Phase II-III Research Articles

P52 - Topic: AS08-Treatment/AS08g-Clinical trials - Phase II-III: EFFICACY OF CPX-351 AS FIRST LINE TREATMENT FOR HIGHER RISK (HR) MDS/CMML. A STUDY BY THE GFM

P52 - Topic: AS08-Treatment/AS08g-Clinical trials - Phase II-III: EFFICACY OF CPX-351 AS FIRST LINE TREATMENT FOR HIGHER RISK (HR) MDS/CMML. A STUDY BY THE GFM

Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice

Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL. To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials. The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity. From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications. Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

Donafenib Versus Sorafenib in First-Line Treatment of Unresectable or Metastatic Hepatocellular Carcinoma: A Randomized, Open-Label, Parallel-Controlled Phase II-III Trial

PURPOSEDonafenib, a novel multikinase inhibitor and a deuterated sorafenib derivative, has shown efficacy in phase Ia and Ib hepatocellular carcinoma (HCC) studies. This study compared the efficacy and safety of donafenib versus sorafenib as first-line therapy for advanced HCC.PATIENTS AND METHODSThis open-label, randomized, parallel-controlled, multicenter phase II-III trial enrolled patients with unresectable or metastatic HCC, a Child-Pugh score ≤ 7, and no prior systemic therapy from 37 sites across China. Patients were randomly assigned (1:1) to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until intolerable toxicity or disease progression. The primary end point was overall survival (OS), tested for noninferiority and superiority. Efficacy was primarily assessed in the full analysis set (FAS), and safety was assessed in all treated patients.RESULTSBetween March 21, 2016, and April 16, 2018, 668 patients (intention-to-treat) were randomly assigned to donafenib and sorafenib treatment arms; the FAS included 328 and 331 patients, respectively. Median OS was significantly longer with donafenib than sorafenib treatment (FAS; 12.1 v 10.3 months; hazard ratio, 0.831; 95% CI, 0.699 to 0.988; P = .0245); donafenib also exhibited superior OS outcomes versus sorafenib in the intention-to-treat population. The median progression-free survival was 3.7 v 3.6 months (P = .0570). The objective response rate was 4.6% v 2.7% (P = .2448), and the disease control rate was 30.8% v 28.7% (FAS; P = .5532). Drug-related grade ≥ 3 adverse events occurred in significantly fewer patients receiving donafenib than sorafenib (125 [38%] v 165 [50%]; P = .0018).CONCLUSIONDonafenib showed superiority over sorafenib in improving OS and has favorable safety and tolerability in Chinese patients with advanced HCC, showing promise as a potential first-line monotherapy for these patients.

The Effect of Differential Weathering on The Magnetic Properties of Paleosols: A Case Study of Magnetic Enhancement vs. Magnetic Depletion in the Pleistocene Blackwater Draw Formation, Texas

The type-section of the Blackwater Draw Formation (BDF) consists of a series of five paleosol horizons developed on eolian deposits and an overlying surficial soil. Previous work has shown that magnetic properties (e.g., χ, ARM, and IRM) as a function of depth in this type-section, display both magnetically enhanced and magnetically depleted signals for different paleosols. To better understand the magnetic mineralogy responsible for these varying responses, various rock-magnetic experiments, scanning electron microscopy, and Mössbauer spectroscopy were conducted on representative samples from the six soil units which constitute the BDF type-section. Our results show that sub-micron hematite [with a minor contribution from single-domain sized hematite (Hc = ∼500 mT) dominates all the soils in terms of weight percent concentration. Whereas, low coercivity (Hc = ∼35 mT or less) magnetite/maghemitized-magnetite grains, largely in the PSD state (Mr/Ms=∼0.14 +/– 0.03588, Hcr/Hc=∼2.68 +/– 0.298789), dominate the magnetic signal. Magnetically depleted soils show a relatively higher proportion of goethite, while magnetically enhanced soils show an increased contribution from SP/SSD magnetite/maghemite phases.By combining our data-set with geochemically-derived climofunctions, we have correlated the magnetically preserved, depleted, and enhanced sections of the type-section to three distinct environmental phases (I-III). The basal sediments of Phase I displays relatively homogenous (neither enhanced nor depleted) magnetic properties due to relatively arid conditions and minimal alteration of southerly derive eolian sands. Conversely, Phase II-III represents a change in weathering intensities and provenance, resulting in a mix of southerly derived sands and northerly derived silts. Phase II, experienced greater precipitation levels, resulting in the dissolution of Fe-oxide phases and thus magnetic depletion. The uppermost Phase III experienced intermediate precipitation intensities resulting in magnetic enhancement.Using previously published age models we tentatively interpret these changing environmental conditions to be influenced by the Middle-Pleistocene Transition (1.2-0.7 Ma), where the Earth’s climatic cycles shifted from a ∼41 kyr to ∼100 kyr cycles. However, ambiguities persist due to uncertainties in the currently published age model. Due to the complexity of the magnetic signal, we recommend future studies utilize a holistic approach, incorporating rock-magnetic, geochemical, and microscopy observations for more accurate reconstruction of regional paleoenvironments.

