Daily Report: 01/16/2024

Phase 1 Trials

Endocrinology: Obesity (with or without type 2 diabetes)

A phase 1 randomized, double-blind, placebo-controlled study investigated the effect of an adaptive infusion of the glucagon-like peptide-1/glucagon receptor co-agonist G3215 in 26 adults with overweight or obesity, resulting in a significant mean body weight loss of 2.39 kg with G3215 compared to 0.84 kg with placebo (p < .05) (1). The study also observed a reduction in food consumption and no deterioration in glycaemia, along with an improved lipid profile and a broad reduction in circulating amino acids.

Reference

Hope DCD, Ansari S, Choudhury S, Alexiadou K, Tabbakh Y, Ilesanmi I, Lazarus K, Davies I, Jimenez-Pacheco L, Yang W, Ball LJ, Malviya R, Reglinska B, Khoo B, Minnion J, Bloom SR, Tan TM. Adaptive infusion of a glucagon-like peptide-1/glucagon receptor co-agonist G3215, in adults with overweight or obesity: Results from a phase 1 randomized clinical trial. Diabetes Obes Metab. 2024 Jan 16. doi: 10.1111/dom.15448. Epub ahead of print. PMID: 38229453.

Oncology: Metastatic Castration-Resistant Prostate Cancer (mCRPC)

A Phase 1 study investigated the effect of ORIC-101 in combination with enzalutamide in 41 patients with mCRPC progressing on enzalutamide and found that the disease control rate at 12 weeks was 25.8% (80% CI: 15.65%, 38.52%) at the recommended phase 2 dose (RP2D) of 240 mg ORIC-101 and 160 mg enzalutamide daily (1). However, this did not meet the prespecified target rate, leading to the termination of the study.

Reference

Abida W, Hahn AW, Shore N, Agarwal N, Sieber P, Smith MR, Dorff T, Monk JP, Rettig MB, Patel R, Page A, Duff M, Xu R, Wang J, Barkund S, Pankov A, Wang A, Junttila M, Multani PS, Daemen A, Chow Maneval E, Logothetis CJ, Morris MJ. Phase 1 Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer Progressing on Enzalutamide. Clin Cancer Res. 2024 Jan 16. doi: 10.1158/1078-0432.CCR-23-3508. Epub ahead of print. PMID: 38226958.

Oncology: Advanced Solid Tumors

A Phase 1 study (PATRIOT) investigated the effect of ceralasertib in 67 patients with advanced solid tumors and found that the recommended phase 2 dose was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Results included 5 (8%) confirmed partial responses, 34 (52%) stable disease, and 27 (41%) progressive disease, with durable responses observed in tumors with ARID1A loss and DNA damage-response defects (1). [ClinicalTrials.gov: NCT02223923, EudraCT: 2013-003994-84; Funded by Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre]

Reference

Dillon MT, Guevara J, Mohammed K, Patin EC, Smith SA, Dean E, Jones GN, Willis SE, Petrone M, Silva C, Thway K, Bunce C, Roxanis I, Nenclares P, Wilkins A, McLaughlin M, Jayme-Laiche A, Benafif S, Nintos G, Kwatra V, Grove L, Mansfield D, Proszek P, Martin P, Moore L, Swales KE, Banerji U, Saunders MP, Spicer J, Forster MD, Harrington KJ. Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation. J Clin Invest. 2024 Jan 16;134(2):e175369. doi: 10.1172/JCI175369. PMID: 37934611; PMCID: PMC10786692.

Oncology: Advanced Gastric Cancer in Older Patients

Phase 2 Studies

A Phase II study investigated the combination of S-1 and docetaxel as first-line treatment in 31 older patients (aged 75 years or older) with advanced gastric cancer (1). The treatment regimen included docetaxel at 40 mg/m^2 and S-1 at 80 mg/m^2 in 3-week cycles. The primary endpoint was the overall response rate, with secondary endpoints including safety, progression-free survival, time to treatment failure, and overall survival. The study reported a response rate of 45.2%, with a median progression-free survival of 5.8 months, a 1-year survival rate of 58.1%, and a median survival time of 16.1 months. Major adverse events included neutropenia, febrile neutropenia, anemia, anorexia, and fatigue. The study concluded that S-1 plus docetaxel is a feasible and effective first-line treatment for older patients with advanced gastric cancer.

Reference

Kawase T, Imamura H, Kawabata R, Matsuyama J, Nishikawa K, Yanagihara K, Yamamoto K, Hoki N, Kawada J, Kawakami H, Sakai D, Kurokawa Y, Shimokawa T, Satoh T. Phase II study of S-1 plus docetaxel as first-line treatment for older patients with advanced gastric cancer (OGSG 0902). Int J Clin Oncol. 2024 Feb;29(2):134-141. doi: 10.1007/s10147-023-02437-4. Epub 2024 Jan 16. PMID: 38227090.

Hematology/Oncology: Graft-versus-Host Disease in Hematopoietic Stem Cell Transplant Recipients

A randomized Phase 2 double-blinded, placebo-controlled clinical trial assessed the efficacy of oral Vitamin A in preventing graft-versus-host disease (GVHD) in 80 pediatric and young adult hematopoietic stem cell transplant recipients (1). Participants received either a high-dose Vitamin A or placebo pre-transplant. The primary endpoint was the incidence of acute GVHD at day +100. Results showed that acute GVHD incidence was 12.5% in the Vitamin A group and 20% in the placebo group (p=0.5), with chronic GVHD incidence at 5% and 15% respectively (p=0.02) at 1 year. The study reported a lower incidence of acute GI GVHD and chronic GVHD in the Vitamin A arm, with minimal toxicity observed. The study concluded that pre-transplant oral Vitamin A is a low-toxicity, cost-effective method to reduce GVHD. Trial Registration: ClinicalTrials.gov Identifier: NCT03202849.

