TALAPRO-2: Part 2 (P2) of the placebo-controlled phase 3 study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5092-TPS5092
Author(s):  
Neeraj Agarwal ◽  
Neal D. Shore ◽  
Curtis Dunshee ◽  
Lawrence Ivan Karsh ◽  
Beth Sullivan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Group Performance ◽  
Parp Inhibitor ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Metastatic Breast ◽  
Prior Treatment ◽  
Rank Test ◽  
Double Blind Study

TPS5092 Background: ENZA is approved to treat men with CRPC. TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. A combination of TALA with ENZA in mCRPC may improve clinical outcomes. TALAPRO-2 (NCT03395197) is a 2-part study to evaluate the efficacy, safety, pharmacokinetics and (patient) pt-reported outcomes of the combination treatment. The focus here is on P2 of TALAPRO-2. Methods: Approximately 860 pts are planned to be enrolled in P2 from multinational sites. Pts are aged ≥18 years, have asymptomatic/mildly symptomatic mCRPC, Eastern Cooperative Oncology Group performance status ≤1, no brain metastases, and have not received taxanes/novel hormonal therapy (NHT). P2 is a randomized double-blind study that will evaluate safety, efficacy, and pt-reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA (160 mg QD). Pts will be randomized to 1 of 2 treatment groups: TALA + ENZA, or matching placebo + ENZA. Randomization will be stratified by prior treatment with NHT for castration-sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no) and DDR mutation status (deficient vs. nondeficient/unknown). The primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death. The key secondary endpoint is overall survival (OS). Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8-12 weeks thereafter. The analyses of rPFS will be compared between TALA in combination with ENZA and placebo in combination with ENZA by using a 1-sided stratified log-rank test. OS will be evaluated separately in the all comers and the DDR-deficient populations. Pt recruitment is ongoing. Results: n/a. Conclusions: n/a. Clinical trial information: NCT03395197.

TALAPRO-2: A two-part, placebo-controlled phase III study of talazoparib (TALA) with enzalutamide (ENZA) in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS337-TPS337 ◽  
Author(s):  
Neeraj Agarwal ◽  
Neal D. Shore ◽  
Curtis Dunshee ◽  
Lawrence Ivan Karsh ◽  
Beth Sullivan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Primary Endpoint ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Prior Treatment ◽  
Secondary Endpoint ◽  
Phase Iii ◽  
Parp Inhibition ◽  
Rank Test ◽  
Double Blind Study

TPS337 Background: ENZA is approved to treat men with CRPC. TALA is a poly(ADP-ribose) polymerase (PARP) inhibitor that inhibits PARP1/PARP2 and traps PARP on DNA, preventing DNA damage repair (DDR), and causing cell death in BRCA1/2-mutated cells. TALA is approved in the US to treat germline BRCA1/2-mutated HER2- locally advanced/metastatic breast cancer. A combination of TALA with ENZA in mCRPC may improve clinical outcomes. Methods: Eligible patients (pts) in parts (P) 1 and 2 of this study are aged ≥18 years; have asymptomatic/mildly symptomatic mCRPC, ECOG PS ≤1, and no brain metastases; and have not received taxanes/novel hormonal therapy (NHT). P1 is an open label study to confirm the starting dose of TALA to be given in combination with ENZA. P2 is a randomized double-blind study that will evaluate the safety, efficacy and pt reported outcomes of TALA (0.5 mg QD) + ENZA (160 mg QD) vs placebo + ENZA in 2 cohorts (C). C1: pts with mCRPC (all comers) (N = 560); C2: pts with DDR gene mutations likely to sensitize to PARP inhibition (DDR deficient) (N = 300). Randomization will be stratified by prior treatment with NHT for castration sensitive prostate cancer (CSPC) or prior treatment with taxane-based chemotherapy for CSPC (yes/no), and DDR mutation status (deficient vs. nondeficient/unknown). For P1, the primary endpoint is safety; the secondary endpoint is pharmacokinetics of TALA and ENZA. For P2, the primary endpoint is radiographic progression-free survival (rPFS), defined as time to progression in soft tissue per RECIST v1.1 or in bone per PCWG3 criteria or death and evaluated separately in all comers (C1) and DDR-deficient (DDR-deficient pts from C1 and C2 combined, N = 380 pts) populations. The key secondary endpoint is overall survival. Efficacy will be assessed by radiography every 8 weeks up to week 25 and every 8-12 weeks thereafter. P2 analysis for rPFS is powered at 90% and 85% using a 2-sided log-rank test with alpha of 0.025, respectively, in the all comers and DDR deficient populations. This study was sponsored by Pfizer Inc. Clinical trial information: NCT03395197.

