Bayesian dose regimen assessment in early phase oncology incorporating pharmacokinetics and pharmacodynamics.

Phase I dose-finding trials in oncology seek to find the maximum tolerated dose of a drug under a specific schedule. Evaluating drug schedules aims at improving treatment safety while maintaining efficacy. However, while we can reasonably assume that toxicity increases with the dose for cytotoxic drugs, the relationship between toxicity and multiple schedules remains elusive. We proposed a Bayesian dose regimen assessment method (DRtox) using pharmacokinetics/pharmacodynamics (PK/PD) to estimate the maximum tolerated dose regimen (MTD-regimen) at the end of the dose-escalation stage of a trial. We modeled the binary toxicity via a PD endpoint and estimated the dose regimen toxicity relationship through the integration of a dose regimen PD model and a PD toxicity model. For the first model, we considered nonlinear mixed-effects models, and for the second one, we proposed the following two Bayesian approaches: a logistic model and a hierarchical model. In an extensive simulation study, the DRtox outperformed traditional designs in terms of proportion of correctly selecting the MTD-regimen. Moreover, the inclusion of PK/PD information helped provide more precise estimates for the entire dose regimen toxicity curve; therefore the DRtox may recommend alternative untested regimens for expansion cohorts. The DRtox was developed to be applied at the end of the dose-escalation stage of an ongoing trial for patients with relapsed or refractory acute myeloid leukemia (NCT03594955) once all toxicity and PK/PD data are collected.

Bayesian modeling of a bivariate toxicity outcome for early phase oncology trials evaluating dose regimens.

Most phase I trials in oncology aim to find the maximum tolerated dose (MTD) based on the occurrence of dose limiting toxicities (DLT). Evaluating the schedule of administration in addition to the dose may improve drug tolerance. Moreover, for some molecules, a bivariate toxicity endpoint may be more appropriate than a single endpoint. However, standard dose-finding designs do not account for multiple dose regimens and bivariate toxicity endpoint within the same design. In this context, following a phase I motivating trial, we proposed modeling the first type of DLT, cytokine release syndrome, with the entire dose regimen using pharmacokinetics and pharmacodynamics (PK/PD), whereas the other DLT (DLTo ) was modeled with the cumulative dose. We developed three approaches to model the joint distribution of DLT, defining it as a bivariate binary outcome from the two toxicity types, under various assumptions about the correlation between toxicities: an independent model, a copula model and a conditional model. Our Bayesian approaches were developed to be applied at the end of the dose-allocation stage of the trial, once all data, including PK/PD measurements, were available. The approaches were evaluated through an extensive simulation study that showed that they can improve the performance of selecting the true MTD-regimen compared to the recommendation of the dose-allocation method implemented. Our joint approaches can also predict the DLT probabilities of new dose regimens that were not tested in the study and could be investigated in further stages of the trial.

Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.

BACKGROUND: Alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), has been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are receiving statin therapy. Larger and longer-term studies are needed to establish safety and efficacy. METHODS: We conducted a randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable side-effect profile), with or without other lipid-lowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. RESULTS: At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was -62 percentage points (P<0.001); the treatment effect remained consistent over a period of 78 weeks. The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%). In a post hoc analysis, the rate of major adverse cardiovascular events (death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P=0.02). CONCLUSIONS: Over a period of 78 weeks, alirocumab, when added to statin therapy at the maximum tolerated dose, significantly reduced LDL cholesterol levels. In a post hoc analysis, there was evidence of a reduction in the rate of cardiovascular events with alirocumab. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY LONG TERM ClinicalTrials.gov number, NCT01507831.).

Efficacy and Safety of Alirocumab in Patients with Heterozygous Familial Hypercholesterolemia and LDL-C of 160 mg/dl or Higher.

