Rationale and design of a phase II trial of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for N0/N1mi, HER2 + early breast cancer (PHAEDRA).

BACKGROUND: The de-escalation treatment in patients with low-risk HER2-positive early breast cancer (eBC) is an attractive strategy to avoid unnecessary treatment and improve the quality of life of patients. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor (TKI), has shown efficacy in patients with advanced HER2-positive breast cancer. Meanwhile, nanoparticle albumin-bound (nab)-paclitaxel reveals survival benefit over solvent-based paclitaxel and eliminates the toxicities associated with the solvent. However, the efficacy and safety of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for low-risk HER2 + eBC patients have not been evaluated. METHODS: This is a multicenter, open-label, single-arm phase II study. A sample size of 261 patients with tumor ≤ 3 cm, lymph node-negative (N0) or micrometastatic (N1mi), HER2 + breast cancer will be recruited. Eligible patients will receive nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 400 mg once daily for one year. The primary endpoint is invasive disease-free survival. A sub-study will be conducted to investigate different prophylactic strategies for diarrhea, which is the most common adverse event of pan-HER TKIs. One hundred and twenty patients from the main study will be randomly (1:1) allocated to receive loperamide either during the first cycle (4 mg tid on days 1-7, then 4 mg bid on days 8-21) or the first 2 cycles (4 mg tid on days 1-7, then 4 mg bid on days 8-42). The primary endpoint of the sub-study is the incidence of grade ≥ 3 diarrhea. DISCUSSION: This is the first prospective study of pyrotinib in combination with nab-paclitaxel as adjuvant therapy for patients with low-risk HER2-positive eBC. It would probably provide robust evidence for de-escalating strategy of HER2-positive eBC and appropriate management for pyrotinib-related diarrhea. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04659499 . Registered on December 9, 2020.

Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial.

BACKGROUND: Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax. METHODS: This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia. Patients received 3-day chloroquine plus oral single-dose tafenoquine as dispersible tablets (50 mg) or film-coated tablets (150 mg). Dosing groups were assigned by body weight, predicted to achieve similar median exposures as the approved 300 mg dose for adults: patients who weighed 5 kg or more to 10 kg received 50 mg, those who weighed more than 10 to 20 kg received 100 or 150 mg, those who weighed more than 20 to 35 kg received 200 mg, and patients who weighed more than 35 kg received 300 mg. Population pharmacokinetic analysis was done to develop a paediatric population pharmacokinetic model. The primary outcome was the tafenoquine area under the concentration-time curve extrapolated to infinity (AUC[0-∞]) by patient body weight in the pharmacokinetic population (all patients who received tafenoquine with at least one valid pharmacokinetic sample) estimated from a paediatric population pharmacokinetic model. A key prespecified secondary outcome was 4-month recurrence-free efficacy. This trial is registered with ClinicalTrials.gov, NCT02563496. FINDINGS: Between Feb 6, 2017, and Feb 17, 2020, 60 patients were enrolled into the study: 14 (23%) received tafenoquine 100 mg, five (8%) 150 mg, 22 (36%) 200 mg, and 19 (32%) 300 mg. The paediatric population pharmacokinetic model predicted adequate tafenoquine exposure at all doses. The predicted median AUC(0-∞) was 73·8 (90% prediction interval [PI] 46·9-117·0) µg × h/mL with the 50 mg dose for patients who weighed 5 kg or more to 10 kg, 87·5 (55·4-139·0) µg × h/mL with the 100 mg dose for body weight more than 10 to 20 kg, 110·7 (70·9-174·0) µg × h/mL with the 200 mg dose for body weight more than 20 to 35 kg, and 85·7 (50·6-151·0) µg × h/mL with the 300 mg dose for body weight more than 35 kg. 4-month recurrence-free efficacy was 94·7% (95% CI 84·6-98·3). Adverse events were consistent with previous studies, except for the seven (12%) of 60 patients who had post-dose vomiting or spitting with the 50 mg dispersed tablet. Following mitigation strategies, there were no additional occurrences of this adverse event. There were no deaths during the study. INTERPRETATION: For the prevention of P vivax relapse in children, single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting. FUNDING: GlaxoSmithKline and Medicines for Malaria Venture. TRANSLATIONS: For the Vietnamese and Spanish translations of the abstract see Supplementary Materials section.

