Download Initiation Slides - Clinical Trials Unit Glasgow

HIPROC (SA164)
Hedgehog Inhibitor and Paclitaxel in Relapsed Ovarian Cancer:
A Phase I/Ib Trial of the Oral Hedgehog inhibitor, LY2940680, in Combination with
Weekly Paclitaxel in Patients with Platinum-Resistant, Recurrent Ovarian Cancer
or Recurrent, Advanced, Solid Tumours.
EudraCT: 2014-004695-37
ISRCTN15903698
Chief Investigator: Dr Rosalind Glasspool
Sponsor: NHS Greater Glasgow & Clyde
Co-ordinating Centre: CRUK CTU Glasgow
INVESTIGATOR INITIATION PRESENTATION
(VERSION 1.1, 08 SEP 2015)
TRIAL DETAILS
• The trial is being co-ordinated by CRUK via the Cancer Research UK Clinical Trials Unit, Glasgow (CRUK CTU)
• Sponsor of the trial is Greater Glasgow & Clyde Health Board (GG&CHB)
• Chief Investigator is Dr Rosalind Glasspool
•Funded by CRUK (New Agents Committee) and also by Eli Lilly and Company as part of the ECMCCombinations Alliance
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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 trial requirements prior to signing off the
initiation acknowledgment sheet.
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The trial will be conducted according to ICH GCP guidelines
The trial will be conducted in accordance with the EU Directive 2001/20/EC
The trial will be 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
TRIAL TEAM
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Chief Investigator :
Dr Rosalind Glasspool
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Trial Statistician:
Jim Paul
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Project Manager:
Karen Allan
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Sponsor Pharmacist:
Dr Samantha Carmichael
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Pharmacovigilance Manager:
Lindsey Connery
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Clinical Trial Coordinator:
Craig Campbell
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Clinical Trial Monitor:
Barbara Ross
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Sponsor Representative:
Paul Dearie
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Translational Research Lead:
Prof Iain McNeish
TRIAL DESIGN AND OBJECTIVES
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This is a phase I/Ib, open-label, non-randomised, multi-centre, dose escalation trial of LY2940680 administered by a
continuous oral schedule in combination with weekly intravenous paclitaxel.
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The dose escalation phase will use a standard 3 + 3 design.
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All patients will receive up to 6 cycles of paclitaxel 80mg/m2 given by intravenous infusion over 1 hour on day 1, 8 and 15 of
a 28 day cycle. The starting dose of LY2940680 will be 100mg once daily and the planned escalation dose levels are 200mg
once daily and 400mg once daily.
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Once the recommended dose has been determined, an additional cohort of 12 patients with platinum resistant high grade
serous, G3 endometrioid carcinoma or carcinosarcoma of the ovary, primary peritoneum or fallopian tube, will be enrolled
in the dose expansion phase.
Primary objective (Dose Escalation Phase):
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To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of LY2940680 as continuous oral daily
dosing in combination with weekly paclitaxel (80mg/m2, IV, days 1, 8 and 15 every 28 days) in patients with advanced
cancers.
Primary objective (Dose Expansion Phase):
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To establish the safety and tolerability of the combination of LY2940680 at the recommended phase 2 dose (RP2D) with
weekly paclitaxel (80mg/m2, IV, days 1, 8 and 15 every 28 days) in patients with recurrent platinum resistant ovarian cancer.
ELIGIBILITY CRITERIA (1)
Inclusion Criteria of the Dose Escalation Phase:
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Histologically or cytologically confirmed advanced solid tumours refractory to standard therapy or for whom weekly
paclitaxel is considered, by the investigator, to be an appropriate therapy.
Inclusion Criteria of the Dose Expansion Phase:
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Histologically confirmed high grade serous or G3 endometrioid epithelial ovarian, fallopian tube or primary peritoneal
cancer with progressive or recurrent disease (patients with carcinosarcoma are eligible but mucinous, clear cell carcinoma
and grade 1 or 2 tumours are not eligible). Progression may be defined radiologically by RECIST1.1 or by CA125 criteria in
combination with clinical symptoms or signs indicative of progression. Asymptomatic rise of CA125 alone will not be defined
as progressive disease. Progression of disease must have occurred within 6 months of the last dose of platinum
chemotherapy.
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≥ 1 previous platinum based chemotherapy. This may have been given in the adjuvant setting.
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No previous treatment with single agent weekly paclitaxel for relapsed disease. Weekly paclitaxel may have been given in
the first line setting if given in combination with platinum chemotherapy.
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No contra-indication to an image guided biopsy and tumour amenable to image guided biopsy.
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Measurable or non-measurable disease.
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Patients must have archival formalin-fixed paraffin-embedded tissue from their original diagnosis available for the purposes
of translational research (tissue from primary surgery, delayed primary surgery or interval debulking is acceptable).
