Phase IIb Trial Research Articles

Selective IL-13 inhibitors for the treatment of atopic dermatitis.

BackgroundAtopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases worldwide. AD pathogenesis is multifactorial, involving environmental and genetic factors. IL-13 stands out as one of the main cytokines in the pathophysiology of AD. Currently, dupilumab, which targets both IL-4 and IL-13 signalling, is the only biologic agent approved for the treatment of moderate-to-severe AD. New targeted biologic therapies are being developed, such as lebrikizumab and tralokinumab, two selective IL-13 inhibitors. This article reviews the role of IL-13 in AD and the most recent data on lebrikizumab and tralokinumab.MethodsA narrative review of the literature was written after retrieving relevant articles in the PubMed database (up until December 2020) using the following keywords present in the title, abstract or body: atopic dermatitis; interleukin 13; IL-13; tralokinumab; lebrikizumab, biologic therapy.DiscussionA phase IIb trial showed that all three dosing regimens evaluated (lebrikizumab 125 mg every 4 weeks (Q4W), 250 mg Q4W or 250 mg every 2 weeks) achieved rapid and dose-dependent efficacy concerning the signs and symptoms of AD, with a statistically significant improvement, at week 16. Tralokinumab was studied in three phase III clinical trials and reached its primary endpoints at week 16 (ECZTRA 1 and 2 in monotherapy and ECZTRA 3 with concomitant topical corticosteroids), with response maintained over time. Both lebrikizumab and tralokinumab exhibited good safety profiles in AD trials, with adverse effects usually being comparable between the control and treatment groups.ConclusionThe evidence supports the hypothesis that selective antagonism of IL-13 is sufficient to control AD, providing an improvement in the patient’s quality of life. Therefore, the development of lebrikizumab and tralokinumab represents a new and exciting phase in the management of AD.

Pharmacological Insights Into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure.

Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal hemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterized, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+ influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more ‘adenosine-like’ signaling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted hemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients.

Spesolimab, an Anti-Interleukin-36 Receptor Antibody, in Patients with Palmoplantar Pustulosis: Results of a Phase IIa, Multicenter, Double-Blind, Randomized, Placebo-Controlled Pilot Study.

IntroductionPalmoplantar pustulosis (PPP) is a chronic, inflammatory skin disease, with high disease burden, that is often refractory to treatment. There is a high unmet clinical need for the treatment of patients with PPP. The objectives of this study were to evaluate the safety and efficacy of spesolimab, a novel anti-interleukin-36 receptor antibody, in patients with PPP.MethodsThis was a phase IIa, multicenter, double-blind, randomized, placebo-controlled pilot study comparing 900 mg spesolimab (n = 19), 300 mg spesolimab (n = 19), and placebo (n = 21) administered intravenously every 4 weeks until week 12 in patients with PPP. The primary efficacy endpoint was the achievement of Palmoplantar Pustulosis Area and Severity Index 50 (PPP ASI50) at week 16, defined as achieving an ≥ 50% decrease from baseline PPP ASI.ResultsAt week 16, 31.6% of patients in both spesolimab dose groups achieved PPP ASI50 versus 23.8% receiving placebo (risk difference 0.078; 95% confidence interval –0.190, 0.338). Thus, the primary endpoint was not met. Spesolimab was well tolerated with no clinically relevant treatment-emergent safety signals observed.ConclusionsPPP severity declined over time in all treatment groups after the start of treatment, with a faster decline in the spesolimab arms than in the placebo arm, indicating a potential treatment effect for spesolimab. Limitations to the study included a small sample size and lower overall disease severity than expected at baseline. It is possible that the primary efficacy endpoint may have coincided with natural disease resolution in some patients. Further effects of the efficacy of spesolimab in PPP are being explored in a phase IIb trial.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00504-0.

Real-life experience with the combination of polatuzumab vedotin, rituximab, and bendamustine in aggressive B-cell lymphomas.