Pyrotinib in Patients with HER2-Amplified Advanced Non-Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial.

PURPOSE: In this study, we aimed to evaluate the efficacy and safety of pyrotinib, a pan-HER inhibitor, in patients with HER2-amplified non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this prospective, multicenter, single-arm trial (ChiCTR1800020262), patients with advanced NSCLC with HER2 amplification, as determined by next-generation sequencing, were enrolled and administered pyrotinib orally at 400 mg per day. The primary endpoint was 6-month progression-free survival (PFS) rate. Other endpoints included objective response rate (ORR), disease control rate (DCR), PFS, overall survival (OS), and safety. RESULTS: The enrolled cohort included 27 patients with HER2 amplification. The 6-month PFS rate was 51.9% [95% confidence interval (CI), 34.0-69.3]. The median PFS (mPFS) was 6.3 months (95% CI, 3.0-9.6 months), and median OS was 12.5 months (95% CI, 8.2-16.8 months). Pyrotinib elicited a confirmed ORR of 22.2% (95% CI, 10.6%-40.8%). Patients administered pyrotinib as first-line treatment achieved an mPFS of 12.4 months. Moreover, 30.8% of the patients who had progressed on EGFR tyrosine kinase inhibitor (TKI) responded to pyrotinib. Patients with brain metastases had an ORR of 40%. Treatment-related adverse events (TRAE) occurred in all patients (grade 3, 22.2%), but no grade 4 or higher TRAEs were documented. Diarrhea was the most frequent TRAE (all, 92.6%; grade 3, 7.4%). Loss of HER2 amplification was detected upon disease progression. CONCLUSIONS: Pyrotinib provided antitumor efficacy with a manageable safety profile in HER2-amplified patients with NSCLC.

Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients.

Brain metastasis is a common cause of death in HER2-positive breast cancer patients. Currently, it is mainly treated by whole-brain radiotherapy. Pyrotinib is an irreversible pan-ErbB inhibitor, which has demonstrated promising tumor-suppressing activity and acceptable tolerance in previous phase trials. In the present study, we evaluated the efficacy of pyrotinib on HER2-positive brain metastatic breast cancer patients treated with whole-brain radiotherapy. A total of 20 such patients were separated into pyrotinib plus capecitabine and capecitabine-only groups in a 1:1 ratio. All patients met either the primary or secondary endpoints. Oral admission of pyrotinib together with radiotherapy can significantly increase the overall response rate, progression-free survival, time to progression and duration of response of HER2+ brain metastatic breast cancer patients, without causing extra adverse events. In addition, pyrotinib can enhance the radiosensitivity of in-vitro cultured HER2+ breast cancer cell lines. The outcome of our study suggests that pyrotinib might be an effective medication to enhance the tumor radiosensitivity of HER2-positive brain metastatic breast cancer patients.

Pyrotinib combined with thalidomide in advanced non-small-cell lung cancer patients harboring HER2 exon 20 insertions (PRIDE): protocol of an open-label, single-arm phase II trial.

BACKGROUND: Standard therapy for human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC) is lacking. The clinical benefits with pan-HER inhibitors (afatinib, neratinib, and dacomitinib), anti-HER2 antibody drug conjugate (ADC) trastuzumab emtansine, and an emerging irreversible tyrosine kinase inhibitor (TKI) poziotinib were modest. Another new ADC trastuzumab deruxtecan showed encouraging outcomes, but only phase I study was completed. Pyrotinib, another emerging irreversible epidermal growth factor receptor (EGFR)/HER2 dual TKI, has been approved in HER2-positive breast cancer in 2018 in China. It has shown promising antitumor activity against HER2-mutant NSCLC in phase II trials, but pyrotinib-related diarrhea remains an issue. The antiangiogenic and immunomodulatory drug thalidomide is a cereblon-based molecular glue that can induce the degradation of the IKAROS family transcription factors IKZF1 and IKZF3. The use of thalidomide can also decrease gastrointestinal toxicity induced by anti-cancer therapy. METHODS: This is an open-label, single-arm phase II trial. A total of 39 advanced NSCLC patients with HER2 exon 20 insertions and ≤ 2 lines of prior chemotherapy will be recruited, including treatment-naïve patients who refuse chemotherapy. Patients are allowed to have prior therapy with immune checkpoint inhibitors and/or antiangiogenic agents. Those who have prior HER2-targeting therapy or other gene alterations with available targeted drugs are excluded. Eligible patients will receive oral pyrotinib 400 mg once daily and oral thalidomide 200 mg once daily until disease progression or intolerable toxicity. The primary endpoint is objective response rate. DISCUSSION: The addition of thalidomide to pyrotinib is expected to increase the clinical benefit in advanced NSCLC patients with HER2 exon 20 insertions, and reduce the incidence of pyrotinib-related diarrhea. We believe thalidomide is the stone that can hit two birds. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04382300 . Registered on May 11, 2020.