Treatment patterns among patients with advanced urothelial carcinoma following discontinuation of PD1/L1 inhibitor therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 414-414
Author(s):  
Alicia K. Morgans ◽  
Simrun Kaur Grewal ◽  
Zsolt Hepp ◽  
Rupali Fuldeore ◽  
Shardul Odak ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Real World ◽  
Chart Review ◽  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Unmet Need ◽  
Case Series ◽  
Treatment Patterns

414 Background: There are a lack of published real-world data on treatment patterns for patients with locally advanced or metastatic urothelial carcinoma (la/mUC) previously treated with programmed death 1/ligand 1 inhibitor (PD-1/L1i) therapy. The objective of this study was to characterize the clinical characteristics and treatments among patients with la/mUC following discontinuation of first-line (1L) or second-line (2L) PD-1/L1i therapy. Methods: We performed a retrospective chart review at 26 geographically diverse clinical sites in the US. Patients aged ≥18 years with histologically or cytologically confirmed urothelial carcinoma and radiographic evidence of metastatic or locally advanced disease were identified. Included patients had initiated and subsequently discontinued PD-1/L1i therapy in the 1L or 2L setting for la/mUC between May 15, 2016-July 31, 2018. All patients had follow-up through October 31, 2019. Data were summarized using descriptive statistics. Results: Among the 300 patients included in the chart review, 198 (66%) received PD-1/L1i therapy as 1L and 102 (34%) as 2L therapy. Mean (SD) age at la/mUC diagnosis was 69.4 (8.7) years, and a majority of patients were male (66.0%) and White (74.7%). Consistent with age, most patients (82.7%) had comorbidities at la/mUC diagnosis; 39.7% hypertension, 23.7% coronary artery disease, 17.7% pulmonary disease, and 9.3% renal disease. At initiation of therapy, a higher proportion of patients who received 1L PD-1/L1i therapy had an Eastern Cooperative Oncology Group performance status of 2 or more than patients who received 2L PD-1/L1i therapy (36.8% vs 22.5%, respectively). Following discontinuation of PD-1/L1i therapy, 34% (n = 68) received subsequent therapy in 2L and 29% (n = 30) in third-line (3L). The most common subsequent therapies in 2L were gemcitabine monotherapy (24%), gemcitabine plus cisplatin or carboplatin (22%), PD-1/L1i therapy (22%), and taxane monotherapy (19%). The most common subsequent therapies received in 3L were taxane monotherapy (50%), pemetrexed (17%), and PD-1/L1i therapy (16%). Overall, switching from one PD-1/L1i therapy to another distinct PD-1/L1i therapy occurred in approximately 20% of patients, with “better efficacy/survival” noted by treatment teams as the most common reason for switching therapy among this subgroup. Conclusions: In this real-world case series, only a minority of patients with la/mUC who discontinued PD-1/L1i therapy received subsequent therapy. Among those that did, no clear standard of care was observed and approximately one-fifth of patients were treated with a second PD-1/L1i therapy after the first failed to control disease. Collectively, the data highlight significant unmet need for patients with la/mUC who discontinue PD-1/L1i therapy.

LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS477-TPS477 ◽  
Author(s):  
Philip Agop Philip ◽  
Jill Lacy ◽  
Scot D. Dowden ◽  
Javier Sastre ◽  
Venu Gopal Bathini ◽  
...  
Keyword(s):  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Open Label ◽  
Primary Tumors

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.