Long-term follow up of patients with mesothelioma treated with dendritic cell therapy in three phase I trials.

2618 Background: Immunotherapy targeting PD-(L)1 has become indispensable in the treatment of many malignant tumors. Recently, checkpoint inhibition using anti-PD-1 in combination with anti-CTLA-4 was proved to be effective in patients with malignant pleural mesothelioma (MPM). However, the minority of patients benefit from this treatment. The lack of immunotherapy efficacy in the majority of patients with mesothelioma can be explained by the fact that mesothelioma is a tumor with an “immune-desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of dendritic cells (DCs), which were cultured, activated, and exposed to antigens ex-vivo, this “immune-desert” phenotype might be turned into an “inflamed” phenotype. Previously, we performed and published three phase I trials using activated DCs, which support this concept. Here, we report the long-term survival of the patients treated with DCs in these three phase 1 studies. Methods: We collected the survival data of the phase 1 trials using DC therapy in patients with MPM. In the first two trials, DCs loaded with autologous tumor lysate were used, while in the third allogeneic tumor lysate was used to load the DCs (Mesopher). Results: Between 2006 and 2015, in the three studies combined, 29 patients with MPM were treated with DC vaccination. At data cut-off, the median OS was 27 months (95% confidence interval (CI): 21 – 47 months). OS at 2 years was 55.2% (95% CI: 39.7%-76.6%), OS at 5 years was 20.7% (95% CI: 10.1%-42.2%). Conclusions: The long-term follow up of MPM patients treated with DC vaccination in the three separate phase 1 trials show a promising signal, with a 2-year OS of over 50% and a 5-year OS of over 20%. In addition, 2 patients are alive after 10 years of treatment. In our opinion, these findings show the potency of DC vaccination therapy in long-term activation of the immune system. DC vaccination therapy in patients with MPM is currently being investigated in a large, randomized phase II-III trial (NCT03610360) and in pancreatic cancer. Additional biomarker studies, as well as treatment combinations with for example ICI, could further improve the outcomes of DC-vaccination therapy. Clinical trial information: NCT02395679. [Table: see text]

Targeting Neuromyelitis Optica Pathogenesis: Results from Randomized Controlled Trials of Biologics.

Advances in neuromyelitis optica spectrum disorder pathogenesis have allowed the development of targeted drugs. These treatments act on core elements of the disease, including the pro-inflammatory IL-6 pathway (tocilizumab and satralizumab), B cells (rituximab and inebilizumab), and complement (eculizumab). According to recent phase II-III trials, biologics significantly reduced the risk of relapses in aquaporin-4-seropositive patients, whereas results were less striking in the small cohorts of aquaporin-4-seronegative patients. Most adverse events were mild to moderate, with systemic symptoms (headache, arthralgia) or infections (upper respiratory and urinary tracts) being most commonly reported.

