Plain Language Summary of the iNNOVATE study: ibrutinib plus rituximab is well-tolerated and effective in people with Waldenström's macroglobulinemia.

WHAT IS THIS SUMMARY ABOUT?: This article provides a short summary of 5-year results from the iNNOVATE trial. The original paper was published in the Journal of Clinical Oncology in October 2021. People with Waldenström's macroglobulinemia (WM) were randomly divided into two groups of 75 people each. One group received a combination treatment composed of two drugs, ibrutinib plus rituximab, and the other group took placebo ("sugar pill") plus rituximab. Ibrutinib (also known by the brand name Imbruvica®) is a drug that reduces cancer cells' ability to multiply and survive. Ibrutinib is an FDA-approved drug for the treatment of WM. Rituximab is a drug that helps the immune system find and kill cancer cells. Participants in the trial were treated and their health monitored for up to 5 years (63 months). WHAT WERE THE RESULTS?: During the 5 years of monitoring, more people who took ibrutinib plus rituximab experienced an improvement in their disease and lived longer without their disease getting worse compared to those who took placebo plus rituximab. Side effects from ibrutinib and rituximab were manageable and generally decreased over time. Participants in both study groups reported improvements in quality of life, but those who took ibrutinib plus rituximab reported significantly greater improvement in their quality of life (as measured by FACT-An score) compared to those who took placebo plus rituximab. WHAT DO THE RESULTS MEAN?: These results show that ibrutinib plus rituximab is better than rituximab alone in people with WM and that ibrutinib plus rituximab is safe and effective in the long term. This information confirms the role of ibrutinib plus rituximab as a standard of care for WM. Clinical Trial Registration: NCT02165397 (ClinicalTrials.gov).

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study.

PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis.

Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

A phase 2 study of ibrutinib in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

OBJECTIVE: We evaluated ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, combined with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma who had received 1-3 prior therapies. METHODS: This was a phase 2, single-arm, open-label, multicentre study (NCT02902965). The primary endpoint was progression-free survival (PFS). RESULTS: Seventy-six patients were enrolled; 74 received ≥1 dose of study treatment. After median follow-up of 19.6 months, median PFS was 8.5 months (95% CI: 6.2-10.8); median overall survival was not reached. Overall response rate was 57% (95% CI: 45-68), and median duration of response was 9.5 months (95% CI: 6.9-10.6). Grade 3/4 AEs occurred in 73% of patients and fatal AEs occurred in 15% of patients. Incidence of major haemorrhage was 5%; one patient died from cerebral haemorrhage. After an observed increased incidence of serious (42%) and fatal (11%) infections, enrolment was suspended to implement risk-minimisation measures. The safety profile was otherwise consistent with known safety profiles of the individual drugs. CONCLUSION: Ibrutinib combined with bortezomib and dexamethasone elicited clinical responses. However, efficacy assessments conducted at potential restart of enrolment indicated that the targeted PFS could not be reached with additional patient enrolment, and the study was terminated.

Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma - The SHELTER study.

BACKGROUND & AIMS: No established therapies for patients with hepatocellular carcinoma (HCC) and progression on first-line sorafenib treatment currently exist. This phase I/II trial investigated safety, pharmacokinetics and potential biomarkers of the histone deacetylase inhibitor resminostat and a combination therapy with resminostat and sorafenib. METHODS: Patients with HCC and radiologically confirmed progression on sorafenib were treated in an exploratory, multi-center, open-label, uncontrolled, non-randomized, parallel group phase I/II study. In the combination group (n=38) four dose levels ranged from daily 200 to 600mg resminostat plus 400 to 800mg sorafenib. The monotherapy group (n=19) received 600mg resminostat. RESULTS: 57 patients received treatment. Most common adverse events were gastrointestinal disorders, thrombocytopenia and fatigue. Median maximal histone deacetylase inhibition and highest increase in H4-acetylation matched Tmax of resminostat. Sorafenib or the Child-Pugh score did not affect typical pharmacokinetics characteristics of resminostat. Efficacy assessment as progression-free survival-rate after 6 treatment cycles (12weeks, primary endpoint) was 12.5% for resminostat and 62.5% for resminostat plus sorafenib. Median time to progression and overall survival were 1.8 and 4.1months for resminostat and 6.5 and 8.0months for the combination, respectively. Zinc finger protein 64 (ZFP64) baseline expression in blood cells was found to correlate with overall survival. CONCLUSIONS: The combination of sorafenib and resminostat in HCC patients was safe and showed early signs of efficacy. Sorafenib did not alter the pharmacokinetic profile of resminostat or its histone deacetylase inhibitory activity in vivo. A prognostic and potentially predictive role of ZFP64 for treatment with resminostat should be further investigated in HCC and possibly other cancer indications. LAY SUMMARY: No established therapy for patients with advanced hepatocellular carcinoma and progression under first-line systemic treatment with sorafenib currently exists. Epigenetic modulation by inhibition of histone deacetylases might be able to overcome therapy resistance. This exploratory phase I/II clinical study in patients with radiologically confirmed progression under first-line treatment with sorafenib investigated the histone deacetylases inhibitor resminostat as single agent or in combination with continued application of sorafenib. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered at www.clinicaltrials.gov as NCT00943449.