Transplant-ineligible relapsed/refractory (rr) diffuse large B-cell lymphoma (DLBCL) patients represent an unmet medical need. Polatuzumab vedotin (Pola), an anti-CD79b antibody-drug-conjugate (ADG), with bendamustine- rituximab(BR) has recently gained approval for these patients, both in the USA and Europe, based on the GO29365 phase IIb trial. Real-life data with Pola are extremely limited. We report the outcomes of 61 Greek patients, who received Pola-(B)R mainly within a compassionate use program. Treatment was given for up to six 21-day cycles. Bendamustine was omitted in three cases due to previous short-lived responses. Fourty-nine rrDLBCL(efficacy cohort-EC) and 58 rr aggressive B-NHL (safety cohort-SC) patients received at least 1 Pola-BR cycle. Twenty-one (43%) patients of the EC responded with 12/49 (25%) CR and 9/49 (18%) PR as best response. Median progression-free survival, overall survival and duration of response were 4.0, 8.5, and 8.5 months respectively, while 55% of patients experienced a grade ≥3 adverse event, mainly hematologic. Treatment discontinuations and death during treatment were mainly due to disease progression. Twenty-two (41%) patients received further treatment; 11/22 are still alive, including one after CAR-T cells, and two after stem cell transplantation. Our data confirm that Pola-BR is a promising treatment for rrDLBCL patients, inducing an adequate response rate with acceptable toxicity. Pola-BR could be used as bridging therapy before further consolidative treatments.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

Phase IIb trial of oral ModraDoc006/r as a tolerable and effective option in comparison with intravenous docetaxel in metastatic castration-resistant prostate cancer (mCRPC).

132 Background: ModraDoc006 is a novel, oral tablet formulation of docetaxel. To enhance bioavailability, it is co-administered with ritonavir (r), an inhibitor of cytochrome P450 3A4 and P-glycoprotein. The oral combination, denoted ModraDoc006/r, has potential advantages in terms of patient convenience, elimination of infusion-related reactions and avoiding prophylactic steroid administration, as well as safety benefits. Safety and preliminary efficacy of ModraDoc006/r in mCRPC were established in a prior phase Ib trial. Methods: This is an open label 1:1 randomized phase IIb trial of ModraDoc006/r bi-daily once weekly (BIDW) regimen versus IV docetaxel 75 mg/m2 q day 21. Initially, BIDW 30-20 mg ModraDoc006 combined with 200-100 mg ritonavir was administered on days 1, 8 and 15 of a 21-day cycle. After 39 patients, the dose of ModraDoc006 was reduced to 20-20 mg BIDW to improve GI tolerability. All patients received 5 mg oral prednisone BID. Imaging is obtained every 8-9 weeks for the first 24 weeks, every 12 weeks thereafter. Initially mCRPC patients with RECIST 1.1 measurable disease were eligible; this was amended to evaluable disease per Prostate Cancer Working Group 3 (PCWG3) to allow for wider recruitment. No prior taxane therapy is allowed. The primary efficacy endpoint is radiographic progression free survival (rPFS) per PCWG3 criteria. Secondary objectives include objective response rate, PSA-PFS, time to skeletal related events, disease control rate, duration of response and safety. Patient reported outcomes, QoL and FACT-P questionnaires are assessed. It is expected that ModraDoc006/r will be as effective as IV docetaxel. A sample size of approximately 50 evaluable patients per arm will provide a point estimate of the primary endpoint of rPFS for this study. Results: At the data cut-off of 30 Nov 2020, 90 patients were enrolled in US and EU: 44 patients had been randomized to IV docetaxel and 46 to ModraDoc006/r, with 58 patients currently on treatment. Preliminary PSA response rates and rPFS were noted to be comparable in both treatment arms. ModraDoc006/r was mainly associated with mild and reversible GI-toxicity, of which grade and incidence were reduced at 20-20 mg compared to the initial dose-level of 30-20 mg ModraDoc006. Myelosuppression and neurotoxicity were low to negligible in the ModraDoc006/r arm, with low accompanying levels of alopecia. Conclusions: Adverse events of cytopenias and alopecia were lower with ModraDoc006/r, and preliminary efficacy appears comparable in both arms. Oral chemotherapy option has become critically important during the COVID-19 pandemic. Preliminary data reveals that ModraDoc006/r is an attractive oral option in mCRPC with favorable toxicity profile and comparable efficacy. Clinical trial information: NCT04028388.

Abstract PD14-08: Primary efficacy results from AIPAC: A double-blinded, placebo controlled, randomized multinational phase IIb trial comparing weekly paclitaxel plus eftilagimod alpha (soluble LAG-3 protein) vs. weekly paclitaxel plus placebo in HR-positive metastatic breast cancer patients