The Effectiveness of Lapatinib in HER2-Positive Metastatic Breast Cancer Patients Pretreated With Multiline Anti-HER2 Treatment: A Retrospective Study in China.

BACKGROUND: The aim of this study was to evaluate the effectiveness of lapatinib in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: We retrospectively reviewed the medical records of patients who received lapatinib for salvage treatment at any line setting from January 1, 2007 to August 31, 2019 at Shandong Cancer Hospital and Institute. RESULTS: A total of 115 (89.1%) patients were included in the study. In the overall cohort, the median disease-free survival (DFS) was 19.0 months; the median progression-free survival (PFS), 6.3 months; and median overall survival (OS), 88.0 months, with 32.2% of patients alive at 5 years. In the second line setting, the median PFS among trastuzumab, lapatinib, and trastuzumab plus lapatinib were 4.2 months, 5.2 months, and 7.3 months, respectively (P = 0.004). No significant differences between the median PFSs and OSs of the different line salvage treatments with lapatinib was observed (all P > 0.05). For brain metastasis patients, the median PFSs in first line, second line, and more than 3 lines were 7.2 months, 4.5 months, and 6.3 months, respectively. CONCLUSIONS: Our findings suggest that patients would benefit more from trastuzumab plus lapatinib than from lapatinib or trastuzumab alone for second line treatment in the advanced stages of the disease. Lapatinib could be used as an alternative selection for HER2-positive metastasic breast cancer patients when there is disease progression after trastuzumab or pyrotinib treatment, which is used as part of China's national health insurance.

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria.

BACKGROUND: For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments are expected to increase compliance and improve treatment outcomes, and thereby may slow the development of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine (400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa (focusing on children ≤ 5 years) and Asia. METHODS: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy, safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African patients ≤ 5 years. The exposure-response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13 mutations were explored. RESULTS: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures. CONCLUSION: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years, the population of interest, and vomiting most likely had a negative impact on efficacy. Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https://clinicaltrials.gov/ct2/show/NCT02497612?term=NCT02497612&draw=2&rank=1.

Estimated impact of tafenoquine for Plasmodium vivax control and elimination in Brazil: A modelling study.

BACKGROUND: Despite recent intensification of control measures, Plasmodium vivax poses a major challenge for malaria elimination efforts. Liver-stage hypnozoite parasites that cause relapsing infections can be cleared with primaquine; however, poor treatment adherence undermines drug effectiveness. Tafenoquine, a new single-dose treatment, offers an alternative option for preventing relapses and reducing transmission. In 2018, over 237,000 cases of malaria were reported to the Brazilian health system, of which 91.5% were due to P. vivax. METHODS AND FINDINGS: We evaluated the impact of introducing tafenoquine into case management practices on population-level transmission dynamics using a mathematical model of P. vivax transmission. The model was calibrated to reflect the transmission dynamics of P. vivax endemic settings in Brazil in 2018, informed by nationwide malaria case reporting data. Parameters for treatment pathways with chloroquine, primaquine, and tafenoquine with glucose-6-phosphate dehydrogenase deficiency (G6PDd) testing were informed by clinical trial data and the literature. We assumed 71.3% efficacy for primaquine and tafenoquine, a 66.7% adherence rate to the 7-day primaquine regimen, a mean 5.5% G6PDd prevalence, and 8.1% low metaboliser prevalence. The introduction of tafenoquine is predicted to improve effective hypnozoite clearance among P. vivax cases and reduce population-level transmission over time, with heterogeneous levels of impact across different transmission settings. According to the model, while achieving elimination in only few settings in Brazil, tafenoquine rollout in 2021 is estimated to improve the mean effective radical cure rate from 42% (95% uncertainty interval [UI] 41%-44%) to 62% (95% UI 54%-68%) among clinical cases, leading to a predicted 38% (95% UI 7%-99%) reduction in transmission and over 214,000 cumulative averted cases between 2021 and 2025. Higher impact is predicted in settings with low transmission, low pre-existing primaquine adherence, and a high proportion of cases in working-aged males. High-transmission settings with a high proportion of cases in children would benefit from a safe high-efficacy tafenoquine dose for children. Our methodological limitations include not accounting for the role of imported cases from outside the transmission setting, relying on reported clinical cases as a measurement of community-level transmission, and implementing treatment efficacy as a binary condition. CONCLUSIONS: In our modelling study, we predicted that, provided there is concurrent rollout of G6PDd diagnostics, tafenoquine has the potential to reduce P. vivax transmission by improving effective radical cure through increased adherence and increased protection from new infections. While tafenoquine alone may not be sufficient for P. vivax elimination, its introduction will improve case management, prevent a substantial number of cases, and bring countries closer to achieving malaria elimination goals.

