Quality initiative (QI) in unresectable stage III non-small cell lung cancer (NCSLC): Impact on time-to-treatment (TTT) for immunotherapy post chemoradiation (CRT).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18780-e18780
Author(s):  
Mike Gart ◽  
Hinco J. Gierman ◽  
Daniel P. Petro ◽  
Rushir J. Choksi ◽  
Prateesh Varughese ◽  
...  

e18780 Background:In August 2019 Integra Connect (IC) partnered on a QI with University of Pittsburgh Medical Center (UPMC) to improve outcomes in patients with stage 3 and 4 NSCLC. This report details the findings and interventions in the unresectable stage 3 cohort of the QI. The addition of durvalumab (D) in the PACIFIC trial (Antonia et al. NEJM 2017) after completion of CRT in stage 3 patients who had not progressed showed significant Progression Free Survival and Overall Survival (OS) benefit with Food and Drug Administration approval on 2/16/2018 in this setting. An update (Gray et al. Thoracic Oncol 2020) on 10/14/2019 noted superior OS in patients in whom randomization to D occurred 1-14 days post CRT vs. those with interval 15-42 days (HR 0.43 vs. 0.79). Data suggest that CRT renders tumors more responsive to immunotherapy (McCall et al. Clin Can Res 2018). As part of the QI, we explored the question whether time from CRT to D (TTT) could be shortened. Methods:From the UPMC and IC real-world-data (RWD) databases, we identified 182 patients with Stage 3 unresectable NSCLC treated with CRT between 2/16/18 (D approval) and 11/16/20 for manual chart abstraction. We calculated the TTT from the latest day of radiation or chemotherapy to the first D dose. Time-to-scan (TTS) used a similar methodology. If post-CRT scan data was not found, those patients were excluded from TTS analysis. We captured caregiver perception with surveys and used RWD to determine the proportion of eligible patients treated with D, categorizing the data into 3 successive time periods: Phase 1 (240 days): 2/16/18 approval of D to Gray update 10/14/19, Phase 2 (321 days): 10/15/19 to physician leadership intervention 8/31/20, Phase 3 (76 days): 9/1/20 to 11/16/20. Patients were excluded in phase 3 who started CRT after 11/16/20 to allow for up to 2 months to start D. Our plan included baseline and ongoing monitoring of metrics complemented with physician leadership intervention to address identified gaps in care. Results: Median age of the 182 patients was 68 (range 46-87) with 60% male. Of eligible patients, 121 (66.5%) received at least 1 dose of D. Median TTS improved 16 days from Phase 1 to Phase 3 while TTT concomitantly improved 17 days (Table ). Conclusions: This QI resulted in simultaneous shortening of TTS and TTT following physician intervention with establishment of TTS as a key potential driver of TTT which ultimately may result in improved OS. To do so required overcoming the traditional paradigm of imaging 4-6 weeks post-CRT to capture maximal response with that of early imaging aimed at assuring no progression had occurred. This, as well as proportion treated with D and its resulting duration, plus any subsequent treatments that might indicate relapse, continue to be monitored in a real-time dashboard.[Table: see text]

Blood ◽  
2018 ◽  
Vol 132 (23) ◽  
pp. 2446-2455 ◽  
Author(s):  
Ian W. Flinn ◽  
Peter Hillmen ◽  
Marco Montillo ◽  
Zsolt Nagy ◽  
Árpád Illés ◽  
...  

Abstract Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL. Patients were randomized 1:1 to oral duvelisib 25 mg twice daily (n = 160) or ofatumumab IV (n = 159). The study met the primary study end point by significantly improving progression-free survival per independent review committee assessment compared with ofatumumab for all patients (median, 13.3 months vs 9.9 months; hazard ratio [HR] = 0.52; P < .0001), including those with high-risk chromosome 17p13.1 deletions [del(17p)] and/or TP53 mutations (HR = 0.40; P = .0002). The overall response rate was significantly higher with duvelisib (74% vs 45%; P < .0001) regardless of del(17p) status. The most common adverse events were diarrhea, neutropenia, pyrexia, nausea, anemia, and cough on the duvelisib arm, and neutropenia and infusion reactions on the ofatumumab arm. The DUO trial data support duvelisib as a potentially effective treatment option for patients with RR CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02004522.


2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS213-TPS213 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Antoine Adenis ◽  
Jean-Sebastien Aucoin ◽  
Carlo Barone ◽  
Narikazu Boku ◽  
...  

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.


