Independent Data Monitoring Committee Research Articles

A systematic survey of adaptive trials shows substantial improvement in methods is needed

ObjectivesTo investigate the design, conduct, and analysis of adaptive trials through a systematic survey and provide recommendations for future adaptive trials. Study Design and SettingWe systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases up to January 2020. We included trials that were self-described as adaptive trials or applied adaptive designs. We identified three frequently used adaptive designs and summarized their methodological details in terms of design, conduct, and analysis. Lastly, we provided recommendations for future adaptive trials. ResultsWe included a total of 128 trials in this study. The primary motivations for using adaptive design were to speed up the trials and facilitate decision-making (n = 29, 31.5%). The three most frequently used methods were group sequential design (GSD) (n = 71, 55.5%), adaptive dose-finding design (ADFD) (n = 35, 27.3%), and adaptive randomization design (ARD) (n = 26, 20.3%). The timing and frequency of interim analysis were detailed in three-fourths of the GSD trials (n = 55, 77.5%) and in half of the ADFD trials (n = 19, 54.3%); however, more than half of the ARD trials (n = 15, 57.7%) did not provide this information. Some trials selected a different outcome than the primary outcome for interim analysis (GSD: n = 7, 12.7%; ADFD: n = 8, 27.6%; ARD: n = 7, 50.0%), but the majority of these trials did not provide explicit reasons for this choice (GSD: n = 7, 100.0%; ADFD: n = 7, 87.5%; ARD: n = 5, 71.4%). More than half (n = 76, 59.4%) of trials did not mention the accessibility of supporting documents, and two-thirds (n = 86, 67.2%) did not state the establishment of independent data monitoring committees (IDMCs). Moreover, unplanned adjustments were observed during the conduct of one-sixth adaptive trials (n = 22, 17.2%). Based on our findings, we provide 14 recommendations for improving adaptive trials in the future. ConclusionSubstantial improvements were needed in methods of adaptive trials, particularly in the areas of interim analysis, the establishment of independent data monitoring committees, and unplanned adjustments. In this study, we offer recommendations from both general and specific aspects for researchers to carefully design, conduct, and analyze adaptive trials.

Updated Protocol for the Phase 3, Randomized, Double-Blinded Lex-210 Study of Four-Factor Prothrombin Complex Concentrate in Patients with Acute Major Bleeding on Factor Xa Inhibitor Therapy

Background and Significance: Despite significantly reduced risk of intracranial hemorrhage compared with vitamin K antagonists, direct oral anticoagulant therapy with factor Xa inhibitors (FXaI) is associated with similar incidences of other major bleeds. Although hemostatic agents such as prothrombin complex concentrates (PCCs) are often used (off-label), the efficacy and safety of PCCs for managing FXaI-related bleeding requires further investigation. This study aims to evaluate superior hemostatic efficacy of high-dose vs low-dose four-factor (4F) PCC (Octaplex®; Octapharma) in adults with FXaI-related major bleeding. Study Design and Methods: LEX-210 (NCT04867837) is a Phase 3, multicenter, prospective, randomized, double-blinded, group-sequential, parallel-group, adaptive design study. Significant modifications have recently been made to the study design. Patients aged ≥18 years with acute major bleeding (e.g., gastrointestinal, intracranial) and baseline anti-factor Xa activity of ≥100 ng/mL are eligible. To increase rate of recruiting suitable patients into the study, the eligibility criteria have been optimized. For inclusion (full criteria in Table 1), baseline anti-factor Xa activity of ≥100 ng/mL may be either confirmed by locally available tests (including retrospectively by the central laboratory) or suspected by the investigator and later confirmed by the central lab. Prospective written informed consent will be obtained from all patients or patients' legally authorized representative prior to enrolment. If this is not possible, in countries outside the US where it is permitted under local regulations or approved by local ethics committees, deferred consent procedures may be applied. Key exclusion criteria (Table 2) include acute trauma for which FXaI reversal alone would not be expected to control bleeding, and thromboembolic events in the last 3 months. In addition, hypersensitivity to heparin and platelet inhibitors are specified. Patients will be excluded if they score <7 on the Glasgow Coma Scale (with allowances for intubation), or have expected survival of <24 hours. While patients scheduled for surgery in <12 hours are excluded, minor surgeries and invasive procedures for diagnostic or therapeutic reasons are allowed, or if intended to address a second (non-index) bleeding event. Patients will be randomized 1:1 to 50 or 15 IU/kg 4F-PCC. The primary objective is to demonstrate superior hemostatic efficacy of the higher dose in patients with major bleeding associated with FXaI. Hemostatic efficacy through 24 hours after receipt of 4F-PCC will be evaluated by an independent data monitoring and endpoint adjudication committee using objective criteria, with a binary outcome of effective or ineffective. Secondary endpoints include change in endogenous thrombin potential (baseline to 1 hour after 4F-PCC), 30-day rates of thromboembolic events, and all-cause mortality. The study is conducted in accordance with the ethical principles laid down in the Declaration of Helsinki The proportion of patients with an effective outcome will be compared between groups using a one-sided z-test. The primary statistical model will be adjusted for the baseline anti-factor Xa activity as determined retrospectively by the central laboratory. A logistic regression model for the success rate using treatment group (dose level) and the anti-factor Xa activity as fixed effects will be used to determine the one-sided z-statistic. LEX-210 launched in Q4 2021 and will be performed across ~60 sites in North America and the European Continent. Target enrollment is ~260 patients, assuming a 30% dropout rate. So far, 26 sites in the US, Italy, Germany, and Spain have been initiated, with 5 patients enrolled. Study completion is anticipated in Q3 2024.