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling.

BACKGROUND: Severe asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling. METHODS AND RESULTS: Immunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice. CONCLUSION: This study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.

A phase 1b trial of the CXCR4 inhibitor mavorixafor and nivolumab in advanced renal cell carcinoma patients with no prior response to nivolumab monotherapy.

Background The CXCR4 chemokine receptor promotes tumor survival through mechanisms that include suppressing antitumor immune responses. Mavorixafor (X4P-001) is an oral, selective, allosteric CXCR4 inhibitor that decreases the recruitment of immunosuppressive cells into the tumor microenvironment and increases activated cytotoxic Tcell infiltration. Methods Patients with metastatic clear cell renal cell carcinoma (ccRCC) unresponsive to nivolumab monotherapy received oral mavorixafor 400 mg daily plus 240 mg intravenous nivolumab every 2 weeks. Results Nine patients were enrolled, median age 65 years. At baseline 4 had progressive disease (PD) and 5 had stable disease (SD). One of 5 patients with SD at study entry on prior nivolumab monotherapy had a partial response (PR) on combination treatment; all 4 patients with PD at study entry had a best response of SD with the combination treatment (median duration: 6.7 months; range: 3.7-14.7). Four patients discontinued therapy due to treatment-related adverse events (AEs). Grade ≥ 3 drug-related AEs were elevated alanine and aspartate aminotransferase (2 patients each); and autoimmune hepatitis, chronic kidney disease, increased lipase, maculopapular rash, and mucosal inflammation (1 patient each). A robust increase in levels of chemokine (C-X-C motif) ligand 9 CXCL9 on mavorixafor appeared to correlate with clinical benefit. Conclusions The CXCR4 inhibition mediated by mavorixafor, in combination with PD-1 blockade to enhance antitumor immune responses in patients unresponsive to checkpoint inhibitor monotherapy, is worthy of further study. Mavorixafor and nivolumab combination therapy in patients with advanced ccRCC demonstrated potential antitumor activity and a manageable safety profile.Trial registration: ClinicalTrials.gov identifier: NCT02923531. Date of registration: October 04, 2016.

A Randomized Double-Masked Phase 2a Trial to Evaluate Activity and Safety of Topical Ocular Reproxalap, a Novel RASP Inhibitor, in Dry Eye Disease.