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Patients with synchronous tumours e.g. ovarian and endometrial or history of prior malignancy are eligible provided that
there is biopsy evidence that the disease measurable on CT and/or MRI is ovarian in origin
ELIGIBILITY CRITERIA (2)
The following inclusion criteria will be required for ALL patients:
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Written informed consent
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Performance status ≤1 (ECOG)
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Estimated life expectancy ≥ 3 months
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Age ≥ 18 years
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Adequate haematological, renal and hepatic function as defined by:
o Haemoglobin (Hb)≥ 10g/dl
o Neutrophil Count≥ 1.5 x 109/l
o Platelets≥ 100 x 109/l
o INR <2 x ULN and prothrombin time and activated partial thromboplastin time < 1.5 x ULN in the absence of
therapeutic anticoagulation
o Glomerular Filtration rate of ≥50 mL/ min (calculated using the Wright formula (Appendix IV) or measured by
EDTA clearance. If both are performed the EDTA clearance should be used).
o Total bilirubin ≤1.5 x ULN and ALT and AST ≤ 2.5 x ULN
o Sodium above the lower limit of the institutional normal range
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No history of ≥grade 2 peripheral neuropathy at any time during prior treatment and no greater than grade 1 residual
peripheral neuropathy.
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No use within the last 7 days of or requirement to continue medications that are strong inhibitors of CYP3A4 (Appendix V).
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No prior treatment with LY2940680 or other Hedgehog pathway inhibitor.
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Female patients with reproductive potential (i.e. patients whose reproductive organs remain in place and who have not
passed the menopause) must have a negative serum pregnancy test within 7 days of trial enrolment and agree to use two
highly effective forms of contraception (as detailed in section 7.1.12) during and for 6 months after last dose of treatment.
Male patients (for the dose escalation phase) of childbearing potential and their female partner must also agree to use a
highly effective form of contraception during and for 6 months after treatment. Men with pregnant or lactating partners
should be advised to use barrier method contraception to prevent exposure to the foetus or neonate
ELIGIBILITY CRITERIA (3)
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No symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastrointestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption, including
ileostomies.
Ability to swallow capsules
No significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable
angina or myocardial infarction within 6 months prior to registration, congestive heart failure ≥NYHA III, severe peripheral
vascular disease, clinically significant pericardial effusion.
A corrected QT interval (QTc) of ≤470 msec on screening electrocardiogram (ECG).
No treatment within 28 days prior to registration with any investigational drug, radiotherapy, immunotherapy,
chemotherapy, hormonal therapy (excluding HRT) or biological therapy. Palliative radiotherapy may be permitted for
symptomatic control of pain from bone metastases, provided that the radiotherapy does not affect target lesions.
No serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including
known hepatitis B and/or C infection and HIV-infection.
No symptomatic CNS metastasis or leptomeningeal carcinomatosis.
No other severe concurrent disease, which may increase the risk associated with trial participation or trial drug
administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this trial,
including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality.
No known, uncontrolled hypersensitivity to the investigational drugs or their excipients.
No psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial
protocol and follow up schedule.
No known SIADH or adrenal insufficiency
There will be no exception to the eligibility requirements at the time of registration. Queries in relation to the eligibility criteria
should be addressed via contact with the CRUK CTU Glasgow prior to registration. Patients are eligible for the trial if all the
inclusion criteria are met and none of the exclusion criteria apply.
SLOT REQUESTS AND SLOT ALLOCATION
*Please note that this applies to the dose escalation phase of the trial only*
Each cohort has an initial 3 places which should be filled using the slot request system. Ethically we
cannot refuse treatment to an eligible patient that has consented to a trial so each site must ensure that
they have a slot on the current dose cohort before the patient has been approached with the patient
Information sheet.
SLOT ALLOCATION
• CRUK CTU will provide a slot request form for the site that should be completed and returned to
the CRUK CTU in order for a slot to be allocated.
• Upon receipt of the slot request form, the CRUK CTU will process the form and allocate the slot if
there is one available.
• Upon confirmation of the slot allocation the site can approach the patient with the patient
information, consent (if patient agrees) and begin the screening process.
• For patients that decline participation or fail to meet the eligibility criteria please contact the CRUK
CTU immediately in order that this slot can be re-allocated.
For slot allocations and requests please contact: Craig Campbell, Clinical Trial Co-ordinator
Tel: 0141 301 7195, Fax: 0141 301 7192, Email: [email protected]
INFORMED CONSENT PROCESS
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Two original Consent Forms must be completed by a clinician (or designee listed on study specific training and delegation log)
Two originals signed and completed by the patient
Date must be prior to registration
Make one photocopy
- Original to be filed in Investigator Site File
- Original to be given to patient (+PIS)
- Photocopy to be filed in hospital notes
Consent Form must not be sent to CRUK CTU Glasgow
FOR ERRORS NOTED AFTER CONSENT
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Explanatory file note is completed and sent to CRUK CTU Glasgow with a copy remaining at site
PATIENT RE-CONSENT
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If the Sponsor requires patients to be re-consented then the new version of patient information sheet and consent form must be
given to patient at the next clinic visit. The consent process should be followed as above.