P31 Efficacy and safety of oral gepotidacin in the treatment of uncomplicated urinary tract infection: results of two randomized, multicentre Phase 3 trials (EAGLE-2 and EAGLE-3)

Abstract Background Uncomplicated urinary tract infections (uUTIs) are among the most prevalent infections worldwide. Currently, treatments are limited by antimicrobial resistance and antibiotic allergy/intolerance. There is an unmet need for new oral antibiotics active against uropathogens resistant to current treatments. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a distinct mechanism of action and binding site and provides well-balanced inhibition of two Type II topoisomerase enzymes. Gepotidacin is under investigation for treatment of uUTI. Methods EAGLE-2 (NCT04020341) and EAGLE-3 (NCT04187144) were near-identical global Phase 3, randomized, parallel-group, double-blind, non-inferiority (10% margin) studies comparing the efficacy and safety of oral gepotidacin (1500 mg twice daily, 5 days) to nitrofurantoin (100 mg [Macrobid] twice daily, 5 days) for the treatment of uUTI. Eligible female patients were aged ≥12 years with ≥2 uUTI symptoms and urinary nitrite or pyuria (Figure 1). Per latest US FDA guidance, the primary endpoint, therapeutic response at test-of-cure (Days 10–13), was evaluated in patients with qualifying uropathogen(s) (≥105 cfu/mL) susceptible to nitrofurantoin. Therapeutic success was combined clinical success (complete resolution of symptoms) and microbiological success (reduction of uropathogen[s] to <103 cfu/mL) without additional systemic antimicrobials. Data below are from a predefined interim analysis (IA) with efficacy/futility stopping criteria, conducted by an Independent Data Monitoring Committee (IDMC). Results A total of 2986 randomized patients (EAGLE-2: N=1474; EAGLE-3: N=1512) were included in the IA. See Table 1 for key efficacy results available to IDMC that led to their recommendation to stop both studies for efficacy (non-inferiority) with no concerning safety findings. Table 1.Therapeutic, clinical, and microbiological response at test-of-cure (data available to IDMC)EndpointGepotidacin 1500 mg BIDNitrofurantoin 100 mg BIDTreatment difference (gepotidacin – nitrofurantoin) (95% CI)aEAGLE-2N=320N=287 Therapeutic success162 (50.6%)135 (47.0%)4.3% (−3.6%, 12.1%) Clinical success210 (65.6%)187 (65.2%)1.2% (−6.3%, 8.7%) Microbiological success232 (72.5%)194 (67.6%)5.2% (−2.1%, 12.5%)EAGLE-3N=277N=264 Therapeutic success162 (58.5%)115 (43.6%)14.6% (6.4%, 22.8%) Clinical success188 (67.9%)167 (63.3%)4.4% (−3.5%, 12.3%) Microbiological success200 (72.2%)151 (57.2%)15.0% (7.2%, 22.9%)Study success rules were based on pre-defined interim analysis rules. Both studies were stopped for non-inferiority as the observed Z statistics of 3.5554 (EAGLE-2) and 5.8838 (EAGLE-3) were greater than the non-inferiority boundaries of the respective studies (2.065 for EAGLE-2 and 2.098 for EAGLE-3). Following pre-specified hierarchical testing strategy, superiority was then demonstrated in EAGLE-3 (observed one-sided P value of 0.0003 less than the superiority boundary [0.018]).Calculated using Miettinen–Nurminen test adjusting for age and recurrence history.These endpoints were evaluated in patients with all qualifying uropathogens determined to be susceptible to nitrofurantoin.BID, twice daily. Conclusions In two large Phase 3 trials using the latest, stringent, FDA efficacy endpoint, gepotidacin demonstrated non-inferiority in one trial and superiority in the other versus nitrofurantoin in the treatment of uUTI with an acceptable safety and tolerability profile. These data will be further described. Gepotidacin has the potential to be a useful oral antibiotic to treat uUTI and its evaluation in Phase 3 trials is an important step in addressing a significant unmet need.

Observation vs. radiotherapy in primary mediastinal B-cell lymphoma patients with complete response to standard immunochemotherapy: The IELSG37 randomized trial.

LBA7505 Background: Primary mediastinal B-cell lymphoma (PMBCL) has a good prognosis if remission is rapidly achieved with dose‐intensive immunochemotherapy. In these patients mediastinal radiotherapy (RT) may consolidate responses; however, it increases the risk of second malignancies and coronary or valvular heart disease. The IELSG37 trial was planned with a non-inferiority design to test whether RT can be omitted in patients who achieve a complete metabolic response (CMR) after immunochemotherapy. Methods: Patients with newly diagnosed PMBCL were eligible. Initial rituximab and anthracycline-based therapy was chosen according to local practice. CMR was defined, upon central review of positron emission computed tomography (PET/CT) scans, as Deauville score 1 to 3, according to the Lugano classification. Responding patients were randomized to observation (OBS) or consolidation RT (30 Gy). Randomization was stratified on gender, chemotherapy regimen, country, and PET/CT score. The primary endpoint was progression-free survival (PFS) after randomization. The sample size (540 patients to enrol, and 376 to randomize) was calculated assuming a 30-month PFS probability of 0.85 in both arms, with alpha at 0.05, 80% power and a hazard ratio (HR) of 1.77 as non-inferiority margin. Results: At a median follow-up of 30 months, the number of observed events was considerably lower than expected, hence, the Independent Data Monitoring Committee (IDMC) of the trial recommended to complete the planned total accrual without increasing the study size or duration. The primary endpoint analysis was performed, according to the IDMC recommendation, with ≥80% of patients having a minimum follow-up of 30 months. 545 patients (209 men, 336 women) were enrolled. Induction immunochemotherapy was completed and response assessed in 530 patients, 268 of them (50.6%) achieved a CMR and were randomly allocated to OBS (n = 132) or RT (n = 136). The PFS at 30 months was 98.5% (95%CI, 94.3 – 99.6) in the RT arm and 96.2% (95%CI, 91.1-98.4) in the OBS arm (P = 0.278). The estimated relative effect of radiotherapy vs observation in terms of hazard ratio (HR) was 0.47 (0.12-1.89) without adjustments and 0.79 (0.19-3.31) after stratification for the variables used for randomization. At 30 months the absolute risk reduction from RT was 2.3% (-1.5 to 6.2) unadjusted, and 0.8% (-3.0 to 8.3) with stratified HR. The number needed to treat is high (43 patients, unadjusted, and 126 after stratification). The 5-year overall survival was 99% in both arms. Longer follow-up is needed to examine late toxicity. Conclusions: This study is the largest prospective study of PMBCL ever conducted and although the event rate did not reach the assumed level, its evidence supports the omission of RT in patients achieving a CMR after immunochemotherapy.