2021 ◽  
Vol 12 ◽  
Author(s):  
Katarzyna Kotulska ◽  
Aviva Fattal-Valevski ◽  
Jana Haberlova

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.


2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS195-TPS195 ◽  
Author(s):  
Markus H. Moehler ◽  
Min-Hee Ryu ◽  
Keun-Wook Lee ◽  
Hasan Senol Coskun ◽  
Rachel Wong ◽  
...  

TPS195 Background: Outcomes with first-line (1L) chemotherapy for GC/GEJC are limited and new strategies to increase efficacy without added toxicity are needed. Avelumab, a human anti-PD-L1 IgG1 monoclonal antibody, is approved for metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma after progression on platinum therapy (US). In phase 1 studies in advanced GC/GEJC, avelumab showed antitumor activity and a manageable safety profile, including in a subgroup of patients (pts) without progression on 1L chemotherapy who received avelumab as maintenance therapy. JAVELIN Gastric 100 (NCT02625610) is a global, randomized, open-label, phase 3 trial comparing maintenance therapy with avelumab vs continuation of 1L chemotherapy in pts with advanced GC/GEJC who have not progressed after 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy. Methods: Eligible pts have histologically confirmed, unresectable, measurable, locally advanced or metastatic GC/GEJC adenocarcinoma, no prior chemotherapy for advanced disease, no prior therapy targeting T-cell coregulatory proteins, and ECOG PS of 0–1. Pts are not preselected based on PD-L1 expression and pts with HER2+ tumors are excluded. Approximately 466 pts who achieve at least stable disease following 12 weeks of 1L oxaliplatin/fluoropyrimidine chemotherapy will be randomized 1:1 to receive maintenance therapy with either avelumab 10 mg/kg by IV infusion Q2W or continuation of 1L chemotherapy. Maintenance therapy is given until disease progression, unacceptable toxicity, or withdrawal. Primary endpoints are overall survival and progression-free survival. Secondary endpoints include best overall response, quality of life measures, safety (NCI-CTCAE v4.03), and tumor biomarkers. Responses are evaluated per RECIST 1.1 and adjudicated by independent review committee. Enrollment is ongoing at sites in North/South America, Asia-Pacific, and Europe. Clinical trial information: NCT02625610.


Author(s):  
Erin Davidson ◽  
Prachi Arora

Highlights Abstract Background: Insertion of peripheral vascular access devices (PIVC) is fundamental to patient care and may affect patient outcomes. Baseline data of PIVC insertions at a large medical center revealed that catheters required multiple insertion attempts, catheter hubs were manipulated to place extension sets, increasing the risk of complications, dwell times did not meet current standards, nurses experienced blood-exposure risk, and overall compliance with the hospital documentation policy was suboptimal. A 3-phase quality improvement project was conducted to address these concerns. Methods: In Phase 1, an assessment of the current state of PIVC insertions and care was conducted using a mixed-methods approach consisting of an observational audit of insertion and maintenance practices, and retrospective chart reviews. In Phase 2, PIVC policies and practices were updated to reflect current standards. A new advanced design PIVC device was adopted, and education was provided to all staff. In Phase 3, the impact of these changes on key PIVC measures was assessed 1 year later. Results: The analysis of the data found several improvements following implementation of an integrated IV catheter system: first-stick success rate increased from 73% to 84%, staff blood exposure was reduced from 46.67% to 0% (P = .01), improper securement of PIVC catheters was reduced from 11% to 0% (P = .002), and documentation compliance rate increased from 68% to 80%. The median PIVC dwell time doubled (from 2 days to 4 days). Conclusion: Changes to policy, practices, and products plus education can improve the PIVC first-stick success, dwell time, documentation, and staff safety.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4114-4114
Author(s):  
Andrew Scott Paulson ◽  
Daneng Li ◽  
Max W. Sung ◽  
Christopher Tucci ◽  
John S. Kauh ◽  
...  