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If a patient cannot re-consent (i.e. patient is terminally ill) then a file note should be written to explain this as well as this being
documented in the patient’s notes.
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The re-consent log in the Investigator Site File should be kept up to date.
CONSENT WITHDRAWAL
When the patient specifically asks to withdraw their consent at any point in the trial. If this occurs:
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Document clearly in the patient notes that the patient has withdrawn consent, the level of consent withdrawal (i.e withdrawal from
treatment only or complete withdrawal with no follow-up data to be collected) and the reason (if the patient has given any)
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Complete the consent withdrawal notification form (NB this is only required if patient withdraws consent completely from the trial,
e.g. if patient withdraws from treatment only this does not need to be completed)
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Send the consent withdrawal notification form to the CRUK CTU
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No further follow-up should be collected on the patient from that point onwards (should the patient have withdrawn this level of
consent)
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Please note that SAEs will continue to be collected even if a patient has withdrawn consent and this should be explained to the
patient
PATIENT REGISTRATION FOR TRIAL TREATMENT
All patients must be registered onto the trial prior to commencement of any trial treatment.
 All screening evaluations must be performed as per trial protocol section 4.1.4 (please note that all evaluations should be performed
within 8 days of treatment administration except for medical history and disease evaluation)
 Check that patient fulfils eligibility criteria as per trial protocol section 3.2 and 3.3
There will be no exceptions to the eligibility requirements at the time of registration. Queries in relation to the eligibility criteria should be
addressed prior to calling for registration. 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 Registration Form
Site staff must contact the CRUK CTU to register the patient. Registrations to the trial can be done by either telephone or fax on the
following numbers:
Tel no: 0141 301 7195
Fax no: 0141 301 7192*
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
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Each patient will be allocated a unique sequential patient ID number for the trial.
TREATMENT AND DURATION
LY2940680 and Paclitaxel are considered Investigational Medicinal Products (IMPs) for the purpose of this trial.
Paclitaxel 80mg/m2 IV, days 1, 8 and 15 every 28 days for up to 6 cycles
LY2940680 PO Daily Days 1-28 of a 28 day cycle.
Dose Escalation Phase:
Dose Level LY2940680 Dose PO
-1
100mg on alternate days
1
100mg once daily
2
200mg once daily
3
400mg once daily
Interim dose levels may be added depending on data from prior cohorts.
Dose Expansion Phase:
Recommended dose as determined in the dose escalation phase.
LY2940680 will be continued as a single agent after completion of chemotherapy, until disease progression or
unacceptable toxicity or withdrawal of the patient.
PREPARATION, ADMINISTRATION AND DOSE GUIDELINES
The investigator or a delegated individual (e.g. pharmacist) must ensure that the trial drug is dispensed in accordance
with the protocol, local standard operating procedures and applicable regulatory requirements.
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The batch number, dose prescribed, quantity and expiry of the LY2940680 supplied must be recorded in the
accountability logs. Both bulk stock and individual patient accountability logs must be completed.
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Patients will be required to return all bottles (including empty bottles) of trial medication at the beginning of the
next cycle of treatment. Any remaining capsules must be documented in the accountability logs. Any evidence
of non-compliance with the prescribed dosing must be reported to the local PI.
LY2940680 is to be administered prior to the paclitaxel infusion except on day 1 of cycle 1 when it will be omitted to
allow PK sampling of paclitaxel alone. LY2940680 treatment will start on day 2 of cycle 1. This will only be in the dose
escalation phase.
Patients should be instructed to take each dose of LY2940680 at the same time each day/alternate day +/- 2 hours. If
a dose is omitted and it is beyond the 2 hour window it should not be replaced and the patient should continue the
dosing schedule, starting with the next dose. If a patient vomits after taking a dose, it should not be replaced and the
patient should continue the dosing schedule, starting with the next dose. All missed doses should be recorded in the
patient diary card.
Patients must be advised not to drink grapefruit juice from 7 days before Day 1 of cycle 1 and for the duration of the
treatment with LY2940680.
Full instructions regarding management, labelling and accountability the trial drug is given in a separate IMP
Management Document for the trial.
CONCOMITANT & PROHIBITED THERAPIES
Concomitant Therapies:
Grapefruit juice and drugs that are strong inhibitors of CYP3A4 (see protocol Appendix V) should not be used from 7 days
prior to day 1 of treatment and for the duration of the trial due to the potential drug interactions with paclitaxel. As
recommended in the Summary of Product Characteristics for paclitaxel, drugs that are strong inhibitors or inducers of
CYP2C8 (see protocol Appendix VI) should be used with caution due to their potential to affect metabolism of paclitaxel.
