Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI Trial
This phase II trial tests whether the addition of radiation to the primary tumor, typically given with stereotactic ablative radiation therapy (SABR), in combination with standard of care immunotherapy improves outcomes in patients with renal cell cancer that is not recommended for surgery and has spread from where it first started (primary site) to other places in the body (metastatic). Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision.
This method may kill tumor cells with fewer doses of radiation over a shorter period and cause less damage to normal tissue. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, avelumab, and pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are in a class of medications called antiangiogenic agents.
They work by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving SABR in combination with standard of care immunotherapy may help shrink or stabilize the cancer in patients with renal cell cancer.
Study details:
PRIMARY OBJECTIVE:. I. To determine whether the addition of stereotactic ablative radiotherapy (SABR) to the primary tumor in combination with immunotherapy improves outcomes compared to immunotherapy alone in patients with metastatic, unresected, renal cell carcinoma (RCC).
The primary endpoint is nephrectomy and radiographic progression-free survival (nrPFS) with progression determined as per iRECIST criteria. SECONDARY OBJECTIVES:. I.
To assess the safety, toxicity and tolerability of the two treatment strategies as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5 in each treatment arm. II. To assess the objective response rate (ORR) by Immune-related Response Evaluation Criteria in Solid Tumors (iRECIST) in each treatment arm.
III. Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified indications (nephrectomy and radiographic progression-free survival \[nrPFS\]2). IV.
Radiographic progression-free survival (rPFS). V. To assess overall survival (OS) in each treatment arm.
VI. To assess the time to subsequent second-line therapy or death in each treatment arm. VII.
To assess the rate of cytoreductive nephrectomy in each treatment arm. VIII. To assess treatment-free survival in patients who discontinue therapy for reason other than radiographic disease progression.
IX. To assess the ORR by Response Evaluation Criteria in Solid Tumors (RECIST) version 1. 1 and iRECIST in the primary renal mass.
EXPLORATORY OBJECTIVES:. I. To assess composite nrPFS in the predefined histological subgroups below:.
Ia. Clear cell versus non-clear cell histology; Ib. International Metastatic RCC database consortium (IMDC) intermediate versus poor risk group; Ic.
Systemic treatment with immunotherapy-immunotherapy combination versus immunotherapy-vascular endothelial growth factor (VEGF) targeted therapy combination; Id. Sarcomatoid versus non sarcomatoid variant. II.
To identify prognostic and predictive biomarkers of response to SABR in the context of immunotherapy based treatment via assessment of tissue and blood based biomarkers. III. To evaluate the abscopal effect of SABR with systemic therapy.
IIIa. Compare ORR in non-irradiated target lesions in the control arm patients undergoing immunotherapy alone to the experimental arm undergoing SABR + immunotherapy. IV.
To evaluate the impact of treatment on level of inferior vena cava (IVC) thrombus. V. To compare accruing center identified iRECIST progression and centrally identified iRECIST progression events on computed tomography (CT).
OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive one of the following immunotherapy regimens per physician discretion: nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes every 3 weeks for 4 doses followed by nivolumab IV over 30 minutes every 2 or 4 weeks; pembrolizumab IV over 30 minutes every 3 or 6 weeks and axitinib orally (PO) twice daily (BID); avelumab IV over 60 minutes every 2 weeks and axitinib PO BID; nivolumab IV over 30 minutes every 2 or 4 weeks and cabozantinib PO once daily (QD); OR pembrolizumab IV over 30 minutes every 3 or 6 weeks and lenvatinib PO QD. Treatment with immunotherapy continues in the absence of disease progression or unacceptable toxicity.
Patients also undergo computed tomography (CT) scan or magnetic resonance imaging (MRI) throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial. ARM II: Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I.