Locally Advanced, Unresectable Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline

2016 ◽  
Vol 34 (22) ◽  
pp. 2654-2668 ◽  
Author(s):  
Edward P. Balaban ◽  
Pamela B. Mangu ◽  
Alok A. Khorana ◽  
Manish A. Shah ◽  
Somnath Mukherjee ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Radiation Therapy ◽  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Unresectable Pancreatic Cancer ◽  
Free Survival ◽  
American Society ◽  
Comorbidity Profile

Purpose To provide evidence-based recommendations to oncologists and others for treatment of patients with locally advanced, unresectable pancreatic cancer. Methods American Society of Clinical Oncology convened an Expert Panel of medical oncology, radiation oncology, surgical oncology, gastroenterology, palliative care, and advocacy experts and conducted a systematic review of the literature from January 2002 to June 2015. Outcomes included overall survival, disease-free survival, progression-free survival, and adverse events. Results Twenty-six randomized controlled trials met the systematic review criteria. Recommendations A multiphase computed tomography scan of the chest, abdomen, and pelvis should be performed. Baseline performance status and comorbidity profile should be evaluated. The goals of care, patient preferences, psychological status, support systems, and symptoms should guide decisions for treatments. A palliative care referral should occur at first visit. Initial systemic chemotherapy (6 months) with a combination regimen is recommended for most patients (for some patients radiation therapy may be offered up front) with Eastern Cooperative Oncology Group performance status 0 or 1 and a favorable comorbidity profile. There is no clear evidence to support one regimen over another. The gemcitabine-based combinations and treatments recommended in the metastatic setting (eg, fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine plus nanoparticle albumin-bound paclitaxel) have not been evaluated in randomized controlled trials involving locally advanced, unresectable pancreatic cancer. If there is local disease progression after induction chemotherapy, without metastasis, then radiation therapy or stereotactic body radiotherapy may be offered also with an Eastern Cooperative Oncology Group performance status ≤ 2 and an adequate comorbidity profile. If there is stable disease after 6 months of induction chemotherapy but unacceptable toxicities, radiation therapy may be offered as an alternative. Patients with disease progression should be offered treatment per the ASCO Metastatic Pancreatic Cancer Treatment Guideline. Follow-up visits every 3 to 4 months are recommended. Additional information is available at www.asco.org/guidelines/LAPC and www.asco.org/guidelines/MetPC and www.asco.org/guidelineswiki .

scholarly journals Digital Detection of Sarcopenia in Pancreatic Cancer: Additional Utilization to Plan Patient Management

2021 ◽  
Author(s):  
Mustafa Jalal ◽  
Jennifer A Campbell ◽  
Jonathan Wadsley ◽  
Andrew D Hopper
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Pancreatic Cancer ◽  
Skeletal Muscle Index ◽  
Ecog Ps ◽  
Cancer Network

Abstract Purpose: The presence of a sarcopenia adversely affects the prognosis of patients with pancreatic cancer. There is an emerging role for using computed tomography (CT) to calculate skeletal muscle index (SMI) and the presence of sarcopenia. The aim of this study was to assess if detecting ‘digital sarcopenia’ is feasible and can contribute to the management of patients with locally advanced pancreatic cancer (LAPC).Methods: Patients diagnosed with LAPC referred for endoscopic ultrasound guided biopsy (EUS-B) by our regional cancer network were identified. Age, body mass index (BMI), and Eastern Cooperative Oncology Group performance status (ECOG-PS) was noted. CT images were analysed for SMI and the presence of sarcopenia. Decision outcomes on receiving chemotherapy or not were collected from the regional oncology database. Results: In total 51/204 (25%) patients with LAPC who underwent EUS-B were not given chemotherapy and received BSC only. The prevalence of sarcopenia (p=0.0003), age ≥ 75 years old (p=0.03) and ECOG-PS 2-3 (p=0.01) were significantly higher in the patents receiving BSC only. Logistic regression analysis demonstrated that SMI was the only independent associated factor identifying patients with LAPC who were treated with BSC only and not chemotherapy after adjusting for age and ECOG-PS. Conclusion: Our study has shown that digital skeletal muscle analysis at the time of a diagnostic CT for patients with pancreatic cancer is feasible and can detect sarcopenia and malnourished patients who are much less likely to take up chemotherapy. These patients could be triaged to oncology assessment prior to EUS-B to avoid unnecessary investigations.

