WIRE - Novel Treatments in Renal Cell Cancer

NCT03741426 | Unknown Phase 2 DMC

• 1 other identifier: WIRE
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 2

Brief Summary

Evaluation of proof of mechanism with relation to ktrans and/or CD8 count when 3 different IMPs are given as monotherapy or as combination therapy. These would be administered in the "window of opportunity", prior to nephrectomy in surgically resectable renal cell cancer

Conditions

Renal Cell Cancer

Keywords

Olaparib; Cediranib; Durvalumab

Outcome Measures

Primary Outcomes (2)

• Proof-of-Mechanism (ktrans): to assess for 30% ktrans change between pre-IMP treatment and IMP End of Treatment DCE-MRI

  Cediranib and Olaparib single IMP, Cediranib and Olaparib in combination IMP arms, having received at least 14 days' worth of IMP

  Change between Screening and 72 hours before surgery

• Proof-of-Mechanism (CD8): to assess for 30% change between pre-IMP treatment and IMP End of Treatment in CD8 positive T-cells. This will be based on IHC assessment via histoscore

  Durvalumab single IMP, durvalumab and olaparib combination IMP arms. having received at least 14 days' worth of IMP. Also assessed on D14 of IMP

  Change between Screening and 72 hours before surgery

Secondary Outcomes (3)

• Number of participants with, and severity of, Adverse Events

  From consent to 3 months post-surgery

• Change in primary tumour size assessed by DCE-MRI

  Between days -28 to 0 and 72 hrs before surgery, having received at least 2 weeks' worth of IMP

• Tumour Response

  Between days -28 to 0 for all patients.At 72 hrs before surgery if metastases are present,having received at least 2 wks' worth of IMP).Then every 8 wks until end of study (study ends=3 mths post surgery) or until progression

Study Arms (5)

Arm 1- Cediranib

EXPERIMENTAL

Cediranib tablet oral 20mg once daily for a minimum of 2 weeks up until 36 hours before nephrectomy.

Drug: Cediranib

Arm 2- Olaparib

EXPERIMENTAL

Olaparib tablet oral 300mg twice daily for a minimum of 2 weeks up until the morning of nephrectomy.

Drug: Olaparib

Arm 3- Olaparib and Cediranib

ACTIVE COMPARATOR

Olaparib tablet oral 300mg twice daily for a minimum of 2 weeks up until the morning of nephrectomy AND Cediranib tablet oral 20mg once daily for a minimum of 2 weeks up until 36 hours before nephrectomy.

Drug: Olaparib; Drug: Cediranib

Arm 4- Durvalumab

EXPERIMENTAL

Durvalumab 1500mg intravenous infusion once, a maximum of 4 weeks prior to nephrectomy.

Drug: Durvalumab

Arm 5- Olaparib and Durvalumab

ACTIVE COMPARATOR

Olaparib tablet oral 300mg twice daily for a minimum of 2 weeks up until the morning of nephrectomy. Durvalumab 1500mg intravenous infusion once, a maximum of 4 weeks prior to nephrectomy.

Drug: Olaparib; Drug: Durvalumab

Interventions

Olaparib DRUG

Olaparib 300mg twice daily, oral medication administered for at least 2 weeks and up until the morning of nephrectomy. Arms 2, 3 and 5

Also known as: AZD2281, KU-0059436, LYNPARZA

Arm 2- Olaparib; Arm 3- Olaparib and Cediranib; Arm 5- Olaparib and Durvalumab

Cediranib DRUG

Cediranib 20mg once daily, oral medication administered for at least 2 weeks until 36 hours prior to nephrectomy. Arms 1 and 3

Also known as: AZD2171

Arm 1- Cediranib; Arm 3- Olaparib and Cediranib

Durvalumab DRUG

Durvalumab 1500mg intravenous infusion administered once, no greater than 4 weeks prior to nephrectomy

Also known as: MEDI4736

Arm 4- Durvalumab; Arm 5- Olaparib and Durvalumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ≥ 3 months. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. Have biopsy proven clear cell RCC. Have a surgically resectable tumour as determined by the treating Urologist Have any T or N status, M0. Have any T or N status, M1 (but if M1, the subject must be deemed suitable for cytoreductive nephrectomy at time of enrolment).
• No prior exposure to PARP inhibitors (including but not limited to olaparib), tyrosine kinase inhibitors (including but not limited to cediranib, sunitinib, pazopanib, axitinib or cabozantinib), immunotherapy or immune checkpoint inhibitors (including but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies), nor prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, or sirolimus). 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 baseline by CT or MRI and is suitable for repeated assessment. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose of trial treatment. It is acceptable for the measurable lesion to be planned for removal at surgery.
• Have adequate organ and marrow function, as defined below (measured within 28 days of first dose of trial medication):
• Haemoglobin ≥ 100 g/L Platelet count ≥ 135 x 109/L Neutrophil count ≥ 1.8 x 109/L Peripheral blood smear with no features of myelodysplastic syndrome or acute myeloid leukemia.
• Serum creatinine ≤1.5x the institutional ULN concurrent with creatinine clearance ≥51mL/min (calculated by Cockcroft and Gault equation)
• Adequate hepatic function:
• Alanine Aminotransferase (ALT) ≤2.5x the institutional upper limit of normal (ULN) unless liver metastases are present, in which case it must be ≤5x the institutional ULN, AND Total bilirubin ≤1.5x the institutional ULN unless in the presence of Gilbert's syndrome (persistent or recurrent hyperbilirubinaemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology), AND
• 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 amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy) Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• For women of childbearing potential a negative urine or serum pregnancy test must be performed within 28 days of study treatment and confirmed prior to treatment on day 1.
• Patient is willing and able to comply with the protocol for the duration of the trial.

