with the current regimen, treatment with that regimen should be discontinued. As in section 6.23, if the febrile neutropenia events occurred during treatment with gemcitabine + docetaxel, and patient has recovered from the toxicity after no longer than a 3 week delay, the patient may proceed on to the doxorubicin portion of the study. If the patient experiences a febrile neutropenia event during doxorubicin, study treatment should be discontinued.
• If treatment with gemcitabine + docetaxel is stopped for toxicity, the patient may proceed on to treatment with doxorubicin provided blood counts, liver function, and other toxicities permit chemotherapy treatment with doxorubicin within 3 weeks of the discontinuation of the gemcitabine + docetaxel.
• There will be no dose modifications on the basis of uncomplicated granulocyte nadirs lasting less than 7 days.
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Treatment Modifications (REGIMEN 1) - 5
• In addition to the dose modifications listed Day 8 Gemcitabine and Docetaxel dose adjustments should be made according to the table below:
• Note: ANC (absolute neutrophil count) >1000/mcl = ANC 1.0 x 109/liter (L).Plt (platelets) 100,000/mcl = Plt 100 x 109/L.Dose reduction on Day 8 does not count as one of the two permitted protocol dose reductions for toxicity. The next cycle may be started at previous doses, provided that blood counts have recovered as detailed in 6.23. If a dose reduction is required on Day 8 of a cycle, subsequent Day 8 doses should only be reduced in subsequent cycles if the criteria for reduction or omission of the day 8 doses are met on that cycle’s Day 8 of treatment.
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Treatment Modifications (REGIMEN 1) - 6
• Hepatic dysfunction during gemcitabine + docetaxel:
• If bilirubin increases to greater than institutional upper limits of normal when checked on Day 1, repeat the bilirubin on or prior to Day 8, prior to giving the docetaxel. If the bilirubin has returned to normal, proceed with docetaxel on Day 8. If the bilirubin remains greater than institutional normal limits on Day 8, give only gemcitabine on Day 8. The patient will thus receive no docetaxel that cycle. If the bilirubin does not recover by Day 8 of the next cycle, study treatment may be continued but will continue without docetaxel until the bilirubin returns to within institutional normal limits. If the bilirubin returns to within institutional normal limits, the docetaxel may be added back to the regimen.
• Elevations of 5 x ULN or higher in SGOT (AST), SGPT (ALT), or alkaline phosphatase requires delay in subsequent study treatment for a maximum of 2 weeks until recovered to less than or equal to 2.5 x ULN, AND reduction of one dose level for all subsequent cycles. Treatment with gemcitabine and docetaxel will be discontinued in patients whose SGOT (AST), SGPT (ALT), or alkaline phosphatase elevations fail to recover to less than or equal to 2.5 x ULN within 2 weeks.
• Hepatic dysfunction during doxorubicin:
• If bilirubin increases to greater than 1.5 x institutional upper limits of normal, delay the doxorubicin by up to 2 weeks. If the bilirubin does not recover after two weeks delay, the patient will be removed from study treatment.
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Treatment Modifications (REGIMEN 1) - 7
• Hypersensitivity reactions to Docetaxel:
• There are no dose reductions for hypersensitivity reactions. Please refer to section 6.5 of the protocol for guidance of management of acute hypersensitivity to docetaxel.
• Other Non-Haematologic Toxicity likely attributable to gemcitabine and/or docetaxel or doxorubicin:
• In the event of Grade 3 or 4 neurotoxicity, treatment will be delayed 1 week. If neurotoxicity has resolved to less than or equal to Grade 1, then the patient may continue on study with docetaxel dose reduction of one dose level in the current and all subsequent cycles (no dose adjustment is required for gemcitabine).
• If the Grade 3 or 4 neurotoxicity has not resolved to less than or equal to Grade 1 after a two-week delay, the docetaxel will be discontinued. Patients will continue to receive gemcitabine.
