Phase IIb Trial Research Articles

Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Safety and efficacy of RT234 vardenafil inhalation powder on exercise parameters in pulmonary arterial hypertension: phase II, dose-escalation study design

BackgroundPulmonary arterial hypertension (PAH) is a progressive disease characterized by high mean pulmonary arterial pressure (≥ 20 mmHg) and remodeling of the vascular arteries. Approved therapies improve symptoms and delay clinical worsening in the long term, but they do not relieve acute exertional symptoms. RT234, a drug/device combination (Respira Therapeutics, Palo Alto, CA, USA) that delivers the phosphodiesterase 5 inhibitor vardenafil to the lungs via inhalation, has been shown to reduce pulmonary vascular resistance in patients with PAH. This study aims to evaluate whether RT234 can increase oxygen capacity during cardiopulmonary exercise testing (CPET) in patients with PAH.MethodsThis prospective, multi-center, open-label, two-cohort, dose-escalation, phase IIb trial in patients with PAH will evaluate the safety and efficacy of RT234 in improving exercise parameters. The trial began in September 2020 and is expected to be completed by early 2024. Patients eligible for enrollment will have a right heart catheterization–confirmed diagnosis of PAH, a 6-minute walking distance of ≥ 150 m, a minute ventilation/carbon dioxide production slope of ≥ 36, and will be on up to three stable oral and/or inhaled (not parenteral) PAH-specific background therapies. The estimated sample size is 86 patients, who will be divided into two dose cohorts. Cohort 1 will receive 0.5 mg RT234, and cohort 2 will receive 1.0 mg RT234. Each cohort will contain two subgroups based on the number of PAH background medications (up to two vs three). The trial will assess patients’ changes from baseline in peak oxygen consumption (VO2) during CPET 30 minutes after a single dose of 0.5 mg or 1.0 mg RT234, the change in the 6-minute walking distance, and the pharmacokinetics and safety profile of single doses of RT234.ConclusionThis is the first trial involving an as-needed medication for PAH. The trial will provide insights into the safety and efficacy of as-needed RT234 in treating the acute symptoms of PAH during exercise and will inform the design of further trials.Trial registration number: ClinicalTrials.gov identifier NCT04266197.

219. A Randomized, Double-Masked, Placebo-Controlled Phase IIB Trial of Azithromycin and Trimethoprim-Sulfamethoxazole as Bacterial STI Prophylaxis in Pregnant Women with HIV

Abstract Background This phase IIB randomized clinical trial was designed to test the efficacy of a novel regimen to prevent bacterial sexually transmitted infections and malaria in pregnant women with HIV in Cameroon, where HIV prevalence in pregnancy is 5.7%. Here we present the analysis of STI rates. Methods Pregnant women in prenatal care with confirmed HIV, gestational age < 28 weeks and singleton pregnancies were randomized to monthly azithromycin (AZ) 1 gram daily for 3 days and daily trimethoprim-sulfamethoxazole (TMPS) or the standard regimen of daily TMPS with monthly placebo AZ. The main outcome of interest was the proportion of women with a composite STI measure: chlamydia, gonorrhea and/or incident syphilis at delivery. Nucleic acid amplification testing (NAAT) for CT/NG was performed on provider-collected vaginal swabs. Incident syphilis was defined serologically as a newly positive treponemal test or 4 fold increase in RPR/VDRL titer since baseline. The proportion was compared by relative risk with 95% confidence intervals and a significant p value set at < 0.05. Results A total of 308 women were enrolled at three hospital facilities between March 2018 and August 2020. In all, 155 women were randomized to the AZ/TMPS arm and 153 women to the TMPS arm. A total of 260 women (84%) had delivery samples collected. Both groups were similar with median age 32 years, maternal education (71% secondary school or university), HIV diagnosis 3 years prior, and 94% reported excellent adherence to antiretroviral therapy (ART). Median CD4 count was 473 cells/mm3 (IQR 326-663). At baseline, prevalence of chlamydia was 1.4%, gonorrhea 1.0% and syphilis 1.9%. There was no difference in the proportion of women with the composite STI measure (3.2% in the AZ/TMPS arm and 3.3% in the TMPS arm; RR 0.78 (95% CI 0.21 – 2.84); p=0.70). Adverse birth outcomes were lower in the AZ/TMPS arm, but not significantly (preterm delivery 5% vs 10.3% [p=0.1], low birthweight 2.8% vs 5.1% [p=0.34], composite adverse birth outcome 8.4% vs 13.1% [p=0.19]. Table 1:Baseline Characteristics of Study Participants (n=308)Table 2:Efficacy Outcomes at Delivery by Arm - Intention to Treat Analysis (n= 278) Conclusion The addition of monthly azithromycin to standard daily TMPS prophylaxis in pregnant women living with HIV in Cameroon did not reduce the rate of bacterial STI at delivery. Women reported excellent ART adherence and rates of STI, malaria, and adverse birth outcome were low. Disclosures Katia J. Bruxvoort, PhD, MPH, Dynavax: Grant/Research Support|Gilead: Grant/Research Support|Glaxosmithkline: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support|Seqirus: Grant/Research Support.