Any medications which are considered necessary for the patient's welfare, and which it is believed will not interfere with
the trial medication, may be given at the discretion of the Investigator, providing the medications, the doses, dates and
reasons for administration are recorded in the CRF.
In addition, any unplanned therapeutic or surgical procedure performed during the trial period must be recorded in the
CRF.
G-CSF is only permitted for management of febrile neutropenia, and should not be given prophylactically.
All concomitant therapy taken at any point from 4 weeks before registration up to and including the end of treatment
visit will be documented in the appropriate section of the trial CRFs and in the patient’s medical records along with dose,
frequency and therapeutic indication.
Prohibited Therapies:
No other chemotherapy, immunotherapy, hormonal therapy or other novel agent is to be permitted while the patient is
receiving trial medication. Grapefruit juice and drugs that are strong inhibitors of CYP3A4 (see Appendix V) should not be
used from 7 days prior to day 1 of treatment and for the duration of the trial.
DOSE LIMITING TOXICITIES (DLTs)
Dose limiting toxicity (DLT) will be based on the clinical and laboratory toxicity assessments (NCI-CTC version 4) that
occur in the period commencing with the first dose of trial treatment on day 1 of cycle 1 until the day 28 of cycle 1
that are deemed to be related to either component of the combination treatment. DLTs are defined as any of the
following:
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Failure to deliver >75% of planned LY2940680 doses due to toxicity and omission of >1 dose of paclitaxel
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≥ Grade 3 neutropenia with sepsis or fever >38.5°C
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Grade 4 neutropenia lasting > 7 days
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Grade 4 thrombocytopenia (of any duration)
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≥ Grade 3 Nausea and vomiting not controlled by maximal antiemetics
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Grade 3 hyponatraemia that is drug related and does not resolve in ≤ 7 days or grade 4hyponatraemia that is
drug related
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Any other ≥ Grade 3 toxicity
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≥ Grade 2 peripheral neuropathy
A hypersensitivity reaction to paclitaxel is not a dose limiting toxicity.
In all cases of suspected DLT, clinical judgement should be the final arbiter as to whether or not the event should be
categorised as a DLT.
EVALUABLE PATIENTS
Note that assessment of DLTs is restricted to DLT evaluable patients.
DLT evaluable patients must have completed at least one full cycle of treatment and have completed planned
toxicity assessments or have experienced a DLT.
Patients who do not complete the first treatment cycle (with >75% of LY2940680 and at least 2 doses of
paclitaxel) for reasons other than toxicity will not be evaluable for DLT and will be replaced.
***Please note, during the dose escalation phase, sites will be required to submit DLT forms weekly during
the DLT Assessment Period***
DOSE ESCALATION DECISION
The decision to escalate to the next dose cohort will be made by a Safety Review Committee meeting with
clinical representation from each of the participating sites.
These meetings will take place regularly throughout the dose escalation phase of the trial.
The decision to dose escalate will be based on clinical and laboratory safety parameters.
ASSESSMENTS (1)
Pre-treatment Evaluations
Where >42 days has elapsed between tumour imaging and the start of trial treatment, tumour imaging must be repeated.
Day 1 of each cycle of treatment the following will be performed:
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Blood tests:
o FBC and differential
o Urea and electrolytes, creatinine, liver function, bone profile, magnesium, glucose, LDH, creatine kinase (CK) and morning cortisol (am
cortisol)
o Coagulation
o Tumour marker
o Translational sample for ctDNA
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Urine pregnancy test where applicable (for women of child bearing potential, (i.e. patients whose reproductive organs remain in place and who
have not passed the menopause)
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ECG
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Concomitant medications
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Symptoms and toxicity assessment (assessed using CTCAE V4)
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Vital signs (pulse and BP)
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Weight
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Physical examination
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ECOG performance status
Treatment Evaluations
On Day 8 and 15 of each cycle the following will be performed:
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Concomitant medications
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Symptoms and toxicity assessment (assessed using CTCAE V4)
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FBC and differential
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Urea and electrolytes, creatinine and liver function
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Vital signs (pulse and BP)
All assessments may be performed up to 24 hours prior to the planned visit/treatment day.
Cycle 1 day 21-28 or Cycle 2: Tumour biopsy (optional). If having a biopsy, patients must have FBC and coagulation within 24 hours before the biopsy and
parameters must meet local guidelines for a biopsy.
ASSESSMENTS (2)
Maintenance LY2940680
After completion or termination of chemotherapy, patients may continue on LY2940680 alone until progression, unacceptable toxicity, withdrawal of consent
or the investigator considers it no longer to be in the best interest of the patient.
