| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Surgically resectable renal cell cancer (Stage M0/M1) |
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| E.1.1.1 | Medical condition in easily understood language |
| Surgically resectable renal cell cancer (Stage M0/M1) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038389 |
| E.1.2 | Term | Renal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038389 |
| E.1.2 | Term | Renal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To assess proof-of-mechanism as defined by biological evidence of treatment(s)affecting the expected pathway. This will be measured by meeting any of the following criteria:
- A reduction of 30% from baseline in how porous the tumour capillaries are, and therefore how well the tumour is fed by blood vessels. This is measured using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI), in which the participants would receive a contrast agent. This scan looks at ktrans, which is calculated by studying the amount of contrast agent in the blood around the tumour. A reduction in how well the tumour is fed should, in theory, lead to shrinkage of the tumour.
- Observation of changes in relevant cellular pathways defined for each treatment arm:
- For VEGFR TKIs (Cediranib)and also Olaparib, decrease in CD31 (30% reduction compared to baseline). CD31 is an indicator of tumour angiogenesis (when a tumour makes its own blood supply) and is higher when a tumour is making its own bl |
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| E.2.2 | Secondary objectives of the trial |
- To assess safety as defined by any delay in surgery of greater than 3 months; measured using CTCAE V5.0 criteria.
- To evaluate the primary tumour size change using mpMRI.
- Tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1
- To assess the change in pre and post treatment tumour capillary permeability, measured using mpMRI including DCE-MRI (ktrans) (for durvalumab single arm and durvalumab and olaparib combined arm).
-To assess the change in pre- and post treatment intra-tumoural CD8 positive T cells (for cediranib and olaparib single arms and cediranib and olaparib combined arm)
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
• Aged ≥18 years and over.
• Predicted life expectancy ≥ 16 weeks.
•Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.
• •Have biopsy proven clear cell RCC.
• •Allow access to archival FFPE tumour tissue from biopsy and nephrectomy.
• •Have a surgically resectable tumour as determined by the treating Urologist
• T1b or above, any N status, M0, OR have any T or N status, M1 (but if M1, the participant must be deemed suitable for cytoreductive nephrectomy at time of enrolment).
• No prior exposure to PARP inhibitors, tyrosine kinase inhibitors, immunotherapy or immune checkpoint inhibitors, nor prior treatment with an mammalian target of rapamycin (mTOR) inhibitor. Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed.
• At least 1 measurable lesion according to RECIST Version 1.1 at screening that can be accurately assessed at by MRI and is suitable for repeated assessment.
• Have adequate organ and marrow function
• Creatinine clearance ≥30mL/min (calculated by Cockcroft and Gault equation
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months without an alternative medical cause (Protocol has further details of what this means- word count)
• For women of childbearing potential a negative serum pregnancy test must be performed within 28 days of study treatment and confirmed prior to treatment on day 1.
• Male patients must be willing to use a condom during treatment and for 3 months after the last dose of trial treatment when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also be willing to use a highly effective form of contraception if they are of childbearing potential
• Patient is willing and able to comply with the protocol for the duration of the trial.
• Adequately controlled thyroid function, with no symptoms of thyroid dysfunction
Some drug-specific Inclusion criteria apply, truncated due to word count
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|
| E.4 | Principal exclusion criteria |
• cT1a N0 M0-staged Renal Cell Cancer
• Participants with brain metastases. A scan to confirm the absence of brain metastases is not required.
• Participants with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days prior to start of treatment.
• History of leptomeningeal carcinomatosis.
• Body weight ≤30kg
• Contraindication to cediranib, olaparib, durvalumab or chimeric or humanized antibodies or fusion proteins.
• Specifically participants with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the trial.
• History of hypersensitivity to active or inactive excipients of cediranib, olaparib or durvalumab.
