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Testing the Addition of Stereotactic Radiation Therapy With Immune Therapy for the Treatment of Patients With Unresectable or Metastatic Renal Cell Cancer, SAMURAI Study (SAMURAI)

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ClinicalTrials.gov Identifier: NCT05327686
Recruitment Status : Recruiting
First Posted : April 14, 2022
Last Update Posted : August 1, 2022
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Brief Summary:
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 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.

Condition or disease Intervention/treatment Phase
Metastatic Renal Cell Carcinoma Stage III Renal Cell Cancer AJCC v8 Stage IV Renal Cell Cancer AJCC v8 Unresectable Renal Cell Carcinoma Biological: Avelumab Drug: Axitinib Drug: Cabozantinib Biological: Ipilimumab Drug: Lenvatinib Biological: Nivolumab Biological: Pembrolizumab Radiation: Stereotactic Ablative Radiotherapy Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 240 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Stereotactic Ablative Radiation Therapy (SABR) for Metastatic Unresected Renal Cell Carcinoma (RCC) Receiving Immunotherapy (SAMURAI)
Actual Study Start Date : June 30, 2022
Estimated Primary Completion Date : June 15, 2028
Estimated Study Completion Date : June 15, 2032


Arm Intervention/treatment
Active Comparator: Arm I (standard of care immunotherapy)
Patients receive one of the following immunotherapy regimens per physician discretion: nivolumab 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 PO 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 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.
Biological: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Axitinib
Given PO
Other Names:
  • AG-013736
  • AG013736
  • Inlyta

Drug: Cabozantinib
Given PO

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Drug: Lenvatinib
Given PO
Other Names:
  • E7080
  • ER-203492-00
  • Multi-Kinase Inhibitor E7080

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Experimental: Arm II (SABR, standard of care immunotherapy)
Patients undergo SABR on 3 different days over 1-3 weeks and receive immunotherapy as in Arm I.
Biological: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Axitinib
Given PO
Other Names:
  • AG-013736
  • AG013736
  • Inlyta

Drug: Cabozantinib
Given PO

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • Ipilimumab Biosimilar CS1002
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Drug: Lenvatinib
Given PO
Other Names:
  • E7080
  • ER-203492-00
  • Multi-Kinase Inhibitor E7080

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • CMAB819
  • MDX-1106
  • NIVO
  • Nivolumab Biosimilar CMAB819
  • ONO-4538
  • Opdivo

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Radiation: Stereotactic Ablative Radiotherapy
42 Gy in 3 fractions
Other Names:
  • SABER
  • SABR, SBRT
  • Stereotactic Ablative Radiation Therapy




Primary Outcome Measures :
  1. Nephrectomy and radiographic progression-free survival (nrPFS) [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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).


Secondary Outcome Measures :
  1. Percentage of participants with complete or partial response [ Time Frame: From randomization to last follow-up, up to 8 years ]
    Best overall response is determined by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).

  2. Percentage of participants with complete or partial response in the primary renal mass [ Time Frame: From randomization to last follow-up, up to 8 years ]
    Best overall response is determined by the Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).

  3. Radiographic progression-free survival (rPFS) [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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 Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).

  4. Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified reasons (nrPFS2) [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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 Response Evaluation Criteria in Solid Tumors version 1.1 criteria modified for immunotherapy trials (iRECIST).

  5. Overall survival [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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.

  6. Second-line therapy-free survival [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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.

  7. Percentage of participants who undergo cytoreductive nephrectomy [ Time Frame: From randomization to last follow-up, up to 8 years ]
  8. Treatment-free survival [ Time Frame: From randomization to last follow-up, up to 8 years ]
    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.

  9. Percentage of participants with grade 3+ and with grade 4+ treatment-related adverse events [ Time Frame: From randomization to last follow-up, up to 8 years ]
    Common Terminology Criteria for Adverse Events (CTCAE) 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 8 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)

    • 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 prior systemic therapy for metastatic renal cell carcinoma (RCC) 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 < 45 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05327686


Locations
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United States, Illinois
Carle on Vermilion Recruiting
Danville, Illinois, United States, 61832
Contact: Daniel Barnett, MD    217-383-3273    daniel.barnett@carle.com   
Principal Investigator: Daniel Barnett, MD         
Carle Physician Group-Effingham Recruiting
Effingham, Illinois, United States, 62401
Contact: Daniel Barnett, MD    217-383-3273    daniel.barnett@carle.com   
Principal Investigator: Daniel Barnett, MD         
Carle Physician Group-Mattoon/Charleston Recruiting
Mattoon, Illinois, United States, 61938
Contact: Daniel Barnett, MD    217-383-3273    daniel.barnett@carle.com   
Principal Investigator: Daniel Barnett, MD         
Carle Cancer Institute Recruiting
Urbana, Illinois, United States, 61801
Contact: Daniel Barnett, MD    217-383-3273    daniel.barnett@carle.com   
Principal Investigator: Daniel Barnett, MD         
The Carle Foundation Hospital Recruiting
Urbana, Illinois, United States, 61801
Contact: Daniel Barnett, MD    217-383-3273    daniel.barnett@carle.com   
Principal Investigator: Daniel Barnett, MD         
Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
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Principal Investigator: William A Hall NRG Oncology
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Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT05327686    
Other Study ID Numbers: NRG-GU012
NCI-2022-02189 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-GU012 ( Other Identifier: NRG Oncology )
NRG-GU012 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: April 14, 2022    Key Record Dates
Last Update Posted: August 1, 2022
Last Verified: July 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Pembrolizumab
Nivolumab
Ipilimumab
Avelumab
Lenvatinib
Axitinib
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs