HC-7366 / HiberCell - LARVOL DELTA

A Phase 1b, Open-Label, Safety, Tolerability, and Efficacy Study of HC-7366 in Combination with Belzutifan (WELIREGTM) in Patients with Advanced or Metastatic Renal Cell Carcinoma, NCT06234605 (KCRS 2024) - P1 | "Abstract 4615. This study is in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA"

Clinical • Combination therapy • IO biomarker • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • VHL

Combining HC-7366 with belzutifan in patients with renal cell carcinoma to alter tumor and microenvironment: Pharmacokinetic and pharmacodynamic (PK/PD) analysis of a phase 1b study. (ASCO 2026) - P1 | "Early clinical findings suggest HC-7366 + BEL is associated with modulation of angiogenic and immune-related pathways in ccRCC, providing a rationale for the combination with ICIs and/or VEGFR-TKIs. Avg max change with treatment."

Clinical • IO biomarker • P1 data • PK/PD data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Metabolic Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor • Von Hippel-Lindau Syndrome • ASNS • ATF4 • CD8 • EPAS1 • HAVCR2 • HIF1A • KIM1 • LAG3 • PD-1

Pharmacokinetics and pharmacodynamics of the GCN2 activator HC-7366 in a phase 1a study in patients with advanced solid tumors. (ASCO 2026) - P1 | "PK/PD evaluation of HC-7366 showed a favorable PK profile, with dose-proportional exposure and a half-life suitable for QD dosing. Drug exposure, pathway engagement, and mechanistic biomarkers suggested 40-75 mg as the optimal dose range. Importantly, the metabolic effects suggest suitability for development in metabolically rewired cancers, including renal cell carcinoma (NCT06234605)."

Clinical • First-in-human • Metastases • P1 data • PK/PD data • Colorectal Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • ASNS • EPAS1 • HIF1A • IGF1

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with locally advanced (inoperable) or metastatic renal cell carcinoma. (ASCO 2026) - P1 | "HC-7366, alone or in combination with BEL, was generally well tolerated. Preliminary efficacy analyses indicate favorable disease control, characterized by a high DCR and low primary PD. Efficacy and safety data by cohort."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Oncology • Renal Cell Carcinoma • Solid Tumor

…Findings from a phase 1b trial (NCT06234605) presented in a poster at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting (Cancer Network) - "In the 20-mg, 40-mg, and 60-mg combination arms, the biologic ORR was 0%, 37%, and 37%, respectively; the confirmed ORR was 0%, 26%, and 37%. Moreover, the disease control rate (DCR) was 71%, 89%, and 84%. The median time to response was not found in the 20-mg cohort but was 3.8 months in the 40-mg cohort and 3.7 months in the 60-mg cohort. The 6-month progression-free survival (PFS) rate was 43%, 58%, and 73% in the respective arms. In the monotherapy arm, the biologic ORR was 15%, with no confirmed responders to treatment observed. The DCR was 62%, with a median time to response of 1.6 months. The 6-month PFS rate was 15%."

P1 data • Renal Cell Carcinoma

HiberCell to Present Preliminary Results from the Phase 1b Trial of GCN2 Activator HC-7366 when Combined with WELIREG (belzutifan) for the Treatment of Late-Line Clear Cell Renal Cell Carcinoma (ccRCC) at the Upcoming 2026 ASCO Annual Meeting (GlobeNewswire) - "Data from Phase 1b dose escalation and expansion trial (n=69) shows a favorable safety profile, with manageable adverse events consistent with the known profiles of the respective drugs. Encouraging preliminary signals of efficacy for the higher dose combination cohorts of HC-7366 with belzutifan were observed.....Translational analyses demonstrate clear evidence of HC-7366 pathway engagement and a pharmacodynamic profile differentiating the combination from the known effects of HC-7366 and belzutifan monotherapy. Second Dose Expansion Cohort (Expansion 2) fully enrolled, with updated results from both Expansion 1 and Expansion 2 expected in 2H 2026 and full results to be reported at a future date."

P1 data • Trial status • Clear Cell Renal Cell Carcinoma

Off-target activation of GCN2 by BRAFV600inhibitors attenuates melanoma outgrowth (AACR 2026) - "Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4...This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2...We further describe the activation of GCN2 signaling in melanoma patient-derived xenograft models treated with dabrafenib and trametinib, and observe a significant decrease in disease-free survival in a cohort of human melanoma patients with altered GCN2 pathway components. Finally, we describe the benefits of combining the next-generation "paradox breaker" RAF inhibitor naporafenib with a GCN2 activator, HC-7366, in A375 melanoma cells. Thus, GCN2 is emerging as a promising cotreatment candidate in melanoma and potentially beyond."

Lung Cancer • Melanoma • Oncology • Solid Tumor • ATF4

Combination of the GCN2 activator HC-7366 with VEGFR-TKI results in greater efficacy than VEGFR-TKI alone or VEGFR-TKI/HIF-2i combinations in ccRCC (AACR 2026) - P1 | "HC-7366 alone achieved 63% tumor growth inhibition (TGI), whereas cabozantinib alone induced 30% regression (1/8 PR) and lenvatinib alone produced 95% TGI...Furthermore, in a single mouse trial of 10 RCC PDX models, addition of HC-7366 to axitinib improved outcomes in 8/10 PDX models and was superior to the belzutifan/axitinib doublet in multiple models...A phase 1b clinical trial is now ongoing to evaluate the safety, tolerability, and efficacy of both HC-7366/belzutifan and HC-7366/cabozantinib doublets in metastatic ccRCC (NCT06234605). These results will form a foundation for future evaluation of triplet combinations that integrate HC-7366, VEGFR-TKIs, and HIF-2 inhibitors."

Clinical • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1 • HIF1A

HiberCell to Present Preclinical Data Demonstrating the Enhanced Antitumor Activity of HC-7366 in Combination with VEGFR-TKIs in Clear Cell Renal Cell Carcinoma (ccRCC) (GlobeNewswire) - "The poster will present data showing that HC-7366 enhanced the activity of multiple VEGFR-TKIs, including lenvatinib, cabozantinib, and axitinib in preclinical metastatic ccRCC models, with HC-7366 and VEGFR-TKI doublets outperforming the combination of HIF-2α inhibitor and VEGFR-TKI in several preclinical patient-derived xenograft models. The data further support HC-7366 as a potential strategy to overcome VEGFR-TKI resistance in metastatic ccRCC and provide rationale for clinical evaluation of HC-7366 and VEGFR-TKI combinations in ccRCC."

Preclinical • Clear Cell Renal Cell Carcinoma

HC-7366, a potent GCN2 activator, complements belzutifan, a HIF-2⍺ antagonist, by providing combination benefit in belzutifan-sensitive models and monotherapy activity in belzutifan-resistant models (AACR 2024) - P1 | "Belzutifan is currently being tested in indications beyond RCC, so we evaluated the combination in VHLwt endometrial cancer model, MFE-280. Consistent with RCC models, the combination of HC-7366 and belzutifan resulted in tumor stasis with activation of ISR, enhanced inhibition of HIF and cell cycle markers in the combination vs belzutifan monotherapy.Together, these findings suggest that HC-7366 enhances belzutifan activity and serves as a rationale supporting clinical evaluation of this therapeutic combination."

Monotherapy • Clear Cell Renal Cell Carcinoma • Endometrial Cancer • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • EPAS1 • HIF1A

A Phase 1b Study of HC-7366, an Agonist of ISR With Immunotherapy in Kidney Cancer (SHARK) (clinicaltrials.gov) - P1 | N=35 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Jul 2026 ➔ Mar 2026

Enrollment open • First-in-human • Trial initiation date • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

HC-7366, a potent GCN2 kinase activator, augments osimertinib therapy to delay resistance in EGFR mutant NSCLC models (AACR 2024) - P1 | "We found a proliferation reduction by Ki67 and an increase in apoptotic proteins CHOP, PUMA, and cleaved caspase 3. Taken together, these data reveal that combination of HC-7366 and osimertinib, and potentially other EGFR TKIs, may be an effective treatment strategy at targeting adaptive resistance mechanisms."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ATF4 • CASP3 • CCND1 • CDK4 • EGFR • HIF1A • TIMM17A

A Phase 1b Study of HC-7366, an Agonist of ISR With Immunotherapy in Kidney Cancer (SHARK) (clinicaltrials.gov) - P1 | N=35 | Not yet recruiting | Sponsor: M.D. Anderson Cancer Center

First-in-human • New P1 trial • Genito-urinary Cancer • Kidney Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Phase 1b study of HC-7366 alone and in combination with venetoclax and azacitidine in relapsed/refractory Acute Myeloid Leukemia (ASH 2025) - P1 | "Initiation of triplet dose escalation is planned for Q3 2025. (NCT06285890)Funding: MDACC NCI Cancer Center Support Grant, HiberCell, Inc."

Combination therapy • P1 data • Acute Myelogenous Leukemia • Central Nervous System Leukemia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • MCL1

Activation of GCN2 By HC-7366 Results in Significant Anti-Tumor Efficacy As Monotherapy and Overcomes Resistance Mechanisms When Combined with Venetoclax in AML (ASH 2023) - P1 | "Venetoclax (anti-BCL2) is approved for elderly patients with acute myeloid leukemia (AML) in combination with hypomethylating agents such as azacitidine or decitabine. Our in vitro and in vivo results demonstrate that HC-7366 is a potent GCN2 activator with strong antitumor activity in AML as a single agent and in combination with venetoclax. The potential of HC-7366 to counteract multiple known resistance mechanisms to venetoclax could provide a viable treatment option for patients with relapsed/refractory AML when used in combination with venetoclax."

