Showing papers by "Charles D. Blanke published in 2023"

Abstract CT162: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts

Abstract: Background: Dual checkpoint inhibition with anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be efficacious in numerous malignancies. This study presents the first results of ipilimumab and nivolumab in the clear cell gynecologic cancer cohorts of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg IV every 6wk) plus nivolumab (240mg IV every 2wk). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed CR and PR); progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity are secondary endpoints. Results: Evaluable patients were as follows: clear cell ovarian cancer (N=19); clear cell endometrial cancer (N=8); clear cell cervical (N=5) (median ages, 53, 66, and 59 years; cohorts 46, 45, and 42, respectively) In the clear cell ovarian cancer cohort, ORR was 21.1% [CR, 15.8%, n=3; PR, 5.3%, n=1]; clinical benefit rate (CBR) (includes stable disease ≥6 months) was 31.6% (6/19 patients). Among three patients with confirmed CR, two patients showed 100% regression (with ongoing response at 36+ months and 37+ months respectively), and the other patient showed 67% regression (due to lymph node < 1.0cm), but eventually progressed after 722 days. One confirmed PR patient achieved 75% regression (ongoing response at 53+ months). Of note, three patients achieved unconfirmed PR; one showed 34% regression (5 months); another, 38% (51.5+ months); and another, 58% regression (5 months). The ORR when including unconfirmed PR is 36.8% (7/19). Median PFS was 3.7 months (95% confidence interval (CI); 1.7-∞). Median OS was 21.7 months (6.4-∞). In the clear cell endometrial cancer cohort, ORR was 0%; CBR, 25% (2/8 patients). Of note, one patient achieved unconfirmed PR with 69% regression (4 months). The ORR when including unconfirmed PR is 12.5% (1/8). Median PFS was 2.0 months (95% confidence interval; 1.8-na). Median OS was 4.3 months (4.2-na). In the clear cell cervical cancer cohort, ORR was 0%; CBR, 20.0% (1/5 patients). Median PFS was 2.2 months (95% CI; 1.9-na). Median OS was 23.6 months (95% CI; 15.3-na). The most common adverse events, in the three cohorts combined, were nausea (37.5%, n=12), fatigue (34.4%, n=11), anorexia (31.2%, n=10), hypothyroidism (31.2%, n=10), and pruritus (28.1%, n=9). Grade 3-4 adverse events were reported in 17 cases (53.1%) with no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in 19 clear cell ovarian cancer patients resulted in an ORR of 21.1% and CBR of 31.6%, with two durable CRs ongoing at 3+ years; CBR was 25% and 20%, respectively, in clear cell endometrial and cervical cohorts, with no objective responses, albeit with only 8 and 5 patients per cohort. Correlative studies to determine response/resistance markers are ongoing. Further prospective studies in rare gynecologic malignancies are warranted. Citation Format: Young Kwang Chae, Christopher W. Ryan, Naing Aung, William R. Robinson, Megan Othus, Elad Sharon, David M. O'Malley, Floortje J. Backes, Charles D. Blanke, Ramez N. Eskander, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the clear cell ovarian, endometrial, cervical cancer cohorts [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 CT162.

Plasma 25-hydroxyvitamin D levels and survival in stage III colon cancer: Findings from CALGB/SWOG 80702 (Alliance).

Abstract: PURPOSE To assess whether higher plasma 25-hydroxyvitamin D (25[OH]D) are associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. PATIENTS AND METHODS Plasma samples were collected from 1437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of CRP, IL-6, and sTNF-R2. RESULTS Vitamin D deficiency (25(OH)D<12 ng/ml) was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, non-deficient vitamin D status (≥12 ng/ml) was significantly associated with improved DFS, OS and TTR (all Plog-rank<0.05), with multivariable-adjusted hazard ratios of 0.68 (95% confidence interval [CI], 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnon-linearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (P mediation=0.04) for DFS and 11.8% (P mediation=0.05) for OS, whereas CRP and IL-6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS Non-deficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate if adjuvant vitamin D supplementation improves patient outcomes.

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART SWOG 1609) in patients with refractory gallbladder cancer (cohort 48).