Safety of perioperative hyperthermic intraperitoneal chemotherapy with gemcitabine in patients with resected pancreatic adenocarcinoma: a pilot study of the clinical trial EudraCT 2016-004298-41.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with gemcitabine, after cytoreductive surgery, may reduce the tumor progression of pancreatic cancer through the reduction of the neoplastic volume and the subpopulation of residual pancreatic cancer stem cells, improving the survival of patients with pancreatic cancer and decreasing the recurrence of the disease. A pilot study is performed with the first ten patients in the experimental group. A randomized study (phase II-III clinical trial) that requires a population of 42 patients, with 21 patients in each group. All patients have a diagnosis of ductal adenocarcinoma of the pancreas, which will be surgically resected with curative intention. (I) Group I: after an R0 resection, patients receive individualized adjuvant treatments. (II) Group II: after an R0 resection, HIPEC is performed with gemcitabine (120 mg/m2 for 30 min), and they also receive individualized adjuvant treatments. To analyze the safety of the procedure, the main variables measured were as follows: grades of complications by means of the Clavien-Dindo system: pancreas surgery complications (e.g., pancreatic fistula, perioperative hemorrhage, delayed gastric emptying, biliary fistula), operative mortality, and laboratory parameters to control system functions. Values were measured three times: preoperatively, twenty-four hours after surgery, and on the 7th postoperative day. From 2018 to 2019, 31 patients were recruited for our clinical trial. Fifteen patients were excluded because of intraoperative unresectability or a different intraoperative histologic diagnosis. Ten patients were included in the experimental group (resection plus HIPEC gemcitabine). The mean age was 65±7 years, and six patients were female (60%). We confirmed the histologic diagnosis of ductal pancreatic adenocarcinoma in all patients prior to HIPEC. Total pancreatectomy was performed in five patients. The surgical median time was 360 min, and the hospital stay was 11 days. Four patients showed complications classified as Clavien-Dindo type II and one showing type I. Six patients were classified as having stage III tumors. To date, no hospital mortality, locoregional recurrence, or differences between the two groups in terms of perioperative complications, biochemical and gasometric values, or Clavien-Dindo complication grades were observed. Our clinical pilot study demonstrated a similar perioperative outcome that allows the trial until main objectives are achieved.

Immune Checkpoints Inhibitors and Chemotherapy as First-Line Treatment for Metastatic Urothelial Carcinoma: A Network Meta-Analysis of Randomized Phase III Clinical Trials.

Simple SummaryOn the basis of the efficacy and tolerable safety profiles of immune checkpoints inhibitors (ICIs) in second-line metastatic urothelial carcinoma (mUC) patients, some emerging clinical trials focus on the first-line treatment. Thus, we conducted a network meta-analysis (NMA) to assess and compare the response and toxicity of ICIs in naïve-chemotherapy mUC setting. According to our results, combination therapy (either ICIs plus chemotherapy (CTX) or ICIs plus ICIs) had a higher priority in terms of overall survival. Concerning monotherapy, ICIs are not inferior to CTX in terms of OS. In view of the adverse effect, ICIs are very tolerable, and combination therapy did not lead to a higher incidence of grade 3–5 AEs when compared with CTX.Immune checkpoints inhibitors (ICIs) were considered as second-line treatments in metastatic urothelial carcinoma (mUC) based on better survival benefit and safety profile than chemotherapy (CTX). We aimed to assess different ICIs regimens in the efficacy and safety for front-line treatments in mUC patients. A comprehensive literature search was performed and Phase II-III randomized controlled trials (RCTs) on ICIs for patients with mUC were included. The outcome was evaluated by overall survival (OS), progression of free survival (PFS), objective response rate (ORR), and grade 3–5 adverse events. Network meta-analysis was used to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were applied to rank the included treatments for each outcome. Results: The survival benefit of a single ICI was non-inferiority to chemotherapy (CTX). Although no superior effects were indicated, combination therapy (either ICIs plus CTX or ICIs plus ICIs) presented better OS compared with CTX alone. In terms of PFS, combination therapy produced a noticeable benefit over CTX. Regarding the SUCRA ranking, atezolizumab plus CTX was associated with the best ranking for OS and pembrolizumab plus CTX was the best in PFS. In terms of safety, a single ICI had better safety profile than CTX and combination therapy had a similar risk of grade 3–5 adverse events with CTX. Conclusions: Our NMA results revealed that combination therapy has better ranking compared with monotherapy in OS and acceptable AEs. ICIs alone present non-inferior OS but a lower incidence of AEs compared with CTX.

Development of SARS-CoV-2 vaccines.

