- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03189186
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
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:
- 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).
- One or more optional biopsies at day 53, day 106 and day 169 after cryoablation.
- 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.
- 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.
Study Type
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
California
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Orange, California, United States, 92868
- UC Irvine Health Department of Urology
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Be willing and able to provide written informed consent/assent for the trial.
- Be >18 years of age on day of signing informed consent.
- Have measurable disease based on RECIST 1.1.
- 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.
- Have a performance status of 0 or 1 on the ECOG Performance Scale.
- Demonstrate adequate organ function as defined in days of treatment initiation.
- All screening labs should be performed within 10 days of treatment initiation.
- 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.
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.
- 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:
- 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.
- 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.
- Has a known history of active TB (Bacillus Tuberculosis)
- Hypersensitivity to pembrolizumab or any of its excipients.
- 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.
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.
- 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.
- 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.
- 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.
- Has known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- 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.
- Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- 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.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Pembrolizumab
Advanced (stage II and above with multiple tumors or vena cava) and metastatic Renal Cell Carcinoma will be first treated with cryoablation on a large primary tumor and then given 200 mg pembrolizumab every 3-week for 3 cycles, followed by cytoreductive or partial/radical nephrectomy.
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 a complete tumor remission, disease progression, unacceptable toxicity, subject refusal, or subject death due to any cause.
|
Same as arm description
Other Names:
Cryoablation uses liquid argon in metal needles to freeze tumors.
Tumor cells are ruptured due to the forming ice crystals and die.
Cryoablation is standardly used in tumors less then 4cm in diameter.
Nephrectomy is the surgical excision of either the entire kidney or a small portion of the kidney.
Nephrectomy is standardly used to treat renal cell cancer.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Overall Response Rate
Time Frame: 24 weeks after cryoablation
|
Tumor responses to pembrolizumab and cryoablation combination followed by partial, radical or cytoreductive nephrectomy on secondary lesions.
The tumor responses will be defined by CT images according to RECIST version 1.1.,
and reviewed by an experienced oncologist.
The primary endpoint will be percentage of patients who achieve a best ORR, including both partial and complete responses.
|
24 weeks after cryoablation
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Progression-free Survival
Time Frame: Follow-up will be for 24 months
|
PFS is defined as time from cryoablation initiation to time of first documented disease progression or death due to any cause.
|
Follow-up will be for 24 months
|
Overall Survival
Time Frame: Follow-up will be for 24 months
|
OS is time from cryoablation to death due to any cause.
OS will be assessed at standard clinic visits.
|
Follow-up will be for 24 months
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Jaime Landman, MD, UC Irvie Department of Urology
Publications and helpful links
General Publications
- Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, Dronca R, Gangadhar TC, Patnaik A, Zarour H, Joshua AM, Gergich K, Elassaiss-Schaap J, Algazi A, Mateus C, Boasberg P, Tumeh PC, Chmielowski B, Ebbinghaus SW, Li XN, Kang SP, Ribas A. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44. doi: 10.1056/NEJMoa1305133. Epub 2013 Jun 2. Erratum In: N Engl J Med. 2018 Nov 29;379(22):2185.
- Hruby GW, Fine JK, Landman J. Ultrasound-guided percutaneous ablation of a renal mass in a renal allograft. Urology. 2006 Oct;68(4):891.e5-6. doi: 10.1016/j.urology.2006.05.019.
- Ames CD, Vanlangendonck R, Venkatesh R, Gonzales FC, Quayle S, Yan Y, Humphrey PA, Landman J. Enhanced renal parenchymal cryoablation with novel 17-gauge cryoprobes. Urology. 2004 Jul;64(1):173-5. doi: 10.1016/j.urology.2004.02.033.
- Okhunov Z, Juncal S, Ordon M, George AK, Lusch A, del Junco M, Nguyentat M, Lobko II, Kavoussi L, Landman J. Comparison of outcomes in patients undergoing percutaneous renal cryoablation with sedation vs general anesthesia. Urology. 2015 Jan;85(1):130-4. doi: 10.1016/j.urology.2014.09.013. Epub 2014 Nov 14.
- Lusch A, Graversen JA, Liss MA, Landman J. Ablative techniques: Radiofrequency and cryotherapy, which is the best? Arch Esp Urol. 2013 Jan-Feb;66(1):71-8.
- Waitz R, Solomon SB, Petre EN, Trumble AE, Fasso M, Norton L, Allison JP. Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 2012 Jan 15;72(2):430-9. doi: 10.1158/0008-5472.CAN-11-1782. Epub 2011 Nov 22.
- Zeng Z, Shi F, Zhou L, Zhang MN, Chen Y, Chang XJ, Lu YY, Bai WL, Qu JH, Wang CP, Wang H, Lou M, Wang FS, Lv JY, Yang YP. Upregulation of circulating PD-L1/PD-1 is associated with poor post-cryoablation prognosis in patients with HBV-related hepatocellular carcinoma. PLoS One. 2011;6(9):e23621. doi: 10.1371/journal.pone.0023621. Epub 2011 Sep 1.
- Massari F, Santoni M, Ciccarese C, Santini D, Alfieri S, Martignoni G, Brunelli M, Piva F, Berardi R, Montironi R, Porta C, Cascinu S, Tortora G. PD-1 blockade therapy in renal cell carcinoma: current studies and future promises. Cancer Treat Rev. 2015 Feb;41(2):114-21. doi: 10.1016/j.ctrv.2014.12.013. Epub 2015 Jan 6.
- Zeelenberg IS, van Maren WW, Boissonnas A, Van Hout-Kuijer MA, Den Brok MH, Wagenaars JA, van der Schaaf A, Jansen EJ, Amigorena S, Thery C, Figdor CG, Adema GJ. Antigen localization controls T cell-mediated tumor immunity. J Immunol. 2011 Aug 1;187(3):1281-8. doi: 10.4049/jimmunol.1003905. Epub 2011 Jun 24.
- Keerthikumar S, Gangoda L, Liem M, Fonseka P, Atukorala I, Ozcitti C, Mechler A, Adda CG, Ang CS, Mathivanan S. Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes. Oncotarget. 2015 Jun 20;6(17):15375-96. doi: 10.18632/oncotarget.3801.
Study record dates
Study Major Dates
Study Start (ACTUAL)
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ACTUAL)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Urologic Neoplasms
- Urogenital Neoplasms
- Neoplasms by Site
- Kidney Diseases
- Urologic Diseases
- Adenocarcinoma
- Neoplasms, Glandular and Epithelial
- Kidney Neoplasms
- Carcinoma, Renal Cell
- Carcinoma
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Pembrolizumab
Other Study ID Numbers
- 2016-2961
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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