Phase-I Trial of Pembrolizumab and Percutaneous Cryoablation Combination Followed by Nephron-Sparing Surgery or Cytoreductive Nephrectomy in Locally Advanced and Metastatic Renal Cell Carcinomas

Followed by Nephron-Sparing Surgery or Cytoreductive Nephrectomy in Locally Advanced and Metastatic Renal Cell Carcinomas

Patients will undergo a screening process as per standard of care to identify disease type and severity. Careful history and physical examination will also take place to rule out major heart, lung, or kidney disease and pregnancy that may affect how they will respond to the treatment. Patients with advanced (stage II and above with multiple tumors or tumors within vessels) and metastatic Renal Cell Carcinoma will be first treated with cryoablation on a large primary tumor and then given 200 mg pembrolizumab every 3-weeks 3 cycles , followed by partial/radical nephrectomy. Pembrolizumab is a biologic drug that adheres to the cell death receptors on white blood cells preventing there death and leading to an increased immunologic response. Cryoablation will be used in these patients to initially trigger and immune response to cancerous cells that is then magnified by the drug. After the surgery, patients will resume pembrolizumab for additional 5 cycles or up to a total of 2 years if a partial response is observed at the discretion of the treating medical oncologist or urologist until complete tumor remission, disease progression, unacceptable toxicity, patient refusal, or patient death due to any cause.

Baseline procedures:

Each patient will undergo a careful history and physical examination to rule out major cardiac, pulmonary or renal disease. All subjects will undergo:

1. Baseline biopsy of a secondary tumor or a metastatic tumor at the time of cryoablation. Tumor specimens will also be collected during surgery (cytoreductive, partial or total nephrectomy).
2. One or more optional biopsies at day 53, day 106 and day 169 after cryoablation.
3. Blood samples: will be collected at baseline before or at time of cryoablation, at the end of the second cycle of pembrolizumab treatment and during surgery (cytoreductive, partial or total nephrectomy) for evaluation of biomarkers and pharmacokinetic analyses.
4. Complete radiologic assessment in the form of CT scan at baseline and a CT scan after the third cycle of pembrolizumab followed by routine imaging every 6 weeks as is consistent with the standard of care for mRCC. 5. Routine laboratory analysis: basic metabolic panel (BMP), liver function panel (LFTs) and complete blood count (CBC), will be collected prior to each cycle of pembrolizumab administration and at the time of cryoablation and cytoreductive or partial/total nephrectomy.

Cryoablation:

Patients will be asked to have nothing by mouth during at least 8 hours prior to ablation. Patients will only be taken for cryoablation if INR is <1.5, PTT is within normal limits and platelet count is greater than 50,000/microL. Preoperative imaging, namely contrast enhanced CT scan, will be used to assess the tumor proximity to local structures. Number of cryoprobes utilized will be determined by the size, geometry, and morphology of the primary tumor. CT guidance will be used to place the cryoprobes 1 to 1.5 cm apart.

Two 10 minute freeze cycles with an intervening 8 minute thawing period will be used in accordance with data indicating improved efficacy with the double-freeze thaw cycle. The size of the iceball created will be consistent with a tumor-free margin of at least 5-10 mm. CT scans at 3-4 minute intervals will be used to assure adequate margins.

Pembrolizumab:

Pembrolizumab treatment will begin 1 day following cryoablative treatment and will continue until a complete tumor remission, disease progression, unacceptable toxicity, subject refusal, or subject death due to any cause.

Surgery After 3 cycles (9 weeks) of pembrolizumab therapy, patients will undergo partial/ radical or cytoreductive nephrectomy of the primary renal tumor.

Duration of follow-up Subjects will be followed for a total of 24 months. Subjects removed from treatment due to unacceptable adverse events will be followed until resolution or stabilization of adverse event. Follow up will be every 8 weeks (+2 weeks) from study registration with imaging studies and physical exam every 8 weeks for the first 8 months, then every 12 weeks (+ 2 weeks) until 24 months.

Inclusion Criteria:

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 measurable disease based on RECIST 1.1.

4. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.

5. Have a performance status of 0 or 1 on the ECOG Performance Scale.

6. Demonstrate adequate organ function as defined in days of treatment initiation.

7. All screening labs should be performed within 10 days of treatment initiation.

8. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.

   Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

10. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.

2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.

3. Has a known history of active TB (Bacillus Tuberculosis)

4. Hypersensitivity to pembrolizumab or any of its excipients.

5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.

6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   • Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.

8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.

9. Has active autoimmune disease that has required systemic treatment in the past 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.

10. Has known history of, or any evidence of active, non-infectious pneumonitis.

11. Has an active infection requiring systemic therapy.

12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.