The coronavirus disease 2019 (COVID-19) pandemic has posed significant challenges globally. Continuous transmission of the virus is mostly due to insufficient infection control measures and a lack of vaccines. Therefore, this review aimed to identify and describe possible vaccines for the prevention of COVID-19. A systematic review of the scientific literature was performed through electronic searches of the main databases to identify published reports or studies on vaccines under development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Websites from international organizations, institutes of health and research, Google, and references from identified studies were also reviewed. Studies examining the mechanisms of infection, immunopathology, and genomics were excluded. A total of 141 vaccines in development against SARS-CoV-2 were identified. The technologies used include weakened and inactive viruses, viral vectors, nucleic acids, and proteins. So far, 13 vaccines (9.2%) are under clinical evaluation; only the AZD1222 vaccine is under clinical evaluation Phase II-III. Ad5-nCoV and mRNA-1273 vaccines showed to produce neutralizing antibodies and also to be safe. Despite efforts invested in developing SARS-CoV-2 vaccines, more research is still required. The vaccine developers, international health organizations, and the decision-makers of health policies must carry out conjunct cooperation to face the different challenges and guarantee the development of an effective vaccine.

Clinical utility of circulating tumor cells: an update.

The prognostic role of circulating tumor cells (CTCs) has been clearly demonstrated in many types of cancer. However, their roles in diagnostic and treatment strategies remain to be defined. In this review, we present an overview of the current clinical validity of CTCs in nonmetastatic and metastatic cancer, and the main studies or concepts investigating the clinical utility of CTCs. In particular, we focus on breast, lung, colorectal, and prostate cancer. Two major topics concerning the clinical utility of CTC are discussed: treatment based on CTC count or CTC variations, and treatment based on the molecular characteristics of CTCs. Although some of these studies are inconclusive, many are still ongoing, and their results could help to define the role of CTCs in the management of cancers. A summary of published or ongoing phase II‐III trials is also presented.

PDG65 Matching-Adjusted Indirect Comparison: Prolgolimab Versus Other Immune Therapies for Adult Patients with Advanced Melanoma in the Russian Federation

Prolgolimab is the first Russian original PD-1 inhibitor to treat one of the most aggressive types of cancer – metastatic or unresectable melanoma. Currently, there are no head-to-head trials comparing efficacy of prolgolimab with other immune therapies for advanced melanoma. This study implements a matching-adjusted indirect comparison (MAIC) technique to assess the comparative efficacy of prolgolimab with other PD-1 inhibitors in monotherapy (nivolumab, pembrolizumab) and in combination with CTLA-4 inhibitor (nivolumab + ipilimumab) in patients with advanced melanoma. In the absence of a common comparator between trials, unahchored MAIC methodology was applied. Patient-level data for prolgolimab from Phase II-III MIRACULUM trial were re-weighted to match identified potential prognostic factors and effects modifiers from published summary efficacy results of pembrolizumab (KEYNOTE-006), nivolumab (CheckMate-066), and nivolumab + ipilimumab (CheckMate-067) trials. Matched-on characteristics included Eastern Cooperative Oncology Group (ECOG) status (0 vs 1-2), PD-L1 status (positive/negative), LDH level (normal/elevated), brain metastases (yes/no). Pairwise comparisons using hazard ratios (HRs) were performed for overall survival (OS) and progression-free survival (PFS) after 1 year from treatment initiation. To calculate HRs, the one-sample log-rank test was used. Statistical significance was assessed based on a chi-square distribution. Effective sample sizes (ESS) of the prolgolimab patients were 52.40 after matching to pembrolizumab, 43.59 after matching to nivolumab, and 36.49 after matching to nivolumab + ipilimumab. No significant differences (all p > 0.05) were etablished between prolgolimab and other considered immune therapies for both OS and PFS outcomes. In this unanchored MAIC, prolgolimab showed comparable efficacy with other PD-1 inhibitors in monotherapy (nivolumab, pembrolizumab) and in combination with CTLA-4 inhibitor (nivolumab + ipilimumab) based on OS and PFS after 1 year from therapy initiation in patients with metastatic or unresectable melanoma. This analysis may be relevant for clinical decision-making, thus improving the treatment of patients with advanced melanoma.

