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

• ClinicalTrials.gov Identifier: NCT04895748
• Recruitment Status: Recruiting
• First Posted: May 20, 2021
• Last Update Posted: October 7, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Carcinoma, Renal Cell	Drug: DFF332; Drug: RAD001; Drug: PDR001; Drug: NIR178	Phase 1

Detailed Description:

This is 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 consists of two parts, dose escalation and dose expansion. The dose escalation part of the study will initially evaluate DFF332 single agent. Dose escalation groups receiving DFF332 in combination with Everolimus or DFF332 in combination with Spartalizumab plus Taminadenant will open after at least two dose levels of single agent DFF332 have been evaluated.

The dose expansion part of single agent will include two treatment arms: Arm1A will enroll ccRCC patients (age 18 yo or above) and Arm1B will enroll patients with malignancies harboring HIF stabilizing mutations (age 12 yo and above). These include 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 will enroll patients with ccRCC and include Arm2A (DFF332 with Everolimus) and Arm3A (DFF332 with Spartalizumab plus Taminadenant).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 30, 2021
• Estimated Primary Completion Date: April 29, 2025
• Estimated Study Completion Date: April 29, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1 Dose Escalation DFF332; DFF332 Single Agent	Drug: DFF332; Hif2alpha inhibitor
Experimental: Arm 2 Dose Escalation DFF332 + Everolimus; Combination treatment DFF332 + Everolimus	Drug: DFF332; Hif2alpha inhibitor; Drug: RAD001; mTOR inhibitor; Other Name: Everolimus
Experimental: Arm 3 Dose Escalation DFF332 + Spartalizumab + Taminadenant; Combination treatment DFF332 + Spartalizumab + Taminadenant	Drug: DFF332; Hif2alpha inhibitor; Drug: PDR001; anti-PD-1; Other Name: Spartalizumab; Drug: NIR178; Adenosine A2A antagonist receptor; Other Name: Taminadenant
Experimental: Arm 1a Dose Expansion DFF332 in ccRCC; DFF332 Single Agent in patients with ccRCC (age 18 years old and above)	Drug: DFF332; Hif2alpha inhibitor
Experimental: Arm 1b Dose Expansion DFF332 in HIF stabilizing malignancies; DFF332 Single Agent in patients with HIF stabilizing malignancies (age 12 years old and above)	Drug: DFF332; Hif2alpha inhibitor
Experimental: Arm 2a Dose Expansion DFF332 + Everolimus in ccRCC; Combination treatment DFF332 + Everolimus in patients with ccRCC (age 18 years old and above)	Drug: DFF332; Hif2alpha inhibitor; Drug: RAD001; mTOR inhibitor; Other Name: Everolimus
Experimental: Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC; Combination treatment DFF332 + Spartalizumab + Taminadenant in patients with ccRCC (age 18 years old and above)	Drug: DFF332; Hif2alpha inhibitor; Drug: PDR001; anti-PD-1; Other Name: Spartalizumab; Drug: NIR178; Adenosine A2A antagonist receptor; Other Name: Taminadenant

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 3 years ]
   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
2. Number of participants with dose interruptions and dose reductions [ Time Frame: 3 years ]
   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. Dose intensity for DFF332 for dose escalation and expansion [ Time Frame: 3 years ]
   Dose intensity will be computed as the ratio of actual cumulative dose received and actual duration of exposure
4. Incidence of Dose Limiting Toxicities (DLTs) in Cycle 1 (28 days) for DFF332 as a single agent and in combinations [ Time Frame: 28 days ]
   Number of participants with DLTs