Patients also undergo CT scan or MRI throughout the trial. Patients may also undergo a bone scan as clinically indicated and blood sample collection throughout the trial. After completion of study treatment, patients are followed up every 6 months for 5 years, and then annually for 3 years.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
- Pathologically (histologically or cytologically) proven diagnosis of renal cell carcinoma prior to registration
- Node-positive unresectable (TxN1Mx) or metastatic (TxNxM1) based on the following diagnostic workup: History/physical examination within 45 days prior to registration; CT/magnetic resonance imaging (MRI) of the chest/abdomen/pelvis within 45 days prior to registration
- Patients must have IMDC intermediate (1-2 factors) or poor risk disease (>= 3 factors)
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- Patients with measurable disease (node positive or metastatic) as defined by RECIST version 1.1 excluding the primary renal tumor
- Patient not recommended for or refused immediate cytoreductive nephrectomy
- Candidate for standard of care therapy with either immuno-oncology (IO)-IO or IO-VEGF combination regimen
- Primary renal tumor measuring 20 cm or less in anterior to posterior dimension only on axial imaging
- Age >= 18
- Karnofsky performance status >= 60 within 45 days prior to registration
- Hemoglobin >= 8 g/dL (transfusions are allowed) (within 45 days prior to registration)
- Platelet count >= 50,000/mm^3 (within 45 days prior to registration)
- Absolute neutrophil count (ANC) >= 1500/mm^3 (within 45 days prior to registration)
- Calculated (Calc.) creatinine clearance >= 30 mL/min (within 45 days prior to registration): Creatinine clearance (CrCl) >= 30 mL/min estimated by Cockcroft-Gault Equation; For African American patients specifically whose renal function is not considered adequate by the formula above, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) should be used for calculating the related estimated glomerular filtration rate (GFR) with a correction factor for African American race creatinine clearance for trial eligibility, where GFR >= 30 mL/min/1.73m^2 will be considered adequate
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within 45 days prior to registration)
- Aspartate aminotransferase and alanine aminotransferase (AST and ALT) =< 3 x upper limit of normal (ULN) or < 5 x ULN if hepatic metastases present (within 45 days prior to registration)
- Patients with known human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Testing is not required for entry into protocol
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
- The patient must agree to use a highly effective contraception, including men with vasectomies if they are having sex with a woman of childbearing potential or with a woman who is pregnant, while on study drug and for 6 months following the last dose of study drug. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal
- The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
Exclusion criteria
- Patients with planned treatment of all metastatic disease with definitive therapy including either surgery, ablative (non-palliative) doses of radiation, or intervention of some type (definitive interventional radiology techniques) to ALL metastatic sites rendering the patient without extra-renal measurable disease. Patients NOT planned for definitive treatment of all metastatic sites are eligible. Lesions radiated palliatively are not eligible for response assessment
- Patients with untreated or unstable brain metastases or cranial epidural disease: Note: Patients who have been adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator are eligible. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to registration as documented by MRI or CT imaging or deemed stable by clinical investigator
- Prior radiotherapy to the kidney that would result in overlap of radiation therapy fields treatment of the primary tumor
- Any systemic therapy for metastatic renal cell carcinoma (RCC) that was initiated > 90 days before registration, note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration)
- Severe, active comorbidity defined as follows: Active autoimmune disease requiring ongoing therapy including systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications daily. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies; Active tuberculosis (purified protein derivative [PPD] response without active tuberculosis [TB] is allowed); Uncontrolled hypertension (systolic blood pressure [BP] >= 190 mmHg or diastolic BP > 110 mmHg); Major surgery requiring hospital admission =< 28 days prior to registration; Any serious (requiring hospital stay or long term rehab) non-healing wound, ulcer, or bone fracture within 45 days prior to registration; Any arterial thrombotic (ST elevation myocardial infarction [STEMI], non-ST elevation myocardial infarction [NSTEMI], cerebrovascular accident [CVA], etc) events within 180 days prior to registration; Active New York (NY) Heart Association class 3-4 heart failure symptoms; Moderate or severe hepatic impairment (Child-Pugh B or C); Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) within 180 days prior to registration. (Any asymptomatic or treated pulmonary embolism or asymptomatic treated deep venous thrombosis > 30 days prior to registration is allowed); Unstable cardiac arrhythmia within 180 days prior to registration; History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, bowel obstruction, or gastric outlet obstruction within 180 days prior to registration; History of or active inflammatory bowel disease; Malabsorption syndrome within 45 days prior to registration
- Pregnancy and individuals unwilling to discontinue nursing. For women of child bearing potential must have a negative pregnancy test =< 45 days prior to registration
Eligibility
Age eligible for study : NA
Healthy volunteers accepted : No
Gender eligible for study: ALL
Things to know
Study dates
Study start:
Primary completion:
Study completion finish:
Study type
TREATMENT
Phase
- PHASE2
Study ID
NCT05327686
Intervention or treatment
BIOLOGICAL: Avelumab
DRUG: Axitinib
PROCEDURE: Biospecimen Collection
PROCEDURE: Bone Scan
DRUG: Cabozantinib
PROCEDURE: Computed Tomography
BIOLOGICAL: Ipilimumab
DRUG: Lenvatinib
PROCEDURE: Magnetic Resonance Imaging
BIOLOGICAL: Nivolumab
BIOLOGICAL: Pembrolizumab
RADIATION: Stereotactic Ablative Radiotherapy
Conditions
- Metastatic Renal Cell Carcinoma
- Stage III Renal Cell Cancer AJCC v8
- Stage IV Renal Cell Cancer AJCC v8
- Unresectable Renal Cell Carcinoma
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Research sites nearby
Closest Location:
Peter MacCallum Cancer Centre
Select from list below to view details:
Peter MacCallum Cancer Centre
Melbourne, Victoria, Australia
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Who is running the clinical trial?
