Reported in the 2018 NEJM (378; 1277) article, the combination of checkpoint inhibitors
ipilimumab (anti-CTLA-4 antibody) and nivolumab (anti-PD-1 antibody) phase III trial
Checkmate 214 demonstrated statistically significant (P<0.0001) improvement of overall
response rate (ORR) at 42% (95% confidence interval (CI), 37-47%) compared to standard of
care (SOC) sunitinib at 27% (95% CI, 22-31%) in treatment naïve advanced or metastatic clear
cell renal cell carcinoma (ccRCC). This study also showed increased survival benefit of
Ipi+Nivo over sunitinib in the IMDC intermediate-poor risk ccRCC patients. Accordingly, the
Ipi+Nivo was just approved by U.S. FDA in April 2018 for treating metastatic ccRCC. Hence,
the investigators hypothesized that the combination of durvalumab and tremelimumab is
similarly efficacious in advanced or metastatic RCC. Furthermore, the investigators also
hypothesize that the administration of personalized neoantigen DNA vaccine will further
enhance anti-tumor immune response in RCC.
- Diagnosis of histologically confirmed metastatic/advanced (inoperable) renal cell
carcinoma with clear cell or non-clear cell histology.
- Measurable disease by RECIST 1.1
- Must have progressed on at least one but no more than two lines of targeted therapies
or have increasing incidences and intolerability of ≥ Gr.2 AE (CTCAE) toxicity from
ongoing targeted therapies. Targeted therapies that cause immediate toxicities and
result in discontinuation of treatment within 4 weeks after the start of individual
treatments are not considered as progression.
- Consented for genome sequencing and data sharing.
- Life expectancy of at least 12 weeks.
- At least 18 years of age.
- Karnofsky performance status ≥ 70%
- Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,000/mcL
- Platelets ≥ 75,000/mcL
- Hemoglobin ≥ 9.0 g/dL
- Serum bilirubin ≤ 1.5 x institutional upper limit of normal (IULN). This does not
apply to patients with confirmed Gilbert's syndrome, who will be allowed in
consultation with their physician
- AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN; for patients with hepatic metastases, ALT and
AST ≤ 4 x IULN
- Measured creatinine clearance > 40 mL/min or calculated creatinine clearance > 40
mL/min as determined by Cockcroft-Gault using actual body weight
- Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. Women will be considered post-menopausal if they have
been amenorrheic for 12 months without an alternative medical cause. The following
age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
- Women ≥50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).
- Received any immuno-oncology agents including, but not limited to, other anti CTLA-4,
including tremelimumab anti-PD-1, anti-PD-L1 including durvalumab, and anti-programmed
cell death ligand 2 (anti-PD-L2) antibodies, excluding therapeutic anticancer
vaccines. Patients with prior adjuvant or neoadjuvant treatment of targeted therapies
for RCC are eligible.
- A history of other malignancy ≤ 2 years previous with the exception of basal cell or
squamous cell carcinoma of the skin which were treated with local resection only or
carcinoma in situ of the cervix.
- Currently receiving any other investigational agents.
- Spinal cord compression or clinically active central nervous system metastasis,
defined as untreated and symptomatic, or requiring therapy with corticosteroids.
Subjects with treated brain metastasis that are no longer symptomatic may be included.
A minimum of 2 weeks must have elapsed between the end of radiation and the study
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to durvalumab, tremelimumab, vaccines, or other agents used in
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria -Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
after consultation with the Study Physician.
- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab or tremelimumab may be included only after consultation with
the Study Physician.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, or serious chronic
gastrointestinal conditions associated with diarrhea.
- Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms
calculated from 3 ECGs (within 15 minutes at 5 minutes apart).
- History of leptomeningeal carcinomatosis.
- History of syncopal or vasovagal episode as determined by medial record and history in
the 6-month period prior to first vaccination administration.
- Individuals in whom a skinfold measurement of the cutaneous and subcutaneous tissue
for eligible injection sites (left and right medial deltoid region) exceeds 40 mm.
- Individuals in whom the ability to observe possible local reactions at the eligible
injection sites (deltoid region) is, in the opinion of the investigator, unacceptably
obscured due to a physical condition or permanent body art.
- Therapeutic or traumatic metal implant in the skin or muscle of either deltoid region.
- Any current chronic or active neurologic disorder, including seizures and epilepsy,
requires active medical management.
- Current use of any electronic stimulation device, such as cardiac demand pacemakers,
automatic implantable cardiac defibrillator, nerve stimulators, or deep brain
- Major surgical procedure (as defined by the PI) within 28 days prior to the first dose
of durvalumab and tremelimumab. Note: Local surgery of isolated lesions for palliative
intent is acceptable.
- History of allogenic organ transplantation.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg)
result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies).
Patients with a past or resolved HBV infection (defined as the presence of hepatitis B
core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
- Current or prior use of immunosuppressive medication within 14 days before the first
dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
serum/urine pregnancy test within 14 days of study entry. All patients must be willing
to employ effective birth control from screening to 90 days after the last dose of
durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab
- Known HIV-positive status. These patients are ineligible because of the potential
inability to generate an immune response to vaccines.