Characteristics of African Americans (AAs) treated with sipuleucel-T (sip-T): Comparison of clinical trial and real-world experience.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 272-272 ◽  
Author(s):  
Ronald F. Tutrone ◽  
Chiledum Ahaghotu ◽  
Andrew J. Armstrong ◽  
Celestia S. Higano ◽  
Matthew R. Cooperberg ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Gleason Score ◽  
Randomized Clinical Trials ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Specific Antigen ◽  
Cellular Immunotherapy ◽  
The Us

272 Background: AA men are underrepresented in randomized clinical trials (RCTs) for prostate cancer, despite an almost 2-fold greater incidence in AA vs Caucasian populations. Sip-T is an autologous cellular immunotherapy approved by the FDA and EMA for the treatment of certain patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. AA enrollment in three sip-T phase 3 RCTs was 5.8% (n=43). While no definitive conclusions were drawn, median overall survival (OS) suggested AAs benefit from sip-T. PROCEED, an ongoing phase 4 registry, expanded efforts to increase AA enrollment to better characterize this population and the safety, product parameters (PP), and OS of AAs treated with sip-T. Methods: PROCEED enrolled 1973 pts treated with commercial sip-T within 6 months of registration. Efforts, such as selecting racially diverse sites and highlighting AA enrollment in PROCEED communications and investigator meetings, were used to boost AA enrollment. Baseline Gleason score, Eastern Cooperative Oncology Group performance status (ECOG), prostate-specific antigen (PSA), and alkaline phosphatase (ALP) were compared between RCTs and PROCEED. Safety and survival analyses are ongoing. Results: PROCEED AA enrollment was 11.7% vs 7.1% US RCT nonwhite enrollment rate and approaches the US AA population of 13.7%. Baseline AA pt characteristics were: lower median PSA and ALP levels in PROCEED vs RCTs, higher ECOG >0 in PROCEED vs RCTs, and higher Gleason score ≥8 in PROCEED vs RCTs (Table). Conclusions: Efforts to boost AA enrollment in PROCEED to a proportion comparable to the US AA population succeeded. The lower baseline PSA of AAs in PROCEED is similar to the PSA observed in the entire PROCEED population. Safety, PP, and OS will be reported with longer follow-up. Clinical trial information: NCT01306890. [Table: see text]

Phase II study evaluating the effect of concomitant ramucirumab (RAM) on the pharmacokinetics (PK) of irinotecan (IRI) and its metabolite SN-38 when coadministered with folinic acid (FA) and 5-fluorouracil (5-FU) (FOLFIRI) in patients (pts) with advanced malignant solid tumors.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 691-691 ◽  
Author(s):  
Ding Wang ◽  
Fadi S. Braiteh ◽  
James J. Lee ◽  
Crystal Shereen Denlinger ◽  
Dale Randall Shepard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Standard Therapy ◽  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Plasma Concentrations ◽  
Eastern Cooperative Oncology Group ◽  
Primary Objective ◽  
Time Curve ◽  
Safety Population

