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

ClinicalTrials.gov Identifier: NCT04895748

Novartis Reference Number: CDFF332A12101

Last Update: Apr 22, 2022

See if you pre-qualify

All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

This is 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 will 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.

Condition 
Carcinoma, Renal Cell
Phase 
Phase 1
Overall status 
Recruiting
Start date 
Nov 30, 2021
Completion date 
Feb 24, 2025
Gender 
All
Age(s)
12 Years and older (Child, Adult, Older Adult)

Interventions

Drug
DFF332
Hif2alpha inhibitor
Drug
RAD001
mTOR inhibitor
Drug
PDR001
anti-PD-1
Drug
NIR178
Adenosine A2A antagonist receptor

Eligibility Criteria

Inclusion Criteria:

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

Exclusion Criteria:

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.
Presence of Grade ≥ 2 toxicity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAEv5.0), from prior cancer therapy with the exception of neuropathy (inclusion of patients with neuropathy of Grade 2 or less is permitted), ototoxicity, and alopecia.
Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply.

Study Locations

United States
City of Hope National Medical Center
Recruiting
Duarte, 91010 - California
Contact: (+1 626 256 4673 Ext 85013) Sumanta Kumar Pal
United States
Massachusetts General Hospital
Recruiting
Boston, 02114 - Massachusetts
Contact: Madison Guay - [email protected] - Xin Gao
United States
Washington University School of Medicine Main Center
Recruiting
Saint Louis, 63110 - Missouri
Contact: Andrew Atkocius (314-454-8293) - [email protected] - Joel Picus
United States
Memorial Sloan Kettering Cancer Center
Recruiting
New York, 10065 - New York
Contact: Leah Greene - [email protected] - Ritesh R Kotecha
United States
University of Texas MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(8)
Recruiting
Houston, 77030 - Texas
Contact: Margarita Brooks (713-563-7231) - [email protected] - Nizar Tannir
United States
Czech Republic
Novartis Investigative Site
Recruiting
Brno, 656 53
Czech Republic
Czech Republic
France
Novartis Investigative Site
Recruiting
Villejuif Cedex, 94800
-
France
Italy
Novartis Investigative Site
Recruiting
Milano, 20133
MI
Italy
Japan
Novartis Investigative Site
Recruiting
Koto ku, 135 8550
Tokyo
Japan
Spain
Novartis Investigative Site
Recruiting
Barcelona, 08035
Catalunya
Spain

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 
Name: 
Novartis Pharmaceuticals
Phone: 

Have a question?

Call 1-888-669-6682 or email [email protected]