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, hydroxamate, pan–histone deacetylase (HDAC) inhibitor under investigation across hematologic malignancies and solid tumors. Clinical development includes single‑agent studies in non‑Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and combinations such as abexinostat plus pazopanib in renal cell carcinoma (RCC). A randomized phase 3 RCC study of pazopanib with or without abexinostat (RENAVIV; NCT03592472) remains recruiting as of April 2025. (pmc.ncbi.nlm.nih.gov, ichgcp.net, trial.medpath.com)

Mechanism of action

• Class: oral pan‑HDAC inhibitor (targets class I/II HDACs), producing hyperacetylation of histone and non‑histone proteins and downstream effects including cell‑cycle arrest, apoptosis, immunomodulation, and inhibition of angiogenesis. Abexinostat shows rapid absorption and a short half‑life that informed a twice‑daily, “week‑on/week‑off” schedule to sustain target coverage. (pmc.ncbi.nlm.nih.gov)
• In RCC, combination with VEGF inhibition is mechanistically motivated by HDAC‑mediated stabilization of HIF‑1α; HDAC inhibition may downregulate HIF‑1α and help reverse resistance to anti‑angiogenic therapy. (ascopubs.org)

Efficacy

Hematologic malignancies (single‑agent) - Multicenter phase 2 (100 patients; NHL/CLL): overall response rate (ORR) 28% (CR 5%). Subtype ORR: follicular lymphoma (FL) 56%, T‑cell lymphoma 40%, diffuse large B‑cell lymphoma 31%. (pmc.ncbi.nlm.nih.gov) - Phase 2 extension in relapsed/refractory FL and mantle cell lymphoma (abstract): reported FL ORR 64% with durable responses. (ashpublications.org) - China phase 1 dose‑escalation/expansion in relapsed/refractory B‑cell NHL (n=10 efficacy‑evaluable at cutoff): ORR 40% overall; in FL, ORR 50%; median PFS in FL 8.38 months. (pmc.ncbi.nlm.nih.gov)

Solid tumors (combinations) - Phase Ib abexinostat + pazopanib (51 patients; RCC subset n=22): overall ORR 21%; in RCC, ORR 27% with median duration of response ~9–10.5 months and multiple durable responses, including in pazopanib‑refractory disease. Long‑term follow‑up describes “exceptional responders” with multi‑year disease control. (pmc.ncbi.nlm.nih.gov, ascopubs.org)

Ongoing late‑phase study - RENAVIV (NCT03592472): randomized, double‑blind, phase 3 of pazopanib ± abexinostat in advanced/metastatic RCC; status “recruiting” with an estimated primary completion in 2026. No phase 3 efficacy results reported yet. (ichgcp.net, trial.medpath.com)

Safety

Across studies, the class‑typical toxicities are prominent: - Hematologic: thrombocytopenia, neutropenia, anemia. In the Haematologica phase 2 (2‑weeks‑on/1‑week‑off), grade ≥3 thrombocytopenia occurred in 80%, neutropenia 27%, anemia 12%. Schedule intensity influenced cytopenias. (pmc.ncbi.nlm.nih.gov) - Gastrointestinal/constitutional: nausea, diarrhea, fatigue. (pmc.ncbi.nlm.nih.gov) - Combination with pazopanib: most frequent grade ≥3 related AEs included fatigue (16%), thrombocytopenia (16%), and neutropenia (10%); transaminase elevations also observed. Recommended phase 2 dose identified as abexinostat 45 mg/m² BID (intermittent schedule) plus pazopanib 800 mg daily. (ascopubs.org)

Additional notes

• Pharmacokinetics: oral tmax ~0.5–1 hour; terminal half‑life ~4 hours in earlier clinical PK work, supporting BID dosing four hours apart. (pmc.ncbi.nlm.nih.gov)
• Recent China phase 1 confirmed 80 mg BID as the recommended phase 2 dose with manageable safety and preliminary activity in B‑cell NHL. (pmc.ncbi.nlm.nih.gov)

Further reading

• Phase 2 NHL/CLL (Haematologica 2017, full text): Safety and efficacy of abexinostat. (pmc.ncbi.nlm.nih.gov)
• Phase Ib RCC/solid tumors (JCO 2017, full text): Abexinostat + pazopanib results and rationale. (pmc.ncbi.nlm.nih.gov)
• Long‑term follow‑up of abexinostat + pazopanib (2024–2025): updated outcomes and biomarker correlations. (pubmed.ncbi.nlm.nih.gov, ascopubs.org)
• FL/MCL phase 2 abstract (ASH): single‑agent activity in FL and MCL. (ashpublications.org)
• China phase 1 B‑NHL (2025, full text): safety/PK and early efficacy. (pmc.ncbi.nlm.nih.gov)
• RENAVIV phase 3 RCC trial record (status and timelines). (ichgcp.net)

Notes: All figures above reflect the publications’ data cuts (e.g., Haematologica 2017; JCO 2017; updates through 2024–2025) and may evolve with ongoing trials.

Last updated: Sep 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.