Abstract Background:Eftilagimod alpha (efti, IMP321),a soluble LAG-3 protein (LAG-3Ig) that binds to a subset of MHC class II molecules, mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. AIPAC (Active Immunotherapy PAClitaxel; NCT02614833) investigatedcombinations of the APC activator efti + weekly paclitaxel compared to paclitaxel + placebo in metastatic breast carcinoma (MBC) patients (pts). Methods:The placebo-controlled, double-blinded, 1:1 randomized, multinational, phase IIb trial enrolled pts with measurable disease, hormone receptor-positive (HR+) MBC with indications for first line weekly paclitaxel without indication for HER2/neu targeted therapy. Pts received paclitaxel (80 mg/m² IV at D1, D8, D15 plus efti (30 mg) or placebo at D2, D16 (injected SC every 2 weeks) for 6 cycles (1 cycle = 4 weeks). Maintenance phase followed in which pts benefitting from treatment received efti or placebo for an additional 52 weeks. Primary endpoint was progression-free survival (PFS) (RECIST1.1) determined by blinded independent central read (BICR). Secondary endpoints included local read PFS, RECIST 1.1 tumor response, pharmacodynamic effects, quality of life and overall survival. The study was powered (80 %) to detect 0.667 hazard ratio (HR) based on 5% one-sided alpha and planned to enroll 226 pts. Results: From Jan 2017-Jul 2019, 227 pts were randomized. All except 1 received ≥ 1 treatment and were included in the full analysis set [(efti (n = 114); placebo (n = 112)]. Data cut-off was 10th Jan 2020 with 12 month median follow-up. HR for PFS assessed by BICR was 0.93 [95 % CI 0.67-1.30], p =0.341. In the efti group 63 % (95% CI 52- 71%) were progression free at 6 months compared to 54 % (95% CI 43-63%) in the placebo group. ORR was 48.3 % in the efti group compared to 38.4 % in the placebo group as assessed by BICR (p=0.118). Efti increased numbers of PBMCs and T cells (CD4 and CD8) significantly compared to placebo. In predefined subgroups such as pts with low monocytes at baseline, luminal B subtype or age <65 years, clinically meaningful improvement in PFS was observed. TEAE rates leading to death (or discontinuation) in the two groups were similar, at 1.8 % (5.3 %) and 2.7 % (6.3 %) for the efti and placebo groups, respectively. Three pts (1.3 %) were withdrawn from treatment due to grade 3-4 immediate hypersensitivity reactions to efti, while 4 pts (1 in efti group vs. 3 in placebo group) were withdrawn from the study due to grade 2-3 hypersensitivity to paclitaxel. The most frequent (≥10%) TEAEs ≥ grade 3 were gamma-glutamyl transferase increase (19.3% vs 29.5%), aspartate aminotransferase increase (8.8% vs 10.7%) and neutropenia (15.8% vs 14.3%) reported in the efti and placebo group, respectively. Injection site reaction (34.2% vs 3.6%) and injection site erythema (30.7% vs 1.8%) were more frequent in efti versus placebo arms. Conclusion: Efti did not prolong overall median PFS in women with HR+ MBC receiving first line chemotherapy. Tested in a randomized setting against placebo in pts receiving paclitaxel, efti is well tolerated and did not add clinically significant toxicity while inducing a sustained, significant increase in CD8 T cells in blood and clinical benefits in some predefined subgroups. Relevant subgroups and overall survival will be investigated. BICRInvestigatorEfti+paclitaxel(N= 114)Placebo+paclitaxel(N= 112)Efti+paclitaxel(N= 114)Placebo+paclitaxel(N= 112)Median PFS, months (95% CI)7.29 (6.64-7.46)7.29 (5.52-7.46)7.16 (5.65-7.39)6.70 (5.52-7.33)HR (95% CI)0.93 (0.67-1.30)0.92 (0.69-1.23)P value0.3410.305Mean PFS [SE], months7.12 [0.37]6.64 [0.38]6.81 [0.33]6.30 [0.31] Citation Format: Hans Wildiers, Anne Armstrong, Eveline Cuypere, Florence Dalenc, Luc Dirix, Steve Chan, Frederik Marme, Carolina Pia Schröder, Jens Huober, Jill Wagemans, Peter Vuylsteke, Jean-Philippe Jacquin, Etienne Brain, Sherko Kümmel, Zsuzsanna Pápai, Luca Perjesi, Christian Mueller, Chrystelle Brignone, Frederic Triebel. Primary efficacy results from AIPAC: A double-blinded, placebo controlled, randomized multinational phase IIb trial comparing weekly paclitaxel plus eftilagimod alpha (soluble LAG-3 protein) vs. weekly paclitaxel plus placebo in HR-positive metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD14-08.

