NCT04895748

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies

A Phase I/Ib, Open-label, Multi-center Study of DFF332 as a Single Agent and in Combination With Everolimus or IO Agents in Patients With Advanced/Relapsed ccRCC and Other Malignancies With HIF2α Stabilizing Mutations

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 40 (actual)
• Sponsor: Novartis Pharmaceuticals · Industry
• Sex: All
• Age: 18 Years – 100 Years
• Healthy volunteers: Not accepted

Summary

This was a first in human study of DFF332, a small molecule that targets a protein called HIF2α. By acting on HIF2α, DFF332 may be able to stop the growth of certain types of cancer. DFF332 was planned to be tested at different doses as single agent and in combination with Everolimus (RAD001, an mTOR inhibitor), and also in combination with Spartalizumab (PDR001, an anti-PD1) plus Taminadenant (NIR178, an adenosine A2A receptor antagonist), in patients with advanced clear cell renal cell carcinoma and other malignancies with HIF stabilizing mutations.

Detailed description

This was a first in human (FIH), Phase I/Ib, open-label, multi-center study of DFF332 as a single agent and in combination with Everolimus or Spartalizumab plus Taminadenant in patients with advanced clear cell renal cell carcinoma and other malignancies with HIF stabilizing mutations. The study consisted of two parts, dose escalation and dose expansion. The dose escalation part of the study initially evaluated DFF332 single agent. Dose escalation groups receiving DFF332 in combination with Everolimus or DFF332 in combination with Spartalizumab plus Taminadenant were planned to be opened after at least two dose levels of single agent DFF332 had been evaluated. The dose expansion part of single agent included two treatment arms: Arm1A was planned to enroll ccRCC patients (age 18 yo or above) and Arm1B was planned to enroll patients with malignancies harboring HIF stabilizing mutations (age 12 yo and above). These included the following: * Malignancies with VHL mutations (e.g. Von Hippel-Lindau disease) * Malignancies with FH mutations (e.g. Hereditary leiomyomatosis and renal cell carcinoma) * Malignancies with mutations in SDHD, SDHAF2, SDHC, SDHB, SDHA (e.g. Hereditary paraganglioma and pheochromocytoma syndrome) * Malignancies with EPAS1/HIF2A mutations * Malignancies with ELOC/TCEB1 mutations The expansion part of the combination therapies was planned to enroll patients with ccRCC and to include Arm2A (DFF332 with Everolimus) and Arm3A (DFF332 with Spartalizumab plus Taminadenant). Novartis halted enrollment of study CDFF332A12101 in September 2023 due to business reasons and not due to safety concerns. The DFF332 single agent dose expansion arms and the dose escalation and expansion of the combination arms did not open.

Conditions

• Carcinoma, Renal Cell

Interventions

Type	Name	Description
DRUG	DFF332	Hif2alpha inhibitor
DRUG	RAD001	mTOR inhibitor
DRUG	PDR001	anti-PD-1
DRUG	NIR178	Adenosine A2A antagonist receptor

Timeline

• Start date: 2021-11-30
• Primary completion: 2026-02-13
• Completion: 2026-02-13
• First posted: 2021-05-20
• Last updated: 2026-03-03

Locations

11 sites across 7 countries: United States, Czechia, France, Italy, Japan, Singapore, Spain

Regulatory

• FDA-regulated drug study