Transcript Initiation Slides - CRUK Clinical Trials Unit, Glasgow

OPSROC (Optimum Therapy in Platinum Sensitive
Relapsed Ovarian Cancer
A prospective randomized Phase III trial of carboplatin /
gemcitabine / bevacizumab vs carboplatin / pegylated liposomal
doxorubicin / bevacizumab in patients with platinum-sensitive
recurrent ovarian cancer
INITIATION SLIDES
(Version 3: 06 May 2014)
STUDY DETAILS
• The study is being co-ordinated in the UK by the Cancer Research UK Clinical Trials Unit, Glasgow (CRUK CTU)
• UK Sponsor is Greater Glasgow & Clyde Health Board (GG&CHB)
• Main Sponsor is the AGO Study Group, Germany
• Lead UK Investigator is Dr Rosalind Glasspool
• Chief Investigator is Professor Jacobus Pfisterer
• Study is funded by the AGO Study Group in Germany and endorsed in the UK by CRUK
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Please note this presentation has been prepared as part of your site initiation.
These slides are a compliment to the protocol, all site staff must have read
and understood the protocol and the study requirements prior to signing off
the initiation acknowledgment sheet. A UK Appendix to the protocol has been
produced and this should compliment or supersede the study protocol.
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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
STUDY TEAM
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Lead UK Investigator :
Dr Rosalind Glasspool (Glasgow)
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Project Manager:
Liz-Anne Lewsley
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Sponsor Pharmacist
Dr Samantha Carmichael
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Pharmacovigilance:
Lindsey Connery / Sinead Traynor
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Clinical Trial Coordinator:
Diann Taggart
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Study Monitor:
Calum Innes
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Sponsor representative:
Dr Maureen Travers
STUDY DESIGN AND OBJECTIVES
This is a prospective, open-label, multinational, randomized, twoarm, superiority Phase III trial.
Primary Objective:
• Investigator-determined progression-free survival (PFS)
Secondary Objectives:
• Overall Survival (OS)
• Biological Progression-free Survival (PFS ) by serum CA125
assessed according to the GCIG criteria
• Quality of Life (QoL) assessed by EORTC QLQ-C30 and QLQ-OV28
• Safety and tolerability
BIO
INFORMED CONSENT PROCESS
Informed consent process:
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Two original Consent Forms: completed by a clinician listed on delegation log and signed and completed by the patient
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Date must be prior to registration/ randomisation.
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Make one photocopy
- Original to be filed in Investigator File
- Original to be given to patient (+PIS)
- Photocopy to be filed in hospital notes
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Consent Form must not be sent to your coordinating trials office
FOR ERRORS NOTED AFTER CONSENT
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Add explanatory note/file note
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New version of Patient Information Sheet must be provided to patients consented with previous version. This must be given to all
patients regardless of treatment stage, during next possible clinic visit.
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Patients who are still on active treatment will be required to repeat the consent process using the updated form. If it is not
appropriate to re-consent patient (i.e. patient terminally ill) please make a note regarding this in the patients case notes and on reconsent log which is filed in your study site file.
CONSENT WITHDRAWAL
If a patient specifically asks to withdraw their consent at any point in the study.
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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)
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Enter patient withdrawal on the eCRF
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No further follow-up should be collected on the patient from that point onwards (if patients have withdrawn consent for follow up
and not just withdrawn from treatment).
ELIGIBILITY CRITERIA – INCLUSION CRITERIA (1)
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Signed written informed consent.
Females aged > 18 years.
Histological confirmed diagnosis of epithelial ovarian carcinoma (including mixed Mullerian
tumors/carcinosarcomas) or fallopian tube carcinoma or primary peritoneal carcinoma. All FIGO stages,
histological grades and types are allowed.
First disease recurrence > 6 months after first-line platinum-based chemotherapy, no prior chemotherapy in
the recurrent setting is allowed. Patients must have stopped any 1st line maintenance treatment with any
type of anticancer treatment including bevacizumab at least 30 days prior to randomization.