Abstract PS10-23: Five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer

Abstract Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial investigating GP2+GM-CSF administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) (NCT00524277) is now complete with 5 year follow-up. The trial enrolled HLA-A02 patients randomized to receive GP2+GM-CSF versus GM-CSF alone. The trial's primary objective was to determine if treatment with GP2, a HER2-derived peptide, reduces recurrence rates. Three and 4 year interim analyses for this trial and 3 Phase I studies showing GP2 to be safe and immunogenic have been previously reported by Mittendorf et al. Methods: Each enrolled and consented GP2-treated patient was scheduled to receive a total of 6 GP2+GM-CSF (500 mcg GP2: 125 mcg GM-CSF) intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for the first 6 months and 4 GP2+GM-CSF booster intradermal injections every 6 months thereafter. Boosters were introduced during the trial, thus some patients did not receive all 4 boosters. Each enrolled and consented placebo patient was scheduled to receive a total of 6 GM-CSF only intradermal injections every 3-4 weeks for the first 6 months and 4 GM-CSF only booster intradermal injections every 6 months thereafter. Results: This 168 patient (ITT: n=180) basket trial across 16 clinical sites explored 96 HER2 3+ patients, who received a standard course of trastuzumab after surgery and subsequently completed the full PIS or placebo, starting the PIS at median 17.1 months after surgery, and 72 HER2 1-2+ patients, who did not receive trastuzumab after surgery and subsequently completed the full PIS or placebo, starting the PIS at median 10.8 months after surgery. Since GP2 is synergistic with trastuzumab, and the HER2 1-2+ patients did not receive trastuzumab, it was prespecified to compare recurrence rates ITT versus per protocol in these 2 distinct, independently reported populations, excluding those patients who did not complete the PIS. GP2 was shown to be well tolerated with no SAEs and elicited a potent immune response measured by local skin tests and immunological assays, which suggest peak immunity is reached at 6 months upon completion of the PIS. After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GP2+GM-CSF, if the patient completed the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 placebo patients treated with GM-CSF (p = 0.0338). The treated versus placebo HER2 3+ patients were well-matched, where 53% were stage T1, 41% were stages T2-T4, 55% were node positive, 58% were HR positive and received endocrine therapy, 77% received adjuvant radiation, 77% received adjuvant chemotherapy, and 89% received trastuzumab. After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 35 HER2 1-2+ patients treated with GP2+GM-CSF, if the patient completed the PIS, was 77.1% (95% CI:59.5, 87.9%) versus 77.6% (95% CI:60.1, 88.2%) in the 37 placebo patients treated with GM-CSF (p = 0.9142). Conclusions: This study demonstrated that completion of the GP2+GM-CSF PIS safely elicited a potent immune response and reduced recurrence rates to 0% in HER2 3+ patients, who received a standard course of trastuzumab after surgery. A pivotal Phase III trial is being initiated to treat HER2 3+ patients in the neoadjuvant setting. GP2 also may be effective when used in parallel to trastuzumab based therapeutics or in combination with trastuzumab based therapeutics in HER2 1-2+ or other HER2 expressing cancers. Citation Format: Snehal S Patel, David B McWilliams, Marisa S Patel, Christine T Fischette, Jaye Thompson, F Joseph Daugherty. Five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2 positive women with operable breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-23.

Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer

HER2-targeted therapy has not benefited patients with low levels of HER2 expression; however, combination therapy may be effective. Primary analysis of a phase IIb trial investigating the HER2-derived vaccine nelipepimut-S (NPS) did not benefit the intention-to-treat population, but subset analysis showed a benefit in triple-negative breast cancer (TNBC) patients. The subset analysis of this multicenter, randomized, single-blind, phase IIb trial identified significant improvement in 36-month disease-free survival (DFS) between NPS (n = 55) and placebo (n = 44) in TNBC (HR 0.25, p = 0.01) and those who express HLA-A24 (HR 0.41, p = 0.05). The TNBC cohort demonstrated improved 36-month DFS in those with HER2 1+ expression (HR 0.17, p = 0.01), HLA-A24 positivity (HR 0.08, p < 0.01), or in those who received neoadjuvant chemotherapy (HR 0.21, p < 0.01). NPS vaccination with trastuzumab was associated with improved 36-month DFS among patients with TNBC. The observed benefit to this high-risk subgroup warrants confirmation in a phase III trial.

