A Phase 2 Study of RP2 With Tivozanib in Patients With Metastatic Renal Carcinoma After Progression to Immunotherapy

Official Summary

This phase II trial tests the effect of RP2 and tivozanib in treating patients with renal cell cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and that is growing, spreading, or getting worse (progressive) after receiving immunotherapy with immune checkpoint inhibitors (ICIs). RP2 is a herpes simplex virus (a viral infection commonly known as the "cold sore virus") that has been changed to infect and destroy tumor cells and to activate (turn on) the human immune system to attack the tumor cells. Tivozanib hydrochloride blocks certain proteins, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Tivozanib hydrochloride is a type of tyrosine kinase inhibitor and a type of antiangiogenesis agent. Giving RP2 and tivozanib may be safe, tolerable, and/or effective in treating patients with metastatic renal cell cancer that has progressed after receiving immunotherapy with ICIs.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 35 participants

Study Arms

• Treatment (RP2, tivozanib) (EXPERIMENTAL)
  Patients receive RP2 intratumorally on days 1, 15, 29, 43, 64, 85, 106, and 127. Treatment repeats every 2 weeks for the first 4 doses and then every 3 weeks for subsequent doses for up to 8 doses in the absence of disease progression or unacceptable toxicity. After completion of the first course of treatment, patients who meet criteria may receive another course of RP2 intratumorally every 3 weeks for up to an additional 8 doses. Patients also receive tivozanib PO QD on days 1-21 of each cycle.

Interventions

• PROCEDURE: Biopsy Procedure — Undergo tumor biopsies
• PROCEDURE: Biospecimen Collection — Undergo urine and blood sample collection
• PROCEDURE: Computed Tomography — Undergo CT
• BIOLOGICAL: Sturlimogene Erparepvec — Given intratumorally
• DRUG: Tivozanib — Given PO

Primary Outcomes

• Objective response rate (Up to 2 years)

Secondary Outcomes

• Progression-free survival (PFS) (From start of treatment to progression or death, whichever occurs first, assessed up to 2 years)
• Overall survival (OS) (From start of treatment to death from any cause, assessed up to 2 years)
• Incidence of adverse events (AEs) (Up to 30 days after last dose of study treatment)
• Baseline characteristics (At baseline)

Eligibility Criteria

Inclusion Criteria:

* Documented informed consent of the participant and/or legally authorized representative

  * Assent, when appropriate, will be obtained per institutional guidelines
* Must be willing to consent to provide fresh tumor biopsy sample or archival tumor biopsy sample obtained within 90 days before the first dose of study treatment

  * If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Male or female who is 18 years of age or older at the time of signed informed consent
* Eastern Cooperative Oncology Group (ECOG) 0 or 1
* Histologically confirmed renal cell carcinoma with a clear-cell or sarcomatoid component
* Patients must have received exactly one prior line or two prior lines of systemic therapy in the advanced or metastatic setting, including mandatory exposure to both an immune checkpoint inhibitor (ICI) and one antiangiogenic tyrosine kinase inhibitor (TKI). Prior treatment with hypoxia inducible factor (HIF)-α inhibitors is not permitted. Patients who received adjuvant immunotherapy and experienced disease recurrence within 6 months of completing treatment may also be eligible, and such therapy will count toward prior lines
* Has injectable tumor(s), which alone or in aggregate, total at least 1 cm in diameter of RP2
* Has at least 1 measurable tumor of ≥ 1 cm in longest diameter (or ≥ 1.5 cm shortest diameter for lymph nodes) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
* Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
* White blood cell (WBC) count ≥ 2.0 x 10\^9/L
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3

  * NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
* Platelets ≥ 100,000/mm\^3

  * NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
* Hemoglobin ≥ 9g/dL

  * NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease)
* Aspartate aminotransferase (AST) ≤ 3.0 x ULN
* Alanine aminotransferase (ALT) ≤ 3.0 x ULN
* Creatinine clearance of ≥ 30 mL/min per the Cockcroft-Gault formula or serum creatinine \< 1.5 x upper limit of normal (ULN)
* If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin (PT) ≤ 1.5 x ULN
* If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants
* Left ventricular ejection fraction (LVEF) ≥ 50%

  * Note: To be performed within 28 days prior to day 1 of protocol therapy
* QT interval corrected for heart rate using Bazetts's formula (QTcB) ≤ 480 ms

  * Note: To be performed within 28 days prior to day 1 of protocol therapy
* Women of childbearing potential (WOCBP) must have a negative serum beta-human chorionic gonadotropin (β-hCG) test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG within 72 hours before the first dose and a negative urine pregnancy test on dose 1 day 1
* Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at and for at least (a) 90 days after the last dose of RP2 or for one month after the last dose of tivozanib. Men must also agree to refrain from donating sperm during the treatment period and for at least 90 days after the last dose of RP2

  * Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

Exclusion Criteria:

* Received a live vaccine within 28 days before the first dose of study treatment

  * Note: Seasonal influenza vaccines for injection or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are generally inactivated vaccines and are allowed. Live/attenuated vaccines (such as the intranasal influenza vaccines) are not allowed
* Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study treatment

  * Note: Patients who have entered the follow-up phase of an investigational study may participate if it has been 4 weeks after the last dose of the previous investigational agent
* Systemic anticancer therapies within 4 weeks of the first dose of study drug. The prior anti-PD-1 or anti-PD-L1 containing regimen is excluded from this requirement
* Received prior treatment with an oncolytic virus therapy
* Received radiotherapy within 2 weeks of start of study treatment. Patients must have recovered from all radiation-related toxicities (except for radiation-induced xerostomia), not require corticosteroids, and not have had radiation pneumonitis. A 1

Trial Locations

• City of Hope Medical Center, Duarte, California, United States
• City of Hope at Irvine Lennar, Irvine, California, United States

Study Officials

• Charles B Nguyen — PRINCIPAL_INVESTIGATOR
  City of Hope Medical Center

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