Clinical • IO biomarker • Monotherapy • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ATF4 • FLT3 • PSAT1 • S100A8

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). (ASCO 2025) - P1 | "in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson [email protected], 651.312.5831."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

HiberCell Announces Successful Completion of Dose Escalation and Enrollment Update for Ph1b Study Evaluating HC-7366 in Combination with WELIREG (belzutifan) in Advanced ccRCC (The Manila Times) - "HiberCell, Inc...today announced the successful completion of the dose escalation portion of its Phase 1b study evaluating HC-7366—an activator of the integrated stress response (ISR) kinase GCN2—in combination with...WELIREG (belzutifan) for the treatment of advanced clear cell renal cell carcinoma (ccRCC)....All three dose levels tested cleared the respective dose-limiting toxicity (DLT) evaluations. Based on the favorable safety and PK/PD profile, the 40 mg and 60 mg doses of HC-7366 were selected for further evaluation in combination with belzutifan....Enrollment for the 60 mg cohort is ongoing and is expected to complete before the end of the second quarter of 2025."

Trial status • Clear Cell Renal Cell Carcinoma

A phase 1b, open-label, safety, tolerability, and efficacy study of HC-7366 in combination with belzutifan in patients with advanced or metastatic renal cell carcinoma (NCT06234605). (ASCO-GU 2025) - P1 | "in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Sponsor contact: Paulette Mattson [email protected], 651.312.5831."

Clinical • Combination therapy • Metastases • P1 data • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • EPAS1

RCC-TIP: A Hibercell phase I study of HC-7366 and belzutifan (DAVAGU 2024) - No abstract available.

HiberCell Receives FDA Fast Track Designation for HC-7366 for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia (AML) (GlobeNewswire) - "HiberCell, Inc...is pleased to announce that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation to HC-7366 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia."

Fast track • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Congratulations | Pharmaron Holds Eleventh Annual Symposium [Google translation] (Sina Corp) - "Pharmaron held its 11th Symposium on Synthetic and Medicinal Chemistry on the 21st September, 2024, in Beijing, China....Mr. Chris Thomas, Pharmaron, UK, disclosed the medicinal chemistry path to 'The Discovery of HC-7366: An Orally Bioavailable and Efficient GCN2 Kinase Activator ', in a collaboration between HiberCell and Pharmaron, which has successfully entered into phase 1b clinical trial."

Clinical • Oncology

HiberCell Announces First Patient Dosed in Phase 1b Clinical Trial, Evaluating HC-7366 in Combination with Venetoclax and Azacitidine for the Treatment of Acute Myeloid Leukemia (AML) (GlobeNewswire) - "HiberCell, Inc...is pleased to announce the first patient dosed in a clinical trial evaluating HC-7366 in combination with standard of care agents venetoclax and azacitidine for advanced acute myeloid leukemia (AML)....The initiation of this study along with our recently announced study of HC-7366 in clear cell renal cell carcinoma marks the continued advancement of HC-7366 and HiberCell....We look forward to seeing data for these studies throughout 2024 and 2025....The study aims to determine the recommended Phase 2 dose (RP2D) of HC-7366 in combination with venetoclax and azacitidine in a R/R AML population. The study will enroll up to 18 patients."

P1 data • Trial status • Acute Myelogenous Leukemia • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Malignancies • Oncology

Phase I Study of HC-7366 With Azacitidine and Venetoclax for Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=18 | Recruiting | Sponsor: M.D. Anderson Cancer Center | Not yet recruiting ➔ Recruiting | Initiation date: Aug 2024 ➔ May 2024

Enrollment open • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

HiberCell Announces First Patient Dosed in Clinical Collaboration with Merck, Evaluating HC-7366 in Combination with WELIREG (belzutifan) in patients with advanced ccRCC (GlobeNewswire) - "HiberCell...is pleased to announce the dosing of the first patient in a Phase 1b study evaluating HC-7366, an activator of integrated stress response (ISR) Kinase GCN2, in combination with Merck’s oral hypoxia-inducible factor-2α (HIF-2α) inhibitor WELIREG (belzutifan) for the treatment of advanced clear cell renal cell carcinoma (ccRCC). The Phase 1b study (NCT06234605) will evaluate the safety, tolerability, and preliminary efficacy of HC-7366 in combination with belzutifan in patients with advanced ccRCC. This trial will also determine a recommended Phase 2 dose (RP2D) of HC-7366 in combination with fixed-dose belzutifan, 120 mg po qd."

Trial status • Clear Cell Renal Cell Carcinoma • Von Hippel-Lindau Syndrome

HiberCell Announces Recent Publication and Poster Presentations for its Novel GCN2 Activator, HC-7366 (GlobeNewswire) - "HiberCell...announced the publication of 'Discovery of HC-7366: An Orally Bioavailable and Efficacious GCN2 Kinase Activator' in the Journal of Medicinal Chemistry along with two poster presentations on this same molecule which will be highlighted at the American Association for Cancer Research (AACR) Annual Meeting 2024....'Our publication in the Journal of Medicinal Chemistry illustrates that that HC-7366 is a refined GCN2 activator with a superior PK/PD profile, enhanced selectivity, and robust preclinical efficacy'....Our first poster features the remarkable preclinical activity of HC-7366 as monotherapy and in combination with belzutifan in clear cell renal cell carcinoma models (ccRCC)....Our second presentation details preclinical data demonstrating the ability of HC-7366 to augment osimertinib therapy to counteract resistance mechanisms in models of EGFR mutant NSCLC."

Preclinical • Clear Cell Renal Cell Carcinoma • Non Small Cell Lung Cancer