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

NCT04895748 | Terminated Phase 1 FDA Drug

• 2 other identifiers: CDFF332A121012024-513379-41
• Study Type: interventional
• Target: 40
• Locations: 7 countries
• Sites: 11

Brief 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.

Conditions

Carcinoma, Renal Cell

Keywords

ccRCC; RCC; Kidney; DFF332; NIR178; PDR001; RAD001; Everolimus; Spartalizumab; Taminadenant; Von Hippel-Lindau Disease; Hereditary leiomyomatosis and renal cell cancer syndrome; Paraganglioma; Pheochromocytoma

Outcome Measures

Primary Outcomes (4)

• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)

  Number of participants with AEs/SAEs to characterize the safety and tolerability of DFF332 as a single agent, in combination with Everolimus (RAD001), and in combination with Spartalizumab (PDR001) plus Taminadenant (NIR178) in patients with advanced clear cell Renal Cell Carcinoma (ccRCC) and advanced malignancies with Hypoxia Inducible Factor (HIF) stabilizing mutations

  3 years

• Number of participants with dose interruptions and dose reductions

  Number of participants with dose interruptions and dose reductions to characterize the tolerability of DFF332 as a single agent, in combination with Everolimus (RAD001), and in combination with Spartalizumab (PDR001) plus Taminadenant (NIR178) in patients with advanced ccRCC and advanced malignancies with HIF stabilizing mutations.

  3 years

• Dose intensity for DFF332 for dose escalation and expansion

  Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure

  3 years

• Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for DFF332 as a single agent and in combinations

  Number of participants with DLTs

  28 days

Secondary Outcomes (7)

• Overall Response Rate (ORR)

  3 years

• Best Overall Response (BOR)

  3 years

• Progression Free Survival (PFS) for Recommended Dose (RD) only

  3 years

• Duration of Response (DOR) for Recommended Dose (RD) Only

  3 years

• Disease Control Rate (DCR)

  3 years

Study Arms (7)

Arm 1 Dose Escalation DFF332

EXPERIMENTAL

DFF332 Single Agent

Drug: DFF332

Arm 2 Dose Escalation DFF332 + Everolimus

EXPERIMENTAL

Combination treatment DFF332 + Everolimus. This arm did not open.

Drug: DFF332; Drug: RAD001

Arm 3 Dose Escalation DFF332 + Spartalizumab + Taminadenant

EXPERIMENTAL

Combination treatment DFF332 + Spartalizumab + Taminadenant. This arm did not open.

Drug: DFF332; Drug: PDR001; Drug: NIR178

Arm 1a Dose Expansion DFF332 in ccRCC

EXPERIMENTAL

DFF332 Single Agent in patients with ccRCC (age 18 years old and above). This arm did not open.

Drug: DFF332

Arm 1b Dose Expansion DFF332 in HIF stabilizing malignancies

EXPERIMENTAL

DFF332 Single Agent in patients with HIF stabilizing malignancies (age 12 years old and above). This arm did not open.

Drug: DFF332

Arm 2a Dose Expansion DFF332 + Everolimus in ccRCC

EXPERIMENTAL

Combination treatment DFF332 + Everolimus in patients with ccRCC (age 18 years old and above). This arm did not open.

Drug: DFF332; Drug: RAD001

Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC

EXPERIMENTAL

Combination treatment DFF332 + Spartalizumab + Taminadenant in patients with ccRCC (age 18 years old and above). This arm did not open.

Drug: DFF332; Drug: PDR001; Drug: NIR178

Interventions

DFF332 DRUG

Hif2alpha inhibitor

Arm 1 Dose Escalation DFF332; Arm 1a Dose Expansion DFF332 in ccRCC; Arm 1b Dose Expansion DFF332 in HIF stabilizing malignancies; Arm 2 Dose Escalation DFF332 + Everolimus; Arm 2a Dose Expansion DFF332 + Everolimus in ccRCC; Arm 3 Dose Escalation DFF332 + Spartalizumab + Taminadenant; Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC

RAD001 DRUG

mTOR inhibitor

Also known as: Everolimus

Arm 2 Dose Escalation DFF332 + Everolimus; Arm 2a Dose Expansion DFF332 + Everolimus in ccRCC