Patients with measurable or non-measurable disease (according to RECIST v1.1) or CA125 assessable
disease (according to GCIG criteria) or histological proven diagnosis of relapse. Clarification: Patients can
have one or all of these to be eligible to enter the study
In case of cytoreductive surgery for recurrence, patients must be able to commence cytotoxic
chemotherapy within 8 weeks after cytoreductive surgery. The first dose of Bevacizumab can be omitted in
both arms if the investigator decides to start chemotherapy within 4 weeks after debulking surgery for
recurrent disease.
ECOG performance status (PS) 0-2.
Life expectancy > 3 months.
ELIGIBILITY CRITERIA – INCLUSION CRITERIA (2)
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Within 28 days prior to randomization
– Adequate bone marrow function
– Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Platelets (PLT) ≥ 100 x 109/L
• Haemoglobin (Hb) ≥ 9.5 g/dL (haemoglobin may be supported by transfusion or erythropoietin or other
approved hematopoetic growth factors)
– Adequate coagulation parameters (within 28 days prior to randomization)
• Patients not receiving anticoagulant medication who have an International Normalised Ratio (INR) ≤ 1.5 and an
Activated ProThrombin Time (aPTT) ≤ 1.5 x ULN. (The use of full-dose oral or parenteral anticoagulants is
permitted as long as the INR or aPTT is within therapeutic limits (according to institution medical standard) and
the patient has been on a stable dose of anticoagulants for at least two weeks at the time of randomization).
Clarification: LMWH is allowed provided the patient has been stable for 2 weeks (IV heparin is excluded)
– Adequate liver function (within 28 days prior to randomization)
• Serum bilirubin (BR) ≤ 2 x ULN
• Serum transaminases ≤ 2.5 x ULN (≤ 5 x ULN in the presence of liver metastases)
– Adequate renal function (within 28 days prior to randomization):
• Serum creatinine < 1.6 mg/dL (converts to 141.4 mol/l) or creatinine clearance ≥ 40 ml/min
• glomerular filtration rate > 40 ml/min (estimates based on the Cockroft-Gault or Jellife formular are sufficient).
UK sites are also permitted to calculate the GFR using the Wright Formula or measure EDTA clearance.
Urine dipstick for proteinuria < 2+. If urine dipstick is ≥ 2+, 24-hour urine must demonstrate <1 g of protein in 24 hours
Normal blood pressure or adequately treated and controlled hypertension (systolic BP ≤ 140 mmHg and/or diastolic BP ≤ 90
mmHg
ELIGIBILITY CRITERIA – EXCLUSION CRITERIA (1)
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Non-epithelial origin of the ovary, the fallopian tube or the peritoneum (i.e. germ cell tumors).
Ovarian tumors of low malignant potential (e.g. borderline tumors).
Malignancies other than ovarian cancer within 5 years prior to randomization, except for adequately treated
– carcinoma in situ of the cervix
– and/or basal cell skin cancer
– and/or non-melanomatous skin cancer
– and/or carcinoma in situ of the breast
– and/or endometrial carcinoma (FIGO stage ≤ IA).
Patients may have received previous adjuvant chemotherapy for other malignancies (e.g. breast or colorectal carcinoma) if
diagnosed over 5 years ago before randomization with no evidence of subsequent recurrence.
Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal
therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted as are
steroidal antiemetics).
Any previous radiotherapy to the abdomen or pelvis.
Treatment with any other investigational agent, or participation in another clinical trial testing a drug within the past 30 days
before randomization.
Known hypersensitivity to used chemotherapeutic agents in this trial and bevacizumab and its excipients, chinese hamster
ovary cell products or other recombinant human or humanised antibodies. For patients who have had previous carboplatin
reaction which has been controlled, then study entry is at the Investigator’s discretion.
Current or recent (within 10 days prior to randomization) chronic use of aspirin > 325 mg/day.
Surgery (including open biopsy) within 4 weeks prior to anticipated first dose of bevacizumab (allowing for the fact that
bevacizumab can be omitted from the first cycle of chemotherapy). It is strongly recommended that an interval of 7 days is
left between the insertion of any central venous access devices (CVADs) and the onset of bevacizumab treatment.
Any planned surgery during the trial treatment period plus 4 additional weeks to allow for bevacizumab clearance.
ELIGIBILITY CRITERIA – EXCLUSION CRITERIA (2)
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History of VEGF therapy related abdominal fistula or gastrointestinal perforation.