First-in-human, pharmacokinetic and pharmacodynamic phase I study of Resminostat, an oral histone deacetylase inhibitor, in patients with advanced solid tumors.

PURPOSE: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. EXPERIMENTAL DESIGN: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. RESULTS: Nineteen patients (median age 58 years, range 39-70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. CONCLUSIONS: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days.

The oral, once-daily phosphodiesterase 4 inhibitor roflumilast lacks relevant pharmacokinetic interactions with inhaled budesonide.

This open-label, randomized, 3-period crossover study evaluated the pharmacokinetic interaction potential of roflumilast and budesonide following repeated coadministration to healthy male subjects (N = 12). Treatments consisted of oral roflumilast 500 mug, once daily, orally inhaled budesonide 800 mug, twice daily, and concomitant administration of both treatments for 7 days each. Roflumilast and roflumilast N-oxide in plasma and budesonide serum levels were measured by specific assays. Geometric mean test/reference ratios of steady-state pharmacokinetic parameters were evaluated by analysis of variance. Safety and tolerability were monitored. Pharmacokinetic parameters of roflumilast, roflumilast N-oxide, and budesonide after coadministration of roflumilast and budesonide were similar to those after mono-treatment. Compared with budesonide and roflumilast mono-treatments, slightly lower maximum serum/plasma concentration (C(max)) and area under the curve (AUC) values of roflumilast N-oxide and budesonide (ranging from -8% to -16%) were observed with combined treatment. All test/reference ratios were within predefined equivalence acceptance ranges for roflumilast AUC (0.80, 1.25) and C(max) (0.70, 1.43) and for roflumilast N-oxide and budesonide AUC and C(max) (all 0.67, 1.50). Coadministration of roflumilast and budesonide did not alter the steady-state disposition of each other and did not affect safety and tolerability of either drug.

Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.

The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated.

Investigation of a potential food effect on the pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, in healthy subjects.

This open, randomized, single-dose crossover study investigated effects of a high-fat meal on the pharmacokinetics of roflumilast and its major active N-oxide metabolite. Twelve healthy subjects received oral roflumilast 500 microg (2 x 250 microg) after overnight fasting and after breakfast. Blood was sampled up to 54 hours for pharmacokinetic profiling of roflumilast and N-oxide. Geometric mean ratios (fed/fasted) for point estimates (PE) and 90% confidence intervals (CI) were calculated for AUC(0-last), AUC(0-infinity), and C(max) of both compounds. After the meal, roflumilast C(max) (PE, 0.59; 90% CI, 0.49-0.70) was modestly reduced; N-oxide C(max) (PE, 0.95; 90% CI, 0.90-1.01) was unchanged. Roflumilast t(max) was delayed in fed state (2.0 +/- 0.4 hours) versus fasted state (1.0 +/- 0.2 hours); N-oxide t(max) was unaltered. No significant food effect on roflumilast AUC(0-last) (PE, 1.04; 90% CI, 0.90-1.21), AUC(0-infinity) (PE, 1.12; 90% CI, 1.00-1.25), and respective N-oxide AUCs (PE, 0.91; 90% CI, 0.79-1.04; PE, 0.99; 90% CI, 0.92-1.06) occurred. Because roflumilast N-oxide is the major contributor to roflumilast's overall pharmacologic effects, these findings suggest that roflumilast can be taken with or without food.

Identification and characterization of CYP3A4*20, a novel rare CYP3A4 allele without functional activity.

BACKGROUND: The major drug-metabolizing enzyme cytochrome P450 (CYP) 3A4 is genetically conserved. One outlier of Brazilian descent was found in a clinical pharmacokinetic trial exhibiting a 6-fold higher exposure than expected to an investigational drug, shown to be a CYP3A4 substrate. We aimed to investigate the genetic background of this finding. METHODS: The allelic variant of the CYP3A4 gene present in the outlier was sequenced, and the corresponding complementary deoxyribonucleic acid was expressed in yeast and human embryonic kidney cells. The outlier was phenotyped by use of intravenous administration of 1 mg midazolam. Analysis of phenotype and genotype correlation was carried out. The prevalence of the new allele was screened for in a white population. RESULTS: We identified a subject who heterozygously carried a novel CYP3A4 allele, named CYP3A4*20, with a premature stop codon yielding a truncated protein. Heterologous expression revealed that the CYP3A4.20 enzyme does not incorporate heme and thus is devoid of catalytic activity. CYP3A phenotyping in vivo showed that CYP3A4*20 exhibits a clear genotype-phenotype correlation, demonstrated by the subject's low systemic midazolam clearance (2.99 mL x min(-1) x kg(-1)). Genotyping of a white German population (n = 428) and relatives of the subject, as well as a review of published CYP3A4 sequencing data, suggests that CYP3A4*20 is a rare variant allele (<0.06% in white subjects). CONCLUSIONS: CYP3A4*20 represents the first CYP3A4 allele to be identified that has been shown to be devoid of functional activity. It causes an intermediate CYP3A4 metabolizer phenotype in a heterozygous carrier. Subjects of this genotype might be susceptible to side effects during drug therapy with substrates or inhibitors of CYP3A4.