Pharmacokinetics of olverembatinib (HQP1351) in the presence of a strong CYP3A4 inhibitor (itraconazole) or inducer (rifampin) in healthy volunteers.

Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.

First-in-Human Study with Preclinical Data of BCL-2/BCL-xL Inhibitor Pelcitoclax in Locally Advanced or Metastatic Solid Tumors.

PURPOSE: B-cell lymphoma-extra-large (BCL-xL) regulates apoptosis and is an attractive anticancer therapeutic target. However, BCL-xL inhibition also kills mature platelets, hampering clinical development. Using an innovative prodrug strategy, we have developed pelcitoclax (APG-1252), a potent, dual BCL-2 and BCL-xL inhibitor. Aims of this study were to characterize the antitumor activity and safety of pelcitoclax and explore its underlying mechanisms of action (MOA). PATIENTS AND METHODS: Cell line-derived xenograft and patient-derived xenograft (PDX) models were tested to evaluate antitumor activity and elucidate MOA. Subjects (N = 50) with metastatic small-cell lung cancer and other solid tumors received intravenous pelcitoclax once or twice weekly. Primary outcome measures were safety and tolerability; preliminary efficacy (responses every 2 cycles per RECIST version 1.1) represented a secondary endpoint. RESULTS: Pelcitoclax exhibited strong BAX/BAK‒dependent and caspase-mediated antiproliferative and apoptogenic activity in various cancer cell lines. Consistent with cell-based apoptogenic activity, pelcitoclax disrupted BCL-xL:BIM and BCL-xL:PUMA complexes in lung and gastric cancer PDX models. Levels of BCL-xL complexes correlated with tumor growth inhibition by pelcitoclax. Combined with taxanes, pelcitoclax enhanced antitumor activity by downregulating antiapoptotic protein myeloid cell leukemia-1 (MCL-1). Importantly, pelcitoclax was well tolerated and demonstrated preliminary therapeutic efficacy, with overall response and disease control rates of 6.5% and 30.4%, respectively. Most common treatment-related adverse events included transaminase elevations and reduced platelets that were less frequent with a once-weekly schedule. CONCLUSIONS: Our data demonstrate that pelcitoclax has antitumor activity and is well tolerated, supporting its further clinical development for human solid tumors, particularly combined with agents that downregulate MCL-1.

Novel BCL-2 Inhibitor Lisaftoclax in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematologic Malignancies: First-in-Human Open-Label Trial.

PURPOSE: This global phase I trial investigated the safety, efficacy, pharmacokinetics, and pharmacodynamics of lisaftoclax (APG-2575), a novel, orally active, potent selective B-cell lymphoma 2 (BCL-2) inhibitor, in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL) and other hematologic malignancies (HMs). PATIENTS AND METHODS: Maximum tolerated dose (MTD) and recommended phase II dose were evaluated. Outcome measures were safety and tolerability (primary) and pharmacokinetic variables and antitumor effects (secondary). Pharmacodynamics in patient tumor cells were explored. RESULTS: Among 52 patients receiving lisaftoclax, MTD was not reached. Treatment-emergent adverse events (TEAEs) included diarrhea (48.1%), fatigue (34.6%), nausea (30.8%), anemia and thrombocytopenia (28.8% each), neutropenia (26.9%), constipation (25.0%), vomiting (23.1%), headache (21.2%), peripheral edema and hypokalemia (17.3% each), and arthralgia (15.4%). Grade ≥ 3 hematologic TEAEs included neutropenia (21.2%), thrombocytopenia (13.5%), and anemia (9.6%), none resulting in treatment discontinuation. Clinical pharmacokinetic and pharmacodynamic results demonstrated that lisaftoclax had a limited plasma residence and systemic exposure and elicited rapid clearance of malignant cells. With a median treatment of 15 (range, 6-43) cycles, 14 of 22 efficacy-evaluable patients with R/R CLL/SLL experienced partial responses, for an objective response rate of 63.6% and median time to response of 2 (range, 2-8) cycles. CONCLUSIONS: Lisaftoclax was well tolerated, with no evidence of tumor lysis syndrome. Dose-limiting toxicity was not reached at the highest dose level. Lisaftoclax has a unique pharmacokinetic profile compatible with a potentially more convenient daily (vs. weekly) dose ramp-up schedule and induced rapid clinical responses in patients with CLL/SLL, warranting continued clinical investigation.

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial.

BACKGROUND: BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). METHODS: In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. RESULTS: A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. CONCLUSIONS: Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. TRIAL REGISTRATION: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Insulin Glargine Combined with Oral Antidiabetic Drugs for Asians with Type 2 Diabetes Mellitus: A Pooled Analysis to Identify Predictors of Dose and Treatment Response.