Reference

Khandelwal P, Langenberg L, Luebbering N, Lake K, Butcher A, Werling K, Ramos KN, Taggart C, Choe HK, Vasu S, Teusink-Cross A, Koo J, Wallace G, Romick-Rosendale L, Watanabe-Chailland M, Haslam DB, Lane A, Davies SM. A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults. Blood. 2024 Jan 16:blood.2023022865. doi: 10.1182/blood.2023022865. Epub ahead of print. PMID: 38227933.

Phase 2/3 Study

Neurology: Acute Ischemic Stroke

A Phase 2/3 double-blind, parallel-group, placebo-controlled randomized clinical trial, known as the TREASURE trial (Treatment Evaluation of Acute Stroke Using Regenerative Cells), investigated the effect of MultiStem (allogeneic, multipotent adult progenitor cell product) in 206 patients with acute ischemic stroke (1). This trial took place at 44 centers in Japan and included patients aged 20 years or older, with NIHSS scores of 8-20, and acute infarction involving the cerebral cortex. The study aimed to evaluate the safety and efficacy of MultiStem administered within 18 to 36 hours of ischemic stroke onset. The primary endpoints were safety and excellent outcome at day 90, with secondary endpoints at day 365. The results showed no significant difference in outcomes between the MultiStem and placebo groups. The study concluded that while safe, MultiStem did not improve short-term outcomes in ischemic stroke patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Reference

Houkin K, Osanai T, Uchiyama S, Minematsu K, Taguchi A, Maruichi K, Niiya Y, Asaoka K, Kuga Y, Takizawa K, Haraguchi K, Yoshimura S, Kimura K, Tokunaga K, Aoyama A, Ikawa F, Inenaga C, Abe T, Tominaga A, Takahashi S, Kudo K, Fujimura M, Sugiyama T, Ito M, Kawabori M, Hess DC, Savitz SI, Hirano T; TREASURE Study Investigators. Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial. JAMA Neurol. 2024 Jan 16:e235200. doi: 10.1001/jamaneurol.2023.5200. Epub ahead of print. PMID: 38227308; PMCID: PMC10792497.

Phase 3 Studies

Dermatology: Moderate to Severe Plaque Psoriasis

A phase 3b open-label study, part of the POETYK long-term extension (LTE) trials, investigated the effect of deucravacitinib in 1519 patients with moderate to severe plaque psoriasis (1). The study reported that 72.4% of patients achieved a ≥75% reduction in the Psoriasis Area and Severity Index (PASI 75) at Week 52, increasing to 79.7% at Week 112, and 57.9% achieved a static Physician Global Assessment (sPGA) score of 0/1 at Week 52, increasing to 61.1% at Week 112. The safety profile remained consistent over 2 years, with no new safety signals observed.

Reference

Lebwohl M, Warren RB, Sofen H, Imafuku S, Paul C, Szepietowski JC, Spelman L, Passeron T, Vritzali E, Napoli A, Kisa RM, Buck A, Banerjee S, Thaçi D, Blauvelt A. Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase 3 poetyk trials. Br J Dermatol. 2024 Jan 16:ljae014. doi: 10.1093/bjd/ljae014. Epub ahead of print. PMID: 38226713.

Gastroenterology: Diabetic and Idiopathic Gastroparesis

A Phase III randomized placebo-controlled clinical trial investigated the effect of tradipitant in 201 adults with gastroparesis and found that the initial analysis did not meet the pre-specified primary endpoint at Week 12 (1). Post hoc analyses with high blood levels of tradipitant showed statistically significant improvements in nausea severity from Weeks 2 through 12. [ClinicalTrials.gov number, NCT04028492]

Reference

Carlin JL, Polymeropoulos C, Camilleri M, Lembo A, Fisher M, Kupersmith C, Madonick D, Moszczynski P, Smieszek S, Xiao C, Birznieks G, Polymeropoulos MH. The Efficacy of Tradipitant in Patients with Diabetic and Idiopathic Gastroparesis in Phase III Randomized Placebo-Controlled Clinical Trial. Clin Gastroenterol Hepatol. 2024 Jan 16:S1542-3565(24)00050-8. doi: 10.1016/j.cgh.2024.01.005. Epub ahead of print. PMID: 38237696.

Oncology: Renal Cell Carcinoma

A phase III open-label study, the CLEAR trial, compared lenvatinib plus pembrolizumab against sunitinib in treatment-naïve patients with advanced renal cell carcinoma (1). The final prespecified overall survival analysis reported an overall survival hazard ratio of 0.79 (95% CI, 0.63 to 0.99), with median overall survival of 53.7 months for lenvatinib plus pembrolizumab versus 54.3 months for sunitinib. The study also found a median progression-free survival of 23.9 months with the combination therapy compared to 9.2 months with sunitinib, and an objective response rate of 71.3% versus 36.7%, respectively. Treatment-emergent adverse events were observed in over 90% of patients in both treatment groups.

Reference

Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Méndez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Jan 16:JCO2301569. doi: 10.1200/JCO.23.01569. Epub ahead of print. PMID: 38227898.