• Other invasive malignancy within the last 2 years. Participants with previous history of malignancies with a negligible risk of metastasis or death and treated with expected curative intent are eligible at discretion of clinical team- examples in Protocol- word count
• Major surgery within 4 weeks prior to first dose of trial drug (excluding placement of vascular access). If patientparticipants have undergone major surgery more than 4 weeks prior to the scheduled first dose of studytrial drug, they must have fully recovered from the procedure.
• Minor surgery (not including the diagnostic biopsy) within 2 weeks prior to first dose of trial treatment
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Concurrent enrolment in another clinical trial unless it is an observational (non-interventional NOT involving CTIMPs) or translational clinical trial, or during the follow-up period of an interventional clinical trial.
• Receipt of the last dose of anticancer therapy or radiotherapy, chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumour embolisation, monoclonal antibodies) ≤28 days prior to the first dose of trial drug.
• Gastrointestinal abnormalities- see Protocol (word count)
• Any of the following within 12 months prior to trial entry:
o myocardial infarction,
o uncontrolled angina,
o coronary/peripheral artery bypass graft,
o symptomatic congestive heart failure,
o cerebrovascular accident or transient ischemic attack,
o peripheral arterial embolus.
• Current or prior use of immunosuppressive agents within 28 days prior to the of first day of trial drug, including anti-TNF and anti-IL17 agents, with the exceptions of intranasal or inhaled corticosteroids, or systemic corticosteroids at physiological doses which are not to exceed 10mg/day prednisolone (or an equivalent corticosteroid). See Protocol for exceptions (word count)
• Immunocompromised participants (e.g., participants who are known to be serologically positive for human immunodeficiency virus (HIV), or have a history of active primary immunodeficiency).
• Active infection including tuberculosis (clinical history, physical examination and radiographic findings, and Tuberculosis (TB) testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV1/2 antibodies).
o Participants with a past or resolved HBV infection (defined as: presence of hepatitis B core antibody -anti-HBc- and absence of hepatitis B surface antigen –HbsAg-) are eligible.
• As judged by the Investigator, any participant considered a high medical risk due to a serious uncontrolled medical or psychiatric disorder, non-malignant systemic disease or on-going or active infection.
• Persistent toxicities (≥Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia and vitiligo.
• Women who are pregnant, or are lactating or breastfeeding
• Participants with contraindication to MRI including; contraindicated metallic implants, contraindicated coronary stents and pacemakers. Inability to lie flat or still in an MRI scanner for whatever reason (e.g., claustrophobia).
• Judgement by the Investigator that the participant should not participate in the trial.
• Involvement in the planning and/or conduct of the trial
• Previous allogeneic bone marrow transplant or double umbilical cord blood transplantation.
Some drug-specific Exclusion criteria apply, truncated due to word count |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•For Cediranib and Olaparib single IMP, Cediranib & Olaparib in combination IMP arms: the primary outcome measure is a 30% reduction in ktrans, assessed between pre-treatment and end of treatment by mpMRI (including DCE-MRI)
•Durvalumab single IMP, durvalumab and olaparib in combination IMP arms: the primary outcome measure is a 30% increase in CD8 positive t-cells, assessed between the pre-treatment biopsy and post-treatment nephrectomy samples based on Immunohistochemistry assessment via histoscore. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Screening
D15
Pre-surgery Imaging Visit
3 months post-surgery
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|
| E.5.2 | Secondary end point(s) |
All Adverse Events will be graded for severity according to the NCI-CTCAE Toxicity Criteria (Version 5.0).
Tumour response using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and duration of response.
For those arms where not a primary outcome measure, mpMRI including DCE-MRI (ktrans) change will be a secondary outcome measure
For those arms where not a primary outcome measure, and CD8 positive T cells change between pre- and post-treatment will be a secondary outcome measure
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Adverse events- Screening, Day 1, Day 15, Day 22 (depending on timelines), 6 weeks post-surgery, 3 months post-surgery
Tumour response- (from Screening)- pre-surgery
Ktrans and CD8 positive t-cells as secondary endpoints: Screening, D15, Pre-surgery Imaging Visit, 3 months post-surgery
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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