• A patient who presents with Grade 2 peripheral neuropathy requires a docetaxel dose reduction of one dose level and delay in subsequent therapy for a maximum of 2 weeks until recovery to Grade 1. If the patient is re-treated with a docetaxel dose reduction after recovery from a Grade 2 peripheral neuropathy, the dose reduction should remain in the current and all subsequent cycle
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Treatment Modifications (REGIMEN 1) - 8
• Other Non-Haematologic Toxicity likely attributable to gemcitabine and/or docetaxel or doxorubicin:
• Grade 2 (or greater) renal toxicity requires reduction of one dose level for gemcitabine and for docetaxel and delay in subsequent therapy for a maximum of 2 weeks until recovered to Grade 1. Discontinue both gemcitabine and docetaxel (or doxorubicin, if applicable) when Grade 2 or worse renal toxicity does not recover to Grade 1 or less. Since renal toxicity is generally not considered a toxicity of doxorubicin, no dose reduction for doxorubicin is required, unless, in the judgment of the treating physician, the doxorubicin was considered the cause of the renal toxicity.
• HUS (hemolytic uremic syndrome): The diagnosis of HUS should be considered if the patient develops hemolytic anemia with evidence of microangiopathic hemolysis as indicated by elevation of indirect bilirubin or LDH, reticulocytosis, severe thrombocytopenia, and/or evidence of renal failure (elevation of serum creatinine of BUN). Gemcitabine therapy should be discontinued immediately. Renal Failure associated with HUS may not be reversible even with discontinuation of therapy and dialysis may be required. Patients who develop HUS requiring intervention should be removed from study treatment.
• There will be no dose modifications for alopecia or fatigue
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Treatment Modifications (REGIMEN 1) - 9
• Other Non-Haematologic Toxicity likely attributable to gemcitabine and/or docetaxel or doxorubicin
• It is expected that patients with nausea, emesis, diarrhea, or constipation will receive appropriate medical management without dose modification. However, patients with persistent (greater than 24 hours) Grade 3 (or greater) toxicity in spite of optimal medical management require reduction of one dose level for both gemcitabine and docetaxel if the toxicity occurs during the gemcitabine + docetaxel treatment, and for doxorubicin if the toxicity occurs during the doxorubicin treatment, and delay in subsequent study treatment for a maximum of 2 weeks until recovered to Grade 1.
• Other non-hematologic toxicities (including mucositis) with an impact on organ function of Grade 2 (or greater) require reduction of one dose level for both gemcitabine and docetaxel if the toxicity occurs during the gemcitabine + docetaxel treatment, and for doxorubicin if the toxicity occurs during the doxorubicin treatment, and delay in subsequent study treatment for a maximum of 2 weeks until recovered to Grade 1, or pre-therapy baseline.
• In patients who develop Grade 4 oedema considered likely related to gemcitabine and/or docetaxel, gemcitabine and docetaxel will be discontinued.
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General Pharmacy Information -1
The investigational medicinal products in this study are:- Gemcitabine- Docetaxel- Doxorubicin
• All the IMPs for use in the trial will be from sites own stock. There is no provision for funding, reimbursement or discounted stock.
• Although specific formulations are mentioned in the study protocol, UK sites are permitted to use locally approved formulations. This must be confirmed to the CR-UK Clinical Trials Unit during initiation process.
• Chemotherapy doses may be recalculated every cycle during treatment if it is local practice to do so( e.g. automatic updates by electronic prescribing systems). Where it is not local practice to recalculate every cycle the doses MUST be recalculated if the subject’s weight changes by greater than or equal to 10% from baseline.
• BSA calculations should be performed as routine local practice and capped at 2.0m2
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General Pharmacy Information -2
• Chemotherapy doses may be dose banded if it is routine local practice to do so. This must be confirmed to the CR-UK Clinical Trials Unit during initiation process.
• The following are designated Non-Investigational Medicinal Products (NIMPs) for the purpose of the study and do not require extra accountability in addition to standard practice:
- Filgrastim- Pegfilgrastim
• Study specific prescriptions for supplies of Gemcitabine, Docetaxel, Doxorubicin, Pegfilgrastim and Filgrastim must be used.
• At the study site the study medication must be kept in a secure area with restricted access to pharmacy staff.
• IMP accountability logs must be used, logs can be supplied by the CR-UK Clinical Trials Unit for use in the study, or local documentation can be used after approval by CR-UK Clinical Trials Unit
• Drug disposal- used or partially used vials, dose-banded infusions or syringes may be disposed of at site according to local hospital policy with no additional accountability required.
• Full instructions regarding management and accountability is given in the IMP Management and Accountability Manual for the study which will be provided to sites in the pharmacy file.
