A Randomized, Phase 3, Double-blind, Placebo-controlled Study of Pazopanib With or Without Abexinostat in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma(RENAVIV)

More details:

Overview

Abexinostat (PCI‑24781) is an oral, phenyl–hydroxamic acid, pan–histone deacetylase (HDAC) inhibitor under investigation across hematologic malignancies and solid tumors. Early single‑agent activity has been reported in relapsed/refractory follicular lymphoma (FL), and combination activity with pazopanib has been observed in renal cell carcinoma (RCC). A global phase 3 trial (RENAVIV; NCT03592472) is ongoing, testing pazopanib with or without abexinostat in advanced RCC. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Broad inhibition of class I/II HDACs (notably HDAC1/2/3/6/10) increases histone acetylation, induces p21, and promotes apoptosis; reported in vitro Ki values include HDAC1 ~7 nM, with relative selectivity over HDAC8. (onlinelibrary.wiley.com)
• Pharmacokinetics in early studies showed rapid absorption (Tmax ~1 hour) and an elimination half‑life of ~4–5 hours, supporting twice‑daily intermittent dosing. (aacrjournals.org)
• In RCC, the rationale for combining abexinostat with VEGF‑TKIs includes HDAC‑mediated modulation of HIF‑1α/VEGF pathways, potentially reversing resistance to pazopanib. (ascopubs.org)

Efficacy

Hematologic malignancies (single‑agent)
- Phase I/II (NCT00724984) in relapsed/refractory lymphoma (n=55): in FL, investigator‑assessed overall response rate (ORR) 64.3% among 14 evaluable patients (ITT ORR 56.3%); median progression‑free survival (PFS) 20.5 months (1.2–22.3+). In mantle cell lymphoma, ORR 27.3% among evaluable patients (ITT 21.4%); median PFS 3.9 months. Responses were durable in many FL patients. (pubmed.ncbi.nlm.nih.gov)

Solid tumors (combinations)
- Phase I abexinostat+pazopanib in advanced solid tumors with RCC expansion (n=51): recommended phase II dose established (abexinostat 45 mg/m² BID on days 1–4, 8–11, 15–18; pazopanib 800 mg daily). Objective response rate 21% overall and 27% in the RCC subset; durable responses (median duration ~9.1 months; some >3.5 years), including in pazopanib‑refractory patients. (ascopubs.org)
- Updated follow‑up from the same cohort reported median overall survival of 27.65 months in the RCC expansion cohort and supported proceeding to phase 3 evaluation. (ascopubs.org)
- Ongoing randomized phase 3 trial in RCC (RENAVIV; NCT03592472) compares pazopanib plus abexinostat versus pazopanib plus placebo (2:1), with primary endpoint PFS. Status: recruiting as of April–June 2025 updates. (cdek.pharmacy.purdue.edu)

Safety

• Single‑agent in lymphoma (phase II): most common grade 3–4 treatment‑related adverse events were thrombocytopenia (20%), fatigue (16.7%), and neutropenia (13.3%); QTc prolongation was rare; no treatment‑related deaths reported. (pubmed.ncbi.nlm.nih.gov)
• Combination with pazopanib (phase I): dose‑limiting toxicities included fatigue, thrombocytopenia, and elevated AST/ALT. Grade ≥3 related events included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%); responses occurred despite prior pazopanib resistance. (ascopubs.org)

Selected dosing used in trials

• Single‑agent (lymphoma): 45 mg/m² BID on an intermittent “7 days on/7 off” 28‑day cycle identified as the recommended phase II schedule. (pubmed.ncbi.nlm.nih.gov)
• RCC combination (phase 3 plan): abexinostat 80 mg BID on days 1–4, 8–11, 15–18 plus pazopanib 800 mg once daily (28‑day cycles). (cdek.pharmacy.purdue.edu)

Further reading

• Phase I/II single‑agent study in relapsed/refractory lymphoma (efficacy and safety details). Clinical Cancer Research. (pubmed.ncbi.nlm.nih.gov)
• Phase I abexinostat+pazopanib in advanced solid tumors with RCC expansion (full text). Journal of Clinical Oncology. (ascopubs.org)
• Updated survival follow‑up for abexinostat+pazopanib (abstract). Journal of Clinical Oncology 2022. (ascopubs.org)
• RENAVIV phase 3 trial overview and status (NCT03592472). CDEK (Purdue) and My Cancer Genome. (cdek.pharmacy.purdue.edu)

Notes: Additional phase 2 studies in FL and DLBCL are active; readers can search the listed NCT numbers for the latest status and results as they read out. (cdek.pharmacy.purdue.edu)

Last updated: Oct 2025

Inclusion Criteria:

To be enrolled in the study, patients will be required to meet all of the following criteria:

* Patients aged ≥ 18 years at time of study entry.

* Patients have histologically confirmed RCC with clear cell component.

* Patients have locally advanced and unresectable or metastatic disease.

* Measurable disease as assessed only by the investigator (not verified by IRC) according to RECIST version 1.1.

* Patients must not have had any prior vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor treatment in either (neo)adjuvant or locally advanced/metastatic setting. Up to 1 line of prior cytokine or immune checkpoint inhibitor treatment is allowed in either the (neo)adjuvant or metastatic setting provided screening scans indicate progressive disease (PD) during or following completion of treatment.

* Patients have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

* Patients have adequate baseline organ function.

* Patients have adequate baseline hematologic function

* Patient must be at least 2 weeks from last systemic treatment or dose of radiation prior to date of randomization.

Exclusion Criteria:

Patients who meet any of the following criteria at Screening will not be enrolled in the study:

* Has persistent clinically significant toxicities (Grade ≥ 2; per NCI CTCAE version 5 from previous anticancer therapy (excluding alopecia which is permitted and excluding Grades 2 and 3 laboratory abnormalities if they are not associated with symptoms, are not considered clinically significant by the investigator, and can be managed with available medical therapies).

* Has untreated central nervous system (CNS) metastases. Patients with treated CNS metastases are eligible provided imaging demonstrates no new or progressive metastases obtained at least 4 weeks following completion of treatment. CNS imaging during Screening is not required unless clinically indicated.

* Has an additional malignancy requiring treatment within the past 3 years. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ, and non-muscle invasive urothelial carcinoma.

* Poorly controlled hypertension, defined as systolic blood pressure ≥ 160 or diastolic blood pressure ≥ 100 mmHg. Use of anti-hypertensives and rescreening is permitted.

* A new pulmonary embolism or deep venous thrombosis diagnosed within 3 months prior to randomization.

* Has a QTcF interval \> 480 msec.

* New York Heart Association Class III or IV congestive heart failure.

* Use of prohibited medication within 7 days or 5 half-lives, whichever is shorter, prior to first dose of study drug.