Head and Neck Cancer Clinical Research on ClinicalTrials.gov: An Opportunity for Radiation Oncologists

PurposeMany improvements in head and neck cancer (HNC) outcomes are related to optimization of radiation therapy (RT) dose, fractionation, normal-tissue sparing, and technology. However, prior work has shown that the literature of randomized controlled trials is dominated by industry-sponsored trials that have lower rates of incorporating RT. We characterized HNC clinical trials, hypothesizing that RT-specific research questions may be relatively underrepresented among HNC randomized controlled trials. Methods and MaterialsA web query of all open interventional trials on www.ClinicalTrials.gov was performed using search terms “head and neck cancer” and specific HNC subsites. Trial details were captured including the modality used, principal investigator (PI) specialty, funding, and whether the study tested a RT-modality specific hypothesis. Chi-square testing and logistic regression were used to compare groups. ResultsThere were 841 open HNC trials, including definitive (47.6%) and recurrent/metastatic (41.9%) populations. Most trials (71.7%) were phase I or nonrandomized phase II studies, rather than phase III or randomized phase II (28.3%). Among single-arm studies, most (79.6%) incorporated systemic therapy (ST), and fewer (25.2%) incorporated RT. Even fewer phase III and randomized phase II trials tested an RT-specific hypothesis (11.1%), compared with ST-related hypotheses (77.1%; P < .001); trials were more likely to test an RT-hypothesis if the study PI was a radiation oncologist (20.9% vs 6.0%; P < .001). Among RT trials, most early-phase studies tested novel modalities (eg, stereotactic body radiation therapy, proton therapy), whereas most later-phase studies tested dose and fractionation. RT-focused trials had low rates of federal (10.4%) or industry (2.6%) funding. ConclusionsRT-specific research hypotheses are a minority of phase II-III HNC trials, which mostly focus on incorporating ST in the definitive or recurrent/metastatic setting and have higher rates of industry funding. Radiation oncologist PI leadership and increased nonindustry funding access may ensure that RT-specific hypotheses are incorporated into trial design.

Clinical considerations in the design of clinical trial for innovative hepatitis B drugs

The research and development of chronic hepatitis B (CHB) therapeutic drugs has been undergoing rapid development in recent years in order to achieve the World Health Organization's goal of eliminating viral hepatitis as a major public health threat by 2030. The focus of early stage clinical trials (including the first human trial) is the selection of subjects, study design, dose selection, administration method, dose escalation, monitoring, observation and reporting procedures for adverse events/reactions (tolerability evaluation), and criteria for subjects to continue and discontinue administration. Therefore, quantitative pharmacology knowledge is required to analyze the relationship between in vivo drug exposure, efficacy and adverse reactions, and the inclusion of exploratory indicators such as HBV RNA, hepatitis B virus core-related antigen (HBcrAg), etc., to analyze the mechanism and target of innovative drugs and the efficacy of cccDNA in anti-hepatocytes. On the other hand, Phase II-III clinical trials prioritize the optimal dose, efficacy and safety indicators to verify the efficacy and safety of new drugs in a wider range of subjects. This paper refers to the relevant domestic and foreign literature, combined with the author's practical experience in early clinical research, and then briefly introduces the clinical issues that should be paid attention to in the design of clinical trials of CHB innovative drugs.

Clinical considerations for managing dermatology patients on systemic immunosuppressive or biologic therapy, or both, during the COVID-19 pandemic

Clinical considerations for managing dermatology patients on systemic immunosuppressive or biologic therapy, or both, during the COVID-19 pandemic

Effect of using scenario infiltration joint interactive training mode for junior nurse training in the prevention and treatment of pressure sore

