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

NeoAdjuvant Pembrolizumab and STEreotactic Radiotherapy Prior to Nephrectomy for Renal Cell Carcinoma: Investigating Induced Immune Context Changes

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).

Study Overview

• Status: Recruiting
• Conditions: Renal Cell Carcinoma, Clear Cell, Somatic
• Intervention / Treatment: Radiation: Stereotactic Ablative Radiotherapy; Procedure: Nephrectomy; Drug: Pembrolizumab

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shankar Siva, A/Prof; Phone Number: +61 3 8559 7988; Email: Shankar.Siva@petermac.org
• Study Contact Backup: Name: Arun Azad, A/Prof; Phone Number: +61 3 8559 7165; Email: Arun.Azad@petermac.org

Study Locations

• Australia
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Recruiting
      • Princess Alexandra Hospital
      • Contact: David Pryor
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Recruiting
      • Peter MacCallum Cancer Centre
      • Contact: Shankar Siva, A/Prof; Phone Number: +61 3 8559 7988; Email: Shankar.Siva@petermac.org
      • Contact: Arun Azad, A/Prof; Phone Number: +61 3 8559 7165; Email: Arun.Azad@petermac.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient has provided written informed consent
2. Male or female aged 18 years or older at written informed consent
3. Histologically or cytologically confirmed diagnosis of RCC with clear cell, rhabdoid or sarcomatoid components
4. Tumour stage T1B-T3, N0 or N1, M0 or low volume M1 planned for nephrectomy

5. 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
6. ECOG performance status of 0 or 1
7. Women of child birth potential (WOCBP) must have a negative urine or serum pregnancy test within 72 hours prior to randomisation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
8. WOCBP should be willing to use two methods of birth control, or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Patients of childbearing potential are those who have not been surgically sterilised or have not been free from menses for more than 1 year
9. Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
10. Patient agrees to the collection and use of their fresh tumour samples and peripheral blood for translational research
11. Patient is willing and able to comply with the protocol for the duration of the study including undergoing biopsies, treatment, and scheduled visits and examination

Exclusion Criteria:

1. 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
2. Known or active inflammatory bowel disease involving colon and small bowels
3. Previous radiotherapy to the upper abdomen with radiation dose overlap to the involved kidney
4. 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
5. 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
6. 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
7. 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
8. 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
9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients
10. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
11. Has an active infection requiring systemic therapy
12. Has a known history of HIV infection
13. 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
14. 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
15. Has a known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
16. Has received a live virus vaccine within 30 days prior to randomisation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed
17. Has had a prior solid organ transplant
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study drug.
19. Any contraindications for surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: SABR plus nephrectomy; 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; 42Gy delivered in 3 fractions; Other Names: SABR; Procedure: Nephrectomy; Partial or total nephrectomy performed 9-12 weeks after first dose of Pembrolizumab; Other Names: Surgical removal of a kidney
Experimental: Pembrolizumab followed by SABR after cycle 1 plus nephrectomy; 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.	Radiation: Stereotactic Ablative Radiotherapy; 42Gy delivered in 3 fractions; Other Names: SABR; Procedure: Nephrectomy; Partial or total nephrectomy performed 9-12 weeks after first dose of Pembrolizumab; Other Names: Surgical removal of a kidney; Drug: Pembrolizumab; Pembrolizumab 200 mg tobe administered as a 30 minute IV infusion every 21 days for 3 cycles; Other Names: MK-3475

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune response cells in baseline biopsy and post-nephrectomy specimen	Change in immune response from baseline to post-nephrectomy	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab
The tumour-responsive TRM cells inclusive of CD4+ and CD8+ compartments	Percentage of tumour responsive T-cells (inclusive CD4/CD8) after neo-adjuvant treatment	2 weeks prior to nephrectomy
Safety of SABR with or without pembrolizumab in the neo-adjuvant setting	Adverse events, as measured by CTCAE v5.0	60 days post nephrectomy
Change in immune response associated with mPR	Immune response cells in baseline biopsy and post-nephrectomy specimens	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab
Change in PD-L1 and PD-L2 expression in tumour	PD-L1 and PD-L2 expression in baseline biopsy and post-nephrectomy specimens	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological features including contrast enhancement consistent with mPR	Post treatment radiological features including contrast enhancement	2 weeks prior to nephrectomy
Radiological features including size reduction consistent with mPR	Post treatment radiological features including size reduction	2 weeks prior to nephrectomy
Radiological features including maximum tumour diameter consistent with mPR	Post treatment radiological features including maximum tumour diameter	2 weeks prior to nephrectomy
Radiological features including margins consistent with mPR	Post treatment radiological features including margins	2 weeks prior to nephrectomy
Baseline versus post-nephrectomy tissue for immune context changes	To investigate baseline versus post-nephrectomy tissue for immune context changes, using a broad panel of assays which will be further developed through the lifetime of the study	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab
Baseline versus post-nephrectomy tissue immune network signalling	Baseline and post-nephrectomy immune network signalling , using a broad panel of assays which will be further developed through the lifetime of the study	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab
Systemic immune cells in baseline and post-nephrectomy blood samples	To investigate changes in systemic immunity of patients with primary ccRCC treated with SABR with or without pembrolizumab	Baseline and at nephrectomy performed 9-12 weeks after first dose of pembrolizumab

Collaborators and Investigators

• Sponsor: Peter MacCallum Cancer Centre, Australia
• Investigators: Study Chair: Shankar Siva, A/Prof, Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: March 29, 2021
• First Submitted That Met QC Criteria: August 22, 2021
• First Posted (Actual): August 27, 2021

Study Record Updates

• Last Update Posted (Actual): May 16, 2024
• Last Update Submitted That Met QC Criteria: May 15, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab
• Other Study ID Numbers: 19/007

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No