Carboplatin-Cyclophosphamide or Paclitaxel without or with Bevacizumab as First-Line Treatment for Metastatic Triple-Negative Breast Cancer (BOOG 2013-01)

Background: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated. Methods: The Triple-B study is a multicenter, randomized phase IIb trial that aims to prospectively validate predictive biomarkers, including baseline plasma vascular endothelial growth factor receptor-2 (pVEGFR-2), for bevacizumab benefit. mTNBC patients were randomized between CC and paclitaxel (P) without or with bevacizumab (CC ± B or P ± B). Here we report on a preplanned safety and preliminary efficacy analysis after the first 12 patients had been treated with CC+B and on the predictive value of pVEGFR-2. Results: In 58 patients, the median follow-up was 22.1 months. Toxicity was manageable and consistent with what was known for each agent separately. There was a trend toward a prolonged PFS with bevacizumab compared to chemotherapy only (7.0 vs. 5.2 months; adjusted HR = 0.60; 95% CI 0.33–1.08; p = 0.09), but there was no effect on OS. In this small study, pVEGFR-2 concentration did not predict a bevacizumab PFS benefit. Both the intention-to-treat analysis and the per-protocol analysis did not yield a significant treatment-by-biomarker test for interaction (p_interaction = 0.69). Conclusions:CC and CC+B are safe first-line regimens for mTNBC and the side effects are consistent with those known for each individual agent. pVEGFR-2 concentration did not predict a bevacizumab PFS benefit.

A phase IIb, open-label, single-arm study of zanidatamab (ZW25) monotherapy in subjects with advanced or metastatic HER2-amplified biliary tract cancers.

TPS352 Background: Advanced biliary tract cancers (BTCs), including gallbladder cancer (GBC) and cholangiocarcinoma (CC), have a poor prognosis. Zanidatamab (ZW25) is a novel bispecific antibody that targets HER2 domains ECD2 and ECD4, resulting in increased antibody binding density and improved receptor internalization and downregulation relative to trastuzumab. In an ongoing phase I trial (ZWI-ZW25-101; NCT02892123), single-agent zanidatamab was well tolerated and showed promising anti-tumor activity across HER2-expressing solid tumors, including BTCs. These results formed the basis for a phase IIb study of zanidatamab in patients with BTC. Methods: Study ZWI-ZW25-203 (NCT04466891) is a global, multicenter, open-label, single-arm, phase IIb trial designed to evaluate the anti-tumor activity of zanidatamab monotherapy in patients with HER2-amplified, inoperable and advanced or metastatic BTCs, including GBC and CC. Patients must have received at least 1 prior gemcitabine-containing systemic chemotherapy regimen for advanced disease and have experienced disease progression after (or developed intolerance to) their most recent prior therapy. New or archival tumor tissue is required from all patients for HER2 amplification and protein expression testing at a central lab using in situ hybridization (ISH) and immunohistochemistry (IHC) assays. Approximately 100 patients with HER2 amplification by ISH will be enrolled. Zanidatamab 20 mg/kg will be administered intravenously every 2 weeks until one of the treatment discontinuation criteria is met. The primary endpoint of the study is the confirmed objective response rate (ORR) by independent central review per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Secondary endpoints include duration of response (DOR), proportion of patients with DOR ≥ 16 weeks, disease control rate, progression-free survival, overall survival, safety, quality of life, and disease-related pain. The safety and tolerability of zanidatamab will be assessed by recording the frequency and severity of adverse events, serious adverse events, and laboratory abnormalities, as well as the frequency of zanidatamab dose modifications. The study is currently open for enrollment. Clinical trial information: NCT04466891.

Carrageenan as a Preventive Agent Against Human Papillomavirus Infection: A Narrative Review.

Carrageenan, an extract from red algae, was identified over a decade ago as a potent inhibitor of human papillomavirus (HPV) infection in vitro. After this discovery, several studies evaluated carrageenan's anti-HPV activity in cells, experimental animals, and humans. We reviewed the evidence for carrageenan's anti-HPV activity. Studies had to be in vitro, in vivo, or in humans and report on carrageenan's anti-HPV activity. Of the 39 records identified in PubMed and 29 records in Clinicaltrials.gov, 22 records were included after screening: 8 in vitro (including 2 ex vivo), 3 in vivo, 5 in vitro and in vivo, 3 clinical studies, and 3 trial protocols. A total of 12 studies evaluated carrageenan exclusively, whereas 7 considered carrageenan combined with additional antiviral or other agents. One study protocol will evaluate carrageenan exclusively, and 2 others will evaluate carrageenan-combination products. Most clinical studies evaluated carrageenan's ability to prevent HPV acquisition (n = 4), whereas one study explored its ability to promote clearance of existing infection (defined as the absence of HPV DNA detection). Carrageenan's anti-HPV activity was observed consistently across study designs, except in 2 studies: 1 in vitro study where 2 of the HPV types tested were not significantly inhibited by carrageenan and 1 phase IIB trial in gay, bisexual, and other men who have sex with men. This review supports the premise that carrageenan, alone or in combination with other antiviral agents, might be a potential prevention strategy complementary to HPV vaccination for women.