Objective: To explore the application effect of scenario infiltration joint interactive training mode for junior nurse training in the prevention and treatment of pressure sore. Methods: A total of 118 junior nurses starting to work in the First Affiliated Hospital of Air Force Medical University from July 2017 to July 2018 met the inclusion criteria and were divided into routine training (RT) group and scenario infiltration joint interactive training (SIJIT) group using the random number table for prospective randomized controlled trial. There were 2 males and 57 females, aged (23.9±1.2) years in RT group and 3 males and 56 females, aged (23.5±1.3) years in SIJIT group. Before the training, nurses in both groups received theory and practical tests for the prevention and treatment of pressure sore with a homemade theory test paper and operation requirements designed by the training group. The training content was drawn up in 3 themes according to the weak points shown in the test. Nurses in RT group were trained in a large classroom with the help of multimedia teaching technique, and one lesson of 2 h targeting one theme was given once a week.Nurses in SIJIT group were trained by using the SIJIT mode, with online self-study for 2 weeks and then multimedia theory and practical teaching, and interaction in scene. After the training, theoretical and practical tests were conducted again in nurses of two groups. Satisfaction scores of nurses for the training mode, training effect, and curriculum design and answers to open questions about the degree of training satisfaction were investigated through homemade questionnaire for satisfaction degree. Homemade training contents and requirements questionnaire designed by the training group was used to understand the demands of nurses for training contents and requirements in 2 groups. Data were statistically analyzed with chi-square test and independent sample t test. Results: (1) The theoretical and practical scores on the prevention and treatment of pressure sore before the training were (78±11) and (83±10) points respectively in RT group, similar to (79±11) and (84±10) points in SIJIT group (t=0.522, 0.615, P>0.05). The theoretical and operational scores on prevention and treatment of pressure score of nurses after the training were (90±8) and (92±5) points in SIJIT group, significantly higher than (82±10) and (85±9) points in RT group (t=4.581, 5.259, P<0.01). (2) The satisfaction degree scores for training mode, curriculum design, and training effect of nurses in SIJIT group were significantly higher than those in RT group (t=5.169, 7.976, 4.463, P<0.01). Nurses in the 2 groups were satisfied with the curriculum content, and unsatisfied with the curriculum time and the ways of test. (3) The top demand of the training nurses for curriculum content was the treatment of phase Ⅱ-Ⅲ pressure sore, accounting for 81.36% (96/118). Conclusions: The SIJIT has flexible training mode, and reasonable curriculum design and content, which significantly improves the theoretical and operational levels on prevention and treatment of pressure sore of the training nurses and receives recognition of the training nurses.

Network meta-analysis of first-line treatments in transplant-ineligible multiple myeloma patients.

Multiple myeloma (MM) is a complex disease. Lack of direct comparisons among treatments and incorporation of new alternatives make it necessary to perform studies that allow for clinical decision-making. A network meta-analysis (NMA) was developed to evaluate the comparative efficacy among different therapeutic alternatives in newly diagnosed transplant-ineligible MM patients. MEDLINE® and EMBASE® were systematically searched up for these drugs: lenalidomide, thalidomide, bortezomib, and daratumumab. Comparative phase II-III randomized clinical trials (RCTs) were included. Progression-free survival (PFS) was selected as efficacy outcome. The NMA was developed using Bayesian methods. Fixed- and random-effects models were assessed using deviance information criteria. The systematic search yielded 593 results. Ten RCTs were included. No differences were observed between fixed- and random-effects models. The combination of daratumumab, bortezomib, melphalan, and prednisone showed the best HR in PFS (reference treatment). Along with this scheme, the best PFS results were obtained by combination of daratumumab, lenalidomide, and dexamethasone (HR 1.2, 95% CrI 0.64-2.4) and bortezomib with lenalidomide and dexamethasone (HR 1.6, 95% CrI 0.81-3.0). Schemes with the best PFS results were daratumumab treatments and combination of bortezomib, lenalidomide, and dexamethasone, although the latter scheme has been analyzed in heterogeneous populations.

Abstract P2-16-19: Neoadjuvant weekly paclitaxel (wP) and carboplatin (Cb) with trastuzumab (T) and pertuzumab (P) in HER2-positive breast cancer (H+BC): A Brown University oncology group (BrUOG) study