4114 Background: Surufatinib (S) is a targeted inhibitor of tyrosine kinases VEGFR1, 2, and 3; FGFR1; and CSF-1R. A manageable safety profile and statistically significant efficacy of S have previously been demonstrated in patients (pts) with advanced NETs of extrapancreatic (epNET) and pancreatic (pNET) origin in 2 phase 3 randomized trials conducted in China (SANET-ep, NCT02588170; SANET-p, NCT02589821). Pts with epNETs achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p < 0.0001), and pts with pNETs achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p = 0.0011), with S v placebo, respectively. S has recently been approved for the treatment (tx) of pts with epNETs in China. Methods: A phase 1, dose escalation (ESC)/expansion (EXP) trial was conducted to evaluate and confirm the efficacy and safety of S in US pts. ESC was completed, and the maximum tolerated dose and recommend phase 2 dose were determined to be 300 mg, same as previous trials. The EXP completed enrollment of the epNET and pNET cohorts, and the primary endpoint was investigator-assessed PFS rate at 11 mo. Secondary objectives included assessment of safety and PK. Results: 32 pts with heavily pretreated progressive NETs (16 epNET and pNET each) were enrolled in the dose EXP. The median age was 62.2 years (44-75) and 64.4 years (39-72) for epNET and pNET pts, respectively. 65.6% of pts received ≥3 prior lines of tx (median lines of therapy: epNET: 2 [2-5]; pNET: 4 [1-8]), and all pts previously received everolimus and/or sunitinib. As of the data cutoff of 30-Jun-20, 7 pts remained on tx (4 epNET; 3 pNET). The median number of tx cycles was 8.0 (2, 15) for epNET and 8.5 (2, 23) for pNET pts. The PFS rate at 11 mo was 51.1% (95% confidence interval [CI]: 12.8, 80.3) for pts with epNETs and 57.4% (95% CI: 28.7, 78.2) for pts with pNETs. The observed mPFS was 11.50 mo (95% CI: 6.47, 11.50) and 15.18 mo (95% CI: 5.19, NR) for pts with epNETs and pNETs, respectively. An objective response rate (ORR) of 6.3% was observed for pts with epNETs and 18.8% for pts with pNETs. A disease control rate of 90.6% (95% CI: 75.0, 98.0) was observed for all NET pts (93.8% epNET; 87.5% pNET). The safety profile of S remains consistent with previously completed trials. All pts (n = 32) had reported at least 1 adverse event (AE), and 24 pts (75%) reported AEs ≥grade 3. The most common AEs of any grade reported were fatigue (46.9%), hypertension (43.8%), proteinuria (37.5%), diarrhea (34.4%), vomiting (28.1%), and nausea (25.0%). The most commonly reported AEs ≥grade 3 ( > 5%) were hypertension (37.5%); diarrhea (9.4%); and proteinuria, dysphagia, and anemia (6.3% each). AEs leading to tx discontinuation occurred in 21.9% of pts. Conclusions: S has demonstrated antitumor activity in heavily pretreated US pts with progressive NETs with a manageable safety profile that is consistent with 2 completed phase 3 studies. S continues to be studied in other ongoing clinical trials globally. Clinical trial information: NCT02549937.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS1111-TPS1111 ◽  
Author(s):  
Hope S. Rugo ◽  
Fabrice Andre ◽  
Gabor Rubovszky ◽  
Bella Kaufman ◽  
Kenichi Inoue ◽  
...  

TPS1111 Background: Patients (pts) with HR+ breast cancer (BC) often havedysregulatedphosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway, which further leads to resistance to endocrine therapy (ET). In a phase 1 study, alpelisib (BYL719), a PI3Kα-specific inhibitor in combination with fulvestrant (FUL) has demonstrated antitumor activity in pts with estrogen receptor-positive, HER2– advanced BC (ABC) with PIK3CA-altered tumors. SOLAR-1 (NCT02437318) aims to assess the efficacy of ALP + FUL in PIK3CA-mutant and non-mutant tumors in HR+, HER2– ABC setting. Methods: SOLAR-1 is a phase 3, randomized, double-blind study conducted in men and postmenopausal women with HR+, HER2– ABC. Pts are randomly (1:1) allocated to oral alpelisib/placebo (300 mg qd) and intramuscular FUL (500 mg) until disease progression or treatment (tx) discontinuation. Stratification factors are presence of liver and/or lung metastases and prior use of CDK4/6 inhibitors. The eligibility criteria for the targeted BC patient population are shown in the Table. The primary endpoint is progression-free survival (PFS; RECIST v1.1; local assessment), while overall survival (OS) is a key secondary endpoint in the PIK3CA-mutant cohort. Other secondary endpoints are PFS and OS in the PIK3CA non-mutant cohort, the association between PFS and baseline PIK3CAstatus in ctDNA, overall response rate, clinical benefit rate, and safety. Recruitment of the planned 560 pts is currently ongoing. Clinical trial information: NCT02437318. [Table: see text]


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8510-8510
Author(s):  
David E. Kozono ◽  
Tom Stinchcombe ◽  
Joseph Kamel Salama ◽  
Jeffrey Bogart ◽  
William J. Petty ◽  
...  