Design of a Phase 1, Placebo-Controlled Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of PGN-EDODM1 in Adult Participants with Myotonic Dystrophy Type 1 (DM1) (P6-8.004)

<h3>Objective:</h3> The primary objective of this single-ascending dose (SAD) study is to evaluate the safety and tolerability of PGN-EDODM1 in adults living with DM1. Secondary and exploratory objectives include pharmacokinetics (PK), muscle distribution, pharmacodynamics (changes in splicing pattern of transcripts), and select functional outcome measures. <h3>Background:</h3> PepGen’s Enhanced Delivery Oligonucleotide (EDO) cell-penetrating peptide technology is engineered to optimize tissue delivery and cellular uptake of therapeutic oligonucleotides. PGN-EDODM1 is being evaluated for the treatment of DM1. PGN-EDODM1 binds to the pathogenic CUG repeat expansion in <i>DMPK</i> mRNA and reduces sequestration of Muscleblind (MBNL) proteins through a steric blocking mechanism. Release of MBNL proteins is hypothesized to correct DM1 spliceopathy; the root cause of DM1. <h3>Design/Methods:</h3> Males and females 18–50 years of age, inclusive, with genetically confirmed diagnosis of DM1 will be eligible to participate, and will be randomized 3:1 (6 active, 2 placebo) to receive PGN-EDODM1 or placebo in each dose cohort. A muscle needle biopsy (tibialis anterior) will be performed at baseline and at Weeks 4 and 16 post-dosing for measurement of splicing of selected transcripts. An independent data safety and monitoring committee will oversee dose escalation. <h3>Results:</h3> The doses to be assessed will be based on data from the preclinical data and data from the Phase 1 healthy volunteer safety study of our lead EDO, PGN-EDO51. A plan for analysis of safety measures such as vital signs, electrocardiograms, clinical chemistry, urinalysis, and biomarkers will be presented, along with details on proposed functional endpoints and biomarkers to be explored in this study. <h3>Conclusions:</h3> This Phase 1 SAD clinical study will support continued development of PGN-EDODM1 for the treatment of DM1, and will be initiated in 2023. Participants will be invited to enroll in a planned multiple-ascending dose study (MAD) and a subsequent open-label extension study. <b>Disclosure:</b> Dr. Mellion has received personal compensation for serving as an employee of PepGen. Dr. Mellion has stock in PepGen. Dr. Larkindale has received personal compensation for serving as an employee of PepGen. Jennifer Cormier has nothing to disclose. Ms. Hand has received personal compensation for serving as an employee of 4D Molecular Therapeutics. Ms. Hand has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Fulcrum Therapeutics, Inc.. Ms. Hand has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for PepGen Inc. Ms. Hand has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Bluebird Bio. Ms. Vacca has received personal compensation for serving as an employee of PepGen Inc. Ms. Vacca has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PepGen Inc. Ms. Vacca has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Agios Pharmaceuticals. Ms. Vacca has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Nocion Therapeutics. Ms. Vacca has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Relmada Therapeutics. Ms. Vacca has stock in PepGen Inc.. Pallavi Lonkar has nothing to disclose. Dr. Holland has received personal compensation for serving as an employee of PepGen Inc.. Dr. Holland has received intellectual property interests from a discovery or technology relating to health care. Mr. Garg has received personal compensation for serving as an employee of PepGen. Mr. Garg has stock in pepgen. Mr. Foy has received personal compensation for serving as an employee of PepGen Inc.. Dr. McArthur has received personal compensation for serving as an employee of PepGen . Dr. McArthur has stock in PepGen .

Abstract CT045: A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers

Abstract Background: Immune checkpoint inhibitors targeting the PD1/PD-L1 axis have made a breakthrough in advanced solid tumors, leading to improved overall survival (OS) in several cancer types. However, only a minority of patients experience durable responses, requiring further development of anti-tumoral immunotherapies to overcome tumor immune escape. We hypothesized that priming the immune system with TG4001, a vaccine using the highly attenuated Modified Vaccinia virus Ankara as vector expressing the HPV16 E6 and E7 proteins (rendered non-oncogenic) and interleukin-2, would increase the clinical benefit associated with PD-L1 blockade in HPV16+ cancer patients. In the single-arm part of the trial evaluating the combination of TG4001 and avelumab in terms of response rate, the overall response rate (ORR) was 22%. Presence of liver metastases had a profound impact on outcome in terms of ORR and Progression Free Survival (PFS). In patients (pts) without liver metastases an ORR of 32% was observed versus 0% in pts with liver metastases, warranting further development of this combination in this patient population (SITC 2020, Abstract ID 793). Methods: We have designed a randomized open-label two-arms trial evaluating the efficacy of the combination of TG4001 and avelumab versus avelumab alone (NCT03260023). Eligible pts have R/M HPV-16 positive anogenital cancer including cervical, vulvar, vaginal, penile, and anal cancers with no more than one prior line of chemotherapy for R/M disease and no previous exposure to cancer immunotherapy. HPV-16 positivity is determined in a central laboratory. Patients are randomly assigned 1:1 to receive either TG4001 plus avelumab or avelumab alone. Randomization is stratified by primary tumor type (cervical, anal, genital). TG4001 is administered subcutaneously (SC) at 5 × 107 plaque forming units (pfu) Q1w for 5 weeks, Q2w until month 6 and Q12w until progressive disease and avelumab intravenously (IV) at 800 mg Q2w until progressive disease. A total of up to 140 pts are currently being recruited into two cohorts (A and B) in France, Spain, and USA. For Cohort A, consisting of pts without liver metastases at Baseline (BL), a 2-stage sample size adjustment design is used with PFS by RECIST 1.1 as primary endpoint. Plans are to accrue 120 patients following Interim Analysis and Independent Data Monitoring Committee (IDMC) review. Cohort B recruits pts with liver metastases at BL. To be eligible, hepatic disease is restricted in terms of extent and number of lesions. A total of 20 pts will be recruited and analyzed for the percentage of early progressors. Secondary endpoints include overall survival, objective response rate according to RECIST1.1, duration of response, disease control rate. Exploratory endpoints comprise analyses of blood-based parameters and tumor-based proteins and RNA expression and their impact on clinical outcomes. Citation Format: Christophe Le Tourneau, Frédéric Rolland, Amaury Daste, Philippe Cassier, Sébastien Salas, Luis Manso Sánchez, Gerardo Colon-Otero, Lauriane Eberst, Olivier Lantz, Ana Lalanne, Annette Tavernaro, Hakim Makhloufi, Kaïdre Bendjama, Maud Brandely, Jean-Pierre Delord. A randomized phase II trial of TG4001 plus avelumab versus avelumab alone in recurrent/metastatic (R/M) human papilloma virus (HPV)-16 positive anogenital cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT045.