691 Background: The primary objective was to assess the effect of concomitant RAM on the PK of IRI and its metabolite SN-38 when coadministered with FA and 5-FU. Methods: Key eligibility criteria included pts aged ≥18 years with metastatic or locally advanced malignant solid tumors resistant to standard therapy or for which no standard therapy was available, and an Eastern Cooperative Oncology Group performance status of 0 to 2. Pts received intravenous infusions of FOLFIRI and RAM 8 mg/kg on day 1 of a 2-week cycle. FOLFIRI was administered alone in cycle 1; RAM was administered followed by FOLFIRI in all subsequent cycles. Blood for PK was collected at regular intervals after infusions in cycles 1 and 2 to determine IRI and SN-38 plasma concentrations. Pts who completed the first 2 cycles of study treatment were included in the drug-drug interaction (DDI) population. All pts who received at least 1 dose of RAM or FOLFIRI were included in the safety population. Results: The safety population comprised 29 pts, and the DDI population included 25 of these 29 pts. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed drug concentration (Cmax) of IRI and SN-38 were comparable between cycle 1 (FOLFIRI alone) and cycle 2 (RAM+FOLFIRI). The ratios of geometric least-squares (LS) means for IRI were 0.93 (90% CI; 0.83, 1.05) for AUC(0-∞) and 1.04 (90% CI; 0.97, 1.12) for Cmax. The ratios of geometric LS means for SN-38 were 0.95 (90% CI; 0.88, 1.04) for AUC(0-∞) and 0.97 (90% CI; 0.85, 1.12) for Cmax. The most prevalent treatment-emergent adverse events (TEAEs) were fatigue/asthenia (n=19, 65.5%), diarrhea (n=16, 55.2%), neutropenia (n=15, 51.7%), nausea (n=14, 48.3%), and decreased appetite and anemia (n=13 each, 44.8%). Grade ≥3 TEAEs were rare, except for neutropenia in 7 (24.1%) pts. Conclusions: The PKs of IRI and its metabolite, SN-38, were not affected when coadministered with RAM. RAM with FOLFIRI was well-tolerated in this study without new safety concerns. Clinical trial information: NCT01634555.

Larynx Preservation for Patients With Locally Advanced Laryngeal Cancer

2013 ◽  
Vol 31 (7) ◽  
pp. 840-844 ◽  
Author(s):  
June Corry ◽  
Lester Peters ◽  
Stephen Kleid ◽  
Danny Rischin
Keyword(s):  
Vocal Cord ◽  
Group Performance ◽  
Performance Status ◽  
Thyroid Cartilage ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Current Smoker ◽  
Smoking History ◽  
Magnetic Resonance Imaging Scan ◽  
Left Vocal Cord

A 53-year-old man presented with a 6-month history of mild hoarseness, with no associated pain, dysphagia, or stridor. At nasoendoscopy, a lesion was detected involving the whole length of the left vocal cord, with abnormal mucosa also seen in the right ventricle ( Fig 1 ). The left vocal cord movement was impaired. There were no palpable neck nodes. Biopsy under anesthesia revealed moderately differentiated squamous cell carcinoma. He was a current smoker of 30 cigarettes per day (45 pack-year smoking history), and he consumed four standard drinks of alcohol per day. His Eastern Cooperative Oncology Group performance status was 1, and he had no significant comorbidities. Radiologic review of his outside computed tomography scan noted that it was of poor quality, and a magnetic resonance imaging scan was recommended, which showed low-volume T4a disease based on focal thyroid cartilage penetration ( Fig 2 ). A positron emission tomography (PET) scan revealed no evidence of nodal or distant metastasis.

scholarly journals Computed Tomographic Sarcopenia in Pancreatic Cancer: Further Utilization to Plan Patient Management

2021 ◽  
Author(s):  
Mustafa Jalal ◽  
Jennifer A. Campbell ◽  
Jonathan Wadsley ◽  
Andrew D. Hopper
Keyword(s):  
Skeletal Muscle ◽  
Pancreatic Cancer ◽  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Pancreatic Cancer ◽  
Skeletal Muscle Index ◽  
Computed Tomographic ◽  
Ecog Ps