Current, clinically relevant bowel obstruction, including sub-occlusive disease, related to underlying disease.
Patients with evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
Previous Cerebro-Vascular Accident (CVA), Transient Ischaemic Attack (TIA) or Sub-Arachnoid Hemorrhage (SAH) within 6
months prior to randomization.
Prior history of hypertensive crisis or hypertensive encephalopathy. Uncontrolled hypertension (sustained elevation of systolic
blood pressure >140 mmHg and / or diastolic >90 mmHg despite antihypertensive therapy).
Clinically significant (e.g. active) cardiovascular disease, including:
– myocardial infarction or unstable angina within ≤ 6 months of randomization
– New York Heart Association (NYHA) > grade 2 congestive heart failure (CHF)
– poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible)
– peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring
repair or revision)
Left ventricular ejection fraction (LVEF) defined by ECHO/MUGA below the institutional lower limit of normal.
Significant traumatic injury during 4 weeks prior to randomization.
History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI of the brain is mandatory (within 4 weeks
prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to
randomization) in case of suspected spinal cord compression.
History or evidence upon neurological examination of central nervous system (CNS) disease, unless adequately treated with
standard medical therapy (e.g. uncontrolled seizures).
Non-healing wound, active ulcer or bone fracture. Patients with granulating incisions healing by secondary intention with no
evidence of facial dehiscence or infection are eligible but require 3 weekly wound examinations.
ELIGIBILITY CRITERIA – EXCLUSION CRITERIA (3)
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History or evidence of thrombotic or haemorrhagic disorders within 6 months prior to randomization.
Evidence of bleeding diasthesis or significant coagulopathy (in the absence of coagulation).
Fertile woman of childbearing potential not willing to use adequate contraception (oral contraceptives, intrauterine device
or barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) for duration of the clinical trial
and at least 6 months afterwards.
Pregnant or lactating women.
Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable
suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for
treatment related complications.
Requirement of therapeutic anticoagulation using marcumar, warfarin or PTT-prolonging heparin. Clarification: LMWH is
allowed provided the patient has been stable for 2 weeks (IV heparin is excluded)
PATIENT RANDOMISATION
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All patients must be randomized prior to commencement of any treatment.
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All baseline investigations must be performed to confirm patient eligibility prior to randomisation
 Check that patient fulfils eligibility criteria as per study protocol section 4.2 (see previous slides).
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There will be no exceptions to the eligibility requirements at the time of randomisation. Queries in relation to the eligibility
criteria should be addressed prior to calling for randomisation. Patients are eligible for the trial if all the inclusion are met and
none of the exclusion criteria applies.
 Check that patient has given written informed consent as per the informed consent process.
 Complete Enrolment Form and fax to the CRUK CTU
 Please note that sites allocate screening/trial numbers to each patient. This should be a six digit number comprising of your 3digit site number and then sequential 001, 002, 003 etc.,
 Once the patient has completed screening, complete 3 stages of randomisation
1. Screening Randomisation Form and fax to the CRUK CTU
Fax no: ++ 44 141 301 7244*
08.30-17.00 Mon-Thurs and 08.30-16.30 Friday, except public holidays
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The CRUK CTU will give permission for patients to be randomised. You must wait for permission to be given before
proceeding with randomisation
2. Randomisation is performed by faxing the randomisation fax to KKS
Fax no: +49 (0) 6421 28 66517
08.00-15.00 Mon-Thurs and 08.00-13.00 Friday, except public holidays
3. Once randomisation has been completed, you must complete the Oracle Registration Form and fax this to the CRUK CTU on:
Fax no: ++ 44 141 301 7244*
08.30-17.00 Mon-Thurs and 08.30-16.30 Friday, except public holidays
* Faxes received outside of office hours will be processed the next working day
TREATMENT AND DURATION
The trial consists of 2 treatment arms of chemotherapy plus bevacizumab until protocol defined disease
progression or further reason for treatment discontinuation (i.e. intolerable toxicity, withdrawal consent and
others see Protocol Section 13.1). Patients will be randomly assigned (1:1) to either arm.