Combined incentive actions, focusing on primary care professionals, to improve cervical cancer screening in women living in socioeconomically disadvantaged geographical areas: a study protocol of a hybrid cluster randomised effectiveness and implementation trial- RESISTE

IntroductionCervical cancer (CC) causes thousands of deaths each year. Nearly 100% of cases are caused by oncogenic strains of human papillomavirus (HPV). In most industrialised countries, CC screening (CCS) is...

UNISUS study design: a phase 3 superiority study comparing the efficacy, safety, and tolerability of macitentan 75 mg vs macitentan 10 mg in patients with pulmonary arterial hypertension (PAH)

Abstract Background While advances in PAH-specific therapies have substantially improved survival, there is still an unmet need to improve long-term outcomes in PAH. Purpose The UNISUS study is the first head-to-head superiority study in PAH, comparing the time to morbidity or mortality (M/M) with macitentan 75 mg vs macitentan 10 mg in PAH patients. Methods UNISUS, an ongoing multicentre, prospective, double-blind (DB), adaptive, event-driven superiority study randomises PAH patients 1:1 to receive macitentan 75 mg or macitentan 10 mg, with a target enrolment of ∼900 patients. Efficacy and safety are continuously assessed by an independent data monitoring committee (IDMC), who advises on pre-specified adaptive changes in study conduct, including expansion of the study population. An independent clinical event committee adjudicates all M/M events. The initial population was restricted to patients in functional class (FC) II/III, aged 18–75 years and excluded those with portopulmonary hypertension (PoPH) and those who were PAH treatment-naïve or receiving a prostanoid analogue. Stable (≥3 months) background PAH-therapy may be maintained, except for endothelin receptor agonists (ERAs), which must be stopped the day before initiating study drug. The study is comprised of a screening period, a 4-week run-in period (if ERA treatment-naïve or on sub-optimal ERA dose), and an event-driven DB treatment period, followed by a 2-year open-label extension with macitentan 75 mg. Initiation of macitentan 75 mg occurs after a 4-week up-titration step with macitentan 37.5 mg (Figure 1). The primary endpoint is time to first on-treatment M/M event, defined as first of: all-cause death, PAH-related hospitalisation, or PAH-related disease progression (confirmed ≥15% decrease in 6-minute walk distance (6MWD) and either FC worsening or addition of PAH therapy). Other endpoints include change from baseline to Week 24 in 6MWD and PAH-SYMPACT symptom scores; time to PAH-related hospitalisation or death; time to all-cause death (may be supplemented with data from an external control arm derived from the CARE PAH study [NCT04955990]); and the safety and tolerability of the study drugs. Figure 2 shows planned assessments and sub-studies. To maximise patient retention, add-on PAH therapies are allowed after a M/M event and, for patients at risk of withdrawing and unable to attend visits, the investigator may consider options for reduced follow-up. Results After 60 patients had been exposed for ≥8 weeks, the IDMC reviewed unblinded safety/tolerability data and recommended to expand recruitment from the restricted population to the target population (i.e., including patients: with PoPH, in FC II–IV, from any PAH therapy background [including naïve], aged ≥18 years). Conclusion UNISUS is the first head-to-head superiority study in PAH; with over 200 patients enrolled, it is currently recruiting the target population. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Actelion Pharmaceuticals Ltd., a Janssen pharmaceutical company of Johnson &amp; Johnson.

A randomized, non-comparative, phase II study of maintenance OSE2101 vaccine alone or in combination with nivolumab (nivo) or FOLFIRI after induction with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): First interim results of the TEDOPAM GERCOR D17-01 PRODIGE 63 STUDY.

4148 Background: OSE2101 is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts. This study aimed to assess the efficacy and safety of OSE2101 ± anti-PD1 nivo as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction chemotherapy. Methods: TEDOPaM-PRODIGE 63 was initially a 3-arm, open-label, randomized, non-comparative phase II study. Pts with aPDAC, HLA-A2 positive (blood) and no progression after 8 cycles of (modified) FOLFIRINOX were randomized 1:1:1 to receive FOLFIRI (standard Arm A), OSE2101 (subcutaneous injection on D1 Q3W x 6 doses then Q8W until M12 then Q12W up to M24, experimental Arm B) or OSE2101 + nivo (360 mg IV on D1 Q3W x 6 then 480 mg Q4W up to M24, experimental Arm C). FOLFIRI was reintroduced at disease progression in Arms B and C. Primary endpoint was overall survival (OS) rate at 12 months (M12) (Fleming two-stage design, H0: 25%; H1: 50%, one-sided alpha: 2.5%, power: 90%). 156 Pts were planned. Results: Following the occurrence of 2 tumor flares in Arm C, an Independent Data Monitoring Committee (IDMC) recommended to continue FOLFIRI as backbone in experimental Arm B and stop Arm C. Interim analysis results refer to 29 randomized Pts: 9/10/10 in Arm A/B/C, respectively. Median age was 63 years, 52% were men, 55% had ECOG PS 0, and 83% were metastatic. Best response to induction FOLFIRINOX was partial response in 48% and stable disease in 52%. With a median follow-up of 23 months, M12-OS rate was 44%, 40%, and 30% in Arm A, B and C. Other efficacy results are summarized in Table below. No OSE2101-related toxicity of grade ≥ 3 (G≥3) were observed in Arm B; 1 G3 cytokine-release syndrome (OSE2101-related) and 2 tumor flares (nivo-related) leading to death were observed in Arm C. Conclusions: Maintenance OSE2101 monotherapy showed a favorable safety profile and encouraging time to strategy failure warranting further evaluation. OSE2101 + nivo was associated with poorer outcomes leading to close Arm C. Following IDMC recommendation, the study is ongoing with the new design (maintenance FOLFIRI vs. FOLFIRI + OSE2101). Clinical trial information: NCT03806309. [Table: see text]

CYCLONE 2: A phase 2/3, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.