Abstract Purpose The presence of a sarcopenia adversely affects the prognosis of patients with pancreatic cancer. There is an emerging role for using computed tomography (CT) to calculate skeletal muscle index (SMI) and the presence of sarcopenia. The aim of this study was to assess if detecting ‘computed tomographic sarcopenia’ is feasible and can contribute to the management of patients with locally advanced pancreatic cancer (LAPC). Methods Patients diagnosed with LAPC referred for endoscopic ultrasound-guided biopsy (EUS-B) by our regional cancer network were identified. Age, body mass index (BMI), and Eastern Cooperative Oncology Group performance status (ECOG-PS) were noted. CT images were analysed for SMI and the presence of sarcopenia. Decision outcomes on receiving chemotherapy or not were collected from the regional oncology database. Results In total, 51/204 (25%) patients with LAPC who underwent EUS-B were not given chemotherapy and received best supportive care (BSC) only. The prevalence of sarcopenia (p = 0.0003), age ≥ 75 years old (p = 0.03), and ECOG-PS 2–3 (p = 0.01) were significantly higher in the patients receiving BSC only. Logistic regression analysis demonstrated that SMI was the only independent associated factor identifying patients with LAPC who were treated with BSC only and not chemotherapy after adjusting for age and ECOG-PS. Conclusion Our study has shown that computed tomographic skeletal muscle analysis at the time of a diagnostic CT for patients with pancreatic cancer is feasible and can detect sarcopenia and malnourished patients who are much less likely to take up chemotherapy. These patients could be triaged to oncology assessment prior to EUS-B to avoid unnecessary investigations.

A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3153-TPS3153
Author(s):  
Timothy A. Yap ◽  
Anthony W. Tolcher ◽  
Elizabeth Ruth Plummer ◽  
Andreas Becker ◽  
Patricia Fleuranceau-Morel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Group Performance ◽  
Performance Status ◽  
Critical Role ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Mitotic Catastrophe ◽  
Loss Of Function ◽  
To Receive

TPS3153 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response by sensing and responding to DNA replication stress, and by inducing cell cycle arrest to prevent aberrant replication and mitotic catastrophe. Based on extensive preclinical and limited clinical evidence, ATR inhibition is a promising treatment strategy as monotherapy for patients with advanced tumors harboring synthetically lethal conditions, such as alternative lengthening of telomeres (ALT) and inactivating mutations in ARID1A and ATM. M1774 is a potent, selective, orally administered ATR inhibitor that has been shown to exert antitumor activity in patient-derived xenograft tumors and acute myeloid leukemia xenograft tumors that express the ATR inhibition sensitizing mixed lineage leukemia fusion protein. This study (NCT04170153) aims to evaluate the safety and tolerability, maximum tolerated dose, recommended dose for expansion (RDE) and pharmacokinetics (PK) of M1774 (part A1), the effect of food on M1774 PK (part A2), and the efficacy of M1774 in patients with tumors harboring selected mutations (part A3). An additional objective is to assess the pharmacodynamics of M1774 by measuring relative changes in baseline p-CHK1 and γ-H2AX expression in paired tumor biopsies and serial blood samples. Methods: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, adequate baseline hematological, renal and hepatic function, and with locally advanced or metastatic disease refractory to standard therapy are eligible. Patients with tumors bearing loss-of-function (LoF) mutations (determined by site testing or a central trial assay) in ARID1A, ATM, or ATRX and/or DAXX as ALT status surrogate markers; and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, will be enrolled in part A3. In the dose escalation phase (part A1 [open]), 18–24 patients are due to receive M1774 at a starting dose of 5 mg once daily. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. The preliminary food assessment (part A2) will follow a randomized two-sequence two-period crossover design in which ≤12 patients will be randomized (1:1) to receive a single dose of M1774 on Day –7 at the RDE (determined in part A1) in either a fed or fasted condition. After the food assessment, patients will subsequently receive M1774 according to the part A1 dosing schedule. In the preliminary efficacy study (part A3), patients (n = 20–24 for each of the three planned cohorts) with tumors harboring LoF mutations in the genes for ARID1A, ATM, ATRX and/or DAXX, will receive M1774 at the RDE. The primary efficacy endpoint is overall response (RECIST). The study is open and currently recruiting. Patients have been enrolled to seven cohorts in part A1 with no DLTs observed; dose escalation is ongoing. Clinical trial information: NCT04170153.

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