Pre-clinical evaluation of the effect of co-medication with antibiotics and oral steroids in Göttingen Minipigs on the biological activity of the probiotic medicinal product TSO (Trichuris suis ova)

The probiotic medicinal product TSO (Trichuris suis ova) is administered to patients with active ulcerative colitis in an ongoing clinical phase IIb trial where the typical co-medications are steroids (prednisolone or budesonide) and antibiotics (e.g., phenoxymethylpenicillin). The present pre-clinical study evaluates the effects of these co-medications on the biological activity of TSO in Göttingen Minipigs. This translationally relevant pre-clinical model allows administration of TSO with and without oral steroids or antibiotics in a manner similar to the administration to patients, followed by quantification of the biological activity of TSO. The biological activity of TSO was not affected by oral steroids but was reduced by oral antibiotics. Fecal calprotectin, the common marker of intestinal inflammation in patients with UC, did not differ between groups.

Recent Advances in the Diagnosis and Treatment of Neonatal Seizures.

Seizures are the most common neurological emergency in the neonates, and this age group has the highest incidence of seizures compared with any other period of life. The author provides a narrative review of recent advances in the genetics of neonatal epilepsies, new neonatal seizure classification system, diagnostics, and treatment of neonatal seizures based on a comprehensive literature review (MEDLINE using PubMED and OvidSP vendors with appropriate keywords to incorporate recent evidence), personal practice, and experience. Knowledge regarding various systemic and postzygotic genetic mutations responsible for neonatal epilepsy has been exploded in recent times, as well as better delineation of clinical phenotypes associated with rare neonatal epilepsies. An International League Against Epilepsy task force on neonatal seizure has proposed a new neonatal seizure classification system and also evaluated the specificity of semiological features related to particular etiology. Although continuous video electroencephalogram (EEG) is the gold standard for monitoring neonatal seizures, amplitude-integrated EEGs have gained significant popularity in resource-limited settings. There is tremendous progress in the automated seizure detection algorithm, including the availability of a fully convolutional neural network using artificial machine learning (deep learning). There is a substantial need for ongoing research and clinical trials to understand optimal medication selection (first line, second line, and third line) for neonatal seizures, treatment duration of antiepileptic drugs after cessation of seizures, and strategies to improve neuromorbidities such as cerebral palsy, epilepsy, and developmental impairments. Although in recent times, levetiracetam use has been significantly increased for neonatal seizures, a multicenter, randomized, blinded, controlled phase IIb trial confirmed the superiority of phenobarbital over levetiracetam in the acute suppression of neonatal seizures. While there is no single best choice available for the management of neonatal seizures, institutional guidelines should be formed based on a consensus of local experts to mitigate wide variability in the treatment and to facilitate early diagnosis and treatment.

Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)\u2014study protocol for a multicenter randomized double-blind placebo-controlled trial

BackgroundSince decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population.Methods/designA multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day − 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity.DiscussionThe AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis.Trial registrationClinicaltrials.gov NCT04099901. Registered on September 23, 2019. EudraCT: 2018-005046-10.

Non-antibiotic medication use in an Indonesian community cohort 0-18 months of age.

Rational medication use for treatment is mandatory, particularly in children as they are vulnerable to possible hazards of drugs. Understanding the medication use pattern is of importance to identify the problems of drug therapy and to improve the appropriate use of medication among this population. A post-hoc study of the RV3-BB Phase IIb trial to children aged 0-18 months which was conducted in Indonesia during January 2013 to July 2016. Any concomitant medication use and health events among 1621 trial participants during the 18 months of follow-up were documented. Information on medication use included the frequency, formulation, indication, duration of usage, number of regimens, medication types, and therapeutic classes. The majority of participants (N = 1333/1621; 82.2%) used at least one non-antibiotic medication for treatment during the 18-month observation period. A total of 7586 medication uses were recorded, mostly in oral formulation (90.5%). Of all illnesses recorded, 24.7% were treated with a single drug regimen of non-antibiotic medication. The most common therapeutic classes used were analgesics/antipyretics (30.1%), antihistamines for systemic use (17.4%), cough and cold preparations (13.5%), vitamins (8.6%), and antidiarrheals (6.6%). The main medication types used were paracetamol (29.9%), chlorpheniramine (16.8%), guaifenesin (8.9%), zinc (4.6%), and ambroxol (4.1%). Respiratory system disorder was the most common reason for medication use (51.9%), followed by gastrointestinal disorders (19.2%), pyrexia (16.9%), and skin disorders (7.0%). A large number of children were exposed to at least one medication during their early life, including those where evidence of efficacy and safety in a pediatric population is lacking. This supports the need for further research on pediatric drug therapy to improve the appropriate use of medication in this population.