Purpose: To determine whether reproxalap, a novel reactive aldehyde species (RASP) inhibitor, is safe and effective for the treatment of the signs and symptoms of dry eye disease (DED). Methods: In a randomized double-masked parallel-group Phase 2a trial of 3 topical ocular reproxalap formulations (0.1% ophthalmic solution, 0.5% ophthalmic solution, and 0.5% lipid ophthalmic solution), 51 patients with DED were randomly assigned 1:1:1 at a single US site. Eyes were treated bilaterally 4 times daily for 28 days, and standard DED signs and symptoms were assessed at baseline and after 7 and 28 days of dosing. Tear RASP levels were assessed at baseline and at day 28. Results: The effect of treatment on DED signs and symptoms was similar across the treatment arms, and pooled data from the 28-day treatment period demonstrated significant improvement from baseline in Symptom Assessment in Dry Eye Disease score (P = 0.003), Ocular Discomfort Scale score (P < 0.0001), Ocular Discomfort Score and 4-Symptom Questionnaire overall score (P = 0.0004), Schirmer's test (P = 0.008), tear osmolarity (P = 0.003), and lissamine green total staining score (P = 0.002). Improvements in DED symptoms were evident within 1 week of therapy, and effect sizes generally approached or exceeded 0.5. No significant changes in safety measures were observed. Conclusion: The results suggest that the novel RASP inhibitor reproxalap has the potential to mitigate the signs and symptoms of DED, and may represent a new, rapidly and broadly active treatment approach for DED (NCT03162783).

Tafenoquine: a toxicity overview.

Introduction: A century-long history in 8-aminoquinolines, the only anti-malaria drug class preventing malaria relapse, has resulted in the approval of tafenoquine by the U.S. Food and Drug Administration (FDA) and the Australian Therapeutic Goods Administration (TGA) and to date registration in Brazil and Thailand. Tafenoquine is an alternative anti-relapse treatment for vivax malaria and malaria prophylaxis. It should not be given in pregnancy, during lactation of infants with glucose-6-phosphate dehydrogenase (G6PD) unknown or deficient status, and in those with G6PD deficiency or psychiatric illness.Areas covered: This systematic review assesses tafenoquine associated adverse events in English-language, human clinical trials. Meta-analysis of commonly reported adverse events was conducted and grouped by comparison arms.Expert opinion: Tafenoquine, either for radical cure or prophylaxis, is generally well tolerated in adults. There is no convincing evidence for neurologic, ophthalmic, and cardiac toxicities. Psychotic disorder which has been attributed to higher doses is a contraindication for the chemoprophylaxis indication and psychiatric illness is a warning for the radical cure indication. Pregnancy assessment and quantitative G6PD testing are required. The optimal radical curative regimen including the tafenoquine dose along with its safety for parts of Southeast Asia, South America, and Oceania needs further assessment.

Chronic but not acute pharmacological activation of SERCA induces behavioral and neurochemical effects in male and female mice.

Intracellular calcium (Ca2+) homeostasis is a vital process to nerve cell survival and function with an intricate regulatory network. It is well established that the endoplasmic reticulum (ER) is a major intraneuronal Ca2+ storage and that the sarco/endoplasmic reticulum (SR/ER) calcium (Ca2+)-ATPase (SERCA) pump is a key regulator of cytosolic Ca2+ levels. SERCA pumps play a critical role in brain pathophysiology, thus SERCA comprises an emerging pharmacological target for the treatment of brain diseases. Interestingly, preclinical studies in rodents suggest that chronic pharmacological activation of SERCA2 by the quinoline derivative CDN1163 comprises a potential pharmacotherapeutic target in Alzheimer's and Parkinson's diseases. As little is known about the behavioral and neurochemical consequences of CDN1163 administration, in the current study we investigated the potential effects of acute (i.e., at 1 h) and chronic (i.e., 17 days) CDN1163 administration (i.e., 10 mg/kg and 20 mg/kg; intraperitoneally) on locomotor activity and relevant affective behaviors, as well as on monoaminergic neurotransmission in naïve C57BL/6J mice of both sexes. Interestingly, chronic, but not acute, CDN1163 administration induced anxiogenic and depressive-like behavioral effects in mice, as assessed in the open field (OF) test and the forced swim test (FST), respectively. In addition, chronic CDN1163 administration induced sustained sex- and brain region-dependent noradrenergic and serotonergic neurochemical effects ex vivo. Taken together, present findings support the critical role of SERCA-dependent Ca2+ handling in regulating behavior and neurochemical activity, and further highlight the need to consider sex in the development of SERCA-targeting pharmacotherapies for the treatment of debilitating brain disorders.

Restoration of Sarcoplasmic Reticulum Ca2+ ATPase (SERCA) Activity Prevents Age-Related Muscle Atrophy and Weakness in Mice.