TPS198 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&amp;6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&amp;6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 &amp; 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.

Abstract OT1-12-06: Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial

Abstract Background: Pyrotinib is an irreversible pan-ErbB receptor tyrosine kinase inhibitor targeting human epidermal growth factor receptor 1 (HER1), HER2, and HER4. Exploratory studies of neoadjuvant pyrotinib combined with trastuzumab-based standard chemotherapy for HER2-positive (HER2+) early or locally advanced breast cancer (BC) showed promising pathological complete response (pCR) rates of 51.6%-71%, with a manageable toxicity profile. We are to further investigate this combination strategy versus standard therapy in a randomized trial. Trial design: Pyramid is a randomized, multicenter, open-label, two-stage adaptive enrichment phase 2 trial to evaluate the efficacy and safety of pyrotinib plus trastuzumab and nab-Paclitaxel versus pertuzumab plus trastuzumab and nab-Paclitaxel as neoadjuvant treatment in patients with HER2+ early or locally advanced BC (NCT04900311). Eligible patients will be randomized 1:1 to receive four 21-day cycles of pyrotinib (400 mg, po, qd) or pertuzumab (840 mg loading dose, 420 mg maintenance doses, i.v., day 1) with trastuzumab (8 mg/kg loading dose, 6 mg/kg maintenance doses, i.v., day 1) and nab-Paclitaxel (260 mg/m2, day 1 or 125 mg/m2, i.v., day 1/8/15). After completion of neoadjuvant treatment, patients will undergo surgery, followed by standard EC regime for 4 cycles. Subsequent adjuvant therapy will be decided by investigators. Randomization was stratified by hormone receptor (HR) status (ER and/or PR positive vs. negative) and primary tumor size (2&amp;lt;T≤5 cm vs. T&amp;gt;5 cm). There will be two stage of this trial, and population may be enriched to HR-positive based on the results of interim analysis at Stage I. Eligibility criteria: Key inclusion criteria include female, treatment-naïve, histologically confirmed HER2+ invasive BC (cT2-4/cN0-3/cM0), the diameter of primary tumor &amp;gt; 2 cm, known HR status (ER and PR). Specific aims: Primary endpoint is total pathologic complete response (tpCR) rate per central review assessment. Secondary endpoints include invasive disease-free survival, event-free survival, objective response rate, breast-conserving surgery rate, safety. Exploratory endpoint is to investigate the possible predictive biomarkers of efficacy. Statistical methods: A sample size of 220 patients per arm is calculated to provide a power of 80% with a significance level of 0.1 (one-sided) to detect an estimated increase in the tpCR rate from 39% in the pertuzumab group to 49% in the pyrotinib group. Considering a dropout rate of 10%, 490 patients (245 per arm) will be required to be enrolled. A two-stage adaptive enrichment design will be used. The trial will enroll 186 patients at Stage I and an interim analysis will be conducted by an independent data monitoring committee (IDMC) when the pathologic response has been evaluated in at least 132 patients (including at least 66 HR-positive patients) at Stage I. Then, one of five options might be adapted at Stage II depending on the results, including: i. Continue study as planned in whole population; ii. Re-estimate sample size in whole population; iii. Enrich to HR-positive population with pre-defined sample size; iv. Enrich to HR-positive population and re-estimate sample size; v. Early termination. The Clopper-Pearson method will be used to calculate a 95% confidence interval (CI) for the tpCR rate. The CMH chi-square test will be used to compare the tpCR rate between groups and 95% CIs for the difference will be estimated using the Miettinen-Nurminen method. Present accrual and target accrual: Target enrollment will be 490 patients at approximately 20 sites in China. As of June 24, 2021, 4 patients have been enrolled. Contact information: Jin Zhang, MD, Email: zhangjin@tjmuch.com. Citation Format: Jin Zhang, Qiang Liu, Hongchuan Jiang, Jianguo Zhang, Jianghua Ou, Dedian Chen, Fuguo Tian, Yongqing Li, Xiaoming Cheng, Zhong Ouyang. Neoadjuvant pyrotinib versus pertuzumab in combination with trastuzumab and nab-Paclitaxel for patients with HER2-positive early or locally advanced breast cancer (Pyramid): A randomized, multicenter, open-label, phase 2 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-06.

Abstract OT1-18-02: First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial

Abstract Background: Metastatic triple-negative breast cancer (mTNBC) is the most aggressive and heterogeneous breast cancer subtype, with limited therapeutic options. Immune-checkpoint inhibitors (ICI) with chemotherapy are approved as first-line therapy in mTNBC for patients with PD-L1+tumors. The generation of immunosuppressive extracellular adenosine in the tumor microenvironment by the overexpression of ectoenzyme CD73 is a mechanism that could impair ICI and chemotherapy activity. The SYNERGY trial investigates if the addition of an anti-CD73 monoclonal antibody, oleclumab, increases the clinical benefit (CB) to the combination of chemotherapy with an anti-PD-L1 antibody, durvalumab, in previously untreated patients with advanced or mTNBC. Here we present data from a primary analysis including the first 68 evaluable patients. Methods: Patients with previously untreated inoperable locally advanced or mTNBC were randomized between carboplatin AUC 1.5 and paclitaxel 80 mg/m2 q1w x 12 in combination with durvalumab 1500 mg q4w with (Arm A) or without (Arm B) oleclumab 3000 mg q2w x5 followed by 3000 mg q4w according to the recommended phase 2 dose. Maintenance with immunotherapy was continued after chemotherapy. The primary hypothesis is that the addition of oleclumab increases the clinical benefit rate (CBR) at week 24 defined as complete response, partial response or stable disease according to RECIST 1.1. by 20% (1-sided α=0.1 and 80% power with 68 pts/arm; 150 pts to be enrolled). Patients were stratified by PD-L1 status and CD73 immunohistochemistry (IHC) expression assessed on baseline tumor tissue by a central lab. Using the Lan-Demets approach, the stopping boundary was z test &amp;lt; 0.074, p=0.464. Data from this primary analysis for safety and futility were reviewed by an independent data monitoring committee ( IDMC). Results: The 68th evaluable patient reached week 24 on the 2nd Apr 2021. Patients’ baseline characteristics were well balanced between both arms. Grade 3-4 adverse events (AE) occurred in 28/33 patients (84.9%) in Arm A and 21/35 patients (60.0%) in Arm B (p=0.03). Most common grade 3-4 AE were hematological toxicities with neutropenia (Arm A 17/33 [51.5%]; Arm B 12/35 [34.3%], and anemia (Arm A 5/33 [15.2%]; 1/35 [2.9%] in Arm B). There was no increase of immune-related AEs in the arm A with oleclumab. In Arm A, 15/33 patients (45%) met the CB criterion vs. 17/35 patients (49%) in Arm B. The futility boundary was crossed with z-value = -0.2574, p=0.69 (one-sided Fisher's exact). No significant difference in CBR was observed when patients were stratified according to PD-L1 status or CD73 IHC expression. Based on these results, the IDMC recommended to stop further recruitment. Patients under treatment are allowed to continue with durvalumab and oleclumab after being informed of these preliminary results. Of note, at the moment of interim analysis, long-lasting responses were observed with immunotherapy maintenance in both arms. Conclusion: The addition of oleclumab to the combination of chemotherapy by carboplatin and paclitaxel with durvalumab as first-line therapy for advanced or mTNBC did not significantly increase CBR at 6 months. Thus, in arm A the CBR was 45% in the overall population with long-lasting responses and an acceptable toxicity profile. Longer follow-up to evaluate the survival benefit is required. Further investigations evaluating the heterogeneity of this disease using blood and tissue samples collected during trial will shed light on the mechanisms associated with response and resistance to the trial regimens and help to define specific subgroups of patients with TNBC who could benefit from ICI and adenosine targeting agents. Citation Format: Veronique Debien, Christian Maurer, Philippe Aftimos, Florian Clatot, Delphine Loirat, Kevin Punie, François Ghiringhelli, Anhony Gonçalves, Donatienne Taylor, Tom Van den Mooter, Jean-Marc Ferrero, Hervé Bonnefoi, Jean-Luc Canon, François Duhoux, Renaud Poncin, Fernando Bazan, Nicolas Isambert, Philippe Barthelemy, Mariana Brandão, Paulus Kristanto, Michail Ignatiadis, Martine Piccart, Laurence Buisseret. First-line chemo-immunotherapy with durvalumab, paclitaxel and carboplatin with or without anti-CD73 antibody oleclumab in advanced or metastatic triple-negative breast cancer: Preliminary results of the randomized phase II SYNERGY trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-02.

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Entospletinib in Combination with Intensive Induction and Consolidation Chemotherapy in Adults with Newly Diagnosed Nucleophosmin 1-mutated Acute Myeloid Leukemia

Use of a Biodegradable, Contrast-Filled Rectal Spacer Balloon in Intensity-Modulated Radiotherapy for Intermediate-Risk Prostate Cancer Patients: Dosimetric Gains in the BioPro-RCMI-1505 Study.

Background/purposeDose-escalated external beam radiotherapy (RT) is effective in the control of prostate cancer but is associated with a greater incidence of rectal adverse events. We assessed the dosimetric gain and safety profile associated with implantation of a new biodegradable rectal spacer balloon.Materials/methodsPatients scheduled for image-guided, intensity-modulated RT for intermediate-risk prostate cancer were prospectively included in the French multicenter BioPro-RCMI-1505 study (NCT02478112). We evaluated the dosimetric gain, implantation feasibility, adverse events (AEs), and prostate-cancer-specific quality of life associated with use of the balloon spacer.ResultsAfter a scheduled review of the initial recruitment target of 50 patients by the study’s independent data monitoring committee (IDMC), a total of 24 patients (including 22 with dosimetry data) were included by a single center between November 2016 and May 2018. The interventional radiologist who implanted the balloons considered that 86% of the procedures were easy. 20 of the 24 patients (83.3%) received IMRT and 4 (16.7%) received volumetric modulated arc therapy (78-80 Gy delivered in 39 fractions). The dosimetric gains associated with spacer implantation were highly significant (p<0.001) for most variables. For the rectum, the median (range) relative gain ranged from 15.4% (-9.2−47.5) for D20cc to 91.4% (36.8−100.0) for V70 Gy (%). 15 patients (62%) experienced an acute grade 1 AE, 8 (33%) experienced a late grade 1 AE, 1 (4.2%) experienced an acute grade 2 AE, and 3 experienced a late grade 2 AE. No grade 3 AEs were reported. Quality of life was good at baseline (except for sexual activity) and did not markedly worsen during RT and up to 24 months afterwards.ConclusionThe use of a biodegradable rectal spacer balloon is safe, effective and associated with dosimetric gains in modern RT for intermediate-risk prostate cancer.

