NeoAdjuvant Pembrolizumab and STEreotactic Radiotherapy Prior to Nephrectomy for Renal Cell Carcinoma

NCT05024318 | Recruiting Phase 2 DMC

• 1 other identifier: 19/007
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This is a prospective, open label, phase II, randomised, non-comparative clinical trial, evaluating changes in tumour-responsive T-cells following neoadjuvant stereotactic ablative body radiotherapy (SABR) with or without pembrolizumab, prior to nephrectomy, in patients with localised primary clear cell renal cell carcinoma (ccRCC).

Conditions

Renal Cell Carcinoma, Clear Cell, Somatic

Outcome Measures

Primary Outcomes (3)

• mPR post-SABR with or without pembrolizumab

  The mPR rate is defined as \<10% residual tumour at post-nephrectomy specimens

  At nephrectomy performed 9-12 weeks after first dose of pembrolizumab

• CD8+ TRM in baseline biopsy and post-nephrectomy specimen, all measured as a continuous variable.

  To describe changes in tumour-responsive T-cells, TRM CD8+ T-cells from baseline to post-nephrectomy in patients treated with SABR with or without pembrolizumab treatment followed by nephrectomy

  Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

• TCF-1 + tumour infiltrating lymphocytes (TILs) in baseline biopsy and post-nephrectomy specimen, measured as a continuous variable

  To describe changes in TCF-1+ T-cells from baseline to post-nephrectomy in patients treated with SABR with or without pembrolizumab treatment followed by nephrectomy

  Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

Secondary Outcomes (5)

• Immune response cells in baseline biopsy and post-nephrectomy specimen

  Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

• The tumour-responsive TRM cells inclusive of CD4+ and CD8+ compartments

  2 weeks prior to nephrectomy

• Safety of SABR with or without pembrolizumab in the neo-adjuvant setting

  60 days post nephrectomy

• Change in immune response associated with mPR

  Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

• Change in PD-L1 and PD-L2 expression in tumour

  Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

Other Outcomes (7)

• Radiological features including contrast enhancement consistent with mPR

  2 weeks prior to nephrectomy

• Radiological features including size reduction consistent with mPR

  2 weeks prior to nephrectomy

• Radiological features including maximum tumour diameter consistent with mPR

  2 weeks prior to nephrectomy

Study Arms (2)

SABR plus nephrectomy

ACTIVE COMPARATOR

Stereotactic Ablative Radiotherapy (SABR) will be prescribed to a dose of 42Gy in 3 fractions. All radiotherapy treatment be completed within 3 weeks.Patients will undergo nephrectomy within 9-12 weeks after the first dose of treatment.

Radiation: Stereotactic Ablative Radiotherapy; Procedure: Nephrectomy

Pembrolizumab followed by SABR after cycle 1 plus nephrectomy

EXPERIMENTAL

Pembrolizumab 200 mg (flat dose) will be administered as a 30 minute IV infusion every 21 days for 3 cycles. Patients will receive 1 cycle of pembolizumab prior to SABR followed by an additional 2 cycles of pembrolizumab (1 cycle is 21 days). Patients will undergo nephrectomy 9-12 weeks after commencement of treatment.

Drug: Pembrolizumab; Radiation: Stereotactic Ablative Radiotherapy; Procedure: Nephrectomy

Interventions

Pembrolizumab DRUG

Pembrolizumab 200 mg tobe administered as a 30 minute IV infusion every 21 days for 3 cycles

Also known as: MK-3475

Pembrolizumab followed by SABR after cycle 1 plus nephrectomy

Stereotactic Ablative Radiotherapy RADIATION

42Gy delivered in 3 fractions

Also known as: SABR

Pembrolizumab followed by SABR after cycle 1 plus nephrectomy; SABR plus nephrectomy

Nephrectomy PROCEDURE

Partial or total nephrectomy performed 9-12 weeks after first dose of Pembrolizumab

Also known as: Surgical removal of a kidney

Pembrolizumab followed by SABR after cycle 1 plus nephrectomy; SABR plus nephrectomy

Eligibility Criteria

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

You may qualify if:

• Patient has provided written informed consent
• Male or female aged 18 years or older at written informed consent
• Histologically or cytologically confirmed diagnosis of RCC with clear cell, rhabdoid or sarcomatoid components
• Tumour stage T1B-T3, N0 or N1, M0 or low volume M1 planned for nephrectomy
• Patients must have adequate bone marrow, hepatic and renal function documented within 28 days prior to randomisation:
• White Blood Cell (WBC) ≥ 3 X 10\^9/L
• Absolute neutrophil count (ANC) ≥1.5 X 10\^9/L
• Platelets ≥ 100 X 10\^9/L
• Haemoglobin ≥ 100 g/L independent of transfusion
• Serum Creatinine ≤1.5 X Upper Limit of Normal (ULN) or measured or calculated CrCl calculated as per institutional standard ≥ 30 ml/min. GFR can also be used in place of serum creatinine or CrCl.
• Total bilirubin ≤1.5 X ULN except for patients with known Gilbert's Syndrome
• Albumin \> 30 g/L
• AST and ALT ≤1.5 X ULN
• INR or PT ≤1.5 X ULN unless patient is receiving anticoagulant therapy
• ECOG performance status of 0 or 1

You may not qualify if:

• Had prior treatment with any anti-PD-1, or anti-PD-L1, or PD-L2 agent or with an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include antibodies against IDO, PD-L1, IL-2R, and GITR
• Known or active inflammatory bowel disease involving colon and small bowels
• Previous radiotherapy to the upper abdomen with radiation dose overlap to the involved kidney
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomisation
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy exceeding 10 mg daily dose of prednisone or equivalent or any other form of immunosuppressive therapy within 7 days prior to randomisation
• Has an active autoimmune disease that has required systemic treatment in the last 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Has a known additional malignancy that is progressing or has required active treatment in the last 2 years Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ, such as breast cancer in situ, that has undergone potentially curative therapy are not excluded
• Has known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to randomisation
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
• Has an active infection requiring systemic therapy
• Has a known history of HIV infection
• Has known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive)or known active Hepatitis C (defined as HCV RNA \[qualitative\] is detected) infection
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator
• Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (2)

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

RECRUITING

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

RECRUITING

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

pembrolizumab; Nephrectomy

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

Intervention Hierarchy (Ancestors)

Urologic Surgical Procedures; Urogenital Surgical Procedures; Surgical Procedures, Operative

Study Officials

• Shankar Siva, A/Prof

  Peter MacCallum Cancer Centre, Australia

  STUDY CHAIR

Central Study Contacts

Shankar Siva, A/Prof

CONTACT

+61 3 8559 7988; Shankar.Siva@petermac.org

Arun Azad, A/Prof

CONTACT

+61 3 8559 7165; Arun.Azad@petermac.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2021
• First Posted: August 27, 2021
• Study Start: February 8, 2022
• Primary Completion: December 1, 2025
• Study Completion: December 1, 2025
• Last Updated: May 16, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (2)