On day 1 of each 28 day cycle the following will be performed:
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Blood tests:
o FBC and differential
o Urea and electrolytes, creatinine, liver function, bone profile, magnesium, glucose, LDH, creatine kinase (CK) and morning cortisol (am cortisol)
o Coagulation
o Tumour marker
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Urine pregnancy test where applicable (for women of child bearing potential, (i.e. patients whose reproductive organs remain in place and who have
not passed the menopause)
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ECG
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Concomitant medications
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Symptoms and toxicity assessment – (assessed using CTCAE V4)
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Vital signs (pulse and BP)
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Physical examination
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ECOG performance status
End of Treatment Visit
The end of treatment visit will be within 4 weeks of the last dose of trial medication and the following will be performed:
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Blood tests:
o FBC and differential
o Urea and electrolytes, creatinine, liver function, bone profile, magnesium, glucose, LDH, creatine kinase (CK) and morning cortisol (am cortisol)
o Coagulation
o Tumour marker
o Translational sample for ct DNA
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ECG
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Concomitant medications
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symptoms and toxicity assessment – (assessed using CTCAE V4)
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Vital signs (pulse and BP)
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Weight
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Physical examination
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ECOG performance status
ASSESSMENTS (3)
Follow Up
After the end of trial treatment visit patients will continue to be followed up every 8 weeks until disease progression.
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Blood tests:
o FBC and differential
o Urea and electrolytes, creatinine, liver function, bone profile, magnesium, glucose, LDH, Creatine kinase (CK) and morning cortisol (am
cortisol) (CK and am cortisol required only if abnormal before and until resolution)
o Coagulation
o Tumour marker
o Translational sample for ct DNA at the time of progression
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Concomitant medications
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Symptoms and toxicity assessment – (assessed using CTCAE V4)
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Physical examination
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ECOG performance status
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Tumour imaging every 8 weeks until disease progression of for 2 years whichever is sooner
After disease progression, follow-up will be as per standard care.
REPORTING RADIOLOGICAL INVESTIGATIONS TO RECIST CRITERIA
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All radiological investigations must be reported as per protocol / RECIST version 1.1
(http://www.eortc.be/recist/)
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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
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CRUK CTU, Glasgow have produced a worksheet to assist with the documentation of trial
specific reporting and will make this available to any participating site upon request to the
clinical trial monitor
DOSE MODIFICATIONS
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If a patient experiences a dose limiting toxicity, LY2940680 should be stopped until recovery to ≤
grade 1 toxicity or baseline with the exception of alopecia, fatigue, skin rash, nausea, vomiting, or
diarrhoea that can be controlled with supportive treatment.
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LY2940680 should be restarted at one dose level below their starting dose (there will be no reduction
below 100mg on alternate days). Patients who have had a prior dose reduction will be reduced to the
next lowest level.
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No more than 2 dose reductions will be allowed. If patients have further dose limiting toxicity despite
2 dose reductions or they have reached dose level -1, they should stop LY2940680.
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Patients may continue paclitaxel as monotherapy in this situation for the planned number of cycles.
Please refer to protocol Sections 5.9.2 to 5.9.5 for dose modifications of paclitaxel and LY2940680 in
specific situations. Paclitaxel is classes as IMP for the purposes of this trial and as such the CRFs will
still have to be submitted if the patient continues on paclitaxel monotherapy.
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Once a dose reduction has been made, no re-escalation will be permitted unless it was for a
reversible event which has recovered (e.g. decreased GFR due to obstructive uropathy relieved by
stenting).
CHEMOTHERAPY HOLIDAYS
Breaks in paclitaxel treatment for reasons other than toxicity (e.g. holidays) are not
recommended. However if the investigator considers this to be in the best interest of the patient
a break of up to 2 weeks is permitted but the CRUK CTU, Glasgow should be informed
beforehand. Breaks will not be permitted during the first cycle of treatment.
Any breaks not permitted in the protocol must be reported and explained on a protocol deviation
form.
TRANSLATIONAL RESEARCH
*Full details on sample collection and handling are contained in a separate laboratory manual*
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Archival FFPE tumour blocks
Mandatory for all patients
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Blood germline DNA will be taken prior to starting treatment. May be taken at screening, at time of baseline
biopsy or on day 1 of cycle 1. 20 ml whole blood will be collected in EDTA tubes and stored at -80ºC. Plasma for
ctDNA will be taken on day 1 of cycle 1 to 6, at the end of treatment visit and at progression. 20 ml blood will be
collected, clotted on ice, centrifuged and plasma stored at -80ºC
Mandatory for all patients
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2 x 14-16G tumour biopsy cores taken under image (e.g. ultrasound or CT) guidance at trial entry, i.e. after consent
has been taken and screening undertaken but prior to commencement of treatment, for IHC and nucleic acid
extraction. If the radiologist feels that 14-16G cores are not appropriate (e.g. due to site of disease), three 18G
cores may be taken instead
Optional for patients with ovarian/fallopian tube or primary peritoneal cancer on the dose escalation phase
Mandatory for patients on the dose expansion phase
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2 x 14-16G tumour biopsy cores taken on day 21 to 28 of cycle1 or during cycle 2 for IHC and nucleic acid extraction
Optional for patients with ovarian/fallopian tube or primary peritoneal cancer on the dose escalation phase
Optional for patients on the dose expansion phase
PHARMACOKINETIC SAMPLING – DOSE ESCALATION PHASE ONLY
At cycle 1 only:
In order to allow intra-patient PK analysis of paclitaxel alone, LY2940680 alone and of the combination after LY2940680 has
reached steady state (approximately 7 days), the following sample schedule will be used.
