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

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.

• Avelumab (Biological), also known as Bavencio, MSB 0010718C, MSB-0010718C, MSB0010718C: Given IV
• Axitinib (Drug), also known as AG 013736, AG-013736, AG013736, Inlyta: Given PO
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Specimen Collection: Undergo collection of blood
• Bone Scan (Procedure), also known as Bone Scintigraphy: Undergo bone scan
• Cabozantinib (Drug): Given PO
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography: Undergo CT
• Ipilimumab (Biological), also known as Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016, Ipilimumab Biosimilar CS1002, MDX 010, MDX-010, MDX-CTLA4, MDX010, Yervoy: Given IV
• Lenvatinib (Drug), also known as E 7080, E-7080, E7080, ER-203492-00, Multi-Kinase Inhibitor E7080: Given PO
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Nivolumab (Biological), also known as ABP 206, BCD-263, BMS 936558, BMS-936558, BMS936558, CMAB819, MDX 1106, MDX-1106, MDX1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar BCD-263, Nivolumab Biosimilar CMAB819, ONO 4538, ONO-4538, ONO4538, Opdivo: Given IV
• Pembrolizumab (Biological), also known as BCD-201, GME 751, GME751, Keytruda, Lambrolizumab, MK 3475, MK-3475, MK3475, Pembrolizumab Biosimilar BCD-201, Pembrolizumab Biosimilar GME751, Pembrolizumab Biosimilar QL2107, Pembrolizumab Biosimilar RPH-075, Pembrolizumab Biosimilar SB27, QL2107, RPH 075, RPH-075, RPH075, SB 27, SB-27, SB27, SCH 900475, SCH-900475, SCH900475: Given IV
• Stereotactic Ablative Radiotherapy (Radiation), also known as SABER, SABR/SBRT: 42 Gy in 3 fractions

Primary outcomes

• Nephrectomy and radiographic progression-free survival (nrPFS) [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 outcomes

• Percentage of participants with complete or partial response [From randomization to disease progression]: Best overall response is determined by the iRECIST version 1.1.
• Percentage of participants with complete or partial response in the primary renal mass [From randomization to disease progression]: Best overall response is determined by the iRECIST version 1.1.
• Radiographic progression-free survival (rPFS) [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 iRECIST version 1.1.
• Nephrectomy and radiographic progression-free survival excluding nephrectomies that were performed for non-protocol specified reasons (nrPFS2) [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 iRECIST version 1.1.
• Overall survival [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.
• Second-line therapy-free survival [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.
• Percentage of participants who undergo cytoreductive nephrectomy [From randomization to last follow-up, up to 8 years]
• Treatment-free survival [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.
• Percentage of participants with grade 3+ and with grade 4+ treatment-related adverse events [From randomization to last follow-up, up to 8 years]: 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.

Other outcomes

• nrPFS and overall survival [From randomization to last follow-up, up to 8 years]: Exploratory analyses will compare nrPFS and overall survival in four pre-defined subgroups: clear cell versus (vs.) non-clear cell histology, intermediate vs. poor International Metastatic RCC database consortium risk group, treatment with immuno-oncology (IO)-IO vs. IO-vascular endothelial growth factor, and sarcomatoid vs. non sarcomatoid variant. Forest plots will be constructed showing estimated hazard ratios from Cox models and 90% confidence intervals generated within each subgroup. Treatment-by-subgroup interaction terms will be incorporated into the Cox modelling to assess whether the effect of stereotactic ablative radiotherapy (SABR) varies significantly by subgroup; however, these analyses will be considered hypothesis-generating only.
• Prognostic and predictive biomarkers [From randomization to last follow-up, up to 8 years]: Will be accomplished by including the biomarkers in Cox time-to-event regression models for the evaluation of prognostic factors. Treatment-by-biomarker interaction terms will be incorporated into the modelling process to assess for potential predictive markers.
• Abscopal effect of SABR with systemic therapy [From randomization to disease progression]: These analyses will include only patients in the control arm who have not received any palliative radiation therapy and those in the experimental arm who have received protocol defined stereotactic body radiation therapy only without additional radiation therapy. Response rates among lesions outside the renal mass will be determined based in iRECIST criteria and compared using a chi-square test.
• Impact of treatment on the level of inferior vena cava (IVC) thrombus [From randomization to last follow-up, up to 8 years]: Will be assessed by comparing the rates of IVC thromboembolism using Fisher's exact test. Cumulative incidence curves with death as a competing risk will also be generated and compared using the Fine-Gray test.
• Accuracy of accruing center radiologist defined progression as compared with central radiology defined progression [From randomization to last follow-up, up to 8 years]: This will take place at the conclusion of the trial by our diagnostic radiologists. Will determine the number and proportion of center radiologist defined progressions (confirmed per iRECIST) that are validated/not validated upon central review. Will also examine all center radiologist defined pseudo progressions (i.e., not confirmed per iRECIST) and determine the number that are also declared pseudo progressions upon central review.

Sex: All, ages: 18 Years to any

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

228 more sites not listed.

• William A Hall, Principal investigator, NRG Oncology

NIH grants: U10CA180868