NRG Oncology
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
ACTIVE_COMPARATOR: Arm I (standard of care immunotherapy)
| Biological: Avelumab, Drug: Axitinib, Procedure: Biospecimen Collection, Procedure: Bone Scan, Drug: Cabozantinib, Procedure: Computed Tomography, Biological: Ipilimumab, Drug: Lenvatinib, Procedure: Magnetic Resonance Imaging, Biological: Nivolumab, Biological: Pembrolizumab |
EXPERIMENTAL: Arm II (SABR, standard of care immunotherapy)
| Biological: Avelumab, Drug: Axitinib, Procedure: Biospecimen Collection, Procedure: Bone Scan, Drug: Cabozantinib, Procedure: Computed Tomography, Biological: Ipilimumab, Drug: Lenvatinib, Procedure: Magnetic Resonance Imaging, Biological: Nivolumab, Biological: Pembrolizumab, Radiation: Stereotactic Ablative Radiotherapy |
What is the study measuring?
Primary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Nephrectomy and radiographic progression-free survival (nrPFS) | Nephrectomy and radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, nephrectomy, death, or last negative evaluation (censored). nrPFS rates are estimated using the Kaplan-Meier method. Progression is determined by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST). | From randomization to last follow-up, up to 8 years |
Secondary Outcome
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of participants with complete or partial response | Best overall response is determined by the iRECIST version 1.1. | From randomization to disease progression |
| Percentage of participants with complete or partial response in the primary renal mass | Best overall response is determined by the iRECIST version 1.1. | From randomization to disease progression |
| Radiographic progression-free survival (rPFS) | Radiographic progression-free survival time is defined as time from randomization to the date of first radiographic progression, death, or last negative evaluation (censored). rPFS rates are estimated using the Kaplan-Meier method. Radiographic progression is determined by the iRECIST version 1.1. | From randomization to last follow-up, up to 8 years |
| Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified reasons (nrPFS2) | Nephrectomy and radiographic progression-free survival time (excluding nephrectomies that were performed for non-protocol specified reasons) is defined as time from randomization to the date of first radiographic progression, nephrectomy performed for protocol-stated reasons, death, or last negative evaluation (censored). nrPFS2 rates are estimated using the Kaplan-Meier method. Progression is determined by the iRECIST version 1.1. | From randomization to last follow-up, up to 8 years |
| Overall survival | Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Overall survival rates are estimated by the Kaplan-Meier method. | From randomization to last follow-up, up to 8 years |
| Second-line therapy-free survival | Second-line therapy-free survival time is defined as time from randomization to the date of the initiation of second-line therapy, death, or last known follow-up (censored). Second-line therapy-free survival rates are estimated using the Kaplan-Meier method. | From randomization to last follow-up, up to 8 years |
| Percentage of participants who undergo cytoreductive nephrectomy | Not Specified | From randomization to last follow-up, up to 8 years |
| Treatment-free survival | Treatment-free survival time is defined as time from the discontinuation of protocol therapy to the date of death or last follow-up (censored). Treatment-free survival rates are estimated using the Kaplan-Meier method. | From randomization to last follow-up, up to 8 years |
| Percentage of participants with grade 3+ and with grade 4+ treatment-related adverse events | Common Terminology Criteria for Adverse Events 5.0 grades adverse event severity from 1=mild to 5=death. Adverse events recorded as possibly, probably, or definitely related to protocol treatment will be considered to be treatment-related. | From randomization to last follow-up, up to 8 years |
References
Clinical Trials Gov: Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI TrialOther trials to consider
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