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Paclitaxel: Cycle 1, Day 1: Pre infusion. 1, 2, 4 and 6 hours after start of infusion. Day 15 pre infusion, 1, 2, 4 and 6 hours after
start of infusion.
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LY2940680/ LSN3185556: Cycle 1, day 15: Pre LY2940680 and paclitaxel, 3 and 6 hours post dose, Day 21 of LY2940680 (day
22 of overall cycle 1) Pre LY2940680, 3 and 6 hours post dose.
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LY2940680 will be given prior to paclitaxel infusions on days when PK samples are to be taken.
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All PK samples will be stored at site and sent in batches to Analytical Services Unit (ASU), Institute of Cancer Sciences,
University of Glasgow – part of the Glasgow ECMC. Please refer to the laboratory manual for details of samples handling,
storage and analysis.
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The pharmacokinetic measurement and analysis of paclitaxel concentrations will be performed by the Analytical Services
Unit (ASU), Institute of Cancer Sciences, University of Glasgow – part of the Glasgow ECMC.
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LY2940680 and LSN3185556 plasma concentration analysis will be conducted at a laboratory chosen by Lilly using a
validated LC/MS/MS assay.
SITE SET UP
CRUK CTU GLASGOW
Main REC approval
MHRA approval
Site Initiation Slides
Investigator Site File
Pharmacy Site File
Sample Collection Supplies
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SITE
Study Specific Training and Delegation Log
SSI – R&D Approval
Investigator and Lead Pharmacist CV & GCP Certificates
Clinical Trial Agreement
PIS/CF, GP Letter, Patient Results Letter on Trust headed paper
Lab normal ranges and accreditation certificates (Haem and Biochem)
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INITIATION PROCESS
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SITE ACTIVATION/DRUG SUPPLY
SUPPLY OF TRIAL DRUGS
LY2940680
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Open-label supplies of LY2940680 will be provided free of charge from Eli Lilly and Company to sites for use by
patients in this trial and will be trial specific investigational medicinal product trial stock
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LY2940680 is supplied as 100 mg capsules in packs of 24 capsules. The capsules are size 0 with a dark blue opaque
body and cap
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LY2940680 should be stored at ambient temperature of 10-25ºC
Paclitaxel
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Paclitaxel for use in the trial should be taken from usual pharmacy stock; there is no provision for funding,
reimbursement or discounted stock.
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Shelf stock will not require IMP labelling but all IMP being dispensed to patients must be labelled at site, at the
time of dispensing, in accordance with all applicable regulatory requirements. See separate IMP Management
Document for further details on labelling requirements.
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Paclitaxel is supplied as 6mg/ml concentrate for dilution into IV infusion.
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Paclitaxel may be dose-banded if it is local policy to do so and this must be notified to the CRUK CTU at the time
of initiation.
**Full instructions regarding management, labelling and accountability the trial drug is given in a separate IMP
Management Document for the trial. Please also note there are separate Pharmacy Initiation Slides**
PRESCRIPTION ARRANGEMENTS
Trial prescriptions must be used, but will not be supplied by the sponsor. Sites are responsible for
devising their own prescription form. Prescriptions should include the following information in
addition to standard prescribing details;
• Clearly identify that patients are in the HIPROC trial
• HIPROC patient trial number
Alternatively, electronic prescribing systems can be used. Whichever method of prescribing is
used it must be clear the IMPs are being prescribed as part of the HIPROC 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. A sample prescription can be provided by the sponsor on request.
Full instructions regarding management, labelling and accountability the trial drug is given in a
separate IMP Management Document for the trial.
PATIENT TABLET RETURNS AND DESTRUCTION
Patient returns:
• Tablet counts for LY2940680 should be documented on each HIPROC
Patient Specific Accountability Log – LY2940680
Destruction:
• Destruction must be recorded using the LY2940680 Destruction of Clinical
Trials Supplies Log.
• Patient returns can be destroyed once accountability is completed and
provided that any discrepancies are resolved.
• Expired or unused stock must have written permission from Sponsor prior
to destruction.