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Site Set-up
• CTU Glasgow
- Main REC approval
- MHRA approval - Site Initiation Slides - Investigator File - Pharmacy File - Royal Mail Safeboxes
SITE - SSI - Staff Contact and Responsibilities Sheets - R&D Approval - CVs for Study Team - Clinical Trial Agreement - GCP Certificates for Study Team - PIS, Consent, GP Letter etc on Trust headed
paper - Laboratory normal ranges and accreditation
certificates (Haematology and Biochemistry) - PI completes FDA 1572 form, Financial
Disclosure Form and Supplemental Investigator Data Forms
Initiation Process
SITE ACTIVATED
Activation of site Notification by email
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Informed Consent Process-1
• Two original Consent Forms must be completed by a clinician (or deputy listed on Staff Contacts & Responsibilities Sheet)
• Two originals signed and completed by the patient
• Date must be prior to registration.
• Make one photocopy - Original to be filed in Investigator File - Original to be given to patient (+PIS) - Photocopy to be filed in hospital notes
• The consent form must not be sent to the coordinating clinical trials unit
3131
Informed Consent Process-2
• Errors noticed after consent - Add explanatory note/file note
• New version of Patient Information Sheet must be provided to patients consented with previous version
- Give to all patients regardless of treatment stage, during clinic visit
• Patients who are still on active treatment will be required to repeat the consent process using the updated form
- If not appropriate to re-consent patient (i.e. patient terminally ill) please make a note regarding this in the patients case notes and on re- consent log
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Consent Withdrawal
• This is when the patient specifically asks to withdraw their consent at any point in the study
• Ensure that the level of consent withdrawal is clearly documented in the source data
• If this occurs:
– Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal and the reason (if the patient has given any);
– Inform GOG via follow-up form in SEDES;– No further follow-up should be collected on the patient from that point onwards.
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CRFs
GOG Data Management Forms (to be sent to GOG)• Form R (Registration Form)• Form OSU (Uterine Cancer – On Study Form)• Form C (Surgical Reporting Form) Operative report and discharge summary• Form DR (Pre- Treatment Summary Form)• Form D2M (Solid Tumour Evalaution Form) Baseline• Primary disease: Form F, Pathology Report• Form D2R (Cycle Dose Drug Form)• Form D2M (Solid Tumour Evaluation Form)• Form T (Common Toxicity Reporting Form)• Form Q0 (Treatment Completion Form)• Form Q (Follow-up Form)
A form schedule of when each form is due is included in the protocol
EORTC Paper SAE – Pregnancy Forms (to be sent to EORTC)• SAE form• Pregnancy Form
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CRF Completion
GOG Data Management Forms• Completion guidelines for each form have been provided by Gynaecologic Oncology
Group (GOG) in US, a copy of which will be filed in Investigator Site File.• CRFs for the study are completed via GOG Statistical and Data Centre (SDC)
Electronic Data Entry System (SEDES online application)
EORTC Paper SAE – Pregnancy Forms • Completion guidelines for the SAE and pregnancy forms have been provided by
EORTC, a copy of which will be filed in Investigator Site File.• SAE and pregnancy forms have to be completed and sent via fax to the EORTC
Pharmacovigilance Unit (Fax no +32 2 772 8027)
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Central Pathology Review (Retrospective)
• Central pathology review will be performed retrospectively for all patients entered to the study. This is mandatory for the study.
• Following entry to the study the local pathologist will require to send stained pathology slides for central review by the reference pathologist to confirm eligibility. At least one representative H&E (haematoxylin/eosin) stained slide demonstrating the primary high grade uterine leiomyosarcoma with adequate mitotic rate, nuclear atypia and tumour necrosis (if present).
• Submitted pathology material should be labelled with the patients sequential ID, patient initials, surgical/pathology and block identifier. The local pathologist will also require to send the completed pathology form (form f) and copy of his/her pathology report. Personal data of the patient must be anonymised and replaced with the sequential identification number allocated to the patient at time of randomisation.
• Sites will be provided with a supply of Royal Mail Safeboxes which should be used to send tumour samples to the UK Lead Pathologist for the study (Professor Cyril Fisher). The slides, copies of the pathology form (Form F) and official pathology report should be sent.
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Translational Research
• In this trial, tissue samples will be collected for future translational research.
• The translational research aspect of the trial is not mandatory to patients.
• For patients who have consented to take part in future translational research the local pathologist shall also include blocks or if no blocks available at least 10 unstained slides for translational research
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Pharmacovigilance
ICH GCP and the EU Directive 2001/10 EC require that both investigators and sponsors follow
specific procedures when notifying and reporting adverse events/reactions in clinical Trials. These procedures are described below and on subsequent slides:
• Investigators require to document Adverse Events (AEs) in patient notes and the CRF as required.