Abstract CT106: Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20

Abstract Background EGFR exon 20 insertion gene mutation (ex20ins) accounts for about 4-12% of the total EGFR gene mutations in non-small cell lung cancer (NSCLC) patients. NSCLC patients with EGFR ex20ins is known to be less sensitive to 1st- or 2nd-generation EGFR-TKIs. Although 3rd-generation EGFR-TKI, osimertinib is active against in vitro models of EGFR ex20ins, its efficacy has not yet been fully elucidated. This phase I/II study is conducted to evaluate the clinical efficacy of osimertinib in NSCLC patients with EGFR ex20ins. Method This is a single-arm, multi-center, open-label, non-randomized phase I/II study (UMIN000031929) consisting of stage 1 and stage 2 (Simon's two-stage design). In stage 1, 12 patients receive osimertinib 80mg once daily until they meet the termination criteria, such as, disease progression, severe toxicities, withdrawal etc. In stage 2, 9 patients receive the same dose of osimertinib if more than 1 patient achieve PR or CR in stage 1. At the transition from stage 1 to 2, Independent Data Monitoring Committee (IDMC) will provide recommendation regarding the need for study continuation, termination or dose modification of osimertinib. Patients with advanced or metastatic NSCLC with EGFR ex20ins who have a history of chemotherapy within 0 to 3 regimens are enrolled. Patients with history of EGFR-TKI treatment (gefitinib, erlotinib, afatinib, dacomitinib) can be included if the EGFR-TKI treatment did not show any clinical benefit. Patients with EGFR gene mutations, such as exon 19 deletion, L858R, T790M, G719X, L861Q are excluded. Primary end point is objective response rate (ORR) assessed via Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points are progression-free survival, overall survival, and safety profiles. Blood sampling is obtained at 4-weeks after starting osimertinib to analyze pharmacokinetic parameters. We also perform liquid biopsy for next generation sequencing at before and after acquiring resistance to osimertinib to clarify resistant mechanisms of osimertinib in EGFR ex20ins. We explore the relationship among clinical outcome, side effect, pharmacokinetic parameters and subtype of EGFR ex20ins. Result Recruitment began in June 2018 and by February 2020, 12 patients were enrolled in stage 1 at 6 institutions. Backgrounds of the patients were as follows, the median age was 63 years (range 22-84), female/male 6/6, ECOG PS 0/1 8/4, cStage IIIA/IIIb/IVA/IVB 1/1/2/8. The ORR was 0% (CR/PR 0, SD 8, PD 4), and the DCR was 66.7%. From the result of stage 1, one of the IDMC's recommendations was protocol revision since it is presumed that increasing the dose of osimertinib could be clinically promising. At the conference, the influence of subtype of EGFR ex20ins and blood levels of osimertinib on survival will be evaluated and the results of interim analysis for stage 1 will be presented. Conclusion Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. Funding AstraZeneca. Citation Format: Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katsuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Koichi Goto, Kenzo Soejima. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT106.

Interim analysis of IMMUNEBOOST-HPV: A multicenter, randomized, open label, phase II study evaluating the feasibility, and tolerance of neoadjuvant nivolumab in high-risk HPV driven oropharynx cancer.

6037 Background: Among HPV-positive Oropharyngeal Cancer (OPC) patients (pts), some has a less favorable prognosis (T4, N2/N3, smokers &gt;10 pack-year [p/y]). We assume that neoadjuvant immunotherapy might improve their oncological outcomes, so we tested nivolumab (N) prior to ChemoRadiaTion (CRT). Methods: The study population is restricted to HPV positive OPC pts (both p16+ &amp; HPV-DNA+) with advanced disease (T4, N2/N3) or a smoking history &gt;10 p/y. Pts were randomly allocated 1:2 to receive either cisplatin-based CRT (n=20) or 2 cycles of N 240 mg followed by CRT (n=41). The Primary Endpoint (PE) is the rate of pts who can receive Full Treatment in Due Time (FTDT), according to these criteria: a) 2 N infusions on day 1 and on day 14-16 b) CRT started between days 28-37 after the 1st N infusion c) No RT break ≥1 week d) RT dose received &gt;95% of theoretical dose e) Cisplatin dose received ≥200 mg/m² To achieve FTDT, all criteria are required in the Experimental Arm (EA) while only criteria c), d), and e) are required in the Control Arm (CA). In the EA, the trial was designed in 2 steps, with FTDT rate of 88% considered as inacceptable versus an alternative of 98%, a type I error of 0.10, and a type 2 error of 0.08. As per protocol, patient accrual was temporarily suspended after inclusion of 19 pts in the EA (1st step) and results were reviewed by an Independent Data Monitoring Committee (IDMC). To resume pts’ inclusion, FTDT had to be achieved in 18 pts in the EA. Results: From 07/2019 to 09/2020, 30 pts were enrolled including 11 in the CA (demographics are summarized in table). 2 pts in the EA did not reach the PE. For the 1st patient, the cisplatin dose was &lt;200 mg/m2 due to grade 1 hearing loss and grade 2 tinnitus (1st cycle: 100 mg/m2, 2nd cycle: 80 mg/m2, no 3rd cycle). For the 2nd patient, CRT began at D38 due to logistical issues (maintenance of RT devices). As this delay was unrelated to N or to patient's condition, the IDMC considered that the inclusions could resume for the 2nd step. 7 N-related Adverse Events (AE) were reported in 4 pts including 3 serious AE (ankylosing spondylitis flare-up, colitis, diabetic ketoacidosis). Conclusions: Neoadjuvant N before CRT seems feasible for the treatment of OPC pts. The trial has reopened to inclusion as recommended by the IDMC. Clinical trial information: NCT03838263. [Table: see text]

HERIZON: A phase 1B/2 open-label study of imu-131 HER2/neu peptide vaccine PLUS standard of care chemotherapy with randomization in phase 2 in patients with HER2/neu overexpressing metastatic or advanced adenocarcinoma of the stomach or gastroesophageal junction.

e16065 Background: The phase 2 part of the study hypothesizes HER-Vaxx (IMU-131) will provide treatment benefits consistent with traditional monoclonal antibodies that target HER2 in patients with confirmed Her2+ advanced or metastatic gastric cancer with a corresponding adaptive immune response without added toxicity. In the phase 1b dose finding part of the study tumor response of patients who received 50ug dose strongly correlated with antibody levels with 50ug selected as the phase 2 dose (Wiedermann et. al., 2019). Phase 2 is a randomized two arm study of either HER-Vaxx plus standard chemotherapy or standard chemotherapy alone. The primary endpoint is overall survival, with progression-free survival, safety and immune related changes in humoral and cellular immunogenicity secondary endpoints. Methods: Patients received SOC chemotherapy for a maximum of 6 cycles with the HER-Vaxx group also receiving 50ug dose of IMU-131 at Baseline/Day 0, Day 14, Day 35, Day 77 and then every 63 days until disease progression. The per protocol pre-planned first interim analysis (OS, PFS and safety) in a total of 27 patients after 15 progression events was reviewed by the independent data monitoring committee (IDMC). Results: Within ITT analysis, 8 of 27 patients died on the control arm and 4 on the HER-Vaxx plus SOC chemotherapy arm with an overall survival HR of 0.418 (2 sided 80% CI: 0.186, 0.942) and a 1-sided p-value of 0.083. Out of 27 patients, 9 patients progressed on the control arm while 6 patients progressed on the HER-Vaxx plus SOC chemotherapy arm with a HR of 0.532 (2 sided 80% CI: 0.267, 1.060) and a 1-sided p-value of 0.086. A robust HER2 specific antibody response developed in the HER-Vaxx arm compared to the control arm whereas there was no difference in safety between the two treatment arms. Conclusions: The IDMC confirmed that the safety of the study was favorable with no added toxicity of HER-Vaxx and SOC chemotherapy with a favorable risk-benefit for the combination. The study has completed enrollment and final data is expected in late 2021. Clinical trial information: NCT02795988.