You may not qualify if:

• Patients with brain metastases. A scan to confirm the absence of brain metastases is not required.
• Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
• History of leptomeningeal carcinomatosis. Body weight \<30kg Contraindication to cediranib, olaparib, durvalumab or chimeric or humanized antibodies or fusion proteins.
• Specifically patients with hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not enter the study.
• History of hypersensitivity to active or inactive excipients of cediranib, olaparib or durvalumab.
• Other invasive malignancy within the last 2 years. Patients 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, for example:
• Carcinoma in situ of the cervix. Basal or squamous cell skin cancer. Localized low to intermediate risk prostate cancer treated with curative intent and absence of prostate-specific antigen (PSA) relapse; or prostate cancer (Stage T1/T2a, Gleason ≤ 6 and PSA \< 10 ng/mL) undergoing active surveillance and treatment naïve.
• Major surgery within 4 weeks prior to first dose of study drug (excluding placement of vascular access).
• Patients must have recovered from side effects of any major surgery. 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 enrollment in another clinical trial unless it is an observational (non-interventional) or translational clinical study, or during the follow-up period of an interventional clinical study.
• 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 study drug (If sufficient wash-out time has not occurred due to the schedule or PK properties of an agent, a longer wash-out period will be required, as agreed by AstraZeneca/MedImmune and the investigators).
• Gastrointestinal abnormalities including:
• refractory nausea and vomiting, inability to take oral medication; requirement for intravenous alimentation; prior surgical procedures affecting absorption including total gastric resection; treatment for active peptic ulcer disease in the past 6 months; active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 120 days without evidence of resolution documented by endoscopy or colonoscopy; malabsorption syndromes. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors, or inducers or substrates for CYP1A2 (see Section 10.8, concomitant therapy).
• Concomitant medications known to prolong the QT interval (see Appendices 4, 5 and 6, concomitant therapy) or with factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age), history of Torsades de pointes.

Sponsors & Collaborators

• CCTU- Cancer Theme: lead
• University of Cambridge: collaborator
• AstraZeneca: collaborator
• Cancer Research UK: collaborator

Study Sites (2)

Addenbrooke's Hospital

Cambridge, England, CB2 2QQ, United Kingdom

RECRUITING

Beatson Institute for Cancer Research

Glasgow, United Kingdom

RECRUITING

Related Publications (3)

• Horvat-Menih I, McLean MA, Birchall J, Zamora Morales MJ, Wylot M, Ursprung S, Woitek R, Serrao E, Grimmer A, Latimer E, Khan AS, Priest AN, Gill AB, Kaggie JD, Graves MJ, Barrett T, Wason JM, Mossop H, Thomas M, Said S, Warren AY, Fife K, Eisen T, Matakidou A, Ince W, O'Carrigan B, Jones JO, Welsh SJ, Mitchell TJ, Armitage JN, Riddick AC, Stewart GD, Gallagher FA. Evaluating the metabolic effects of neoadjuvant treatment in clear cell renal cell carcinoma using hyperpolarized [1-13 C]pyruvate MRI. Abdom Radiol (NY). 2025 Dec 10. doi: 10.1007/s00261-025-05313-z. Online ahead of print.

  PMID: 41369900 DERIVED

• Horvat-Menih I, Li H, Priest AN, Li S, Gill AB, Mendichovszky IA, Francis ST, Warren AY, O'Carrigan B, Welsh SJ, Jones JO, Riddick ACP, Armitage JN, Mitchell TJ, Stewart GD, Gallagher FA. High-resolution and highly accelerated MRI T2 mapping as a tool to characterise renal tumour subtypes and grades. Eur Radiol Exp. 2024 Jul 10;8(1):76. doi: 10.1186/s41747-024-00476-8.

  PMID: 38981998 DERIVED

• Ursprung S, Mossop H, Gallagher FA, Sala E, Skells R, Sipple JAN, Mitchell TJ, Chhabra A, Fife K, Matakidou A, Young G, Walker A, Thomas MG, Ortuzar MC, Sullivan M, Protheroe A, Oades G, Venugopal B, Warren AY, Stone J, Eisen T, Wason J, Welsh SJ, Stewart GD. The WIRE study a phase II, multi-arm, multi-centre, non-randomised window-of-opportunity clinical trial platform using a Bayesian adaptive design for proof-of-mechanism of novel treatment strategies in operable renal cell cancer - a study protocol. BMC Cancer. 2021 Nov 18;21(1):1238. doi: 10.1186/s12885-021-08965-4.

  PMID: 34794412 DERIVED

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

olaparib; cediranib; durvalumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Grant D Stewart

  Cambridge University Hospitals NHS Foundation Trust & University of Cambridge

  STUDY CHAIR

• Brent O'Carrigan

  Cambridge University Hospitals NHS Foundation Trust & University of Cambridge

  PRINCIPAL INVESTIGATOR

Central Study Contacts

CCTU Cancer Theme

CONTACT

01223 256364; cctu.cancer@addenbrookes.nhs.uk

Silvia Tarantino

CONTACT

01223 256364; cuh.wire@nhs.net

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Grant D. Stewart, MBChB, BSc., FRCSEd (Urol), PhD

Model Details: Bayesian Adaptive

Study Record Dates

• First Submitted: October 31, 2018
• First Posted: November 14, 2018
• Study Start: July 27, 2020
• Primary Completion: November 30, 2025
• Study Completion: November 30, 2025
• Last Updated: June 7, 2023

Record last verified: 2023-06

Locations

GB (2)