Renal Cell Carcinoma
Conditions
Keywords
Cancer, Renal cell carcinoma, Clear cell renal cell carcinoma
Brief summary
This is a Phase 1b/2a, open-label, multi-center, dose-escalation and safety/efficacy evaluation trial of Pexa-Vec plus Cemiplimab in patients with metastatic or unresectable renal cell carcinoma (RCC). The trial consists of a dose-escalation stage, where the maximum feasible dose of Pexa-Vec in combination with Cemiplimab will be determined, followed by an expansion stage. During the expansion patients will receive Cemiplimab alone or in combination with Pexa-Vec, which will be administered either through intravenous (IV) or intratumoral (IT) injection.
Detailed description
For Pexa-Vec IV infusions (Part 1 / Part 2: Arm C and Arm D): Day -7, 1, 8, and 15), patients allocated to Part 1 or Part 2: Arm C or Arm D will receive an IV infusion of Pexa-Vec in approximately 250 mL buffered saline. For Pexa-Vec IT Injections (Part 2 Arm A + Arm B), patients in Part 2, Arm A (and those in Arm B who progress on Cemiplimab monotherapy) will receive an IT injection of Pexa-Vec in a volume of buffered saline dependent on size of tumor(s). For administration of Cemiplimab, Cemiplimab will be administered at a dose of 350 mg IV infusion over 30 minutes (±10 minutes) every 3 weeks per manufactures guidelines.
Interventions
BIOLOGICALPexastimogene Devacirepvec (Pexa-Vec)
Pexa-Vec is a vaccinia virus based oncolytic immunotherapy designed to stimulate the immune system following infection and replication within tumor cells
BIOLOGICALCemiplimab
Cemiplimab is a monoclonal antibody to Programmed Death-1 (PD-1)
Sponsors
SillaJen, Inc.
Regeneron Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed metastatic or unresectable clear cell renal cell carcinoma (ccRCC) * Part 2 Arm D ONLY: Patients must be refractory to anti PD-1 or anti-PD-L1 (either as monotherapy or in-combination with other approved checkpoint inhibitors or targeted therapies according to their approved label) and patients must meet all of the following criteria: 1. Received treatment of approved anti PD-1 or anti-PD-L1 (dosed per label of the country providing the clinical site) for at least 6 weeks. History of anti-PD-L1 only is not allowed. 2. Progressive disease after anti PD-1 or anti-PD-L1 will be defined according to RECIST v1.1. The initial evidence of progressive disease is to be confirmed by a second assessment, no less than 4 weeks from the date of the first documented progressive disease, in the absence of rapid clinical progression. (This determination is made by the Investigator; the Sponsor will collect imaging scans for retrospective analysis. Once progressive disease is confirmed, the initial date of progressive disease documentation will be considered the date of disease progression). 3. Documented disease progression within 12 weeks of the last dose of anti PD-1 or anti-PD-L1. Patients who were re-treated or on maintenance with anti-PD-1 or anti-PD-L1 will be allowed to enter the study as long as there is documented progressive disease within 12 weeks of the last treatment date. * Naive to systemic therapy for RCC or have progressed after, or were intolerant of, prior systemic therapy. * Measurable disease based on RECIST v1.1 criteria. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions * Karnofsky performance status of 70-100 * Age ≥20 years old (or appropriate age of consent for the region) * Adequate hematological, hepatic, and renal function
Exclusion criteria
* Known significant immunodeficiency due to underlying illness (e.g., human immunodeficiency virus \[HIV\] / acquired immune deficiency syndrome \[AIDS\]) and/or immune-suppressive medication including high-dose corticosteroids * Part 2 only: Arm A,B,C: Prior treatment with any anti-cancer immunotherapy, including therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (prior IL-2 or interferon allowed) . For Part 1: patients are excluded if they were intolerant to anti-PD-1 or anti-PD-L1 targeted therapies * Major surgery within 4 weeks of study treatment (minor surgical procedures are allowed) * Ongoing severe inflammatory skin condition requiring prior medical treatment * History of eczema requiring prior medical treatment * Tumor(s) invading a major vascular structure (e.g., carotid artery) or other key anatomical structure (e.g., pulmonary airway) OR viable central nervous system malignancy * Clinically significant and/or rapidly accumulating ascites, pericardial and/or pleural effusions. * Symptomatic cardiovascular disease, including but not limited to significant coronary artery disease (e.g., requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months. * Asymptomatic cardiovascular disease (current or past history) unless cardiology consultation and clearance has been obtained for study participation. * Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all Pexa-Vec treatments * Use of interferon/pegylated interferon (PEG-IFN) or ribavirin that cannot be discontinued within 14 days prior to any Pexa-Vec dose * Known active Hepatitis B or Hepatitis C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With Adverse Events From Pexa-Vec Administered by IV Infusions or IT Injections in Combination With IV Cemiplimab | Through study completion without survival follow-up period, an average of 1 year | Safety will be determined by assessing the incidence, severity, and frequency of all treatment-emergent adverse events (TEAEs), Grade 3 or greater AEs, serious adverse events (SAEs), laboratory toxicity, AEs requiring discontinuation of study agent(s), and deaths. The severity of all adverse events and laboratory abnormalities is assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. Safety is monitored from the first dose throughout the treatment period (up to a maximum of 1 year) and up to 28 days after the last dose of study treatment. |