Phase 2 Clinical Study to Evaluate the Efficacy and Safety of Inhaled GB002 for the Treatment of World Health Organization Group 1 Pulmonary Arterial Hypertension

Purpose Despite currently available therapy, the morbidity and mortality of pulmonary arterial hypertension (PAH) remains high. PAH is characterized by abnormal proliferation of pulmonary arterial smooth muscle cells, endothelial cells, and myofibroblasts. GB002 is a unique, highly potent, small molecule that targets PDGFRα/β, CSF1R, and c-KIT and modulates BMPR2, kinases implicated in the development of PAH. GB002 is formulated for inhalation delivery to directly target the diseased lung to limit systemic exposure and thereby potentially improve efficacy and tolerability. A Phase 2 study has been initiated to evaluate the efficacy and safety of inhaled GB002 in adult subjects with World Health Organization (WHO) Group 1 PAH. (NCT04456998). Methods This is a randomized, double-blind, placebo-controlled study. Patients with Functional Class II/III PAH on therapy and with a pulmonary vascular resistance (PVR) greater than or equal to 400 dyne•s/cm5 will be eligible. The planned treatment period is 24 weeks, with a target enrollment of 80 patients. Endpoints The primary endpoint is change in PVR measured by right heart catheterization from baseline to 24 weeks. The key secondary endpoint is change (baseline to 24 weeks) in 6-minute walk test (6MWT). Exploratory endpoints include quality of life, change in risk score, time to clinical worsening, and the following echocardiographic parameters: tricuspid annular systolic velocity, right ventricular (RV) Tei index and right ventricular free wall strain (RVFWS). Sub-studies include 6MWT heart rate expenditure change from baseline to 24 weeks, and changes in pulmonary arterial blood volume measured by CT imaging (baseline to 24 weeks). An Independent Data Monitoring Committee (IDMC) will ensure that benefits and risks remain acceptable during the conduct of the study. In this phase 2 study, the effects of GB002 on hemodynamics, 6MWT and other endpoints at 24 weeks will be assessed. Exploratory biomarkers will be evaluated for target engagement and response to treatment.

Abstract OT2-02-06: Palbociclib in combination with trastuzumab and endocrine therapy (ET) versus treatment of physician's choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): A multi-center, randomized, open-label, phase II trial

Abstract Background: Efficacy Interim results from PATRICIA phase II trial in HER2+/HR+ advanced breast cancer (BC) showed that PAM50 luminal disease was associated with larger and clinically meaningful progression-free survival (PFS) following palbociclib, trastuzumab and endocrine therapy compared to PAM50 non-luminal disease (Ciruelos E. et al, SABCS 2018). Based on these preliminary results, PATRICIA II was designed to select patients based on PAM50 and to include a randomization to a control arm. Trial Design: PATRICIA II is a randomized open-label, adaptive design, phase II study. Eligible patients must have centrally confirmed HR+/HER2+ and PAM50 Luminal A or B intrinsic subtype tumors and have received at least 1 (and no more than 4) prior lines of anti-HER2 regimens for locally advanced or metastatic BC, including a taxane and trastuzumab. Patients are randomized 1:1 to receive trastuzumab in combination with palbociclib at a standard dose of 125 mg/day orally 3 weeks on/1 week off and endocrine therapy (cohort C1) or treatment of physician’s choice (TPC): TDM1 or chemotherapy (gemcitabine, vinorelbine, capecitabine, eribulin, paclitaxel or docetaxel) in combination with trastuzumab (cohort C2). ET options are either an aromatase inhibitor, fulvestrant or tamoxifen. Premenopausal patients (pts) must receive ovarian suppression. Stratification factors include number of previous regimens for advanced BC (1-2 vs 3-4) and the presence of visceral disease (yes vs no). The primary objective is to assess whether the combination of palbociclib, trastuzumab and endocrine therapy is superior to TPC in terms of progression-free survival (PFS) in HER2+, PAM50 Luminal patients. The study has an 80% power with two-sided alpha=0.05 to detect a hazard ratio of 0.62 in favor of the palbociclib arm. An adaptive design will be used to compare both treatment arms. An interim analysis (IA) adjusted for multiplicity from O’Brien-Fleming method and an estimation of the conditional power (CP) will be performed at 70% of the events by an Independent Data Monitoring Committee (IDMC). Key secondary objectives are response rate, overall survival, safety, and Quality of Life. Tumor tissue and blood samples will be collected for biomarker analyses. A total of 516 patients will be screened and 232 patients will be recruited. The trial was activated in June 2019 and the recruitment is ongoing in 20 sites in Spain. The study is sponsored by SOLTI and financially supported by Pfizer. Citation Format: Eva Ciruelos, Patricia Villagrasa, Mafalda Oliveira, Sonia Pernas, Javier Cortes, Silvia Vazquez, Noelia Martínez, Antonia Perello, Begoña Bermejo, Eduardo Martínez, Isabel Garau, Mireia Melé, Alvaro Montaño, Estela Vega, Blanca Cantos, María Jose Echarri, Tomás Pascual, Jordi Canes, Pamela Céliz, Xavier González, Aleix Prat. Palbociclib in combination with trastuzumab and endocrine therapy (ET) versus treatment of physician's choice (TPC) in metastatic HER2-positive and hormone receptor-positive (HER2+/HR+) breast cancer with PAM50 luminal intrinsic subtype (SOLTI-1303 PATRICIA II): A multi-center, randomized, open-label, phase II trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT2-02-06.

Triple-arm trial of pH (Tri-pH) effect on live birth after ICSI in Egyptian IVF facilities: protocol of a randomised controlled trial

IntroductionOne potential stressor that can affect preimplantation and postimplantation embryonic growth after in vitro fertilisation (IVF) is the pH of the human embryo culture medium, but no evidence exists to...