Arm 1 (every 3 weeks)
Bevacizumab
15mg/kg i.v. d1 (until disease progression or
unacceptable toxicity)
Gemcitabine
1000mg/m2 d1 + d8 for 6 cycles
Carboplatin
AUC4 d1 for 6 cycles
Arm 2 (every 4 weeks  every 3 weeks)
Bevacizumab*
10mg/kg i.v. d1 every 2 weeks for 6 cycles
PLD
30 mg/m2 d1 for 6 cycles
Carboplatin
AUC5 d1 for 6 cycles
*In arm 2 bevacizumab (15mg/kg i.v. q3w) will be given as maintenance therapy until disease progression
or unacceptable toxicity if chemotherapy is finished.
SUPPLY OF STUDY DRUGS
Bevacizumab
Bevacizumab will be provided free of charge by Roche to sites for use of patients in
the OPSROC study and will be study specific investigational medicinal product trial
stock.
• Bevacizumab is considered IMP for the purpose of this study
Carboplatin, Gemcitabine and Pegylated Liposomal Doxorubicin
Sites should use their own commercial stock of carboplatin, Gemcitabine and PLD
• These drugs are considered IMP within the UK for this study. Please note that
full instructions regarding management, labelling and accountability all study
drugs is given in a separate IMP Management Document for the study.
The protocol states that Bevacizumab only is IMP for this study however in the UK
all 4 study drugs are considered to be IMP. This is clarified in the UK specific
appendix which is provided as part of the study documentation.
PREPARATION, ADMINISTRATION AND DOSE GUIDELINES (1)
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The investigator or a delegated individual (e.g. pharmacist) must ensure that the study drugs are
dispensed in accordance with the protocol, local standard operating procedures and applicable
regulatory requirements
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For patients randomized in arm 1 bevacizumab will be administered intravenously with a dose of
15mg/kg on day 1 every 3 weeks. The dose of 10mg/kg bevacizumab will be administered
intravenously on day 1 every 2 weeks for patients randomized in arm 2. Bevacizumab will be given
until disease progression or the occurrence of an unacceptable toxicity.
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Bevacizumab must be administered before gemcitabine followed by carboplatin or before PLD
followed by carboplatin.
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Bevacizumab and chemotherapy will be administered at the same visit.
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If any or all chemotherapy is discontinued prior to disease progression, including for toxicity,
bevacizumab will be continued as maintenance therapy with a dose of 15 mg/kg every 3 weeks
until disease progression or the occurrence of an unacceptable toxicity related to bevacizumab.
PREPARATION, ADMINISTRATION AND DOSE GUIDELINES (2)
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Bevacizumab (Avastin®) is supplied as a clear to slightly opalescent, colourless to pale brown, sterile
liquid for intravenous infusion in single-use vials which are preservative-free. Bevacizumab will be
supplied in 5mL glass vials with a 4mL fill (100mg, 25mg/mL) and/or in 20mL glass vials with a 16mL
fill (400mg, 25mg/mL). The formulation contains sodium phosphate, trehalose, polysorbate 20,
and Sterile Water for Injection (SWFI) in addition to bevacizumab active ingredient.
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Upon receipt of the study drug, vials are to be refrigerated at 20C – 80C and should remain
refrigerated until just prior to use. DO NOT FREEZE. DO NOT SHAKE. Keep vial in the outer carton
due to light sensitivity.
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VIALS ARE FOR SINGLE USE ONLY. Vials are used for one patient and may not be used for any other
patient. Vials should not be used after the re-test date shown on the pack.
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Bevacizumab does not contain any antimicrobial preservative; therefore, care must be taken to
ensure the sterility of the prepared solution.
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Chemical and physical in-use stability has been demonstrated for 48 hours at 20C – 300C in 0.9%
sodium chloride solution. From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions are the responsibility of
the user and would normally not be longer than 24 hours at 20C to 80C, unless dilution has taken
place in controlled and validated aseptic conditions
PRESCRIPTION ARRANGEMENTS
Study specific prescriptions for supplies of Bevacizumab, Gemcitabine, Carboplatin and Pegylated
Liposomal Doxorubicin (PLD) must be used. Prescriptions should include the following
information in addition to standard prescribing details:
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clearly identify that patients are in the OPSROC study
patient study number
Alternatively, electronic prescribing systems can be used. Whichever method of prescribing is
used, it must be clear the above are IMPs and are being prescribed as part of the clinical trial.