Cognitive training and brain stimulation in prodromal Alzheimer\u2019s disease (AD-Stim)\u2014study protocol for a double-blind randomized controlled phase IIb (monocenter) trial

BackgroundGiven the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer’s disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted.MethodsThe AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention.SignificanceWith this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with SCD and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD.Trial registrationClinicalTrials.gov, NCT04265378. Registered on 07 February 2020. Retrospectively registered.Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019).Sponsor: University Medicine Greifswald.

Efficacy of Selinexor Based Regimens in Relapsed Refractory Multiple Myeloma: A Systematic Review

Introduction: In Multiple Myeloma (MM), nuclear exporter exportin-1 (XPO1) is a target for selinexor. Selinexor has a promising efficacy and a favorable safety profile in relapsed refractory MM. This systemic review aims to explore the efficacy and safety of selinexor based regimens for the treatment of relapsed refractory multiple myeloma (RRMM). Materials and Methods: We conducted a literature search using four databases (PubMed, Embase, Cochrane library, and ClinicalTrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and keywords for multiple myeloma and Selinexor including trade and generic names from the date of inception to April 13, 2020. Initial databases yielded 115 articles. After excluding review articles, duplicates, and non-relevant articles, we included six clinical trials reporting the efficacy of Selinexor in RRMM. Results: Among a total of 310 enrolled patients, 288 patients were evaluated. Selinexor was given in combination with dexamethasone to 207 and as three drug regimens to 103 RRMM patients. Chen et al. studied the efficacy of selinexor plus dexamethasone (d) in RRMM pts (n=70) in phase I trial achieved an overall response rate (ORR) of 10%, stable disease (SD) of 31% and progressive disease (PD) of 27%. Similarly, Chari et al. studied selinexor + dexamethasone in RRMM pts (n=122) in phase IIb trial, and observed ORR of 28%. The median overall survival (OS) was 8.6 months (95% CI, 6.2 to 11.3) and a median progression-free survival (PFS) was 3.7 months (95% CI, 3.0 to 5.3) with SD of 39% and PD of 21%. Chen et al. studied selinexor in combination with pomalidomide (P) + d in RRMM patients (n=46), achieved an ORR of 50% and the median PFS of 10.4 months. The disease was stable in 24% of patients with a low rate of progression i.e. 2%. In a phase Ib/II trial using selinexor + carfilzomib + d by Gasparetto et al. (n=12), the ORR was 75%, with SD of 16.67%. Selinexor in combination with doxorubicin and d was studied in phase I/II trial by Baz et al. (n=27) with ORR of 15% and SD in 30% of patients. Brojil et al. reported the role of selinexor + bortezomib + d in RRMM (n=11) in phase II trial with partial response (PR) of 80%. The median PFS was 17 months and one-year overall survival (OS) was 100%. The majority of hematological adverse effects were pancytopenia. The main non-hematological adverse effects were pneumonia, and peripheral sensory neuropathy. Conclusion:Selinexor showed promising outcomes in terms of ORR for the treatment of RRMM. The responses in selinexor based three-drug regimens were observed higher as compared to two-drug regimens, providing a benchmark for future studies. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Robust Efficacy Signals in Elderly AML Patients Treated with Iadademstat in Combination with Azacitidine (ALICE Phase IIa Trial)

