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

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ClinicalTrials.gov Identifier: NCT04895748
Recruitment Status : Recruiting
First Posted : May 20, 2021
Last Update Posted : December 8, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 180 participants
Allocation: Non-Randomized
Intervention Model: Parallel 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 : February 24, 2025
Estimated Study Completion Date : February 24, 2025


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




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.



Information from the National Library of Medicine

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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 therapy with 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04895748


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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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         
Japan
Novartis Investigative Site Recruiting
Koto ku, Tokyo, Japan, 135 8550
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04895748    
Other Study ID Numbers: CDFF332A12101
First Posted: May 20, 2021    Key Record Dates
Last Update Posted: December 8, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Carcinoma, Renal Cell
Neoplasms
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Everolimus
Spartalizumab
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action