Prescriptions must either be version controlled or subject to a validation process. Wherever
possible the original prescription should be retained within the pharmacy file but where this is
not possible a copy of the prescription must be retained in the pharmacy file and a copy
accessible by the investigator
DRUG DISPOSAL
Used or partially used vials, dose-banded infusions or syringes of all IMPs may
be disposed of at site according to local hospital policy with no additional
accountability required.
Destruction of unused or expired Bevacizumab, if necessary, should be
undertaken after the Sponsor has given written permission, in line with local
policies and procedures and a destruction log completed. A destruction log
will be provided for use.
DOSE MODIFICATIONS/DELAYS
• Detailed information on dose modifications of Bevacizumab for Toxicity can be found in Section 7.3 of the protocol (grade
3/4 bevacizumab related events, CNS bleeding, Hypertension, Proteinuria, infusion-associated reactions, surgical
procedures and healing complications, thromboembolism, haemorrhage, Reversible Posterior Leucoencephalopathy
Syndrome (RPLS), gastrointestinal perforation, fistula and Congestive Heart Failure (CHF)
• Blood pressure must be closely monitored and documented as per protocol. The management of hypertension is
documented in section 7.3.2 of the protocol. Advice is given on when antihypertensive therapy should be given however
actual medications are not given. Sites should follow local policy on which antihypertensive to prescribe. Site should
provide a copy of local policy at study set-up.
• Detailed information on dose modifications and delays of chemotherapy can be found in Section 7.4 of the protocol.
• Protocol section 6.2.3 Management of Suspected Anaphylactic Reactions. The UK Specific Appendix states that in the
event of a suspected anaphylactic reaction during study drug infusion (bevacizumab) then treatment of this should be as
per local practice.
• Protocol Section 7.3 Management Hypersensitivity/Allergic Reactions (Bevacizumab). This UK Specific Appendix differs
from the protocol. This section in the protocol states that if the patient has any grade of hypersensitivity/allergic
reaction, that bevacizumab should be permanently discontinued however in section 7.3.4 it describes how such reactions
can be managed without discontinuing drug. For clarification, for patients experiencing Grade 3 and 4 reactions patients
should not be rechallenged. For grade < Grade 2 reactions patients may be rechallenged according to local practice and
at the discretion of the treating physician.
• Carboplatin and Gemcitabine; dose modifications/delays for haematological toxicity and non haematological toxicity
(renal toxicity, hepatic toxicity, hypersensitivity to carboplatin and other) are documented in Protocol Section 7.4.1
• Carboplatin and Pegylated Liposomal Doxorubicin; dose modifications/delays for haematological toxicity and nonhaematological toxicity (renal toxicity, cutaneous toxicity, GI toxicity, Cardiac toxicity, hypersensitivity to carboplatin and
other) are listed in Protocol Section 7.4.2
CONCOMITANT THERAPIES
Please refer to section 4.4 of the study protocol:
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Only medications and therapies for treatment of cancer need to be recorded on the eCRF
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All non-cancer therapies that the responsible physician feels are appropriate are allowed in this trial
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Patients should receive full supportive care during and after the administration of bevacizumab and chemotherapy
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This includes transfusion of blood and blood products and/or the use of erythropoietin as clinically indicated, antibiotics
for infective complications and antihypertensives for the management of hypertension
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Anaphylaxis precautions should be observed during administration of bevacizumab, gemcitabine, PLD and carboplatin as
per local practice
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The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits
(according to the medical standard in the institution) and the patient has been on a stable dose of anticoagulants for at
least two weeks at the time of randomization
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Due to a possible risk of bleeding during treatment with bevacizumab patients should not take more than 325 mg o of
aspirin daily (or more than 75 mg clopidogrel daily) at least until discontinuation of bevacizumab therapy
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In case of treatment with other inhibitors of platelet aggregation, such as prasugrel, ticlopidine, tirofibane or
dipryridamol, patients taking these medications should not be included into the trial
ASSESSMENT AND FOLLOW UP
Maintenance Therapy: Patients will continue with maintenance bevacizumab treatment following chemotherapy if there is no
evidence of disease progression or unacceptable toxicity.