Abstract: e16330 Background: Immune checkpoint blockade has improved outcomes in multiple tumor types, however little is known about the efficacy of these agents in rare tumors. We report the results of the gallbladder cohort of SWOG S1609 Dual Anti–CTLA-4 and anti–PD-1 blockade in Rare Tumors (DART). Methods: We performed a prospective, open label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the gallbladder cohort reported here. Eligible patients had progressed following at least one line of standard systemic therapy, and did not have an approved or standard therapy available that had been shown to prolong survival. All participants received nivolumab 240 mg i.v. every 2 weeks and ipilimumab 1 mg/kg i.v. every 6 weeks on a continuous schedule. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity Results: Nineteen patients (79% female) with a median age of 60 years were enrolled and received treatment. The median prior lines of therapy was 2 (range 1-6). The confirmed overall response rate was 16% [complete response, n=1 (5%); partial response, n=2 (11%)] (duration = 35+, 16, 13 mo). The unconfirmed overall response rate and clinical benefit rate were both 32% [complete response, n=1 (5%); partial response, n=5 (26%); stable disease > 6 months, n=0 (0%)]. The 6-month progression-free survival was 26% (95% CI 12-55%); median overall survival was 7.0 months (95% CI, 3.9-19.1 months). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was one death from hepatic failure possibly related to treatment in the setting of progressive liver metastasis and biliary infection. Conclusions: Ipilimumab plus nivolumab demonstrated a 16% ORR in patients with gallbladder cancer including a complete response lasting 35+ months; The unconfirmed overall response rate was 32%. Clinical trial information: NCT02834013 . [Table: see text]

Abstract CT163: A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the small cell carcinoma of the ovary, hypercalcemic type cohort

Abstract: Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have shown to be efficacious in many malignancies, but its potential role in various rare solid cancers is yet to be established. Small cell ovarian carcinoma, hypercalcemic type (SCCOHT) is a rare tumor characterized by loss of SMARC 2/4 function and so presents a novel paradigm for the treatment of SWI/SNF pathway deficient tumors (Petar Jelinic et al., 2018; Marc Tischkowitz et al., 2020). This study presents the first results of ipilimumab and nivolumab used in the SCCOHT cohort (#49) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) >6 months, and toxicity. Results: Five evaluable patients (median age 30) with SCCOHT were analyzed. Objective response rate was 20% (1 CR with 100% regression). The patient with CR has a duration of response (DoR) and OS of 35+ months. Another patient, showed unconfirmed PR with 81% regression (DoR 4 months), this patient went on to have confirmed iCR (CR confirmed by iRECIST) at around 24 months and has OS of 38+ months. At 12 months, 3 patients remain alive and 1 patient remains progression free; overall median PFS was 1.8 months (1.0-∞); median OS was 24 months (4.5-∞). The most common adverse events were fatigue, nausea, pruritus, dry mouth, maculo-papular rash and aspartate aminotransferase elevation (50%, n=2, respectively). There were two incidents (33.3%) of grade 3-4 adverse events. None of the adverse events led to discontinuation. There were no grade 5 adverse events. Conclusion: Ipilimumab plus nivolumab in five patients with the ultra-rare small cell ovarian carcinoma (hypercalcemic type) resulted in one CR durable at 35+ months and one unconfirmed PR with 81% regression. This is the first prospective study demonstrating efficacy of nivolumab and ipilimumab in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in small cell ovarian histologies are needed. Citation Format: Young Kwang Chae, Megan Othus, Sandip P. Patel, Raid Aljumaily, Khine Z. Win, Tanya Pejovic, Sajeve S. Thomas, William R. Robinson, Liam Il-Young Chung, Christine M. McLeod, Helen X. Chen, Elad Sharon, Howard Streicher, Christopher W. Ryan, Charles D. Blanke, Razelle Kurzrock. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the small cell carcinoma of the ovary, hypercalcemic type cohort [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 CT163.

Crisis of the Clinical Trials Staff Attrition After the COVID-19 Pandemic.

Abstract: A survey of clinical research professionals @SWOG indicate that 80% of clinical trial offices are understaffed. Addressing this is critical so progress for people with cancer continues. Read more about lessons learned in the #COVID19 pandemic and how it informs a path forward.

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The vulvar cancers.

Abstract: 5517 Background: Dual checkpoint inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors have proven to be effective in several malignancies but their potential role in various rare solid cancers is yet to be established. The efficacy of immunotherapy in vulvar cancer patients has not been explored. This study presents the first results of ipilimumab and nivolumab in vulvar cancers (cohort 35) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint was objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)); progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity are secondary endpoints. Results: Sixteen evaluable patients (median age, 55.5 years) were analyzed. 14 cases were of squamous cell carcinoma histology and 2 were of poorly differentiated carcinoma. ORR was 18.8% (3/16, 25% when including one unconfirmed PR). There was 1 CR (SCC; PFS of 465 days) and 2 PR (both SCC; one with 57% regression with PFS of 1022 days, another with 53% regression with PFS of 501 days). Of note, there was one SCC patient with unconfirmed PR that showed 69% regression with PFS of 209 days. Overall clinical benefit rate (CBR; no progression > 6months) was 31.3% (5/16). The median PFS was 2.2 months, 6-month PFS 33%, 1-year PFS 20%. The median OS was 7.6 months, 6-month OS 62%, 1-year OS 44%. The most common adverse events were diarrhea, fatigue, pruritus, anorexia, and nausea (25%, n = 4 each). Grade 3-4 adverse events occurred in 25% of patients (n = 4). There was 1 grade 3-4 adverse event (6.7%) that led to discontinuation, and 1 (6.7%) grade 5 death adverse event. Conclusions: Ipilimumab plus nivolumab in vulvar cancers resulted in an ORR of 18.8% and CBR of 31.3%, with durable responses seen. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies exploring the role of immunotherapy in vulvar cancers are warranted. Clinical trial information: NCT02834013 .