PHARMACOVIGILANCE
Clinical Trial Regulations require:
•
Investigators document Adverse Events (AEs) in patient notes and the CRF as required
•
Investigators report Serious Adverse Events (SAEs) immediately to the CRUK CTU
•
The CRUK CTU (on behalf of the Sponsor) will make expedited reports of SAEs that meet the criteria for SUSARs
to the Regulatory Authority (MHRA), REC, Sponsor and Eli Lilley
•
The CRUK CTU will produce Development Safety Update Reports in conjunction with the Chief Investigator
ADVERSE EVENT REPORTING
•
All AEs must be followed;
- until resolution,
- or for at least 30 days after discontinuation of trial medication,
- or until toxicity has resolved to baseline,
- or < Grade 1,
- or until toxicity is considered to be irreversible
•
All AE and toxicities must be graded according to the NCI-CTCAE Version 4.0
•
An exacerbation of pre-existing condition is an AE
•
All AEs must be recorded in full in the patient’s notes with details of the nature of the event, start and stop
dates, severity (the CTCAE grade), seriousness (if the AE is considered serious or non-serious) and causality to
LY2940680 and paclitaxel and outcome
DEFINITION OF A SERIOUS ADVERSE EVENT
A Serious Adverse Event (SAE) is defined as any untoward medical occurrence that is not
necessarily related to protocol treatment that:
•
•
•
•
•
•
Results in death
Is Life-threatening
Requires hospitalisation or prolongation of existing hospitalisation
Results in persistent or significant disability or incapacity
Consists of a congenital anomaly or birth defect
Is considered medically significant by the Investigator
Life threatening:
• The patient is at immediate risk of death from the event as it occurred. It does not include an
event that, had it occurred in a more serious form, might have caused death.
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.
REPORTING SAEs
•
Serious Adverse Events (SAEs) must be reported immediately (within a maximum of 24 hours of
knowledge of the event)
•
SAEs are reported using the current version of the CTU SAE report form for the HIPROC trial
•
Sites must complete the SAE report form and fax the report to Pharmacovigilance at the CRUK CTU
Glasgow fax number 0141 301 7213 with a fax cover sheet which provides the contact details of whoever
has submit the report
•
The CRUK CTU will create a SAE reference number and will send an acknowledgement fax to confirm
receipt
•
The CRUK CTU will request additional information if the event is unexpected
•
CRUK CTU will raise queries for any inconsistent or missing information
•
SAEs must be reported locally by the PI at each site in accordance with the local practice at their site (i.e.
Ethics Committee, R&D Office)
•
SAEs are required to be reported for up to 30 days after discontinuation of trial treatment
•
Any SAE that occurs after 30 days post treatment is also required to be reported if the PI thinks that the
SAE is related to the protocol treatment, and is medically important
PROCEDURE FOR IDENTIFYING UNEXPECTED AND RELATED EVENTS
EXPEDITED REPORTING
SAEs that meet the criteria for SUSARs will be reported to the MHRA, REC, Sponsor and Lilly
where in the opinion of the Chief Investigator the event was:
•
•
Related – that is, resulted from administration of any of the research procedures
AND
Unexpected – that is the type of event not listed as an expected occurrence in the Reference Safety
Information (RSI). The RSI is recorded in the table of Treatment Emergent Adverse Drug Reactions to
LY2940680 recorded in section 7.3.8 of the IB and section 4.8 Undesirable effects of the SmPC
produced by Hospira for Paclitaxel, which have regulatory approval to assess the expectedness of SAEs
within the DSUR reporting period.
CRUK CTU on behalf of the Sponsor is responsible for the expedited reporting of all SUSARs to the required
Regulatory Authorities, Research Ethics Committee (REC), PI at trial sites and the trial Sponsor(s) as well as
Lilly.
•
Fatal or life threatening SUSARs will be reported within 7 days of the CRUK CTU receiving the first
notification of the unexpected event. Any additional information will be reported within eight days of
sending the initial report
•
All other SUSARs will be reported within 15 days of the CRUK CTU receiving the first notification of the
unexpected reaction.
PROCEDURE FOR REPORTING SAEs AND SAE REPORT PROCESSING
CRFs and CRF COMPLETION
CRFs for the trial:
•
Registration Form
•
Pre-Treatment Form
•
Treatment Form
•
Disease Assessment Form
•
End of Treatment Form
•
Follow–Up Form
•
Consent Withdrawal Notification Form
•
Pregnancy Notification Form
•
SAE Form Please note the SAE form is faxed to Pharmacovigilance at the CRUK CTU and the original SAE report is kept at site.
Other trial Pro Formas
•
Slot Allocation Form
•
Dose Limiting Toxicity (DLT) Form
CRF completion:
•
CRF completion guidelines for the trial are currently being developed and will provided to sites when available
•
Entries to the CRFs will be made in black ball-point pen and must be legible. Correction fluid etc. must not be used
•
Any errors must be crossed out with a single stroke, correction inserted and change initialled and dated. An
explanation can be written next to amendment if necessary
•
Please ensure all data submitted on the CRFs is verifiable in source documents
•
Take photocopy of all completed CRFs. Originals to be sent to CRUK CTU Glasgow
CRF completion timelines:
•
Data entry – within 4 weeks of the patient visit Please note that during the dose escalation phase frequent data requests will be
made regarding patients on treatment with regard to adverse events, laboratory results and concomitant medications.