PURPOSE: Even with statins and other lipid-lowering therapy (LLT), many patients with heterozygous familial hypercholesterolemia (heFH) continue to have elevated low-density lipoprotein cholesterol (LDL-C) levels. ODYSSEY HIGH FH (NCT01617655) assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 monoclonal antibody, versus placebo in patients with heFH and LDL-C ≥ 160 mg/dl despite maximally tolerated statin ± other LLT. METHODS: Patients were randomized to subcutaneous alirocumab 150 mg or placebo every 2 weeks (Q2W) for 78 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. RESULTS: Mean baseline LDL-C levels were 196.3 mg/dl in the alirocumab (n = 71) and 201.0 mg/dl in the placebo groups (n = 35). Significant mean (standard error [SE]) reductions in LDL-C from baseline to week 24 were observed with alirocumab (-45.7 [3.5] %) versus placebo (-6.6 [4.9] %), a difference of -39.1 (6.0) % (P < 0.0001). Absolute mean (SE) LDL-C levels were reduced from baseline by 90.8 (6.7) mg/dl with alirocumab at week 24, with reductions maintained to week 78. Treatment-emergent adverse events were generally comparable between groups. Injection-site reactions were more frequent in the alirocumab group (8.3 %) versus placebo (5.7 %); most were mild in severity and did not result in study medication discontinuation. CONCLUSIONS: In patients with heFH and very high LDL-C baseline levels despite maximally tolerated statin ± other LLT, alirocumab 150 mg Q2W demonstrated significant reductions in LDL-C levels with 41 % of patients achieving predefined LDL-C goals. Alirocumab was generally well tolerated.

Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial.

AIMS: To compare the efficacy [low-density lipoprotein cholesterol (LDL-C) lowering] and safety of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin 9, compared with ezetimibe, as add-on therapy to maximally tolerated statin therapy in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia. METHODS AND RESULTS: COMBO II is a double-blind, double-dummy, active-controlled, parallel-group, 104-week study of alirocumab vs. ezetimibe. Patients (n = 720) with high cardiovascular risk and elevated LDL-C despite maximal doses of statins were enrolled (August 2012-May 2013). This pre-specified analysis was conducted after the last patient completed 52 weeks. Patients were randomized to subcutaneous alirocumab 75 mg every 2 weeks (plus oral placebo) or oral ezetimibe 10 mg daily (plus subcutaneous placebo) on a background of statin therapy. At Week 24, mean ± SE reductions in LDL-C from baseline were 50.6 ± 1.4% for alirocumab vs. 20.7 ± 1.9% for ezetimibe (difference 29.8 ± 2.3%; P < 0.0001); 77.0% of alirocumab and 45.6% of ezetimibe patients achieved LDL-C <1.8 mmol/L (P < 0.0001). Mean achieved LDL-C at Week 24 was 1.3 ± 0.04 mmol/L with alirocumab and 2.1 ± 0.05 mmol/L with ezetimibe, and were maintained to Week 52. Alirocumab was generally well tolerated, with no evidence of an excess of treatment-emergent adverse events. CONCLUSION: In patients at high cardiovascular risk with inadequately controlled LDL-C, alirocumab achieved significantly greater reductions in LDL-C compared with ezetimibe, with a similar safety profile. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01644188.

ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.

AIMS: To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). METHODS AND RESULTS: In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; -57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; -51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). CONCLUSION: In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. CLINICAL TRIAL REGISTRATION: Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).

Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study.

BACKGROUND: The ODYSSEY COMBO I study (http://clinicaltrials.gov/show/NCT01644175) evaluated efficacy and safety of alirocumab as add-on therapy to stable maximally tolerated daily statin with or without other lipid-lowering therapy in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia. METHODS: This multicenter, phase 3, randomized (2:1 alirocumab vs placebo), double-blind, 52-week trial enrolled 316 patients with established coronary heart disease or coronary heart disease risk equivalents and hypercholesterolemia. Alirocumab (75 mg every 2 weeks [Q2W]) or placebo Q2W was self-administered subcutaneously via 1 mL prefilled pen. The alirocumab dose was increased to 150 mg Q2W (also 1 mL) at week 12 if week 8 low-density lipoprotein cholesterol (LDL-C) was ≥70 mg/dL. The primary efficacy end point was percent change in LDL-C from baseline to week 24 (intention-to-treat analysis). RESULTS: At week 24, estimated mean (95% CI) changes in LDL-C from baseline were -48.2% (-52.0% to -44.4%) and -2.3% (-7.6% to 3.1%) for alirocumab and placebo, respectively, an estimated mean (95% CI) difference of -45.9% (-52.5% to -39.3%) (P < .0001). Low-density lipoprotein cholesterol <70 mg/dL was achieved by 75% alirocumab versus 9% placebo patients at week 24. At week 12, 83.2% of evaluable alirocumab-treated patients remained on 75-mg Q2W. Treatment-emergent adverse events were comparable between groups. CONCLUSIONS: Alirocumab treatment achieved a significantly greater reduction in LDL-C and allowed a greater proportion of patients to achieve LDL-C goals, versus placebo after 24 weeks in high cardiovascular risk patients with suboptimally controlled hypercholesterolemia at baseline despite receiving maximally tolerated statin with or without other lipid-lowering therapy. The frequency of treatment-emergent adverse events and study medication discontinuations were generally comparable between treatment groups.