Impact of exposure to malaria and nutritional status on responses to the experimental malaria vaccine ChAd63 MVA ME-TRAP in 5-17 month-old children in Burkina Faso.

Pactr.org, identifier PACTR201208000404131; ClinicalTrials.gov, identifier NCT01635647.

A systematic review and meta-analysis assessing antiretroviral therapy for treatment-experienced HIV adult patients using an optimized background therapy approach: is there evidence enough for a standardized third-line strategy?

BackgroundThe World Health Organization (WHO) has identified the need for evidence on third-line antiretroviral therapy (ART) for adults living with HIV/AIDS, given that some controversy remains as to the best combinations of ART for experienced HIV-1-infected patients. Therefore, we conducted a systematic review and meta-analysis to (i) assess the efficacy of third-line therapy for adults with HIV/AIDS based on randomized controlled trials (RCT) that adopted the “new antiretroviral (ARV) + optimized background therapy (OBT)” approach and (ii) address the key issues identified in WHO’s guidelines on the use of third-line therapy.MethodsMEDLINE, EMBASE, LILACS, ISI Web of Science, SCOPUS, and Cochrane Central Register of Controlled Trials were searched for RCTs assessing third-line ARV therapy that used an OBT approach between 1966 and 2015. Data was extracted using an Excel-structured datasheet based on the Consolidated Standards of Reporting Trials (CONSORT) recommendations. The primary outcome of this meta-analysis was the proportion of patients reaching undetectable HIV RNA levels (< 50 copies/mL) at 48 weeks of follow-up. Included studies were evaluated using the Cochrane’s Risk of Bias assessment tool. Summarized evidence was rated according to the GRADE approach.ResultsEighteen trials assessing 9 new ARV + OBT combinations defined as third-line HIV therapy provided the efficacy data: 7 phase IIb trials and 11 phase III trials. Four of the 18 trials provided extension data, thus resulting in 14 trials providing 48-week efficacy data. In the meta-analysis, considering the outcome regarding the proportion of patients with a viral load below 50 copies/ml at 48 weeks, 9 out of 14 trials demonstrated the superiority of the new combination being studied (risk difference = 0.18, 95% CI 0.13–0.23). The same analysis stratified by the number of fully active ARVs demonstrated a risk difference of 0.29 (95% CI 0.12–0.46), 0.28 (95% CI 0.17–0.38) and 0.17 (95% CI 0.10–0.24) respectively from zero, one, and two or more active drugs strata. Nine of the 18 trials were considered to have a high risk of bias.ConclusionsEfficacy results demonstrated that the groups of HIV-experienced patients receiving the new ARV + OBT were more likely to achieve viral suppression when compared to the control groups. However, most of these trials may be at a high risk of bias. Thus, there is still not enough evidence to stipulate which combinations are the most effective for therapeutic regimens that are to be used sequentially due to documented multi-resistance.

22MO Efficacy and safety of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer (mTNBC) by baseline HER2 expression level: Subgroup analysis from a phase IIb trial

About 30-40% of mTNBC patients (pts) have tumors with HER2 low expression, which might be a potential target of some novel anti-HER2 agents. Sacituzumab govitecan (SG), a novel Trop2-targeted antibody-drug conjugate, has been approved for second line onwards mTNBC treatment by Singapore and NMPA recently. To better understand the role of SG in the treatment of Chinese mTNBC with different HER2 expression level, subgroup data of EVER-132-001 were analyzed.