•
•
Resolution of queries – within 4 weeks of receipt
All data should be returned to CRUK CTU within 1 week of sign off
PHARMACOVIGILANCE DOCUMENTATION
The Pharmacovigilance section of the site file must be maintained and contain the following
documentation:
•
Copy of all SUSAR and DSUR reports
•
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)
•
Copies of the current and previous RSI (Investigator Brochures for LY2940680 and SmPC for Paclitaxel)
with other related documentation such as the front sheet document
•
All other correspondence from Pharmacovigilance
PATIENT CONFIDENTIALITY/PATIENT IDENTIFIABLE INFORMATION
Confidentiality
• All information collected during the course of the trial will be kept strictly confidential.
Information will be held securely on paper and electronically at the CRUK CTU. The CRUK CTU
will comply with all aspects of the 1998 Data Protection Act and National Health Service
Guidelines for storage, transmittal and disclosure of patient information.
•
Data on patients treated on the study will be held in study case report forms (CRFs), these
files will be identified by a trial number, patient initials and partial date of birth only.
•
Patient identifiable data (such as full name/or initials with date of birth) should not be sent
on email correspondence. If you need to refer to a patient use trial and patient number.
•
Where central monitoring of source documents by CRUK CTU (or copies of source
documents) are required (e.g. scan results of blood results) the personal data of the patients
must anonymised on the report e.g. black out the patient’s name and any other identifiable
information.
•
Where anonymisation of documentation is required, sites are responsible for ensuring no
patient identifiable data is present before sending to CRUK CTU.
MONITORING (1)
Central Monitoring
Trial sites will be monitored centrally by checking incoming forms for compliance with the
protocol, data consistency, missing data and timing. Trial staff will be in regular contact with site
personnel (by phone/fax/email/letter) to check on progress and deal with any queries that they
may have.
On-site and Remote Telephone Monitoring
The 1st visit will take the form of a remote telephone monitoring visit:

The time & date will be agreed with a member of the Site Trial 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 confirmation of the agreed date. This is for
information only and does not require to be completed by the site as this will be done by the
monitor during the remote monitoring visit.

Please set aside 50 to 70 minutes for this call.
MONITORING (2)
The 2nd visit will take the form of an on site monitoring visit:
•
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 the minimum 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 and not
held in trial specific documents i.e. in the completed CRF
•
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 and may be requested to
submit a copy of the Accountability Log[s] prior to the site visit
•
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 log 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:
-
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.
The Investigator requires to inform CRUK CTU of any protocol deviations as soon as possible and
will be required to complete a protocol deviation form providing a full description of the deviation,
corrective and preventative measures.
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.
Registration :
The Investigator should follow the trial’s registration 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
–
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 are responsible for the safety of patients recruited to the trial from their trial site.
Investigators must report Serious Adverse Events to the sponsor as soon as they become
aware of the event.
Investigators must ensure that follow-up SAE reports are provided until the SAE resolves.
Investigators must respond to data queries raised on SAE reports within 7 days.
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.
BUT
•
•
•
•
•
All staff must comply with GCP
Staff should only perform tasks delegated to them on the delegation log
Staff should have the appropriate trial related training on the trial protocol
Staff should ensure that their details are available to the Investigator
Staff should maintain appropriate confidentiality at all times
ARCHIVING ARRANGEMENTS
•
The trial Sponsor will approve when the trial is ready for archiving
•
Sites will be given the date of archive when they are informed of the close-out of the trial
•
Sites are responsible for archiving their own site files and paper CRFs as per their own SOPs
•
A destruction date will be recorded when archiving is taking place
•
The trial Sponsor will approve destruction when relevant
•
Sites will be notified by the CRUK CTU when they can destroy the archived paperwork
CONTACT DETAILS FOR CRUK CTU, GLASGOW
Karen Allan
Craig Campbell
Project Manager
Tel: 0141 301 7959
Fax: 0141 301 7192
E-mail: [email protected]
Clinical Trial Coordinator
Tel: 0141 301 7195
Fax: 0141 301 7192
Email: [email protected]
Lindsey Connery
Pharmacovigilance Manager
Tel: 0141 301 7209
Fax: 0141 301 7213
E-mail: [email protected]
Barbara Ross
Clinical Trial Monitor
Tel: 0141 301 7918
Fax: 0141 301 7187
Email: [email protected]
CRUK CTU, Glasgow
Cancer Research UK Clinical Trials Unit
Level 0, Beatson West of Scotland Cancer Centre
1053 Great Western Road, Glasgow G12 0YN