Adaptive and repeated cumulative meta-analyses of safety data during a new drug development process.

During a new drug development process, it is desirable to timely detect potential safety signals. For this purpose, repeated meta-analyses may be performed sequentially on accumulating safety data. Moreover, if the amount of safety data from the originally planned program is not enough to ensure adequate power to test a specific hypothesis (e.g., the noninferiority hypothesis of an event of interest), the total sample size may be increased by adding new studies to the program. Without appropriate adjustment, it is well known that the type I error rate will be inflated because of repeated analyses and sample size adjustment. In this paper, we discuss potential issues associated with adaptive and repeated cumulative meta-analyses of safety data conducted during a drug development process. We consider both frequentist and Bayesian approaches. A new drug development example is used to demonstrate the application of the methods.

Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies.

BACKGROUND: Individuals with heterozygous familial hypercholesterolemia (heFH) have higher levels of low-density lipoprotein cholesterol (LDL-C) and are predisposed to premature cardiovascular disease. Alirocumab is a fully-human, monoclonal antibody targeted to proprotein convertase subtilisin/kexin type 9 currently in Phase 3 development for the treatment of hypercholesterolemia. Described here are three ODYSSEY Phase 3 trials, FH I (NCT01623115), FH II (NCT01709500) and HIGH FH (patients with heFH and LDL-C levels ≥160 mg/dL) (NCT01617655), in which alirocumab is further evaluated in the heFH population. METHODS: Multicenter, multinational, randomized, double-blind, placebo-controlled studies have been designed to evaluate efficacy and safety of alirocumab in more than 800 patients with heFH who are not adequately controlled with a maximally-tolerated stable daily dose of statin for ≥4 weeks prior to the screening visit, with or without other lipid-lowering therapy. Patients are randomized (2:1) to receive alirocumab or placebo via a 1-mL subcutaneous auto-injection every 2 weeks (Q2W) for 78 weeks. In studies FH I and II, if their Week 8 LDL-C level is ≥70 mg/dL, patients will undergo a dose uptitration from 75 to 150 mg alirocumab Q2W at Week 12. In HIGH FH, patients will receive alirocumab 150 mg Q2W throughout the entire treatment period. The primary efficacy endpoint in all three studies is the percent change in calculated LDL-C from baseline to Week 24. CONCLUSIONS: The ODYSSEY FH studies are three Phase 3 studies aiming to further evaluate the efficacy and long-term safety of alirocumab as an effective therapeutic option for patients with heFH.

Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials.

BACKGROUND: Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin kexin type 9 (PCSK9) under investigation for treatment of hypercholesterolemia and reduction of cardiovascular events. METHODS/DESIGN: The COMBO studies, part of the Phase 3 ODYSSEY clinical trial program, are designed to evaluate the efficacy and safety of alirocumab as add-on therapy to stable, maximally tolerated daily statin, with or without other lipid-lowering therapy (LLT), in a planned 966 patients with hypercholesterolemia at high cardiovascular risk. COMBO I ( http://clinicaltrials.gov/show/NCT01644175) is placebo-controlled, with a double-blind treatment period of 52 weeks, and 306 planned patients who may receive other LLTs in addition to statin therapy. COMBO II ( http://clinicaltrials.gov/show/NCT01644188) has a double-blind treatment period of 104 weeks, comparing alirocumab with ezetimibe in 660 planned patients receiving statin therapy (but no other LLTs). The primary efficacy endpoint is the difference between treatment arms in percent change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 24. Both studies utilized a starting dose of alirocumab 75 mg every 2 weeks (Q2W; administered as 1 mL solution via auto-injector). Patients with LDL-C levels ≥70 mg/dL after 8 weeks of treatment were up-titrated in a blinded manner at week 12 to alirocumab 150 mg Q2W (also 1 mL auto-injector). DISCUSSION: In conclusion, the COMBO studies will provide information on the long-term efficacy and safety of alirocumab in high-risk patients when administered in addition to maximally tolerated statin therapy, with a flexible dosing strategy which allows for individualized therapy based on the degree of LDL-C lowering needed to achieve the desired treatment response. TRIAL REGISTRATIONS COMBO I: NCT01644175 ( NCT01644175). COMBO II: NCT01644188 ( NCT01644188).