• Investigators report Serious Adverse Events (SAEs) immediately and no later than 24 hours from the time the investigator/staff become aware of the event to the EORTC Pharmacovigilance Unit.
• The EORTC Pharmacovigilance Unit will assess all SAEs which occur in the trial in Europe to identify trial SUSARs and will prepare SUSAR reports for submission.
• The EORTC Pharmacovigilance Unit will be responsible for submitting the SUSARs to the MHRA, Main Research Ethics Committee, CR-UK CTU Contacts and UK trial sites.
• The EORTC Pharmacovigilance Unit will forward all SAE reports which occur in Europe to appropriate persons within the EORTC headquarters and enter them into AdEERs.
• EORTC will produce and provide the Development Safety Update Reports (DSURs) for the study.
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Definition of Adverse Event (AE)
• An adverse event is defined as “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a casual relationship with the treatment”
• An adverse event can therefore be any unfavourable and unintended signs (such as rash or enlarged liver), symptoms (such as nausea or chest pain), an abnormal laboratory finding (including results of blood tests, x-rays or scans) or a disease temporarily associated with the use of the protocol treatment, whether or not considered related to the investigational medicinal product
• All AEs must be followed; - until resolution,
- or for at least 30 days after discontinuation of study medication, - or until toxicity has resolved to baseline, - or < Grade 1, - or until toxicity is considered to be irreversible
• The severity of all AEs (serious or non serious) in this trial must be graded according to the NCI-CTCAE Version 4.0. A copy of this can be downloaded from following website:
www.eortc.org\investigators-area\ctc
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Definition of a SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as untoward medical occurrence or effect in a patient , whether or not considered related to the protocol treatment, that any dose:
• Results in death • Is Life-threatening (i.e. an event in which the subject was at risk of death at the time
of the event; it does not refer to an event which hypothetically might have caused death if it was more severe)
• Requires inpatient hospitalization or prolongation of existing patient hospitalization • Results in persistent or significant disability or incapacity • Is a congenital anomaly or birth defect • Is a medically important event or reaction
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Definition of a SERIOUS ADVERSE EVENT- 2
Life threatening:• An event in which the subject was at risk of death at the time of the event; it does
not refer to an event which hypothetically might have caused death if it was more severe.
Requires in-patient hospitalisation:• Is a hospital admission required for treatment of an adverse event even when the
adverse event is not related to the protocol treatment.
Medically important:• Medical and scientific judgment should be exercised in deciding whether other
situations should be considered serious such as important medical events that might not be immediately life threatening or result in death or hospitilisation but might jeopardise the patient or might require intervention to prevent one of the other outcomes listed in the definition.
• ** Note grade 4 anaphylaxis reactions, regardless of whether a hospitalisation is required, also need to be reported as an SAE**
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Exceptions
Exceptions:The following situations do not need reported as SAEs:
• Elective hospitalisation for pre-existing conditions that have not been exacerbated by trial treatment.
• A hospitalisation which was planned before the patient consented for study participation and where admission did not take longer than anticipated.
• A hospitalisation planned for protocol related treatment or protocol related procedure as per institutional standard timelines.
• Social and/or convenience admission to a hospital• Medical or surgical procedure (e.g. endoscopy, appendectomy); the condition that
leads to the procedure is an (S)AE.• Situations where an untoward medical occurrence did not occur (palliative care,
rehabilitation, overdose without occurrence of an adverse event.• Anticipated day to day fluctuations of pre-existing disease(s) or condition(s) present
or detected at the start of the study that do not worsen.
**By EORTC convention, clinical events related to the primary cancer being studied or to the primary cancer
progression are not to be reported as SAEs, even if they meet any of the seriousness criteria from the standard SAE
definition, unless the event is more severe than expected and therefore the investigator considers that their clinical
significance deserves reporting.**
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Reporting Procedure for SAEs (1)
• Serious Adverse Events (SAEs) must be reported immediately (and no later than 24 hours of from the time the investigator or staff became aware of the event)
• SAEs are reported using the EORTC SAE report form provided for the study
• Sites must complete the EORTC SAE report form and fax the report to: EORTC Pharmacovigilance Unit Fax number: +32 2 772 8027
This procedure applies applies to all Serious Adverse Events (SAEs) occurring from the time a subject is registered until :
• For investigational arm: 30 days after last protocol treatment administration and to any SAE that occurs outside of the SAE detection period (after the 30-days period), if it is considered to have a reasonable possibility to be related to the protocol treatment or study participation.