Abstract In H+BC, neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates, but the most common anthracycline-free regimen, every 3-week docetaxel and Cb with T and P (TCHP), causes significant hematologic and non-hematologic toxicities. We conducted a pilot study to assess the efficacy and toxicity of a weekly anthracycline-free regimen, and to assess whether patients (pts) with a suboptimal response to this regimen benefit from switching to doxorubicin/cyclophosphamide (AC). Methods Pts with clinical stage II-III H+BC receive wP 80 mg/m2 and Cb AUC 2 weekly with every 3-week T and P (wPCbTP). Investigators may split the week 1 loading dose of P (840 mg) into two weekly doses, and hold the 2nd dose for early onset toxicity, particularly diarrhea. Pts are restaged after 12 weeks with ultrasound or MRI. Responding pts receive another 6 weeks of wPCbTP, while nonresponders are switched to AC x 4, followed by surgery. Study participation is complete after a 3-month post-op visit. Dose modifications and post-op therapy are at investigator discretion. Results Enrollment (30 pts) is complete. Pathologic findings are available for 23 pts; the other 7 are due to undergo surgery by 10/2019. No pts have required switching to AC for suboptimal response at week 12; 2 have been switched for toxicity (1 each for diarrhea and recurrent cytopenias). pCR (T0/isN0) rates are tabulated below: Pt grouppCR% (95% CI)All18/2378 (56-92) %ER(-)10/1191 (59-100) %ER(+)8/1267 (35-90) %Operable (Stage IIA-IIIA)14/1782 (57-96) %Inoperable (Stage IIIB-C)4/667 (22-96) % In 23 pts, grade 3/4 toxicities observed include neutropenia (10/2, but no febrile neutropenia), anemia (3/0), thrombocytopenia (1/0), diarrhea (4/1), and 5 cases of grade 2 (but no grade ≥3) peripheral neuropathy. One pt each has required hospitalization for recurrent urinary tract, port site or breast infections while not neutropenic. wP has been dose-reduced for neuropathy after week 12 in 8 pts. Two pts discontinued Cb after hypersensitivity reactions in week 10. Treatment was discontinued during weeks 12-18 in 8 pts. P was held during weeks 1-6 for diarrhea in 5 pts and discontinued before week 12 in 3 pts; splitting the loading dose of P has not substantially reduced the incidence or severity of diarrhea. Conclusions Treatment with wPCbTP is associated with a high pCR rate (78%), comparable to those reported with TCHP in multicenter phase II-III trials, and is generally well tolerated, with fewer grade ≥3 toxicities, though diarrhea remains a concern. In some pts, cumulative toxicities make it difficult to continue treatment beyond week 12. Thus far, we have failed to identify a subset of pts in whom to test the efficacy of switching to AC after a suboptimal response to wPCbTP. This regimen appears to be worth exploring further, though we might consider switching to a less toxic regimen, or taking pts with an excellent response to surgery, after week 12. Supported by LifeCycle and the Lura Cook Hull Trust Citation Format: Mary Lorraine Lopresti, Jessica J. Bian, Bachir J Sakr, Rochelle S Strenger, Robert D. Legare, Mary Anne Fenton, Sabrina M Witherby, Don S Dizon, Sonali V Pandya, Ashley R Stuckey, David A Edmondson, Jennifer S Gass, Christine M Emmick, Theresa A Graves, Marlene Cutitar, Adam J Olszewski, William M Sikov. Neoadjuvant weekly paclitaxel (wP) and carboplatin (Cb) with trastuzumab (T) and pertuzumab (P) in HER2-positive breast cancer (H+BC): A Brown University oncology group (BrUOG) study [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 P2-16-19.

Effect size as a tool to identify subpopulations with improved clinical outcomes in metastatic colorectal cancer.

252 Background: ASCO defined meaningful trial endpoints in colorectal cancer (CRC) to include OS HR ≤0.67 (Ellis, JCO 2014). This measure is limited in identifying treatment benefit for subgroups from heterogeneous populations. Effect size (Glass’s Δ) calculates the absolute difference in median clinical outcomes normalized to the control group standard deviation. We hypothesized that durable effect sizes ≥2 would be useful in predicting which trials possess subgroup populations of clinical significance despite a HR &gt; 0.67. Methods: Prospective phase II-III trials in metastatic CRC from the ASCO Meeting Library (2016-2019) were cataloged by clinical outcomes of PFS and OS. Effect size was calculated from trials reporting confidence intervals and compared with absolute difference in clinical outcome, hazard ratio and therapeutic intervention. Trials with an indeterminant HR, yet effect size &gt; 2 were reviewed in subgroup analyses. Results: 385 abstracts were reviewed with 99 clinical analyses available for effect size calculation. Absolute difference in PFS correlated with effect size (R = 0.64) and was inversely proportional to HR (R = -0.63). The absolute difference in OS correlated with effect size (R = 0.69) and was inversely proportional to HR (R = -0.57). When stratified by clinically significant HR (defined ≤0.67), median effect size for PFS was 13.7±13.3 (SD) which was significantly different from HR &gt; 0.67 with median effect size 1.0±3.8 (p &lt; 0.001). Median effect size for OS when stratified by HR ≤0.67 was 3.7±2.5 which was significantly different when compared to endpoints with HR &gt; 0.67 with median effect size 0.9±1.4 (p &lt; 0.003). Subgroup populations with survival benefit included combination checkpoint blockade durvalumab/tremelimumab vs supportive care with effect size 3.1 (HR 0.72; NCT02870920). First-line PFS benefit was predicted in KRAS wildtype liver-limited CRC treated with FOLFOX+cetuximab vs FOLFOX+bevacizumab by effect size of 3.2 (HR 0.80; NCT01836653). Conclusions: Effect size holds potential as a measure to delineate improved clinical outcomes from heterogeneous populations and could identify those trials for which further subgroup analysis should be explored.

