DFF332 / Novartis - LARVOL DELTA

A phase I dose escalation study of the HIF-2 alpha inhibitor DFF332 in patients with advanced clear cell renal cell carcinoma. (PubMed, Clin Cancer Res) - "While clinical responses were limited in the doses evaluated, dose exploration halted prematurely, making it difficult to draw definitive conclusions about the efficacy of DFF332. Further investigation is required to establish a recommended dose regimen, assess its efficacy and safety, and evaluate its full potential as a partner in combination studies."

Journal • P1 data • Cardiovascular • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Hypertension • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1

CDFF332A12101: DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Feb 2025 ➔ Sep 2025 | Trial primary completion date: Feb 2025 ➔ Sep 2025

IO biomarker • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

Dr Pal on the Preliminary Efficacy of DFF332 in Advanced ccRCC (OncLive) - P1 | N=40 | NCT04895748 | Sponsor: Novartis Pharmaceuticals | "Preliminary results from the dose-escalation portion of the study revealed that patients who received DFF332 did not experience severe levels of hypoxia or anemia, which makes the safety profile of DFF332 relatively unique...DFF332 elicited a 52.5% disease control rate, with best responses of partial response and stable disease in 5% and 47.5% of patients, respectively. The best percentage of change in tumor size from baseline per RECIST criteria was 87.5%. Furthermore, at the data cutoff, treatment was ongoing on 27.5% of patients. The median duration of treatment exposure was 17.9 weeks (range, 1.0-75.6)."

P1 data • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

Dr Pal on the Preliminary Efficacy of DFF332 in Advanced ccRCC (OncLive) - "Sumanta Kumar Pal, MD, FASCO, discusses preliminary findings from a phase 1 dose-escalation study of DFF332 in patients with advanced ccRCC."

Video • Renal Cell Carcinoma

Early Data With DFF332, Other Key Biomarker Analyses Continue to Inform Approaches in RCC (OncLive) - "'My hope is that the DFF332 approach may be palatable in combination with other therapies,' Pal added during an interview with OncLive regarding this research...In the interview, Pal highlighted key research efforts underway in the RCC treatment paradigm, including early data with DFF332 and its potential use in combination regimens; the importance of optimizing therapies for non-clear cell RCC and identifying predictive biomarkers to address unmet needs; and the value of recent biomarker analyses from several major trials presented during the ASCO Annual Meeting."

Interview • Renal Cell Carcinoma

DFF332, a novel potent and selective HIF2α transcription factor inhibitor for the treatment of VHL-deficient clear cell renal cell carcinoma (EACR 2024) - "DFF332 anti-tumor efficacy is further confirmed in VHL-deficient ccRCC patient-derived xenograft mouse models.Conclusion DFF332 is a novel potent, selective and orally bioavailable HIF2α inhibitor that is capable of eliciting significant antitumor activity associated with HIF2α pathway inhibition and good tolerability. DFF332 clinical profiling has been initiated in VHL-deficient ccRCC patients."

Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • Von Hippel-Lindau Syndrome • EGLN3 • EPAS1 • HIF1A • VHL

Preliminary safety, pharmacokinetics and clinical activity of DFF332, an oral HIF2α inhibitor, as monotherapy in a phase 1 dose escalation study in patients with advanced clear cell renal cell carcinoma. (ASCO 2024) - P1 | "During this phase I study, the monotherapy of DFF332 has shown a promising safety profile across all doses and schedules. Additionally, there have been indications of clinical activity and a dose-proportional modulation of erythropoietin. Currently, we are conducting an ongoing analysis of the PK and biomarker data, which will be included in the presentation."

Clinical • Metastases • Monotherapy • P1 data • PK/PD data • Anemia • Cardiovascular • Clear Cell Renal Cell Carcinoma • Constipation • Dyslipidemia • Fatigue • Gastroenterology • Gastrointestinal Disorder • Genito-urinary Cancer • Hematological Disorders • Hypertension • Hypertriglyceridemia • Oncology • Solid Tumor

DFF332 Elicits Efficacy and Is Safe in Advanced Clear Cell RCC (OncLive) - "'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 schedules with no dose-limiting toxicities, or treatment-related AEs of greater than 3 in patients with clear cell renal cell carcinoma,' Pal concluded."