• For the observation arm: end of week 24.
• Any secondary malignancy should also be reported in expedited way on a SAE form with the appropriate seriousness criteria!
• All reporting must be done by the principal investigator or authorized staff member (i.e. on the signature list) to confirm the accuracy of the report.
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Reporting Procedure for SAEs (2)
• To enable the Sponsor to comply with regulatory reporting requirements, all initial SAE reports should include the following minimal information:
- Identifiable patient ID- Suspect medicinal product (if applicable)- Identifiable reporting source- Description of medical event and seriousness criteria- Casuality assessment by investigator
• Complete information requested on the SAE form of any reported serious adverse event must be returned within 7 calendar days of the initial report. If the completed form is not collected within this deadline the EORTC Pharmacovigilance Unit will make a written request to the investigator
• Queries sent out by the EORTC Pharmacovigilance Unit need to be answered within 7 calendar days.
• All forms need to be dated and signed by the principal investigator or authorised staff member
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Suspected Unexpected Serious Adverse Reaction (SUSAR)
Definition of SUSAR:• A SUSAR is any unexpected serious adverse reaction that is
unexpected. Unexpected is any reaction that is not a known reaction listed in the Investigator Brochure or Summary of Product Characteristics for the trial treatment.
Procedure for Indentifying a SUSAR:• The EORTC will assess all SAEs which occur in the trial in Europe to
indentify trial SUSARs and will prepare SUSAR reports for submission to the applicable regulatory authorities in each European country participating in the trial.
Reporting of a SUSAR:• The EORTC will be responsible for submitting the SUSARs to the MHRA,
Main Research Ethics Committee, CR-UK CTU contacts and UK trial sites.
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SUSARs -Expedited reporting
• Fatal or life threatening SUSARs will be reported within 7 calendar days
• Non fatal or non- life threatening SUSARs will be reported within 15 calendar days
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Pregnancy Reporting
• Pregnancy occurring during a patient’s participation in this trial, although not considered an SAE, must be notified to the EORTC Pharmacovigilance Unit within the same timelines as an SAE (within 24 hours) on a Pregnancy Notification Form. The outcome of a pregnancy should be followed up carefully and any adverse outcome to the mother or child should be reported.
- Any pregnancy in a female subject diagnosed during the treatment period or within 30 days after the last protocol administration must be reported to the EORTC Pharmacovigilance Unit
- This must be reported within 24 hours of first becoming aware of the event by fax, to the EORTC Pharmacovigilance Unit on a Pregnancy Notification Form
- If an SAE occurs in conjunction with the pregnancy, please also complete an SAE form .
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Development Safety Update Reports
• Development Safety Update Reports (DSURs) will be produced by EORTC for the study .
• The EORTC will submit Development Safety Update Reports to the MHRA, Main Research Ethics Committee, CR-UK CTU Contacts and Trial Investigators.
• The timeline for DSUR preparation and submission is based on the Development International Birth Date (DIBD) (i.e. Date of first approval (or authorisation) for conducting an interventional clinical trial in any country)
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Monitoring
All participating study sites will be monitored by a member of the CR-UK Clinical Trials Unit, Glasgow, Monitoring Team
The 1st visit will take the form of a Remote Telephone Monitoring Visit. (This is scheduled to take place 3 months after first patient randomised at each site)
The 2nd visit will be an On-Site Monitoring Visit. (This is scheduled to take place 12 months after first patient randomised at each site)
The 3rd visit will be an On-Site Monitoring Visit. (This is scheduled to take place 36 months after first patient randomised at each site)
Site closeout visit, this may be combined with a routine on-site monitoring visit.
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Remote Telephone Monitoring Visit
The time & date will be agreed with a member of the Site Study Team & a separate time & date agreed with a member of the Clinical Trials Pharmacy Department.
A pro forma covering the questions which will be covered during the telephone monitoring visit will be sent with confirmation of the agreed date.
Please set aside 50 to 70 minutes for this call.
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On Site Monitoring• All patient source documentation should be made available to enable Source
Document Verification by the Clinical Trial Monitor.
• A full working day is required for on-site visits & arrangements should be in place to facilitate the monitor access on the agreed date.