Please refer to section 5.2 of the study protocol for a detailed description of all on treatment study assessments.
All assessments will be done until disease progression or occurrence of unacceptable toxicity, whichever occurs first.
Assessments are described in table 1A of the protocol. Please note that in UK we are using CT and not gynaecological exam and
ultrasound for tumour assessment. Patients do need CT even if there is no residual disease. (see UK appendix)
Safety Follow Up: In the absence of disease progression and/or start of new anticancer therapy all patients should have a safety
follow-up visit performed 31 months (+/- 7 days) after start of treatment, or if applicable 4 weeks (+/- 7 days) after last dose of
bevacizumab, whichever occurs later. In the event of disease progression and/or start of new anticancer therapy, the safety follow
up visit should be performed prior to the new treatment (or within 4-6 weeks after progression if new treatment has not started
yet). Assessments are described in table 1A of the protocol.
Efficacy Follow up: Efficacy follow up visits regardless of disease status should be performed every 6 months during the first 5
years after study treatment start. Specific follow-up assessments are described in table 1A of the protocol. Clarification: tumour
assessments are only until progression or 30 months
SITE SET UP
CTU GLASGOW
Main REC approval - MHRA approval - Site Initiation Slides
- Investigator File - Pharmacy File
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SITE
SSI - R&D Approval
- Investigator CVs and Lead Pharmacist - Delegation and Training log Clinical Trial Agreement
- GCP Certificates for PIs - PIS, Consent, GP Letter etc on Trust headed paper
- Lab normal ranges (Haem + Biochem), Accreditation certificates.
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INITIATION PROCESS
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SITE ACTIVATED
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DRUG SUPPLY
CRFs and CRF COMPLETION
Data for this trial will be recorded via an Electronic Data Capture (EDC) system MACRO using
eCRF. It will be transcribed by the site from the paper source documents onto the eCRF.
Each member of staff (PI, Research Nurse, Data Manager etc.) involved in the trial requires to
have their own personal login data (username and password). Users of the EDC-System MACRO
will receive training materials (EDC manual) by the data management of KKS, Philipps-University
of Marburg. Every person who gets access to the system has to fill in a registration form (User-ID
request) and has to confirm that they have been adequately trained.
Please note the SAE and Pregnancy forms are faxed to Pharmacovigilance at the CRUK CTU and
the original SAE report is kept at site.
CRF completion:
• For each patient enrolled, an eCRF must be completed and electronically signed
(authorisation of completed visits) by the principal investigator or authorised delegate from
the staff. If a patient is withdrawn from trial the reason must be noted on the eCRF
PHARMACOVIGILANCE
For the purposes of this clinical trial bevacizumab only has been identified in the protocol as IMP by the AGO Study Group. For UK
regulatory purposes all four study drugs are considered IMP (bevacizumab, carboplatin, gemcitabine and PLD)
Clinical Trial Regulations require:
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Investigators document Adverse Events (AEs) in patient notes and the CRF as required
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Investigators report Serious Adverse Events (SAEs) immediately to the CRUK Clinical Trials Unit, Glasgow (CTU)
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The CTU (on behalf of the UK Sponsor) will make expedited reports of SAEs that meet the criteria for SUSARs to the Regulatory
Authority (MHRA) using eSUSAR, Main REC and UK Sponsor for carboplatin, gemcitabine and PLD
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The AGO Study Group (on behalf of the main Sponsor) will make expedited reports of SAEs that meet the criteria for SUSARs to
Eudravigilance for bevacizumab
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The AGO Study Group with provide the CTU with Development Safety Update Reports for bevacizumab. These will then be
amended to include carboplatin, gemcitabine and PLD (in conjunction with the UK Chief Investigator)
ADVERSE EVENT REPORTING
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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
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All AE and toxicities must be graded according to the NCI-CTCAE Version 4.03 (Grade 1-5) and reported in detail on the eCRF
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An exacerbation of pre-existing condition is an AE
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All AEs must be recorded in full in the patients with the nature of the event, start and stop dates, severity, seriousness and
causality to each study drug and outcome
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Please ensure that ‘relatedness’ is documented in the patient source data and also entered correctly on to the eCRF
ADVERSE EVENTS
It is the responsibility of the investigator(s) to report all adverse events in the eCRF.