INTRODUCTION: In Asia, patients with type 2 diabetes mellitus (T2DM) often have suboptimal glycemic control for many years prior to initiating basal insulin. Active titration of basal insulin is also required to improve glycemic outcomes. This pooled analysis was conducted to determine the impact of patient baseline covariates on the required dose of basal insulin and treatment response, for the improved management of Asian patients with T2DM. METHODS: Data on insulin-naïve Asian patients with T2DM who initiated and fully titrated insulin glargine 100 U/mL (Gla-100) for ≥ 20 weeks were pooled from seven randomized, controlled, treat-to-target trials. Covariance and multivariate linear/logistic regression analyses were applied to determine the impact of the baseline covariates on Gla-100 dose (primary outcome) and treatment response (secondary outcomes) at week 24 for patients from Asia (N = 724) and from China alone (n = 249). Based on the multivariate analysis for the primary outcome in the Asian population, a nomogram was developed. RESULTS: The dose of Gla-100 at week 24 was negatively correlated with age and positively correlated with body mass index (BMI) and fasting plasma glucose (FPG) at baseline in both Asian and Chinese populations. In both populations, higher baseline glycated hemoglobin (HbA1c) was associated with a lower reduction in HbA1c from baseline, higher HbA1c at week 24, and a lower chance of achieving HbA1c < 7% at week 24. The constructed nomogram enables calculation of the likely dose of Gla-100 required by Asian patients with T2DM to achieve HbA1c < 7% at week 24. CONCLUSIONS: Higher doses of Gla-100 are likely to be required in younger patients or patients with higher baseline BMI or FPG. The nomogram developed in this study can aid clinicians to titrate the dose of Gla-100 appropriately. Evidence in this pooled analysis also indicates that initiating basal insulin at a lower HbA1c can lead to greater glycemic control. FUNDING: Sanofi China Investment Company.

Prognostic Nomogram for Advanced Hepatocellular Carcinoma Treated with FOLFOX 4

Background: The Oxaliplatin plus 5-Fluorouracil /Leucovorin (FOLFOX4) regimen have been approved by Chinese Food and Drug Administration (CFDA), and covered by health insurance for patients with advanced hepatocellular carcinoma (HCC) in China. However, the efficacy of FOLFOX4 for HCC patients is still under debate. In this study, we aimed to establish a nomogram to identify HCC patients who might benefit from FOLFOX4 chemotherapy base on individual profile. Methods: A total of 184 patients from the EACH study who were treated with FOLFOX4 were included in this analysis. Backward Cox proportional hazards regression combined with clinical experience was used to select variables for construction of the nomogram. The nomogram performance was assessed in terms of discrimination and calibration. The results were validated using bootstrap resampling. Results: Six variables were included in the prognostic models based on their clinical relevance: age, maximum tumor diameter, lymph node status, aspartate aminotransferase (AST), total bilirubin (TBIL) and alpha-fetoprotein (AFP). The calibration curve showed that the predicted survival probabilities closely matched the actual observations. The C-index of the model was 0.75 (95%CI: 0.71-0.80). This value was significantly superior to the one for the following staging systems: BCLC (0.67, P=0.004), CUPI (0.66, P<0.001), AJCC seventh edition (0.63, P=0.002), GRETCH (0.63, P<0.001). Conclusions: The proposed nomogram showed accurate prognostic prediction for 6-month overall survival of patients treated with FOLFOX4 and could be useful for clinicians counseling patients and making treatment decisions.

Lixisenatide Improves Glycemic Control in Asian Type 2 Diabetic Patients Inadequately Controlled With Oral Antidiabetic Drugs: An Individual Patient Data Meta-Analysis.

INTRODUCTION: Lixisenatide is a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus (T2DM). Its efficacy and safety have been assessed in a series of phase 3 studies included in the GetGoal program. In these studies, lixisenatide was found to be superior to placebo in glycemic control. The aim of this meta-analysis was to assess the safety and efficacy of lixisenatide as an adjunct therapy in Asian patients with T2DM in adequately controlled with oral antidiabetic drugs (OADs). METHODS: We performed a meta-analysis from five lixisenatide phase 3 studies. In each of these multiethnic studies, patients with T2DM inadequately controlled (glycated hemoglobin, HbA1c ≥7%) with established OADs were randomized to lixisenatide or placebo for 24 weeks, with a balanced distribution of Asian patients in these two arms (503 and 338 patients in the intent-to-treat population, respectively). RESULTS: Lixisenatide was superior to placebo in reducing HbA1c (weighted, total mean difference -0.57%; P = 0.002). More patients treated with lixisenatide versus placebo achieved HbA1c targets of ≤7% (49.1% vs. 28.4%, P = 0.003). Lixisenatide was superior to placebo in lowering 2-h postprandial glucose (PPG) (weighted, total mean difference -5.50 mmol/l, P = 0.0005). More patients treated with lixisenatide versus placebo achieved 2-h PPG targets of ≤7.8 mmol/l (39.2% vs. 2.2%, P < 0.0001). More patients treated with lixisenatide versus placebo achieved both an HbA1c target of ≤7% and a 2-h PPG target of ≤10 mmol/l (34.8% vs. 2.69%, P < 0.00001). The body weight of the lixisenatide group tended to decrease. Lixisenatide was generally well tolerated. CONCLUSION: Lixisenatide as an adjunct therapy can significantly improve the glycemic control of Asian patients with type 2 DM who do not meet targets for glycemic control with an established OAD regimen. FUNDING: Sanofi (China) Investment Co., Ltd., Shanghai, China.