Introduction: Acute Myeloid Leukemia (AML) is an aggressive hematological malignancy with a higher incidence in older people. Most elderly AML patients are unfit for intensive chemotherapy and their treatment remains a challenge. Remission and survival rates decrease with age, and there is rather limited treatment success with standard (chemo)therapy, leading to 5-year survival rates of 20% or lower. Recent combinations of hypomethylating agents with pro-apoptotic agents such as venetoclax, a Bcl-2 inhibitor, have shown improved therapeutic prospects in early phase clinical trials, which still need to be supported by data from ongoing phase III confirmatory trials. Lysine-specific demethylase 1 (LSD1) participates in malignant transformation in AML. Iadademstat is a differentiating drug that selectively inhibits LSD1 and has shown efficacy in preclinical models, both alone and in combination with other compounds including azacitidine and Bcl-2 inhibitors. A First-in-Man phase I study in refractory-relapsed acute leukemia patients treated with iadademstat in monotherapy showed a good safety profile, strong differentiating activity and preliminary signs of anti-leukemic activity. In the last year, we have reported interim results of the ongoing ALICE clinical trial with progressively more patients treated with iadademstat combined with azacitidine. Now, we report additional positive results in this hard-to-treat population. The efficacy of this combination may offer an alternative therapeutic option for previously untreated elderly AML population. Methods: ALICE is an open-label, single arm, phase IIa clinical trial to assess the safety, tolerability and dose finding of iadademstat in combination with azacitidine for the treatment of elderly AML patients. Secondary end points of the study are to describe the anti-leukemic activity of the combination (overall response rate, time to response and duration of response), to assess the hematological improvement along with PK/PD measures. ALICE includes patients older than 60 yrs, diagnosed with AML according to the WHO classification, who have not received prior treatment for AML other than hydroxyurea and are considered by the investigator as ineligible for intensive chemotherapy or refuse this treatment option. Results: At ASH2020 we will report compiled results of the ALICE study based on a November cut-off, when we expect to have recruited around 24 subjects. At the time this abstract is written, among the 18 currently recruited patients, 13 have had at least 1 bone marrow evaluation and achieved a 77% objective response rate (ORR): 4 Complete Remissions, 2 Complete Remissions with incomplete hematological recovery and 4 Partial Remissions. The current mean duration in the study is 20 weeks, with a mean Time to Response of only 37 days. The Progression Free Survival in the patients under remission is, so far, 250 days and the longest response in CR is above 550 days (still under treatment and in CR). Moreover, those patients with longer treatment periods have also improved or overcome their dependency on blood transfusions. Main safety events include neutropenia and thrombocytopenia in most of the patients, whereas only 3 non-hematological AEs (asthenia, dysgeusia and weight reduction) have been observed. Among the 38 serious AEs reported so far, only 2 were considered as related to iadademstat, corresponding to a differentiation syndrome (Grade 3) and a fatal intracranial hemorrhage on C1D15. Besides the expected hematological impact, the combination appears to be safe and well tolerated. Conclusions: Data to-date support iadademstat as an effective oral agent with a good safety profile compared with other anti-leukemic agents and hence as a meaningful candidate for selective combinations with other agents. Toxicity appears to be predictable, manageable and restricted only to the hematologic compartment. Under azacitidine alone, the historical response rates were 27% in this elderly AML population; the current results are supportive of a significant synergistic effect for iadademstat. The ORR of this combo is, so far, in line with the one shown by venetoclax combinations in similar early phase clinical trials. A confirmatory phase IIb trial is planned. With its oral administration, safety profile and novel MoA, iadademstat combo therapy may increase the therapeutic options for this AML population. Disclosures Salamero: Daichii Sankyo: Honoraria; Pfizer: Consultancy; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Somervaille:Novartis: Consultancy, Honoraria; Imago Bioscience: Research Funding. Gutierrez:Oryzon Genomics: Current Employment. Bullock:Oryzon Genomics: Current Employment. Buesa:Oryzon Genomics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents &amp; Royalties. Bosch:Roche: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Jansen: Honoraria. Montesinos:Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau; Celgene, Pfizer, Abbvie: Consultancy.

Low-Dose Aspirin in High-Risk Individuals With Screen-Detected Subsolid Lung Nodules: A Randomized Phase II Trial.

Lung cancer screening by helical low-dose computed tomography detects nonsolid nodules that may be lung adenocarcinoma precursors. Aspirin’s anti-inflammatory properties make it an attractive target for prevention of multiple cancers, including lung cancer. Therefore, we conducted a phase IIb trial (NCT02169271) to study the efficacy of low-dose aspirin to reduce the size of subsolid lung nodules (SSNs). A total of 98 current or former smokers (67.3% current) undergoing annual low-dose computed tomography screening with persistent SSNs were randomly assigned to receive aspirin 100 mg/day or placebo for 1 year. There was no difference in change in the sum of the longest diameters of target nodules in the placebo and aspirin arm after 12 months of treatment (-0.12 mm [SD = 1.55 mm] and +0.30 mm [SD= 2.54 mm], respectively; 2-sided P = .33 primary endpoint). There were no changes observed in subgroup analyses by individual characteristics or nodule type. One year of low-dose aspirin did not show any effect on lung SSNs. SSNs regression may not be the proper target for aspirin, and/or longer duration may be needed to see SSNs modifications.