Autologous Dendritic Cell Vaccine in Kidney Cancer

The purpose of this study is to estimate the probability of immune response for the combination treatment of dendritic cell vaccine with oral cabozantinib and characterize the safety profile of interventional therapy.

Participants with newly diagnosed, non-metastatic, histologically confirmed, clear cell renal cell carcinoma (ccRCC) who have elected to undergo surgical resection, will receive neoadjuvant autologous Tumor Blood Vessel Antigen (TBVA)-Dendritic Cell Vaccine intradermally every 2 weeks x 2 (days 7(+/-3) and 21(+/-3)) prior to surgery on day 31(+7) with oral cabozantinib 20 mg daily for 10 days. We hypothesize that treated renal tumors will demonstrate maturation and organization of the tumor endothelium with normalization of endothelial markers and formation of tertiary lymphoid structure capable of promoting specific T-cell induction.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically proven clear cell renal cancer that is non-metastatic and amenable to surgical resection with no evidence of metastatic disease or lesions outside of the kidney.
2. 18 years or older (male or female) with an ECOG performance status of 0 or 1.
3. Have serotype HLA-A2+ if receiving vaccine.
4. Capable of understanding and complying with the protocol requirements and have signed the informed consent document.
5. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:

   1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony- stimulating factor support.
   2. White blood cell count ≥ 2500/µL.
   3. Platelets ≥ 100,000/µL without transfusion.
   4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
   5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3x upper limit of normal (ULN). ALP ≤ 5x ULN with documented bone metastases.
   6. Total bilirubin ≤ 1.5x ULN (for subjects with Gilbert's disease ≤ 3x ULN).
   7. Serum albumin ≥ 2.8 g/dl
   8. (PT)/INR or partial thromboplastin time (PTT) test \< 1.3x the laboratory ULN
   9. Serum creatinine ≤ 2.0 ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation: Males: (140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72) Females: \[(140 - age) x weight (kg)/(serum creatinine \[mg/dL\] × 72)\] × 0.85
   10. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1
6. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study treatment.
7. Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria are met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes. In addition, females \< 55 years-of-age must have a serum follicle stimulating (FSH) level \> 40 mIU/mL to confirm menopause). Note: Documentation may include review of medical records, medical examinations, or medical history interview by study site.

Exclusion Criteria:

1. Current (within the preceding 6 weeks) treatment with systemic immunosuppressive agents including steroids except when they are administered as replacement therapy for endocrine dysfunction and do not exceed 10 mg prednisone or equivalent daily.
2. Known or suspected metastatic disease.
3. Active Hepatitis B or Hepatitis C infection or any other active infection requiring intravenous therapy.
4. Blood transfusion within two weeks prior to leukapheresis.
5. Prior treatment with cabozantinib.
6. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within two weeks before first dose of study treatment.
7. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within four weeks before first dose of study treatment.
8. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
9. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

   1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
   2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
10. Prothrombin time (PT/INR) or partial thromboplastin time (PTT) test ≥ 1.3 X the laboratory ULN within 7 days before the first dose of study treatment.
11. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.

    ii. Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment.

    iii. Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose of study treatment.
    1. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #6) for at least 1 week before first dose of study treatment.
    2. Gastrointestinal disorders:

    i. The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction.

    ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment.

    iii. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.
12. Clinically significant hematuria, hematemesis, or hemoptysis of \> 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first dose of study treatment.
13. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation.
14. Lesions invading or encasing any major blood vessels.
15. Other clinically significant disorders that would preclude safe study participation.

    1. Serious non-healing wound/ulcer/bone fracture.
    2. Uncompensated/symptomatic hypothyroidism.
    3. Moderate to severe hepatic impairment (Child-Pugh B or C).
16. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain metastasis) within 2 weeks before first dose of study treatment. Minor surgeries within 10 days before first dose of study treatment. Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
17. Corrected QT interval calculated by the Fridericia formula (QTcF) \> 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment \[add reference for Fridericia formula\].

    Note: If a single ECG shows a QTcF with an absolute value \> 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility.
18. Pregnant or lactating females.
19. Inability to swallow tablets.
20. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
21. Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
22. Any other conditions considered as unacceptable risk by the treating physician.