What side effects are associated with this type of intervention?

Common treatments for Renal Cell Carcinoma (RCC) include tyrosine kinase inhibitors (TKIs) like sunitinib and sorafenib, and immunotherapy agents such as nivolumab and ipilimumab. Known side effects of TKIs include hypertension, fatigue, diarrhea, hand-foot syndrome, and liver toxicity. Immunotherapy agents can cause immune-related adverse events such as colitis, hepatitis, pneumonitis, and endocrinopathies. For treatments targeting HIF pathways, like the investigational DFF332, potential side effects may include those related to hypoxia-inducible factors, but specific data on HIF2α inhibitors are still emerging.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of Renal Cell Carcinoma (RCC). Notably, HIF2α inhibitors like DFF332 are being explored, but other targeted therapies have already been approved. These include tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib, which target VEGFR and other pathways. Additionally, mTOR inhibitors like everolimus have been approved for RCC treatment. Immunotherapy agents such as nivolumab and pembrolizumab, which target PD-1, have also shown efficacy in RCC. These treatments reflect a broad approach to targeting the molecular and immunological aspects of RCC.

What other types of research exist?

Promising novel alternatives to DFF332 for RCC patients include: 1) Bosutinib, a tyrosine kinase inhibitor that has shown efficacy in reducing kidney growth in ADPKD; 2) Combination therapies involving immune checkpoint inhibitors like Pembrolizumab plus Axitinib, which have demonstrated improved outcomes in advanced RCC; 3) Next-generation multitarget tyrosine kinase inhibitors and biologics targeting the VEGF/VEGFR pathway, which are being developed to overcome resistance to current treatments.

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Small Molecule

DFF332 + Combination Therapy for Renal Cell Carcinoma

Phase 1

Waitlist Available

Research Sponsored by Novartis Pharmaceuticals

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

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

For patients age ≥ 16 years: ECOG performance status ≤ 1

Must not have

Patient previously treated with a HIF2α inhibitor

History of seizure disorder & extrapyramidal (EPS) symptoms

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 3 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug called DFF332 in patients with advanced kidney cancer and other cancers with certain genetic mutations. The drug works by blocking a protein that helps the cancer grow.

Who is the study for?

This trial is for adults with advanced clear cell renal cancer (ccRCC) who've tried all standard treatments, including PD-1/L1 inhibitors and VEGF therapies. It's also open to those with certain genetic mutations or syndromes related to other cancers, as long as they have no remaining standard treatment options. People can't join if they have heart issues, uncontrolled illnesses like high blood pressure or infections, recent major surgery, or are pregnant.

What is being tested?

The study tests DFF332 alone and combined with Everolimus (RAD001), Spartalizumab (PDR001), and Taminadenant (NIR178). These drugs target different aspects of cancer growth: HIF2α protein by DFF332; mTOR pathway by RAD001; immune checkpoints by PDR001; and adenosine A2A receptors by NIR178.

What are the potential side effects?

Potential side effects may include typical reactions from targeted cancer therapies such as fatigue, nausea, skin rash, increased risk of infections due to immune system suppression. Specific side effects will depend on the drug combination received.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidney cancer has spread, can't be surgically removed, and has worsened after all standard treatments.

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I am 16 or older and mostly able to care for myself.

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My kidney cancer is confirmed and can be measured.

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My cancer is linked to a genetic condition or has certain gene mutations.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been treated with a HIF2α inhibitor before.

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I have a history of seizures and movement disorders.

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I had major surgery less than 4 weeks ago or haven't recovered from it.

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I have heart problems that affect my daily activities.

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I do not have any uncontrolled illnesses like high blood pressure or active infections.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Dose intensity for DFF332 for dose escalation and expansion

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

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

+1 more

Secondary study objectives

Area under the concentration-time curve (AUC) of DFF332 single agent and combination

Best Overall Response (BOR)

Disease Control Rate (DCR)

+4 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

7Treatment groups

Experimental Treatment

Group I: Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCCExperimental Treatment3 Interventions

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

Group II: Arm 3 Dose Escalation DFF332 + Spartalizumab + TaminadenantExperimental Treatment3 Interventions

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

Group III: Arm 2a Dose Expansion DFF332 + Everolimus in ccRCCExperimental Treatment2 Interventions

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

Group IV: Arm 2 Dose Escalation DFF332 + EverolimusExperimental Treatment2 Interventions

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

Group V: Arm 1b Dose Expansion DFF332 in HIF stabilizing malignanciesExperimental Treatment1 Intervention

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

Group VI: Arm 1a Dose Expansion DFF332 in ccRCCExperimental Treatment1 Intervention

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

Group VII: Arm 1 Dose Escalation DFF332Experimental Treatment1 Intervention

DFF332 Single Agent

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

RAD001

2012

Completed Phase 3

~1570

PDR001

2016

Completed Phase 2

~2890

0 / 9Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Renal Cell Carcinoma (RCC) include HIF2α inhibitors, mTOR inhibitors, and immune checkpoint inhibitors. HIF2α inhibitors, like DFF332, target the hypoxia-inducible factor 2-alpha protein, which plays a crucial role in tumor growth and survival under low oxygen conditions. By inhibiting HIF2α, these drugs can potentially halt cancer progression. mTOR inhibitors, such as Everolimus, block the mTOR pathway, which is involved in cell growth and proliferation, thereby slowing down tumor growth. Immune checkpoint inhibitors, like Spartalizumab, enhance the immune system's ability to recognize and attack cancer cells by blocking proteins that suppress immune responses. These treatments are significant for RCC patients as they offer targeted approaches to disrupt cancer growth and improve survival outcomes.