Sarcopenia has a significant negative impact on healthspan in the elderly and effective pharmacologic interventions remain elusive. We have previously demonstrated that sarcopenia is associated with reduced activity of the sarcoplasmic reticulum Ca2+ ATPase (SERCA) pump. We asked whether restoring SERCA activity using pharmacologic activation in aging mice could mitigate the sarcopenia phenotype. We treated 16-month male C57BL/6J mice with vehicle or CDN1163, an allosteric SERCA activator, for 10 months. At 26 months, maximal SERCA activity was reduced 41% in gastrocnemius muscle in vehicle-treated mice but maintained in old CDN1163 treated mice. Reductions in gastrocnemius mass (9%) and in vitro specific force generation in extensor digitorum longus muscle (11%) in 26 versus 16-month-old wild-type mice were also reversed by CDN1163. CDN1163 administered by intra-peritoneal injection also prevented the increase in mitochondrial ROS production in gastrocnemius muscles of aged mice. Transcriptomic analysis revealed that these effects are at least in part mediated by enhanced cellular energetics by activation of PGC1-α, UCP1, HSF1, and APMK and increased regenerative capacity by suppression of MEF2C and p38 MAPK signaling. Together, these exciting findings are the first to support that pharmacological targeting of SERCA can be an effective therapy to counter age-related muscle dysfunction.

Human epidermal growth factor receptor 2-positive metastatic breast cancer with novel epidermal growth factor receptor -ZNF880 fusion and epidermal growth factor receptor E114K mutations effectively treated with pyrotinib: A case report.

INTRODUCTION: In about 15% to 20% of breast cancer cases, human epidermal growth factor receptor 2 (HER2) over-expression or gene-amplification is associated with poor prognosis. Thanks to the development of target therapies, HER2 positive patients can be managed using HER2-targeting drugs. There are several kinds ofHER2 inhibitors, such as trastuzumab, lapatinib, and pyrotinib. Pyrotinib which exert different functions, of note, the latest generation of the drug, is an irreversible small-molecule tyrosine kinase inhibitor targeting epidermal growth factor receptor (EGFR) (HER1) and/or HER2 and/or HER4. Both lapatinib and pyrotinib potentially target EGFR and/or HER2, but in some instances, induces different responses of patients with EGFR and/or HER2 mutations. This is attributed to the different mutations in EGFR and HER2 genes, which may form distinct types of HER2 dimers, with different binding capacities to drugs. PATIENT CONCERNS: Five years ago, a patient underwent a radical mastectomy in an external hospital. Results of the resection histopathology revealed an invasive ductal carcinoma, pT3N0M0, stage IIB, HER2 positive. The lady patient received 6 cycles of adjuvant chemotherapy and was subjected to adjuvant trastuzumab therapy for 1 year. After a regular 1-year follow-up and in March 2018, she complained of chest pain and visited our hospital. We diagnosed her with metastatic breast cancer, positive for HER2. DIAGNOSIS: positron emission tomography/computed tomography showed multiple metastases in the lung and sternum, while the breast lesions did not progress, the curative effect of which we evaluated as a progressive disease. Then, lapatinib integrated with chemotherapy was administered to the patient. After 5 cycles of the treatment, the patient experienced lower back pain. Through CT examination, it was revealed that she had multiple metastases in the lung and sternum, in addition to new metastases in the lumbar spine and right lobe of the liver. Moreover, magnetic resonance imaging revealed multiple metastases in the brain, and the disease further progressed. The results of circulating tumor DNA assays showed that other than HER2 amplification, novel EGFR-ZNF880 fusion and EGFR E114K mutations developed. INTERVENTIONS: The patient was administered with a combination of pyrotinib with chemotherapy. OUTCOMES: After 2 months of pyrotinib treatment, the metastases of the lung, sternum, lumbar spine, and right lobe of the liver disappeared. Also, the size of the brain metastases reduced while bone metastases were relieved. The curative effect was evaluated as a partial response. Following the results of circulating tumor DNA assays, HER2 amplification, EGFR-ZNF880 fusion, and EGFR E114K mutations disappeared. However, since a small lesion was present in the brain, the patient was subjected to radiotherapy in the head. Notably, after 9 months treatment with pyrotinib, enhanced CT indicated that tumors in the breast, liver, both lungs, brain, and bone were under control. The patient continually received oral pyrotinib, however, a new brain lesion appeared 6 months later. Overall, we managed to regulate the efficacy of pyrotinib for up to 15 months. CONCLUSION: This case report demonstrates that EGFR-ZNF880 fusion and EGFR E114K mutations may contribute or lead to the formation of a special HER2 dimer, which is rapidly resistant to lapatinib but sensitive to pyrotinib. Of note, this is the first report that such a new fusion has been found.

Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy.

Integration of the unique advantages of the fields of drug discovery and drug delivery is invaluable for the advancement of drug development. Here we propose a self-delivering one-component new-chemical-entity nanomedicine (ONN) strategy to improve cancer therapy through incorporation of the self-assembly principle into drug design. A lysosomotropic detergent (MSDH) and an autophagy inhibitor (Lys05) are hybridised to develop bisaminoquinoline derivatives that can intrinsically form nanoassemblies. The selected BAQ12 and BAQ13 ONNs are highly effective in inducing lysosomal disruption, lysosomal dysfunction and autophagy blockade and exhibit 30-fold higher antiproliferative activity than hydroxychloroquine used in clinical trials. These single-drug nanoparticles demonstrate excellent pharmacokinetic and toxicological profiles and dramatic antitumour efficacy in vivo. In addition, they are able to encapsulate and deliver additional drugs to tumour sites and are thus promising agents for autophagy inhibition-based combination therapy. Given their transdisciplinary advantages, these BAQ ONNs have enormous potential to improve cancer therapy.

Randomized Phase 2 Trial of Reproxalap, a Novel Reactive Aldehyde Species Inhibitor, in Patients with Noninfectious Anterior Uveitis: Model for Corticosteroid Replacement.

Purpose: Topical corticosteroids used to treat ocular inflammation are associated with a high risk of clinically significant toxicities. Therefore, corticosteroid-sparing medications to treat ocular inflammation are needed. Noninfectious anterior uveitis (NAU) is a sight-threatening ocular inflammatory condition typically treated with topical corticosteroids. This corticosteroid-controlled comparator trial examines the safety and efficacy of reproxalap, a novel inhibitor of reactive aldehyde species (RASP), for the treatment of ocular inflammation, by using NAU as a model. Methods: Forty-five patients with mild-to-moderate acute NAU were randomly assigned 1:1:1 to receive reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks), prednisolone 1% ophthalmic solution (Pred Forte®, 4 times daily taper for 6 weeks), or a combination of reproxalap 0.5% ophthalmic solution (4 times daily for 6 weeks) and prednisolone 1% ophthalmic solution (twice daily taper for 6 weeks). Results: All treatments improved anterior cell count and grade, and no differences were observed in change from baseline between groups. Reproxalap monotherapy and combination therapy were statistically noninferior to prednisolone. The proportion of patients requiring rescue therapy was comparable across treatment groups. No safety issues were identified for reproxalap-treated patients, whereas treatment with prednisolone resulted in an average increase of intraocular pressure of ∼2 mm Hg. Conclusions: Reproxalap may be a safe and effective alternative to topical corticosteroids for patients with NAU and other forms of ocular inflammation. These results represent initial clinical evidence of the importance of RASP in ocular inflammation and the applicability of RASP inhibition to immune modulation in ocular disease. Clinical trial (NCT02406209).

Tafenoquine for preventing relapse in people with Plasmodium vivax malaria.