• If sites are able to provide printed results/reports these must be filed in the source documents.
• If a site is using electronic data reporting systems or electronic records & hard copies are not available – the clinical trial monitor must be permitted access to the system either by being issued with a temporary login or a member of staff available for the duration of the visit to facilitate electronic access to authorised reports/results.
• Pharmacy visits will include review of Pharmacy Site File – Temperature Logs – Drug Returns – Drug Accountability Logs and Destruction of drug.
• All findings will be discussed at an end of visit meeting and any unresolved issues raised as Action Points.
• Action Points will be followed up by the monitor until resolved.
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Ethical and Regulatory Standards
• Study will be conducted according to ICH GCP guidelines
• Study conducted in accordance with the EU Directive 2001/20/EC
• Trial carried out in accordance with the World Medical Association Declaration of Helsinki (1964) and the Tokyo (1975), Venice (1983), Hong Kong (1989), South Africa (1996), Edinburgh (2000), Washington (2002), Tokyo (2004), Seoul (2008) amendments
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Investigators Responsibilities
The following principles are from ICH GCP Topic E6 and apply to clinical trials of Investigational Medicinal Products:
• Qualifications & Agreements:- The Investigator should be qualified by education, training & experience. - Thoroughly familiar with protocol & medicinal products.- Comply with GCP and applicable regulations.- Permit – monitoring and audit by the sponsor and inspection by regulatory authorities.- Maintain a delegation logs of staff involved in the clinical trial at the trial site.- Ensure that all persons assisting with the trial are adequately informed about the – protocol, IMP and their duties and functions.
• Resources:- The Investigator should have sufficient time to properly conduct and complete the trial within the agreed period.- Have available adequate facilities and qualified staff to conduct the trial properly and safely.
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Investigator Responsibilities
• Medical Care of Trial Subjects:- A qualified physician who is an Investigator (or co-investigator) should be responsible for all trial related medical decisions.- During and following participation the Investigator should ensure adequate medical care for any adverse events (AEs).- The Investigator should make as reasonable effort to ascertain reasons for withdrawal from the trial (although a subject is not obliged to give reasons)
• Ethics:- Before initiating the trial there should be written and dated approval/favourable opinion from the Ethics Committee for the protocol, patient information sheet/consent form and any amendments.
• Compliance with Protocol:- The Investigator should conduct the trial in compliance with the protocol.- Not implement any deviation from the protocol without prior approval/favourable opinion of the IEC and the sponsor.- The Investigator should document and explain any deviation from the protocol.
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Investigator Responsibilities• The IMP :
- Investigator has responsibility for IMP accountability at trial site- Some/all IMP duties at the trial site may be assigned to suitably qualified pharmacist.- Records must be maintained: delivery, inventory, use and destruction- Storage of the IMP should be as specified by the sponsor/regulatory requirements.- The IMP should only be used in accordance with the protocol.- The Investigator (or designee) should explain the correct use of the IMP to each patient.
• Randomisation:- The Investigator should follow the trial’s randomisation procedures as detailed in the protocol.
• Informed consent: - In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement (s), and should adhere to GCP and to the ethical principles that have their origin in the Declaration of Helsinki.
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Investigator Responsibilities
• Reports & records – The investigator is responsible for accuracy, completeness, legibility and timeliness of the data reported to the sponsor.- Data reported on CRFS, from source documents should be consistent with source documents or discrepancies explained.- Corrections should be : dated, initialled, explained (if necessary) and should not obscure the original entry.- All trial documents should be maintained as specified in ICH GCP E6, Section 8 (Essential documents for the conduct of a clinical trial).
• Safety reporting:- Investigators must report Serious Adverse Events to the sponsor (EORTC) as soon as they become aware of the event.
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Other Staff
The Principal Investigator has overall responsibility for the conduct of the clinical trial at the trial site.
BUT
• All staff must comply with GCP.• Staff should only perform tasks delegated to them.• Staff should ensure that their details are available to the Investigator.• Staff should maintain appropriate confidentiality at all times
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Contact Details for CR-UK CTU, Glasgow
CR-UK CTU, Glasgow
Cancer Research UK Clinical Trials Office Level 0, Beatson West of Scotland Cancer Centre
1053 Great Western Road, Glasgow, G12 0YN Tel: +44(0) 141 301 7197Fax: +44(0) 141 301 7946E-mail: [email protected] Email: [email protected]