32923 A multicenter, double-blind, randomized, placebo-controlled, phase IIb dose-finding study to evaluate efficacy and safety of spesolimab in patients with moderate-to-severe palmoplantar pustulosis

Palmoplantar pustulosis (PPP) is a chronic inflammatory disease characterized by sterile pustules on the palms and soles, and has an impact on patient quality of life. Spesolimab is a first-in-class humanized anti-interleukin 36 receptor monoclonal IgG antibody, previously investigated in a phase IIa PPP trial. In this phase IIb trial (NCT04015518), patients with moderate-to-severe PPP were assigned to 1 of 5 groups; they received a total subcutaneous loading dose of 1500/3000 mg spesolimab or placebo for the first 4 weeks followed by 300/600 mg spesolimab or placebo q4w.

EP01.05-009 Simulation-Based Sample Size Estimation for an Early Detection of Lung Cancer Clinical Utility Trial in Indeterminate Pulmonary Nodules

Indeterminate pulmonary nodules (IPN) are a common clinical challenge worldwide. Current management can result in delayed diagnosis and unnecessary invasive procedures, two important indicators of clinical utility (CU). Improved risk stratification using a combination of biomarkers and CT imaging was recently published, mandating a randomized clinical trial to assess its CU. Essential trial design considerations include prevalence of cancer and variation in diagnostic practices across sites. Here, we describe an approach to estimate the sample size for a randomized Phase IIb trial measuring CU of a validated combined risk prediction score (CBM; blood biomarker + radiomics + Mayo risk score).

277O The ReSPECT-GBM™ phase I/IIa trial of rhenium-186 nanoliposome (186RNL) in recurrent glioma via convection enhanced delivery (CED) and planned phase IIb trial

A phase I/IIa dose escalation trial was initiated to determine the safety and recommended phase II dose (RP2D) of 186RNL in patients with recurrent glioma. 186RNL is a source of high energy beta and gamma particles. We report the safety, feasibility, overall survival (OS), RP2D and proposed phase IIb clinical plan.

Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children

BackgroundRTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity.MethodsWe studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041).ResultsRTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities.ConclusionsResults provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.

Cediranib in Combination with Olaparib in Patients without a Germline BRCA1/2 Mutation and with Recurrent Platinum-Resistant Ovarian Cancer: Phase IIb CONCERTO Trial.

The efficacy, safety, and tolerability of cediranib plus olaparib (cedi/ola) were investigated in patients with nongermline-BRCA-mutated (non-gBRCAm) platinum-resistant recurrent ovarian cancer. PARP inhibitor-naïve women aged ≥18 years with platinum-resistant non-gBRCAm ovarian cancer, ECOG performance status of 0-2, and ≥3 prior lines of therapy received cediranib 30 mg once daily plus olaparib 200 mg twice daily in this single-arm, multicenter, phase IIb trial. The primary endpoint was objective response rate (ORR) by independent central review (ICR) using RECIST 1.1. Progression-free survival (PFS), overall survival (OS), and safety and tolerability were also examined. Sixty patients received cedi/ola, all of whom had confirmed non-gBRCAm status. Patients had received a median of four lines of chemotherapy; most (88.3%) had received prior bevacizumab. ORR by ICR was 15.3%, median PFS was 5.1 months, and median OS was 13.2 months. Forty-four (73.3%) patients reported a grade ≥3 adverse event (AE), with one patient experiencing a grade 5 AE (sepsis), considered unrelated to the study treatment. Dose interruptions, reductions, and discontinuations due to AEs occurred in 55.0%, 18.3%, and 18.3% of patients, respectively. Patients with high global loss of heterozygosity (gLOH) had ORR of 26.7% [4/15; 95% confidence interval (CI), 7.8-55.1], while ORR was 12.5% (4/32; 95% CI, 3.5-29.0) in the low gLOH group. Clinical activity was shown for the cedi/ola combination in heavily pretreated, non-gBRCAm, platinum-resistant patients with ovarian cancer despite failing to meet the target ORR of 20%, highlighting a need for further biomarker studies.

Production of a high purity, C-tagged hepatitis B surface antigen fusion protein VLP vaccine for malaria expressed in Pichia pastoris under cGMP conditions.