PDR001 DRUG

anti-PD-1

Also known as: Spartalizumab

Arm 3 Dose Escalation DFF332 + Spartalizumab + Taminadenant; Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC

NIR178 DRUG

Adenosine A2A antagonist receptor

Also known as: Taminadenant

Arm 3 Dose Escalation DFF332 + Spartalizumab + Taminadenant; Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male and female ≥ 18 years of age For Arm 1B: Male and female of age ≥ 12 years of age
• Histologically confirmed and documented clear cell renal cell carcinoma (ccRCC). Disease must be measurable as determined by RECIST v1.1.
• For Arm 1B: histologically confirmed and documented malignancies in the context of the following cancer predisposing syndromes/disorders or harboring somatic mutations on one of these genes:
• 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 Note: Mutations must have been previously identified through local molecular assays.
• Patient with unresectable, locally advanced or metastatic ccRCC with documented disease progression following all standard of care therapy, including PD-1/L1 checkpoint inhibitor and a VEGF targeted therapy as monotherapy or in combination.
• Escalation: No restriction on the number of prior treatments Expansion (with the exception of Arm 1B): Up to 3 prior lines of treatment for advanced/metastatic disease For Arm 1B: Patients must have either metastatic disease or locally advanced disease that is unresectable or that patients be unfit for resection or other treatment modalities. Patients must have received prior standard therapy appropriate for their tumor type and stage of disease, and have no available therapies of proven clinical benefit; or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
• For patients age ≥ 16 years: ECOG performance status ≤ 1 For patients age ≥ 12 and \< 16 years: Lansky performance status ≥ 70

You may not qualify if:

• History of seizure disorder \& extrapyramidal (EPS) symptoms
• Impaired cardiac function or clinically significant cardiac disease, including any of the following:
• Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA Grade ≥ 2), uncontrolled hypertension
• Patients with corrected QT using the Fridericia's correction (QTcF) \> 470 msec for all patients on screening ECG or congenital long QT syndrome Acute myocardial infarction or unstable angina \< 3 months prior to study entry
• History of stroke or transient ischemic event requiring medical therapy
• Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker
• Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:
• ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment.
• ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological therapy (including monoclonal antibodies) or continuous or intermittent small molecule therapeutics or any other investigational agent.
• ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C.
• ≤ 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
• Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
• Patient previously treated with a HIF2α inhibitor.
• Uncontrolled concurrent illness including, but not limited to, ongoing active infection, uncontrolled hypertension, active peptic ulcer disease or gastritis, active bleeding diatheses, including any Patient known to have evidence of acute or chronic hepatitis B, hepatitis C, human immunodeficency virus (HIV), or a psychiatric illness/social situation that in the investigator's opinion would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Patients with chronic HBV or HCV disease that is controlled under antiviral therapy are allowed in the expansion parts but not in the escalation parts.
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (11)

City of Hope National Medical

Duarte, California, 91010, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

WA Uni School Of Med

St Louis, Missouri, 63110, United States

Location

Memorial Sloane Ketterin Cancer Ctr

New York, New York, 10065, United States

Location

Uni Of TX MD Anderson Cancer Cntr

Houston, Texas, 77030, United States

Location

Novartis Investigative Site

Brno, 656 53, Czechia

Location

Novartis Investigative Site

Villejuif, 94800, France

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Koto Ku, Tokyo, 1358550, Japan

Location

Novartis Investigative Site

Singapore, 119228, Singapore

Location

Novartis Investigative Site

Barcelona, 08035, Spain

Location

MeSH Terms

Conditions

Carcinoma, Renal Cell; von Hippel-Lindau Disease; Hereditary leiomyomatosis and renal cell cancer; Paraganglioma; Pheochromocytoma

Interventions

Everolimus; spartalizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neurocutaneous Syndromes; Nervous System Diseases; Angiomatosis; Vascular Diseases; Cardiovascular Diseases; Ciliopathies; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2021
• First Posted: May 20, 2021
• Study Start: November 30, 2021
• Primary Completion: February 13, 2026
• Study Completion: February 13, 2026
• Last Updated: March 3, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

JP (1); ES (1); FR (1); IT (1); US (5); CZ (1); SG (1)