Trial Of Stereotactic Body Radiation Therapy (SBRT) for Oligoprogression on Immune Checkpoint Inhibitors (ICI) in Metastatic Renal Cell Carcinoma

Overview

This Phase II trial will evaluate progression-free survival after Stereotactic Body Radiation Therapy to oligoprogressive (1-5) lesions in metastatic renal cell carcinoma patients on any immune checkpoint inhibitor-containing regimen with last dose of systemic therapy within 3 months prior to trial enrollment.

Description

This Phase II trial will evaluate progression-free survival after Stereotactic Body Radiation Therapy to oligoprogressive (1-5) lesions in metastatic renal cell carcinoma patients on any immune checkpoint inhibitor-containing regimen with last dose of systemic therapy within 3 months prior to trial enrollment. Alternative local therapy (including but not limited to metastectomy or radiofrequency ablation) to one or more of the oligoprogressive lesions is allowed provided at least one of the lesions is receiving Stereotactic Body Radiation Therapy. Stereotactic Body Radiation Therapy will be delivered on nonconsecutive days (if >1 fraction) for a total of 1-5 fractions depending on anatomic site at the treating physicians discretion. Treatment to multiple sites can be delivered sequentially or concurrently, at the treating physicians discretion. Patients will undergo response-assessment imaging (CT chest/abdomen/pelvis with IV contrast and/or PET CT scan and/or MRI plus or minus contrast), and response to treatment will be measured via RECIST. The acute and long-term toxicity will be monitored and graded per CTCAE 5.0 (https://ctep.cancer.gov/). Patients will continue on the same immune checkpoint inhibitor-containing regimen during Stereotactic Body Radiation Therapy planning and delivery, and after completion of Stereotactic Body Radiation Therapy until progression of disease as defined by RECIST criteria. The immune checkpoint inhibitor-containing regimen can be continued beyond RECIST progression of disease if the treating physician feels that a patient will continue to benefit. Each eligible patient will be discussed at a multidisciplinary tumor board in the presence of medical and radiation oncology and will be seen in consultation in a Yale-affiliated radiation oncology department prior to enrollment in the trial.

Eligibility

Inclusion Criteria:

• In order to be eligible for participation in this trial, the subject must:
  1. Be willing and able to provide written informed consent/assent for the trial
  2. Be ≥ 18 years of age on day of signing informed consent.
  3. Have histologically confirmed renal cell carcinoma with metastatic disease detected on imaging. Biopsy of metastasis is preferred but not required
  4. The subject has a performance status of 0, 1, or 2 on the ECOG Performance Scale
  5. The life expectancy is > 6 months
  6. The most recent systemic therapy must be an ICI-containing regimen, delivered for at least 3 months prior to development of oligoprogressive lesions, with the last dose received within 3 months of trial enrollment.
  7. Oligoprogression - defined as documented progression in up to 5 individual lesions with no previous local therapy to those sites using one of the following

     criteria

                  7.1 RECIST 1.1 7.1.1 At least a 20% increase in the sum of diameters of target
                  lesions (long axis for non-nodal lesions, short axis for nodal lesions), using
                  the previous imaging as a baseline 7.1.2 The sum of all diameters must
                  demonstrate an absolute increase of at least 5 mm 7.1.3 The appearance of at
                  least one new unequivocal lesion 7.2 PERCIST 7.2.1 SUVpeak, normalized to lean
                  body mass (SUL) increase by at least 30% and increase by at least 0.8 SUL of the
                  target lesion 7.2.2 Development of at least one new lesion 7.2.3 Increase in
                  target lesion size by 30% 7.2.4 Unequivocal progression of nontarget lesions 7.3
                  Progressive enlargement of a known metastasis on 2 consecutive imaging studies at
                  least 2 months apart with a minimum 5 mm increase in size 7.4 Development of a
                  new soft tissue metastatic lesion at least 5 mm in size or any new bone
                  metastasis
               8. There is no restriction on the total number of metastases
               9. Demonstrate adequate organ function as defined in Table 4, all screening labs
                  should be performed within 28 days of protocol treatment
              10. Female subject of childbearing potential should have a negative urine or serum
                  pregnancy within 72 hours prior to receiving the first dose of SBRT. If the urine
                  test is positive or cannot be confirmed as negative, a serum pregnancy test will
                  be required.
              11. Female subjects of childbearing must use an effective form of birth control
                  during this study. Acceptable and highly effective birth control methods include
                  intra-uterine hormone releasing system as well as other methods of birth control
                  including consistent use of an approved oral contraceptive (birth control pill),
                  an implantable contraceptive, an injectable contraceptive, a double-barrier
                  method, or true abstinence. Oral, implantable, or injectable contraceptives are
                  only considered effective if used properly and started at least 30 days prior to
                  the screening visit and continue for 120 days after last dose of study drug
                  (Reference Section 5.7)
              12. Male subjects should agree to use an adequate method of contraception starting
                  with the first dose of study therapy through 6 months after the last dose of
                  study therapy.
        Exclusion Criteria:
          -  The subject must be excluded from participating in the trial if the subject
               1. Has had radiation therapy within 2 weeks of the first protocol treatment.
               2. Is receiving TKI as part of their most recent systemic therapy regimen for their
                  mRCC.
               3. Has brain-only oligoprogression. Subjects with brain and systemic
                  oligoprogression can still be considered, however treatment of brain metastases
                  will be per standard of care prior to receiving study SBRT.
               4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or
                  any other form of immunosuppressive therapy within 2 weeks of the first protocol
                  treatment. The use of low-dose steroids for management of chronic conditions is
                  allowed (up to 12mg prednisone orally per day or the equivalent).
               5. Has had prior radiation therapy within 2 weeks of the first protocol treatment.
               6. Has a known additional malignancy that is progressing or requires active
                  treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
                  carcinoma of the skin, or in situ cervical cancer that has undergone potentially
                  curative therapy.
               7. Has an active autoimmune disease requiring systemic treatment within the past 3
                  months or a documented history of clinically severe autoimmune disease, or a
                  syndrome that requires systemic steroids or immunosuppressive agents. Subjects
                  with vitiligo or resolved childhood asthma/atopy would be an example of an
                  exception to this rule. Subjects that require intermittent use of bronchodilators
                  or local steroid injections would not be excluded from the study. Those with a
                  history of hypothyroidism who are now stable on hormone replacement will not be
                  excluded. Those with Sjorgen's syndrome will not be excluded from the study.
               8. Has a history of (non-infectious) pneumonitis that required steroids, current
                  pneumonitis or evidence of interstitial lung disease.
               9. Has an active infection requiring systemic therapy.
              10. Is pregnant or breastfeeding, or expecting to conceive or father children within
                  the projected duration of the trial, starting with the screening visit through
                  120 days after the last dose of trial treatment.
              11. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
                  [qualitative] is detected).
              12. Has received a live vaccine within 30 days prior to the first protocol treatment.
              13. Has serious medical comorbidities precluding radiotherapy. These include subjects
                  with lung metastases with interstitial lung disease, connective tissue diseases
                  such as lupus or scleroderma, Crohn's disease in subjects where the GI tract will
                  receive radiation
              14. Substantial overlap with a previously treated radiation volume. Prior
                  radiotherapy is allowed as long as the composite plan meets dose constraints