Virus‐like particles (VLPs) induce strong humoral and cellular responses and have formed the basis of some currently licensed vaccines. Here, we present the method used for the production of R21, a VLP‐based anti‐sporozoite malaria vaccine, under current Clinical Good Manufacturing Practice regulations (cGMP). Previous preclinical studies in BALB/c mice showed that R21 produced almost complete protection against sporozoite challenge with transgenic Plasmodium berghei parasites. Here, we have modified the preclinical production process to enable the production of sufficient quantities of highly pure, clinical‐grade material for use in human clinical trials. The R21 construct was re‐engineered to include a C‐tag to allow affinity‐based separation from the major contaminant alcohol oxidase 1 (AOX 1, ~74 kDa). To our knowledge, this is the first use of C‐tag technology to purify a VLP vaccine candidate for use in human clinical trials. The R21 vaccine has shown high‐level efficacy in an African Phase IIb trial, and multiple clinical trials are underway to assess the safety and efficacy of the vaccine. Our findings support the future use of C‐tag platform technologies to enable cGMP‐compliant biomanufacturing of high purity yeast‐expressed VLP‐based vaccines for early phase clinical trials when clinical grade material is required in smaller quantities in a quick time frame.

TB-PRACTECAL: study protocol for a randomised, controlled, open-label, phase II–III trial to evaluate the safety and efficacy of regimens containing bedaquiline and pretomanid for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis

BackgroundGlobally rifampicin-resistant tuberculosis disease affects around 460,000 people each year. Currently recommended regimens are 9–24 months duration, have poor efficacy and carry significant toxicity. A shorter, less toxic and more efficacious regimen would improve outcomes for people with rifampicin-resistant tuberculosis.MethodsTB-PRACTECAL is an open-label, randomised, controlled, phase II/III non-inferiority trial evaluating the safety and efficacy of 24-week regimens containing bedaquiline and pretomanid to treat rifampicin-resistant tuberculosis. Conducted in Uzbekistan, South Africa and Belarus, patients aged 15 and above with rifampicin-resistant pulmonary tuberculosis and requiring a new course of therapy were eligible for inclusion irrespective of HIV status. In the first stage, equivalent to a phase IIB trial, patients were randomly assigned one of four regimens, stratified by site. Investigational regimens include oral bedaquiline, pretomanid and linezolid. Additionally, two of the regimens also included moxifloxacin (arm 1) and clofazimine (arm 2) respectively. Treatment was administered under direct observation for 24 weeks in investigational arms and 36 to 96 weeks in the standard of care arm. The second stage of the study was equivalent to a phase III trial, investigating the safety and efficacy of the most promising regimen/s. The primary outcome was the percentage of unfavourable outcomes at 72 weeks post-randomisation. This was a composite of early treatment discontinuation, treatment failure, recurrence, lost-to-follow-up and death. The study is being conducted in accordance with ICH-GCP and full ethical approval was obtained from Médecins sans Frontières ethical review board, London School of Hygiene and Tropical Medicine ethical review board as well as ERBs and regulatory authorities at each site.DiscussionTB-PRACTECAL is an ambitious trial using adaptive design to accelerate regimen assessment and bring novel treatments that are effective and safe to patients quicker. The trial took a patient-centred approach, adapting to best practice guidelines throughout recruitment. The implementation faced significant challenges from the COVID-19 pandemic. The trial was terminated early for efficacy on the advice of the DSMB and will report on data collected up to the end of recruitment and, additionally, the planned final analysis at 72 weeks after the end of recruitment.Trial registrationClinicaltrials.gov NCT02589782. Registered on 28 October 2015.

Evaluation of booster injections in maintaining peak immunity in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus GM-CSF alone after adjuvant trastuzumab in women with HER2-positive breast cancer.

LBA550 Background: Injection site reactions (ISR) of booster injections in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial of GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2 have been analyzed. It was demonstrated that GLSI-100 safely elicited a potent immune response versus placebo, along with data showing ISRs correlate to immune response data such as Delayed Type Hypersensitivity (DTH). Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. Injection site reactions were assessed 48-72 hours after the injection. Booster injections were introduced mid-trial so not all patients were dosed with boosters. The largest perpendicular diameters of induration were measured, and the orthogonal mean was calculated to quantify ISRs, providing potential assessments of peak and nadir immunity during the PIS and booster phases of treatment. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, who were in the efficacy population, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). A patient is in the efficacy population if they were treated, followed, and remained disease free over the first 6 months. Boosters were administered to 53 HER2 3+ patients (54%). The median peak ISR during the PIS in GLSI-100 treated patients was 92.1 mm versus 60.5 mm in the GM-CSF only treated control patients. Peak ISR in GLSI-100 treated patients occurred throughout the 10-dose dosing period, including during boosters. During the 6 dose PIS, 84% of the peak ISRs occurred between doses 3 through 6. Each booster is administered 6 months after the last injection, thus the booster ISR is likely measuring the nadir immune response. When comparing the peak ISR during PIS to the boosters, the nadir ISRs of the boosters were approximately 20 mm smaller. Conclusions: Administering GLSI-100 boosters at 6 month intervals to patients produced a consistent nadir ISR approximately 20 mm lower than the maximum PIS ISR of 92.1 mm which is still larger than the maximum ISR in GM-CSF only patients of 60.5 mm. A patient’s immune response a month after booster dosing would theoretically be the peak ISR, which will be measured in future trials by measuring T-cell response and DTH one month after booster injections, further helping to evaluate booster strategies to sustain peak immunity over longer periods of time. Clinical trial information: 00524277.