Clinical data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

DFF332 Elicits Efficacy and Is Safe in Advanced Clear Cell RCC (OncLive) - P1 | N=40 | NCT04895748 | Sponsor: Novartis Pharmaceuticals | "Treatment with the small molecule inhibitor selectively targeting HIF-2α DFF332 elicited clinical activity and had a tolerable safety profile in patients with advanced clear cell renal cell carcinoma (RCC), according to data from a first-in-human phase 1 trial (NCT04895748) presented at the 2024 ASCO Annual Meeting....DFF332 had a disease control rate of 52.5%, 2 patients (5.0%) had a partial response as best response, and 19 patients (47.5%) had stable disease. These confirmed partial responses were observed in 1 patient receiving 25 mg daily and 1 patient receiving 100 mg daily. The median duration of exposure was 17.9 weeks (range, 1.0-75.6). Eleven patients (27.5%) were receiving ongoing treatment at the clinical cutoff date of January 15, 2024."

P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

City of Hope to Present New Research at the American Society of Clinical Oncology (ASCO) Annual Meeting 2024, Highlighting Promising Data on Stem Cell Transplantation, Blood Cancers and Supportive Care Oncology Interventions (Businesswire) - "World-renowned physicians and researchers from City of Hope, one of the largest cancer research and treatment organizations in the United States, will present new findings and offer expert perspectives on leading-edge cancer research and treatment development at the ASCO Annual Meeting 2024, which will take place in Chicago from May 31 to June 4...In total, City of Hope experts will present at 64 sessions, including oral abstracts, rapid oral abstracts, clinical science symposiums and education sessions."

Clinical data • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Malignancies • Kidney Cancer • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

City of Hope Researchers to Present Investigational Treatments for Colorectal, Kidney and Blood Cancers at 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (Businesswire) - P1/1b | N=40 | NCT04895748 | Sponsor: Novartis Pharmaceuticals | "People with an advanced kidney cancer called clear cell renal cell carcinoma (ccRCC) appeared to experience positive medicinal effects from the targeted therapy pill DFF332 while encountering manageable side effects in an ongoing first-in-human phase 1/1B multicenter trial (CDFF332A12101, NCT04895748)....At data cutoff, 16 patients continued to be treated, while 19 patients (48%) stopped receiving the treatment due to disease progression. The most common side effects were fatigue (33%), anemia (30%), increased blood cholesterol and constipation (15%). No extreme adverse effects have been observed so far. At cutoff, 18 patients (45%) had stable disease and two patients (5%) achieved partial response."

P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jul 2025 ➔ Feb 2025 | Trial primary completion date: Jul 2025 ➔ Feb 2025

Combination therapy • Immuno-oncology • IO biomarker • Metastases • Trial completion date • Trial primary completion date • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=180 ➔ 40

Combination therapy • Enrollment change • Enrollment closed • Immuno-oncology • IO biomarker • Metastases • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1; N=180; Recruiting; Sponsor: Novartis Pharmaceuticals; Not yet recruiting ➔ Recruiting

Clinical • Combination therapy • Enrollment open • IO biomarker • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

A Phase I/Ib study of DFF332 as a single agent and in combination with Everolimus or Immuno-oncology therapies in patients with advanced/relapsed ccRCC and other malignancies with HIF2alpha stabilizing mutations. (clinicaltrialsregister.eu) - P1; N=187; Ongoing; Sponsor: Novartis Pharma AG

Clinical • Combination therapy • New P1 trial • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHA • SDHAF2 • SDHB • SDHC • SDHD • VHL

DFF332 as a Single Agent and in Combination With Everolimus & Immuno-Oncology Agents in Advanced/Relapsed Renal Cancer & Other Malignancies (clinicaltrials.gov) - P1; N=180; Not yet recruiting; Sponsor: Novartis Pharmaceuticals

Clinical • Combination therapy • IO biomarker • New P1 trial • Clear Cell Renal Cell Carcinoma • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • SDHB • SDHC • VHL