PolyImmune {Durvalumab (MEDI4736) and Tremelimumab} & Vaccine Orchestrated Treatment for Patients With Advanced/Metastatic Renal Cell Carcinoma

NCT03598816 | Withdrawn Phase 2 DMC FDA Drug FDA Device

• 1 other identifier: 202003083
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (1)

• Safety of the combination of durvalumab & tremelimumab with or without neoantigen DNA vaccine when given to patients with renal cell carcinoma as measured by the percentage of patients with adverse events of grade 3 or higher

  * As graded by the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 * Only adverse events that are possibly, likely, or probably related to the drug or drug combinations

  Completion of cycle 1 (4 weeks)

Secondary Outcomes (3)

• Response rate in patients with renal cell carcinoma treated with durvalumab and tremelimumab with or without neoantigen DNA vaccine by RECIST 1.1 as measured by percentage of patients with radiographic complete response or partial response

  Through completion of treatment (estimated to be 32-36 weeks)

• Rate of progression-free survival (PFS) in patients with renal cell carcinoma treated with durvalumab and tremelimumab with or without neoantigen DNA vaccine

  Through 6 months after completion of treatment (estimated to be 15 months)

• Rate of overall survival (OS) in patients with renal cell carcinoma treated with durvalumab and tremelimumab with or without neoantigen DNA vaccine

  Through 6 months after completion of treatment (estimated to be 15 months)

Study Arms (2)

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine

EXPERIMENTAL

* All patients will receive durvalumab intravenous (IV) at a dose of 10 mg/kg over the course of 60 minutes given every 2 weeks (on Days 1 and 15 of each 28-day cycle) for a total of 8 doses. Durvalumab will be given thereafter as monotherapy at a dose of 209 mg/kg over the course of 60 minutes given every 4 weeks (on Day 1 of each 28-day cycle) for a total of 4 doses * All patients will receive tremelimumab at a dose of 1 mg/kg over the course of 60 minutes given every 4 weeks (on Day 1 of each 28-day cycle) for a total of 4 cycles * The first vaccination will take place two weeks after confirmed disease progression on targeted therapy. This will be Day 1 of the first 28-day cycle of treatment with durvalumab and tremelimumab * The schedule of vaccination is Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, and Cycle 5 Day 1 (for a total of 6 doses)

Drug: Durvalumab; Drug: Tremelimumab; Device: TDS-IM v1.0 System; Biological: Neoantigen DNA Vaccine; Procedure: Research blood draw

Arm 2: Durvalumab + Tremelimumab

EXPERIMENTAL

* All patients will receive durvalumab IV at a dose of 10 mg/kg over the course of 60 minutes given every 2 weeks (on Days 1 and 15 of each 28-day cycle) for a total of 8 doses. Durvalumab will be given thereafter as monotherapy at a dose of 209 mg/kg over the course of 60 minutes given every 4 weeks (on Day 1 of each 28-day cycle) for a total of 4 doses * All patients will receive tremelimumab at a dose of 1 mg/kg over the course of 60 minutes given every 4 weeks (on Day 1 of each 28-day cycle) for a total of 4 cycles.

Drug: Durvalumab; Drug: Tremelimumab; Procedure: Research blood draw

Interventions

Durvalumab DRUG

-Durvalumab infusion will start approximately 1 hour (maximum 2 hours) after the end of the tremelimumab infusion

Also known as: Imfinzi, MEDI4736

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine; Arm 2: Durvalumab + Tremelimumab

Tremelimumab DRUG

-Tremelimumab will be administered first

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine; Arm 2: Durvalumab + Tremelimumab

TDS-IM v1.0 System DEVICE

-Integrated electroporation device

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine

Neoantigen DNA Vaccine BIOLOGICAL

-At each vaccination time point, patients will receive two injections of the neoantigen DNA vaccine, one injection into each deltoid or lateralis.

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine

Research blood draw PROCEDURE

-Baseline, C2D1, C3D1, C5D1, C7D1, and C9D1

Arm 1: Durvalumab + Tremelimumab + Neoantigen DNA Vaccine; Arm 2: Durvalumab + Tremelimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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 enrollment.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to durvalumab, tremelimumab, vaccines, or other agents used in the study.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study treatment.
• 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.

Sponsors & Collaborators

• Washington University School of Medicine: lead
• MedImmune LLC: collaborator

Related Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

durvalumab; tremelimumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• James J Hsieh, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2018
• First Posted: July 26, 2018
• Study Start: August 31, 2020
• Primary Completion: December 31, 2022
• Study Completion: May 31, 2024
• Last Updated: August 13, 2020

Record last verified: 2020-08

Data Sharing

• IPD Sharing: Will not share