DFF332 + Combination Therapy for Renal Cell Carcinoma

Not currently recruiting at 25 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Must not be taking: Anticancer therapies, Live vaccines

Disqualifiers: Seizure disorder, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment, DFF332, for advanced clear cell renal cell carcinoma and other similar cancers with specific genetic mutations. The study tests DFF332 alone and in combination with other drugs to determine its effectiveness in stopping cancer growth by targeting the protein HIF2α. Individuals with measurable clear cell renal cell carcinoma that has advanced or spread after standard treatments may be suitable candidates. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain cancer treatments before starting the study. Specifically, you must not have had chemotherapy, biological therapy, or certain other cancer treatments within a few weeks before the trial begins. The protocol does not specify about other non-cancer medications, so it's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study showed that DFF332 was safe and well tolerated at different doses and schedules, meaning most participants did not experience serious side effects. The study tested DFF332 in people with advanced kidney cancer and confirmed its safety when used alone.

For the combination of DFF332 with Everolimus, researchers expect a similar safety profile. Everolimus has FDA approval for other uses, indicating its safety when used alone.

Less specific information is available for the combination of DFF332 with Spartalizumab and Taminadenant. Since these combinations are being tested in humans for the first time, the main goal is to determine their safety. Early trials focus heavily on safety, so researchers will closely monitor and report any serious side effects.

Overall, existing research suggests DFF332 alone is well tolerated, and the combinations are being carefully studied to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DFF332 for renal cell carcinoma (RCC) because it offers a new approach by targeting hypoxia-inducible factors (HIF), which play a crucial role in cancer cell survival and growth. Unlike traditional RCC treatments that often focus on blocking blood vessel growth, DFF332 aims to disrupt cancer cell adaptation to low oxygen environments, potentially hindering tumor progression in a novel way. This innovative mechanism of action could provide an alternative for patients who do not respond well to existing therapies, offering hope for improved outcomes.

What evidence suggests that this trial's treatments could be effective for renal cell carcinoma?

Research has shown that the small molecule DFF332, one of the treatments in this trial, has potential in treating certain cancers when used alone. In studies, about 5% of patients experienced tumor shrinkage, and nearly 48% had stable disease, meaning their cancer did not worsen. This trial will explore different combinations of DFF332. One arm will study DFF332 combined with Everolimus, a drug that aids in treating kidney cancer and might enhance its effectiveness. Another arm will investigate the combination of DFF332 with Spartalizumab and Taminadenant, which support the immune system and block cancer growth signals, potentially increasing efficacy. These combinations aim to halt cancer growth more effectively by targeting several pathways. ^{1 2 3 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

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.

Inclusion Criteria

I am 12 years old or older.

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

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

Exclusion Criteria

Other protocol-defined inclusion/exclusion criteria may apply

Pregnant or nursing (lactating) women

I have been treated with a HIF2α inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Initial evaluation of DFF332 as a single agent, followed by combination with Everolimus or Spartalizumab plus Taminadenant after two dose levels of single agent have been evaluated

28 days

Dose Expansion

Expansion of single agent and combination arms to further assess safety and efficacy in specific patient groups

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• DFF332
• NIR178
• PDR001
• RAD001

Trial Overview 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.

How Is the Trial Designed?

Group I: Arm 3a Dose Expansion DFF332 + Spartalizumab + Taminadenant in ccRCC Experimental Treatment 3 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 + Taminadenant Experimental Treatment 3 Interventions

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

Group III: Arm 2a Dose Expansion DFF332 + Everolimus in ccRCC Experimental Treatment 2 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 + Everolimus Experimental Treatment 2 Interventions

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

Group V: Arm 1b Dose Expansion DFF332 in HIF stabilizing malignancies Experimental Treatment 1 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 ccRCC Experimental Treatment 1 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 DFF332 Experimental Treatment 1 Intervention

DFF332 Single Agent

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Combination therapies targeting immune checkpoints and vascular endothelial growth factor receptors have significantly improved outcomes for patients with metastatic renal cell carcinoma, leading to durable disease control and prolonged overall survival.

The evolving understanding of the disease at genomic and immunologic levels has resulted in marked improvements in survival rates, making combination approaches the standard of care for first-line treatment, although careful study design is essential for accurate outcome estimation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Selection in First-line Metastatic Renal Cell Carcinoma-The Contemporary Treatment Paradigm in the Age of Combination Therapy: A Review. Navani, V., Heng, DYC.[2022]

In a phase III trial, the multi-kinase inhibitor sorafenib significantly improved median progression-free survival in advanced renal cell carcinoma patients, doubling it from 12 weeks to 24 weeks, with a hazard ratio of 0.44.

Sorafenib also showed a 39% improvement in overall survival and a 10% investigator-assessed response rate, highlighting that many patients experienced clinical benefits beyond traditional tumor regression metrics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging efficacy endpoints for targeted therapies in advanced renal cell carcinoma. Gore, ME., Escudier, B.[2018]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40043000/

A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor ... Overall, two patients (5%) achieved a partial response, and 19 (48%) achieved stable disease as the best overall response. DFF332 showed a ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4513

Preliminary safety, pharmacokinetics and clinical activity of ... Results: Between Nov 30, 2021 to Nov 15, 2023, 40 pts (male, 78%) with a median age of 62.5 (38-79) years received treatment with DFF332. All ...

3. urotoday.com urotoday.com/conference-highlights/asco-2024/asco-2024-kidney-cancer/152466-asco-2024-preliminary-safety-pharmacokinetics-and-clinical-activity-of-dff332-an-oral-hif2-inhibitor-as-monotherapy-in-a-phase-1-dose-escalation-study-in-patients-with-advanced-clear-cell-renal-cell-carcinoma.html

ASCO 2024 The disease control rate was 52.5% with a best response of partial response in two patients (5%) and stable disease in 19 patients (47.5%).

4. onclive.com onclive.com/view/early-data-with-dff332-other-key-biomarker-analyses-continue-to-inform-approaches-in-rcc

Early Data With DFF332, Other Key Biomarker Analyses ... In this phase 1 dose-escalation trial, we looked at a relatively large cohort of patients with metastatic RCC. What efficacy and safety results ...

5. aacrjournals.org aacrjournals.org/clincancerres/article/31/10/1847/762224/A-Phase-I-Dose-Escalation-Study-of-the-HIF-2-Alpha

A Phase I Dose-Escalation Study of the HIF-2 Alpha Inhibitor ... DFF332 may be considered for use in combination with other therapies that have synergistic or additive effects against advanced ccRCC.

6. targetedonc.com targetedonc.com/view/hif-2-inhibitor-monotherapy-shows-preliminary-activity-safety-in-rcc

HIF-2α Inhibitor Monotherapy Shows Preliminary Activity, ... “In summary, in this first-in-human phase 1 study of DFF332, the agent was well tolerated and shown to be safe across all dose levels and ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04895748

Study Details | NCT04895748 | DFF332 as a Single Agent ... 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 ...