| Overall Response Rate | Every 9 weeks until documented progression or discontinuation beyond documented progression. After 1 year, every 12 weeks from EOT visit, up to 36 months. | Overall response rate (ORR) is defined as the proportion of patients whose best overall responses either complete response (CR) or partial response (PR). The best overall response is the best response recorded from the randomization until disease progression. Proportions of patients with a best overall response of CR, disappearance of all target tumors; or PR, at least 30% decrease in the sum of longest diameter of target tumors will be presented by treatment arm along with exact 95% CIs. Analyses will be performed based on central assessments using RECIST v1.1. |
| Number of Participants With Dose Limiting Toxicities of Pexa-Vec Administered by IV Infusions in Combination With Cemiplimab (Part 1 Only) | The 29-day cycle of therapy | Dose-limiting toxicity (DLT) was assessed to determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) of Pexa-Vec. Patients were observed for DLTs during the IV treatment phase through Day 29. DLTs are evaluated based on the severity and frequency of adverse events and laboratory abnormalities using NCI CTCAE Version 5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Every 9 weeks until documented progression or discontinuation beyond documented progression. After 1 year, every 12 weeks from EOT visit, up to 36 months | Defined as the date of the first study treatment to the date of first documented radiographic tumor progression or death due to any cause, whichever occurs first (RECIST v1.1). Progression free survival will be presented descriptively using Kaplan-Meier curves. Summary statistics from the Kaplan-Meier distributions will be determined, including median PFS and 25% and 75% quartiles with corresponding 95% CIs. The proportions of patients. |
| Disease Control Rate | Every 9 weeks until documented progression or discontinuation beyond documented progression. After 1 year, every 12 weeks from EOT visit, up to 36 months | Defined as the proportion of patients whose best overall response is either complete response (CR), partial response (PR), or stable disease (SD). (RECIST v1.1) |
| Overall Survival | Every 9 weeks until documented progression or discontinuation beyond documented progression. After 1 year, every 12 weeks from EOT visit, up to 36 months | Overall survival is defined as the time from first study treatment until death from any cause. For patients not known to have died at the time of the analysis, overall survival will be censored on the date they were last known to be alive. If a patient withdraws early, overall survival will not be censored at the date of withdrawal unless this is the date they were last known to be alive. Date of death will be obtained from the death certificate (preferable) or from a written statement from the primary care or attending physician, or from death registry data. Additionally, for censored date, the latest date of (in the following order): End of Treatment visit(EOT) / Last Radiologic Timepoint(LastRTP) / End of Study(EOS) / Last Drug Date(D.LastDrug) / before cutoff date(2023-02-16) is the censored date. |
Countries
Australia, South Korea, United States
Contacts
STUDY_DIRECTORSillaJen Inc.
SillaJen, Inc.
Participant flow
Recruitment details
Patients with histologically or cytologically confirmed metastatic or unresectable clear cell Renal Cell Carcinoma (RCC) were recruited for this study. The recruitment took place at 17 study centers across the United States, South Korea, and Australia. The first patient was enrolled on June 19, 2018, and the last patient completed the study on February 16, 2023. It was noted that there were some recruitment limitations due to intratumoral injection constraints.
Pre-assignment details
A total of 141 patients were screened for eligibility prior to group assignment, which included 8 patients for Part 1 and 133 patients for Part 2. Of these, 46 patients failed the screening process (2 patients in Part 1 and 44 patients in Part 2). Consequently, a total of 95 eligible patients were enrolled and assigned to the study groups (6 patients in Part 1 and 89 patients in Part 2).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 66 Participants |
| Age, Continuous | 60.3 years STANDARD_DEVIATION 8.53 |
| Baseline Tumor Size | 6.175 Centimeters (cm) STANDARD_DEVIATION 0.502 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Region of Enrollment Australia | 0 Participants |
| Region of Enrollment South Korea | 71 Participants |
| Region of Enrollment United States | 1 Participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 3 | 3 / 15 | 2 / 16 | 5 / 30 | 5 / 28 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 15 / 15 | 15 / 15 | 30 / 30 | 28 / 28 |
| serious Total, serious adverse events | 2 / 3 | 1 / 3 | 6 / 15 | 6 / 15 | 11 / 30 | 11 / 28 |
Outcome results
None listed