Netarsudil and latanoprost ophthalmic solution for the reduction of intraocular pressure in open-angle glaucoma or ocular hypertension

ABSTRACTIntroduction: Netarsudil and latanoprost ophthalmic solution (0.02%/0.005%) is indicated for intraocular pressure (IOP) lowering in open-angle glaucoma (OAG) or ocular hypertension (OHTN). The once-daily agent combines the mechanism of action for each of the individual components and provides a new avenue for long-term intraocular pressure control. This review aims to cover the agent’s current efficacy and safety data and opine as to its role in glaucoma management.Areas covered: This article will cover Phase II-III clinical efficacy and safety data as well as basic science literature pertaining to the agent’s mechanism of action and pharmacodynamics. In selecting articles for inclusion in this review, a literature search using the PubMed database was carried out. Cross-referencing was carried out where applicable. We did not use any date or language restrictions in electronic searches.Expert opinion: Netarsudil and latanoprost ophthalmic solution plays a pivotal role in management of individuals with OAG and OHTN. The agent may be used as first-line therapy to provide substantial IOP-lowering or when additional lowering is indicated and prostaglandins have provided insufficient IOP lowering. The once-daily dosing regimen decreases the risk of inadequate treatment due to nonadherence.

NIMG-34. MULTI-PARAMETRIC MR-PET IMAGING PREDICTS PHARMACOKINETICS AND CLINICAL RESPONSE TO GDC-0084 IN HUMAN RECURRENT HIGH-GRADE GLIOMA

Abstract Alterations in the PI3K pathway are found in the majority of malignant gliomas, but lack of efficacy has caused investigators to question the viability of this target, particularly due to lack of brain penetration. GDC-0084 was specifically optimized to penetrate the brain, targeting both PI3K and mTOR. Since these two targets alter tumor vascularity and metabolism, respectively, we hypothesized that multi-parametric MR-PET could be used to quantify the response, estimate pharmacokinetic (PK) parameters, and predict progression-free survival (PFS) in patients with recurrent malignant gliomas. In this first-in-man, multicenter, phase I, dose-escalation study (NCT01547546), we show in 47 patients that the measured maximum concentration (Cmax) of GDC0084 was associated with a decrease in enhancing tumor volume (P=0.0287) and an increase in fractional anisotropy (FA) (P=0.0418). Post-treatment tumor volume, 18F-FDG uptake, Ktrans, and relative cerebral blood volume (rCBV) were all correlated with Cmax. A linear combination of change in 18F-FDG PET uptake, apparent diffusion coefficient (ADC), FA, Ktrans, vp, and rCBV were able to estimate both Cmax (R2=0.4113, P&lt; 0.0001) and drug exposure (AUC) (R2=0.3481, P&lt; 0.0001). Using this composite multi-parametric MR-PET imaging response biomarker to predict PK, patients with an estimated Cmax &gt;0.1 uM and AUC &gt; 1.25 uM*hr demonstrated significantly longer PFS compared with patients with a lower estimated concentration and exposure (P=0.0039 and P=0.0296, respectively). Results from the current study suggest composite biomarkers created from multi-parametric MR-PET imaging targeting metabolic and/or physiologic processes specific to the drug mechanism of action may be useful for subsequent evaluation of treatment efficacy for larger phase II-III studies.