Current perspectives for external control arms in oncology clinical trials: Analysis of EMA approvals 2016-2021.

Leveraging external control data, especially real-world data (RWD), has drawn particular attention in recent years for facilitating oncology clinical development and regulatory decision-making. Medical regulators have published guidance on accelerating the use of RWD and external controls. However, few systematic discussions have been conducted on external controls in cancer drug submissions and regulatory feedback. This study aimed to identify European oncology drug approvals using external control data to demonstrate clinical efficacy. We included 18 eligible submissions employing 24 external controls and then discussed the use of external control, data sources, analysis methods, and regulators' feedback. The external controls have been actively submitted to the European Medical Agency (EMA) recently. We found that 17 % of the EMA-approved cancer drugs in 2016-2021 used external controls, among which 37 % of the cases leveraged RWD. However, nearly one-third of the external controls were not considered supportive evidence by EMA due to limitations regarding heterogeneous patient populations, missing outcome assessment in RWD, and inappropriate statistical analysis. This study highlighted that proper use of external controls requires a careful assessment of clinical settings, data availability, and statistical methodology. For better use of external controls in oncology clinical trials, we recommend: prospective study designs to avoid selection bias, sufficient baseline data to ensure the comparability of study populations, consistent endpoint measurements to enable outcome comparison, robust statistical methodology for comparative analysis, and collaborative efforts of sponsors and regulators to establish regulatory frameworks.

A Multi-Arm Two-Stage (MATS) design for proof-of-concept and dose optimization in early-phase oncology trials.

The Project Optimus initiative by the FDA's Oncology Center of Excellence is widely viewed as a groundbreaking effort to change the status quo of conventional dose-finding strategies in oncology. Unlike in other therapeutic areas where multiple doses are evaluated thoroughly in dose ranging studies, early-phase oncology dose-finding studies are characterized by the practice of identifying a single dose, such as the maximum tolerated dose (MTD) or the recommended phase 2 dose (RP2D). Following the spirit of Project Optimus, we propose an Multi-Arm Two-Stage (MATS) design for proof-of-concept (PoC) and dose optimization that allows the evaluation of two selected doses from a dose-escalation trial. The design assesses the higher dose first across multiple indications in the first stage, and adaptively enters the second stage for an indication if the higher dose exhibits promising anti-tumor activities. In the second stage, a randomized comparison between the higher and lower doses is conducted to achieve PoC and dose optimization. A Bayesian hierarchical model governs the statistical inference and decision making by borrowing information across doses, indications, and stages. Our simulation studies show that the proposed MATS design yield desirable performance. An R Shiny application has been developed and made available at https://matsdesign.shinyapps.io/mats/.

Safety of Alirocumab (A PCSK9 Monoclonal Antibody) from 14 Randomized Trials.

Previous individual trials of alirocumab (a PCSK9 monoclonal antibody) showed significant low-density lipoprotein cholesterol reductions with overall treatment-emergent adverse event (TEAE) rates comparable with controls. This analysis evaluated safety data from 14 trials (4 phase 2 and 10 phase 3, 8 to 104 weeks; n = 5,234), in 2 pools according to control (placebo/ezetimibe). Overall, 3,340 patients received alirocumab (4,029 patient-years' exposure), 1,276 received placebo, and 618 received ezetimibe. Incidence of deaths, serious TEAEs, discontinuations because of TEAEs, and overall TEAEs were similar between alirocumab and control groups. Alirocumab was associated with a higher incidence of local injection site reactions (7.4% vs 5.3% with placebo; 3.1% vs 2.3% with ezetimibe), pruritus (1.3% vs 0.4% placebo; 0.9% vs 0.5% ezetimibe), and upper respiratory tract infection signs and symptoms (2.1% vs 1.1% placebo; 1.3% vs 0.8% ezetimibe). Incidence of musculoskeletal, neurologic, neurocognitive, ophthalmologic, hepatic events, and TEAEs related to diabetes/diabetes complications was similar between alirocumab and control groups. In a prespecified analysis of phase 3 studies, adjudicated major adverse cardiovascular events (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, and unstable angina requiring hospitalization) occurred in 1.8% alirocumab versus 2.6% placebo patients (hazard ratio 0.69, 95% confidence interval 0.43 to 1.11) and 2.8% alirocumab versus 1.5% ezetimibe patients (hazard ratio 1.4, 95% confidence interval 0.65 to 3.02). In conclusion, pooled safety data from 14 trials demonstrate that alirocumab is generally well tolerated with a favorable safety profile.