8510 Background: CRT is standard treatment (Tx) for pts with unresectable stage III NSCLC. Vel, a potent oral PARP1/2 inhibitor, interferes with repair of chemotherapy- or radiation-induced DNA damage. In a phase 2 study, Vel showed favorable efficacy vs placebo when added to C/P in stage IV NSCLC. The reported phase 1 trial assessed the safety and efficacy of Vel + C/P-based CRT in Tx of stage III NSCLC (NCT02412371). Methods: Eligible pts (≥18 yr, unresectable stage III NSCLC, no prior NSCLC therapy) received Vel + CRT of weekly C area under the curve (AUC) 2 + P 45 mg/m2 weekly + 60 Gy (2 Gy/day) RT over 6–9 weeks (wk). Vel was dose escalated from 60 mg twice daily (BID) to 240 mg BID followed by Vel 120 mg BID added to consolidation therapy (CON) once every 3 wk of C AUC 6 + P 200 mg/m2 for 2 cycles (cohort 1–5). Cohort 6 received Vel 240 mg BID + CRT followed by Vel 240 mg BID + CON. Samples for pharmacokinetic (PK) analysis were collected on wk 4 day –3. The primary endpoint was to establish the recommended phase 2 dose (RP2D) of Vel + CRT/Vel + CON. Results: As of Sep 2018, 48 pts enrolled into cohorts 1–6 at Vel 60 mg/120 mg (n = 7), 80 mg/120 mg (n = 9), 120 mg/120 mg (n = 7), 200 mg/120 mg (n = 8), 240 mg/120 mg (n = 12), and 240 mg/240 mg (n = 5) added to CRT/CON; median age 65 yr (range, 48–81). Vel PK was dose proportional; 39 (81.3%) pts completed therapy. Grade ≥3 Tx-emergent adverse events (AEs) were reported in 37 (77.1%) pts; anemia and febrile neutropenia (10.4% each) were the most common. Serious AEs were observed in 19 (39.6%) pts. Dose-limiting toxicities occurred at 200 mg/120 mg (n = 1; influenza and pneumonia), 240 mg/120 mg (n = 1; insomnia), and 240 mg/240 mg (n = 2; febrile neutropenia, neutropenia, thrombocytopenia, esophagitis, suprapubic pain, sepsis); Vel 240 mg BID + CRT/Vel 120 mg + CON was chosen as the maximum tolerated dose/RP2D. Of 41 pts evaluable for tumor assessment, 26 (63.4%) had a confirmed response. Interim median progression-free survival was 24.1 mo (range, 8.9 – not reached); updated results will be reported. Conclusions: Vel 240 + CRT/Vel 120 mg BID + CON was well tolerated with promising antitumor activity in stage III NSCLC and was determined as RP2D. Clinical trial information: NCT02412371.


2013 ◽  
Vol 5 (1) ◽  
Author(s):  
Abdul Hasan Saragih

This classroom research was conducted on the autocad instructions to the first grade of mechinary class of SMK Negeri 1 Stabat aiming at : (1) improving the student’ archievementon autocad instructional to the student of mechinary architecture class of SMK Negeri 1 Stabat, (2) applying Quantum Learning Model to the students of mechinary class of SMK Negeri 1 Stabat, arising the positive response to autocad subject by applying Quantum Learning Model of the students of mechinary class of SMK Negeri 1 Stabat. The result shows that (1) by applying quantum learning model, the students’ achievement improves significantly. The improvement ofthe achievement of the 34 students is very satisfactory; on the first phase, 27 students passed (70.59%), 10 students failed (29.41%). On the second phase 27 students (79.41%) passed and 7 students (20.59%) failed. On the third phase 30 students (88.24%) passed and 4 students (11.76%) failed. The application of quantum learning model in SMK Negeri 1 Stabat proved satisfying. This was visible from the activeness of the students from phase 1 to 3. The activeness average of the students was 74.31% on phase 1,81.35% on phase 2, and 83.63% on phase 3. (3) The application of the quantum learning model on teaching autocad was very positively welcome by the students of mechinary class of SMK Negeri 1 Stabat. On phase 1 the improvement was 81.53% . It improved to 86.15% on phase 3. Therefore, The improvement ofstudent’ response can be categorized good.


2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?


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