Adverse Events
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An adverse event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical
product and which does not necessarily have to have a causal relationship with this treatment
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An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or
disease temporarily associated with the use of a medicinal product, whether or not considered related to the medicinal product
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Pre-existing conditions (except the underlying malignancy) which worsen during the clinical trial are to be reported as adverse
events.
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Adverse events can become Serious Adverse Events if the fulfil the seriousness criteria as described in section 20.2 of the protocol.
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Intensity of all adverse events will be graded according to the NCI Common Toxicity Terminology Criteria for Adverse Events version
4.03 (CTCAE) on a five-point scale (grade 1-5) and reported in detail on the eCRF.
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Adverse events, especially those for which the relationship to study drug is not “unrelated” should be followed up until they have
returned to baseline status or stabilised. If a clear explanation is established it should be recorded on the eCRF.
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Please ensure that ‘relatedness’ is documented in the patient source data and also entered correctly on to the eCRF (see section
7.1.2.1 Drug – adverse event relationship and also Appendix 1 of the protocol for further details).
Adverse Events of Special Interest
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Adverse Events of Special Interest for Bevacizumab are listed in section 7.1.3 of the protocol and should be closely monitored as
part of study procedures. These are Reversible Posterior Leucoencephalopathy Syndrome (RPLS), grade 3/4 hemorrhagic/bleeding
events, grade 3/4 left ventricular dysfunction (CHF), grade 4 venous thromboembolism, grade 4 hypertension (hypertensive crisis),
grade 4 non-gastrointestinal fistula, grade 4 proteinuria (nephrotic syndrome), any grade of CNS bleeding, any grade of arterial
thromboembolism, any grade of gastrointestinal perforation, any grade of tracheo-esophageal, fistula, any grade of
hypersensitivity/allergic reactions related to Bevacizumab, hypertension, proteinuria, thrombosis/embolism, hemorrhage, CHF,
wound healing, complications in addition to any other serious bevacizumab-related toxicity (grade 3 or 4), grade 4 febrile
neutropenia and/or grade 4 thrombocytopenia.
DEFINITION OF ADVERSE DRUG REACTIONS, SERIOUS
ADVERSE EVENTS AND SUSPECTED UNEXPECTED SERIOUS
ADVERSE REACTIONS
Please see Appendix 2 of the protocol
REPORTING SAEs
***Please note that safety reporting in the UK differs from that documented in the study protocol***
If you have any questions regarding SAE reporting please contact Pharmacovigilance at the CRUK CTU on telephone number 0141
301 7211/7954/7209 or email [email protected].
The study protocol identifies Bevacizumab as the single IMP for the trial. However the UK Regulatory Authority requires that each
of the four drugs administered for the trial are considered as IMPs. The AGO Study Group will manage safety and SUSAR reporting
for Bevacizumab and the CRUK CTU will manage safety and SUSAR reporting for Carboplatin, Gemcitabine and Pegylated
Liposomal Doxorubicin (UK patients only).
Serious Adverse Event (SAE) Reporting Forms must be completed and faxed to the CRUK CTU within 24 hours of your knowledge
of the event. Two SAE forms are required – one for the AGO Study Group (for capturing the relationship of SAEs to Bevacizumab
only) and one for the CRUK CTU (for capturing the relationship of SAEs to all 4 drugs). Please ensure that both are completed and
faxed to: Cancer Research UK Clinical Trials Unit, Glasgow Pharmacovigilance: Fax No. 0141 301 7213
Reporting Responsibilities for Cancer Research UK CTU
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The CRUK CTU Pharmacovigilance Department will forward all SAE reports submitted on the AGO SAE report form (to
capture the relationship of the event to Bevacizumab) to the AGO Study Group who will process these and raise any
necessary queries for missing or inconsistent information.
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The CRUK CTU Pharmacovigilance Department will process all SAE reports submitted on the CTU SAE report form (to capture
the relationship of the event to Carboplatin, Gemcitabine and Pegylated Liposomal Doxorubicin and Bevacizumab).
