Accelerated approval of Oxbryta® (voxelotor): A case study on novel endpoint selection in sickle cell disease.

Sickle cell disease (SCD) is an inherited disease characterized by hemolysis, anemia, and vaso-occlusion leading to substantial morbidity and mortality. Development of prior pharmacologic therapies exclusively utilized vaso-occlusive crisis (VOC) as a clinical efficacy endpoint; however, this focus on VOC did not capture the full extent of disease symptomatology and complications and slowed the development of new therapies. Voxelotor, a hemoglobin S polymerization inhibitor, was recently approved in the United States for the treatment of SCD in adults and adolescents 12 years of age and older through an accelerated approval pathway. The rapid approval and availability of voxelotor was facilitated in a collaborative effort with the US Food and Drug Administration (FDA), using hemoglobin, a biologic surrogate endpoint, as reasonably likely to predict clinical benefit. Use of this new endpoint was supported by FDA-led multistakeholder discussions with physician and patient communities to identify unmet needs and potential clinical trial endpoints, as well as by a company-sponsored analysis of external patient-level data to demonstrate a correlation between hemoglobin change and stroke risk. A two-part phase 3 study was used to allow for rank ordering of key secondary endpoints based on a planned interim analysis. Continued open communication with the FDA was essential to gain agreement on hemoglobin as a novel endpoint and to address the unmet and urgent need of new therapies for SCD.

A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease.

BACKGROUND: Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of sickle cell disease. Therefore, direct inhibition of HbS polymerization has potential to favorably modify disease outcomes. Voxelotor is an HbS polymerization inhibitor. METHODS: In a multicenter, phase 3, double-blind, randomized, placebo-controlled trial, we compared the efficacy and safety of two dose levels of voxelotor (1500 mg and 900 mg, administered orally once daily) with placebo in persons with sickle cell disease. The primary end point was the percentage of participants who had a hemoglobin response, which was defined as an increase of more than 1.0 g per deciliter from baseline at week 24 in the intention-to-treat analysis. RESULTS: A total of 274 participants were randomly assigned in a 1:1:1 ratio to receive a once-daily oral dose of 1500 mg of voxelotor, 900 mg of voxelotor, or placebo. Most participants had sickle cell anemia (homozygous hemoglobin S or hemoglobin Sß0-thalassemia), and approximately two thirds were receiving hydroxyurea at baseline. In the intention-to-treat analysis, a significantly higher percentage of participants had a hemoglobin response in the 1500-mg voxelotor group (51%; 95% confidence interval [CI], 41 to 61) than in the placebo group (7%; 95% CI, 1 to 12). Anemia worsened between baseline and week 24 in fewer participants in each voxelotor dose group than in those receiving placebo. At week 24, the 1500-mg voxelotor group had significantly greater reductions from baseline in the indirect bilirubin level and percentage of reticulocytes than the placebo group. The percentage of participants with an adverse event that occurred or worsened during the treatment period was similar across the trial groups. Adverse events of at least grade 3 occurred in 26% of the participants in the 1500-mg voxelotor group, 23% in the 900-mg voxelotor group, and 26% in the placebo group. Most adverse events were not related to the trial drug or placebo, as determined by the investigators. CONCLUSIONS: In this phase 3 randomized, placebo-controlled trial involving participants with sickle cell disease, voxelotor significantly increased hemoglobin levels and reduced markers of hemolysis. These findings are consistent with inhibition of HbS polymerization and indicate a disease-modifying potential. (Funded by Global Blood Therapeutics; HOPE ClinicalTrials.gov number, NCT03036813.).

Efficacy and Safety of Lampalizumab for Geographic Atrophy Due to Age-Related Macular Degeneration: Chroma and Spectri Phase 3 Randomized Clinical Trials.