BACKGROUND: Plasmodium vivax malaria has a persistent liver stage that causes relapse of the disease and continued P vivax transmission. Primaquine (PQ) is used to clear the liver stage of the parasite, but treatment is required for 14 days. Primaquine also causes haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Tafenoquine (TQ) is a new alternative to PQ with a longer half-life and can be used as a single-dose treatment. OBJECTIVES: To assess the effects of tafenoquine 300 mg (single dose) on preventing P vivax relapse. SEARCH METHODS: We searched the following up to 3 June 2020: the Cochrane Infectious Diseases Group Specialized Register; CENTRAL; MEDLINE; Embase; and three other databases. We also searched the WHO International Clinical Trial Registry Platform and the metaRegister of Controlled Trials for ongoing trials using "tafenoquine" and "malaria" as search terms up to 3 June 2020. SELECTION CRITERIA: Randomized controlled trials (RCTs) that gave TQ to prevent relapse in people with P vivax malaria. We planned to include trials irrespective of whether participants had been screened for G6PD enzyme deficiency. DATA COLLECTION AND ANALYSIS: All review authors independently extracted data and assessed risk of bias. As true relapse and reinfection are difficult to differentiate in people living in endemic areas, studies report "recurrences" of infection as a proxy for relapse. We carried out meta-analysis where appropriate, and gave estimates as risk ratios (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Three individually randomized RCTs met our inclusion criteria, all in endemic areas, and thus reporting recurrence. Trials compared TQ with PQ or placebo, and all participants received chloroquine (CQ) to treat the asexual infection). In all trials, pregnant and G6PD-deficient people were excluded. Tafenoquine 300 mg single dose versus no treatment for relapse prevention Two trials assessed this comparison. TQ 300 mg single dose reduces P vivax recurrences compared to no antihypnozoite treatment during a six-month follow-up, but there is moderate uncertainty around effect size (RR 0.32, 95% CI 0.12 to 0.88; 2 trials, 504 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (2 trials, 504 participants; moderate-certainty evidence). However, we are uncertain if TQ causes more serious adverse events (2 trials, 504 participants; very low-certainty evidence). Both RCTs reported a total of 23 serious adverse events in TQ groups (One RCT reported 21 events) and a majority (15 events) were a drop in haemoglobin level by > 3g/dl (or >30% reduction from baseline). Tafenoquine 300 mg single dose versus primaquine 15 mg/day for 14 days for relapse prevention Three trials assessed this comparison. There is probably little or no difference between TQ and PQ in preventing recurrences (proxy measure for relapse) up to six months of follow-up (RR 1.04, 95% CI 0.8 to 1.34; 3 trials, 747 participants; moderate-certainty evidence). In people with normal G6PD status, there is probably little or no difference in any type of adverse events (3 trials, 747 participants; moderate-certainty evidence). We are uncertain if TQ can cause more serious adverse events compared to PQ (3 trials, 747 participants; very low-certainty evidence). Two trials had higher point estimates against TQ while the other showed the reverse. Most commonly reported serious adverse event in TQ group was a decline in haemoglobin level (19 out of 29 events). Some other serious adverse events, though observed in the TQ group, are unlikely to be caused by it (Hepatitis E infection, limb abscess, pneumonia, menorrhagia). AUTHORS' CONCLUSIONS: TQ 300 mg single dose prevents relapses after clinically parasitologically confirmed P vivax malaria compared to no antihypnozoite treatment, and with no difference detected in studies comparing it to PQ to date. However, the inability to differentiate a true relapse from a recurrence in the available studies may affect these estimates. The drug is untested in children and in people with G6PD deficiency. Single-dose treatment is an important practical advantage compared to using PQ for the same purpose without an overall increase in adverse events in non-pregnant, non-G6PD-deficient adults.

Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the CXCR4 gene. We report the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mavorixafor from a phase 2 open-label dose-escalation and extension study in 8 adult patients with genetically confirmed WHIM syndrome. Mavorixafor is an oral small molecule selective antagonist of the CXCR4 receptor that increases mobilization and trafficking of white blood cells from the bone marrow. Patients received escalating doses of mavorixafor, up to 400 mg once daily. Five patients continued on the extension study for up to 28.6 months. Mavorixafor was well tolerated with no treatment-related serious adverse events. At a median follow-up of 16.5 months, we observed dose-dependent increases in absolute neutrophil count (ANC) and absolute lymphocyte count (ALC). At doses ≥300 mg/d, ANC was maintained at >500 cells per microliter for a median of 12.6 hours, and ALC was maintained at >1000 cells per microliter for up to 16.9 hours. Continued follow-up on the extension study resulted in a yearly infection rate that decreased from 4.63 events (95% confidence interval, 3.3-6.3) in the 12 months prior to the trial to 2.27 events (95% confidence interval, 1.4-3.5) for patients on effective doses. We observed an average 75% reduction in the number of cutaneous warts. This study demonstrates that mavorixafor, 400 mg once daily, mobilizes neutrophil and lymphocytes in adult patients with WHIM syndrome and provides preliminary evidence of clinical benefit for patients on long-term therapy. The trial was registered at www.clinicaltrials.gov as #NCT03005327.