Oral histone deacetylase inhibitor tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results.

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.

4003 Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]

A randomized presurgical trial of alternative dosing of exemestane in postmenopausal women with early-stage ER-positive breast cancer.

519 Background: Successful therapeutic cancer prevention requires definition of the minimal effective dose of the proposed agent. Aromatase inhibitors substantially decreased breast cancer incidence in high risk postmenopausal women in phase III trials but their clinical use in prevention and adherence in adjuvant setting is limited by adverse events. We conducted a randomized presurgical phase IIb trial to evaluate two alternative doses of exemestane. Methods: We conducted a multi-center, pre-surgical, double-blind, 3-arm, non-inferiority phase IIb study in postmenopausal women with histologically confirmed estrogen receptor (ER)-positive breast cancer. Patients were randomized to receive either exemestane 25 mg/day (QD), or 25 mg/three times/week (TIW), or 25 mg once a week (QW) for 4-6 weeks before surgery. Blood and tissue biomarkers were collected at baseline and final visit. The primary aim was a non-inferiority percent change of circulating estradiol relative to the standard dose. Secondary endpoints were the change in Ki-67 and PgR expression in cancer tissue, blood sex hormones, lipid profile, toxicity and menopausal symptoms. For the power calculation we assumed a non-inferiority difference of 6% in the percentage change of estradiol among arms, using a one-sided, two-sample t-test. Assuming a 10% drop-out rate, a total sample size of 180 participants (60 per arm) had 80% power to detect a 6% margin of equivalence. The significance level for the main endpoint was 0.025 to account for multiple comparisons and 0.05 for secondary endpoints. Results: A total of 230 women were screened, 180 agreed to participate and 173 were evaluable for response. The median percent change of estradiol was -98%, -98%, and -70% for exemestane QD (n = 56), TIW (n = 57), and QW (n = 60), respectively, showing no significant difference between QD and TIW arms (p = 0.9). Similarly, no differences were observed for estrone, total estrone and estrone sulfate between QD and TIW arms. The QW arm showed some modulation in all hormones, even though less significantly so. Among the secondary endpoints, Ki-67 and PgR were reduced in all arms, with a median change of -5% vs -7.5% for Ki-67(p = 0.124), and -9 vs -17 for PgR (p = 0.246) in the TIW vs QD arms, respectively. SHBG and HDL-cholesterol had a more favorable profile with the TIW dose compared to the daily dose. Adverse events, measured according to the CTCAE (v4), and menopausal symptoms according to MENQOL were similar in all arms, but the short treatment time may not be representative. Conclusions: Exemestane 25 mg TIW retains a comparable activity than 25 mg QD. This activity was similar in both arms throughout the primary and the main secondary endpoints. This new schedule should be further assessed in prevention studies and in women on adjuvant treatment who do not tolerate the daily dose. Clinical trial information: NCT02598557.

Baseline GP2 immune response as an independent prognostic factor in a phase IIb study evaluating HER2/neu peptide GP2 (GLSI-100) versus. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with breast cancer.