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The AGO Study Group will acknowledge all initial SAE reports received on the AGO SAE report form for Bevacizumab and
CRUK CTU will acknowledge all initial SAE reports received on the CTU SAE report form for Carboplatin, Gemcitabine and
Pegylated Liposomal Doxorubicin and Bevacizumab.
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The AGO Study Group will submit any required SAE reports to Roche for the global safety management of Bevacizumab.
Pregnancy Reporting
Please refer to section 7.2.3 of the protocol for guidance on the reporting of pregnancy in clinical trial patients. Pregnancies must
be reported by completing the pregnancy report form and faxing this immediately to Pharmacovigilance at the CTU (fax details as
above).
PROCEDURE FOR IDENTIFYING UNEXPECTED AND RELATED EVENTS
EXPEDITED REPORTING
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Suspected Unexpected Serious Adverse Reactions (SUSARs) for Bevacizumab will be identified and
reported by the AGO to Eudravigilance.
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SUSARs for Carboplatin, Gemcitabine and Pegylated Liposomal Doxorubicin will be identified and
reported by the CRUK CTU to the UK Regulatory Authority the MHRA only, using eSUSAR.
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Sites will be required to provide any additional information, to identify a SUSAR, quickly and in the
timeframe requested by the AGO Study Group/CRUK CTU. Additionally PV CTU and will submit SUSAR
reports to the UK Main REC, UK Sponsor and assist the AGO Study Group to inform UK sites of SUSARs.
PHARMACOVIGILANCE DOCUMENTATION
The Pharmacovigilance section of the site file must be maintained and contain the following
documentation:
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Copy of all SUSAR and DSUR reports
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All SAE reports that have been submitted by the site (these may be filed with the CRFs if a file note
produced by your site, recording the location of SAE reports, is filed in the site file)
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Copies of the current and previous RSI (IBs for Avastin and SmPCs for carboplatin, gemcitabine and
PLD) with other related documentation such as the front sheet document
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All other correspondence from Pharmacovigilance
MONITORING
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This study will be monitored in adherence to the AGO Study Group monitoring requirements. All UK sites
will undergo site initiation and closeout visits, conducted either by telephone or by on-site visit.
Please set aside 50-70 minutes for telephone monitoring calls
All UK sites will undergo five on-site monitoring visits during the recruitment period of the study, and two
telephone monitoring calls during the follow-up period of the study. These visits will be conducted in
adherence to the CRUK Glasgow Clinical Trials Unit’s Standard Operating Procedures for monitoring clinical
trials.
Investigators and site staff will be notified in advance about forthcoming pre arranged monitoring visits
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
The pharmacy department responsible for the trial will be visited to allow monitoring of the pharmacy site
file and review of security, storage and accountability of trial drugs.
All findings will be discussed at an end of visit and any unresolved issues raised as Action Points
Action Points will be followed up by the monitor until resolved
INVESTIGATOR RESPONSIBILITIES (1)
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.
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)
INVESTIGATOR RESPONSIBILITIES (2)
Ethics:
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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.
These approvals will be provided by the CRUK CTU.
Compliance with Protocol:
The Investigator should conduct the trial in compliance with the protocol.
The investigator should 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.
The IMP :
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The 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.
Registration / Randomisation:
The Investigator should follow the trial’s randomisation procedures as detailed in the protocol.
INVESTIGATOR RESPONSIBILITIES (3)
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.
Reports & records
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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 within 24hrs of becoming
aware of the event.
Investigators must ensure that follow-up SAE reports are provided until the SAE resolves.
Investigators must provide information on any potential SUSARs as quickly as possible.
OTHER STAFF
The Principal Investigator has overall responsibility for the conduct of the clinical trial
at the trial site.
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All staff must comply with GCP.
Staff should only perform tasks delegated to them on the delegation log.
Should have the appropriate study related training on the study protocol.
Staff should ensure that their details are available to the Investigator.
Staff should maintain appropriate confidentiality at all times
CONTACT DETAILS FOR CTU, GLASGOW
Liz-Anne Lewsley
Project Manager
Diann Taggart
Trial Coordinator
Tel:
Fax:
0141 301 7238
0141 301 7228
0141 301 7193
0141 301 7224
E-mail: [email protected]
[email protected]
CRUK CTU, Glasgow
Cancer Research UK Clinical Trials Office
Level 0, Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow G12 0YN