Importance: Geographic atrophy (GA) secondary to age-related macular degeneration is a leading cause of visual disability in older individuals. A phase 2 trial suggested that lampalizumab, a selective complement factor D inhibitor, reduced the rate of GA enlargement, warranting phase 3 trials. Objective: To assess the safety and efficacy of lampalizumab vs sham procedure on enlargement of GA. Design, Setting, and Participants: Two identically designed phase 3 double-masked, randomized, sham-controlled clinical trials, Chroma and Spectri, enrolled participants from August 28, 2014, to October 6, 2016, at 275 sites in 23 countries. Participants were aged 50 years or older, with bilateral GA and no prior or active choroidal neovascularization in either eye and GA lesions in the study eye measuring 2.54 to 17.78 mm2 with diffuse or banded fundus autofluorescence patterns. Interventions: Participants were randomized 2:1:2:1 to receive 10 mg of intravitreous lampalizumab every 4 weeks, sham procedure every 4 weeks, 10 mg of lampalizumab every 6 weeks, or sham procedure every 6 weeks, through 96 weeks. Main Outcomes and Measures: Safety and efficacy assessed as mean change from baseline in GA lesion area at week 48 from centrally read fundus autofluorescence images of the lampalizumab arms vs pooled sham arms, in the intent-to-treat population and by complement factor I-profile genetic biomarker. Results: A total of 906 participants (553 women and 353 men; mean [SD] age, 78.1 [8.1] years) were enrolled in Chroma and 975 participants (578 women and 397 men; mean [SD] age, 77.9 [8.1] years) were enrolled in Spectri; 1733 of the 1881 participants (92.1%) completed the studies through 48 weeks. The adjusted mean increases in GA lesion area from baseline at week 48 were 1.93 to 2.09 mm2 across all groups in both studies. Differences in adjusted mean change in GA lesion area (lampalizumab minus sham) were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P = .80) for lampalizumab every 4 weeks in Chroma, 0.16 mm2 (95% CI, 0.00-0.31 mm2; P = .048) for lampalizumab every 4 weeks in Spectri, 0.05 mm2 (95% CI, -0.13 to 0.24 mm2; P = .59) for lampalizumab every 6 weeks in Chroma, and 0.09 mm2 (95% CI, -0.07 to 0.24 mm2; P = .27) for lampalizumab every 6 weeks in Spectri. No benefit of lampalizumab was observed across prespecified subgroups, including by complement factor I-profile biomarker. Endophthalmitis occurred after 5 of 12 447 injections (0.04%) or in 5 of 1252 treated participants (0.4%) through week 48. Conclusions and Relevance: In Chroma and Spectri, the largest studies of GA conducted to date, lampalizumab did not reduce GA enlargement vs sham during 48 weeks of treatment. Results highlight the substantial and consistent enlargement of GA, at a mean of approximately 2 mm2 per year. Trial Registration: ClinicalTrials.gov Identifier: NCT02247479 and NCT02247531.

Analysis of safety data in clinical trials using a recurrent event approach.

As an important aspect of the clinical evaluation of an investigational therapy, safety data are routinely collected in clinical trials. To date, the analysis of safety data has largely been limited to descriptive summaries of incidence rates or contingency tables aiming to compare simple rates between treatment arms. Many have argued that this traditional approach failed to take into account important information including severity, onset time, and multiple occurrences of a safety event. In addition, premature treatment discontinuation due to excessive toxicity causes informative censoring and may lead to potential bias in the interpretation of safety events. In this article, we propose a framework to summarize safety data with mean frequency function and compare safety events of interest between treatments with a generalized log-rank test, taking into account the aforementioned characteristics ignored in traditional analysis approaches. In addition, a multivariate generalized log-rank test to compare the overall safety profile of different treatments is proposed. In the proposed method, safety events are considered to follow a recurrent event process with a terminal event for each patient. The terminal event is modeled by a process of two types of competing risks: safety events of interest and other terminal events. Statistical properties of the proposed method are investigated via simulations. An application is presented with data from a phase II oncology trial.

Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE: Trastuzumab emtansine (T-DM1), an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab via a stable thioether linker, has shown clinical activity in single-arm studies enrolling patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC) whose disease had progressed on HER2-targeted therapy in the metastatic setting. PATIENTS AND METHODS: Patients (N = 137) with HER2-positive MBC or recurrent locally advanced breast cancer were randomly assigned to trastuzumab plus docetaxel (HT; n = 70) or T-DM1 (n = 67) as first-line treatment until disease progression or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (PFS) and safety. Key secondary end points included overall survival (OS), objective response rate (ORR), duration of objective response, clinical benefit rate, and quality of life. RESULTS: Median PFS was 9.2 months with HT and 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36 to 0.97); median follow-up was approximately 14 months in both arms. ORR was 58.0% (95% CI, 45.5% to 69.2%) with HT and 64.2% (95% CI, 51.8% to 74.8%) with T-DM1. T-DM1 had a favorable safety profile versus HT, with fewer grade ≥ 3 adverse events (AEs; 46.4% v 90.9%), AEs leading to treatment discontinuations (7.2% v 34.8%), [corrected] and serious AEs (20.3% v 25.8%). Preliminary OS results were similar between treatment arms; median follow-up was approximately 23 months in both arms. CONCLUSION: In this randomized phase II study, first-line treatment with T-DM1 for patients with HER2-positive MBC provided a significant improvement in PFS, with a favorable safety profile, versus HT.

Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer.

PURPOSE: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate comprising trastuzumab and DM1, a microtubule polymerization inhibitor, covalently bound via a stable thioether linker. To characterize the pharmacokinetics (PK) of T-DM1 in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, data from four studies (TDM3569g, TDM4258g, TDM4374g, and TDM4688g) of single-agent T-DM1 administered at 3.6 mg/kg every 3 weeks (q3w) were assessed in aggregate. METHODS: Multiple analytes-T-DM1, total trastuzumab (TT), DM1, and key metabolites-were quantified using enzyme-linked immunosorbent assays or liquid chromatography tandem mass spectrometry. PK parameters of T-DM1, TT, and DM1 exposure were calculated using standard noncompartmental approaches and correlated to efficacy (objective response rate) and safety (platelet counts, hepatic transaminase concentrations). Immunogenicity was evaluated by measuring anti-therapeutic antibodies (ATA) to T-DM1 after repeated dosing using validated bridging antibody electrochemiluminescence or enzyme-linked immunosorbent assays. RESULTS: PK parameters for T-DM1, TT, and DM1 were consistent across studies at cycle 1 and steady state. T-DM1 PK was not affected by residual trastuzumab from prior therapy or circulating extracellular domain of HER2. No significant correlations were observed between T-DM1 exposure and efficacy, thrombocytopenia, or increased concentrations of transaminases. Across the studies, ATA formation was detected in 4.5% (13/286) of evaluable patients receiving T-DM1 q3w. CONCLUSIONS: The PK profile of single-agent T-DM1 (3.6 mg/kg q3w) is predictable, well characterized, and unaffected by circulating levels of HER2 extracellular domain or residual trastuzumab. T-DM1 exposure does not correlate with clinical responses or key adverse events.

Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response.

PURPOSE: Expansion and activation of natural killer (NK) cells with interleukin-2 (IL-2) may enhance antibody-dependent cellular cytotoxicity (ADCC), an important mechanism of rituximab activity. Two parallel Phase I studies evaluated combination therapy with rituximab and IL-2 in relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). EXPERIMENTAL DESIGN: Thirty-four patients with advanced NHL received rituximab (375 mg/m(2) i.v. weekly, weeks 1-4) and escalating doses of s.c. IL-2 [2-7.5 MIU daily (n = 19) or 4.5-14 million international units three times weekly (n = 15), weeks 2-5]. Safety, tolerability, clinical responses, NK cell counts, and ADCC activity were evaluated. RESULTS: Maximally tolerated doses (MTD) of IL-2 were 6 MIU daily and 14 million international units thrice weekly. The most common adverse events were fever, chills, and injection site reactions. Dose-limiting toxicities were fatigue and reversible liver enzyme test elevations. Of the 9 patients enrolled at the daily schedule MTD, 5 showed clinical response. On the thrice-weekly schedule at the MTD, 4 of 5 patients responded. Responders showed median time to progression of 14.9 and 16.1 months, respectively, for the two studies. For the same total weekly dose, thrice-weekly IL-2 administration induced greater increases in NK cell counts than daily dosing, and NK cells correlated with clinical response on the thrice-weekly regimen. ADCC activity was increased and maintained after IL-2 therapy in responding and stable disease patients. CONCLUSIONS: Addition of IL-2 to rituximab therapy is safe and, using thrice-weekly IL-2 dosing, results in NK cell expansion that correlates with response. This combination treatment regimen merits additional evaluation in a randomized clinical trial.