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: 3 years ]
   To assess the anti-tumor activity of DFF332 as single agent and combination in patients with advanced ccRCC and with advanced malignancies with HIF stabilizing mutations based on RECIST v1.1
2. Best Overall Response (BOR) [ Time Frame: 3 years ]
   To assess the anti-tumor activity of DFF332 as single agent and combination in patients with advanced ccRCC and with advanced malignancies with HIF stabilizing mutations based on RECIST v1.1
3. Progression Free Survival (PFS) for Recommended Dose (RD) only [ Time Frame: 3 years ]
   To assess the anti-tumor activity of DFF332 as single agent and combination in patients with advanced ccRCC and with advanced malignancies with HIF stabilizing mutations based on RECIST v1.1
4. Duration of Response (DOR) for Recommended Dose (RD) Only [ Time Frame: 3 years ]
   To assess the anti-tumor activity of DFF332 as single agent and combination in patients with advanced ccRCC and with advanced malignancies with HIF stabilizing mutations based on RECIST v1.1
5. Disease Control Rate (DCR) [ Time Frame: 3 years ]
   To assess the anti-tumor activity of DFF332 as single agent and combination in patients with advanced ccRCC and with advanced malignancies with HIF stabilizing mutations based on RECIST v1.1
6. Maximum Concentration (Cmax) of DFF332 single agent and combination [ Time Frame: 3 years ]
   PK parameters will be based on plasma concentration of DFF332 and Taminadenant, whole blood concentration of Everolimus, serum concentration of Spartalizumab
7. Area under the concentration-time curve (AUC) of DFF332 single agent and combination [ Time Frame: 3 years ]
   PK parameters will be based on plasma concentration of DFF332 single agent and in combination.

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Male and female ≥ 18 years of age For Arm 1B: Male and female of age ≥ 12 years of age

2. 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.

3. 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.

4. For patients age ≥ 16 years: ECOG performance status ≤ 1 For patients age ≥ 12 and < 16 years: Lansky performance status ≥ 70

Exclusion Criteria:

1. History of seizure disorder & extrapyramidal (EPS) symptoms

2. 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

3. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:

   1. ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2 weeks prior to the first dose of study treatment.
   2. ≤ 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.
   3. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin C.
   4. ≤ 4 weeks for immuno-oncologic therapy, such as CTLA-4, PD-1, or PD-L1 antagonists.
   5. Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study treatment or who have not recovered for the surgical procedure.
4. Patient previously treated with a HIF2α inhibitor.
5. 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.
6. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
7. 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.
8. Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111

Locations

United States, California

City of Hope National Medical Center; Recruiting

Duarte, California, United States, 91010

Contact +1 626 256 4673 Ext 85013

Principal Investigator: Sumanta Kumar Pal

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02114

Contact: Madison Guay MMGUAY@mgh.harvard.edu

Principal Investigator: Xin Gao

United States, Missouri

Washington University School of Medicine Main Center; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Abigail Reilly 314-454-8293 areilly@wustl.edu

Principal Investigator: Joel Picus

United States, New York

Memorial Sloan Kettering Cancer Center; Recruiting

New York, New York, United States, 10065

Contact: Chelsey Motzkin motzkinc@mskcc.org

Principal Investigator: Ritesh R Kotecha

United States, Texas

University of Texas MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(8); Recruiting

Houston, Texas, United States, 77030

Contact: Margarita Brooks 713-563-7231 mrbrooks@mdanderson.org

Principal Investigator: Nizar Tannir

Czechia

Novartis Investigative Site; Recruiting

Brno, Czech Republic, Czechia, 656 53

France

Novartis Investigative Site; Recruiting

Villejuif Cedex, France, 94800

Italy

Novartis Investigative Site; Recruiting

Milano, MI, Italy, 20133

Japan

Novartis Investigative Site; Recruiting

Koto ku, Tokyo, Japan, 135 8550

Singapore

Novartis Investigative Site; Recruiting

Singapore, Singapore, 119228

Spain

Novartis Investigative Site; Recruiting

Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04895748
• Other Study ID Numbers: CDFF332A12101
• First Posted: May 20, 2021
• Last Update Posted: October 7, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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

Additional relevant MeSH terms:

Carcinoma, Renal Cell; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; 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; Everolimus; Spartalizumab; MTOR Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents; Immune Checkpoint Inhibitors; Antineoplastic Agents, Immunological