e12519 Background: Delayed type hypersensitivity (DTH) skin tests to GP2 were conducted in the randomized, active-controlled, single-blinded, multicenter Phase IIb trial investigating GLSI-100 (GP2+GM-CSF) administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing HER2. Previously it has been reported that subjects with baseline response to GP2 by DTH were more likely to experience a recurrence sooner than those without a positive baseline response. It was of interest to determine if this response was independent of other known prognostic factors. Methods: Patients were randomized and received GLSI-100 (500 mcg GP2: 125 mcg GM-CSF) or control (GM-CSF only) via 6 intradermal injections every 3-4 weeks as part of the Primary Immunization Series (PIS) for 6 months and 4 booster injections every 6 months thereafter. GP2 DTH skin tests were placed at baseline and after the 6th dose. After 48-72 hours, the largest perpendicular diameters of induration were measured and the orthogonal mean was calculated. Induration of over 5mm was considered a positive response. The relationship between prognostic factors such as demographic and disease characteristics and the baseline DTH response were investigated by logistic regression. Results: The study enrolled 180 patients who were HER2 3+ positive and low HER2 expressors (1-2+). After 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GLSI-100, if completing the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 patients treated with GM-CSF (p = 0.0338). Just under 23% of subjects experienced an immune response to GP2 by DTH at baseline. The incidence was similar in patients who were HER2/neu positive and those considered low expressors and was equally distributed across GLSI-100 and placebo-treated subjects. Known prognostic factors such as hormone receptor status, stage at presentation, node status, etc. were evenly distributed across subjects that experienced a baseline DTH response to GP2 and those who did not. Each prognostic factor was investigated in a logistic model to determine if it predicted baseline DTH immune status. The prognostic factors did not predict baseline DTH immune response in the logistic models. There appears to be no correlation between baseline immune response to GP2 and known prognostic factors. Conclusions: Baseline GP2 immune response as measured by the delayed-type hypersensitivity test may be an independent prognostic factor for recurrence. Knowledge of this GP2 immune response may identify a patient with increased risk of rapid recurrence. Clinical trial information: 00524277.

TACTI-003: A randomized phase IIb study of eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab as first-line treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma.

TPS6099 Background: Eftilagimod alpha (efti) is a soluble LAG-3 protein targeting a subset of MHC class II molecules that mediate antigen presenting cell (APC) and CD8 T-cell activation. Data from a non-randomized, phase II trial of efti plus pembrolizumab (TACTI-002) showed encouraging antitumor activity and manageable safety when given as second-line treatment of patients with recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC). TACTI-003 (NCT04811027) is a multicenter, open label, randomized phase IIb trial to investigate efti plus pembrolizumab in the first-line setting for RM-HNSCC. Methods: A total of 154 patients (pts) are currently being recruited into two cohorts (A+B). In cohort A, pts with tumors that are CPS≥1 will be randomly assigned 1:1 to receive either efti (30 mg subcutaneously Q2W for initial 6 months, thereafter Q3W) plus pembrolizumab (400 mg intravenously Q6W) for up to two years or pembrolizumab alone. Randomization will be stratified by CPS (1-19 vs. ≥ 20) and ECOG PS (0 vs. 1). Pts with tumors that are CPS &lt; 1 will receive efti plus pembrolizumab (cohort B). Imaging will be performed every 9 weeks. The primary endpoint (EP) is objective response rate (ORR) by RECIST1.1. Secondary EPs include overall survival, ORR according to iRECIST, time to and duration of response, disease control rate, progression-free survival, occurrence of anti-efti -specific antibodies, safety, and quality of life. Exploratory endpoints comprise biomarkers. The study has been approved by relevant competent authorities, ethic committees and IRBs. Clinical trial information: NCT04811027.

028 Cladribine to halt deterioration in people with advanced multiple sclerosis (ChariotMS)

BackgroundDisease modifying treatments (DMTs) have transformed the management of people with MS (pwMS). However, patients with an EDSS&gt;6.5 (pwAMS) are considered beyond DMT due to (i) focus on ambulation as outcome measure, (ii) assumption that in pwAMS inflammation plays no role, and(iii) disregard for potentially length-dependent neuro-axonal damage. Cladribine is a CNS penetrant, effective, convenient and relatively safe DMT. Cladribine effectively depletes B cell subsets, particularly memory B cells, a potential key mechanism of disease control in pwMS.AimsTo test the efficacy, safety and cost-effectiveness of cladribine tablets in pwAMS (EDSS 6.5–8.5), expand the mechanistic understanding of cladribine in pwAMS and provide evidence for NHS adoption.MethodsRandomised, double-blind, placebo-controlled phase IIb trial. The primary outcome measure is 9-hole peg test speed at 104 weeks vs baseline. To detect a 15% treatment effect in 9-HPT peg speed with 90% power at 5% significance and 20% drop-out we calculated a sample size of n=200 across 20 UK sites.ConclusionsChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for potential add-on therapies. ChariotMS is due to start recruitment nationwide from 1 Sep 2020.david.lieberman@nhs.net