A phase II basket trial of dual anti–CTLA-4 and anti–PD-1 blockade in rare tumors (DART) SWOG S1609: The desmoid tumors (cohort 27).

Abstract: 11516 Background: Dual inhibition with Anti-PD-1 and anti-CTLA4 checkpoint inhibitors is efficacious in many malignancies, but their potential role in numerous rare solid cancers is yet to be established. Desmoid tumors (DT; fibromatosis) are rare tumors of the soft tissue, and the mainstay of treatment is surgery (Richard Riedel, 2022). The utility of immunotherapy in this group of patients has not been explored. This study presents the first results of ipilimumab and nivolumab used in the DT cohort (#27) of the SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial. Methods: DART is a prospective, open-label, multicenter/multi-cohort phase 2 clinical trial of ipilimumab (1mg/kg intravenously every 6 weeks) plus nivolumab (240mg intravenously every 2 weeks). The primary endpoint includes objective response rate (ORR) (RECIST v1.1) (confirmed complete (CR) and partial responses (PR)). Secondary endpoints include progression-free survival (PFS), overall survival (OS), stable disease (SD) > 6 months, and toxicity. Results: Sixteen evaluable patients (median age 37) with desmoid tumors were analyzed. Location of the tumors are: 8, abdomen; 3, lower limb: 2, upper limb; 2, pelvis; and 1, neck. ORR was 18.8% with 3 patients attaining PR: 40% regression with ongoing duration of response (DoR) at over 30+ months; 83% regression (PFS 16 months); and 71% regression (PFS of 8.4 months). Of note, 3 patients had SD (3/16, 18.8%) with some shrinkage of the tumors and a durable response; 23% regression with PFS of 1820+ days; 6% regression with PFS of 902 days; 1% regression with PFS of 1147+ days. Overall clinical benefit rate (CBR; no progression > 6 months) was 62.5%. The median PFS was 17.9 months, 6-month PFS 69%, 1-year PFS 62%. All patients were alive at 1 years; median OS was not assessable as 14 patients are showing ongoing survival. The most common adverse events were fatigue (43.8%, n = 7), nausea (37.5%, n = 6), hypothyroidism (31.3%, n = 5), diarrhea, hyperthyroidism, headache, and adrenal insufficiency (25%, n = 4 each). There were 8 incidents (50%) of grade 3-4 adverse events. 7 adverse events led to discontinuation. There were no grade 5 adverse events. Conclusions: Ipilimumab plus nivolumab in treatment of desmoid tumors resulted in an ORR of 18.8% and CBR of 62.5% with durable responses seen. This is the first prospective study demonstrating efficacy of the combination in this rare disease. Correlative studies to determine response and resistance markers are ongoing. Expanded prospective studies in desmoid tumors are needed. Clinical trial information: NCT02834013 .

SWOG S1823/CCTG GCC1: Translational observational investigational study of the liquid biomarker microRNA 371a-3p in newly diagnosed germ cell tumours—Real-world trial design, rapid accrual, and robust secondary use of data opportunities.

Abstract: TPS5103 Background: With the discovery of the very promising, germ cell malignancy (GCM) specific, liquid biomarker microRNA 371a-3p (miR371), the investigative trajectory has markedly accelerated. With its outstanding, previously-reported specificity and positive predictive value, miR371 likely will become a powerful tool for clinical decision-making. The primary objective of SWOG S1823/CCTG GCC1 [NCT03067181] is to define the operating characteristics of plasma miR371 expression at the time of clinical relapse for low/moderate risk non-seminoma GCM patients on active surveillance. Methods: S1823 is a prospective, observational, adult GCM translational trial which is actively accruing. Broad eligibility includes all newly diagnosed adult GCM patients. Patients are assigned to low (<25% risk of relapse), moderate (25-90% risk of relapse) or high (≥90% risk of harboring active GCM) risk groups. Pragmatic logistics include using Streck tubes and centralized processing for miR371 sample processing and analytics. Research samples were drawn at the time of routine blood draws minimizing patient burden. Source documents are submitted along with case report forms. This data-gathering model gives an important data quality-control check. S1823 began in July 2020 and has since accelerated its accrual to consistently predicted new enrollments of 20-30 cases/month. As of January 2023, the study enrolled 389 low-risk, 114 moderate-risk and 146 high-risk patients (657 total). Interim analysis is planned at the time 40 non-seminoma GCM patients have relapsed and is anticipated in late 2023 to early 2024. 404 centers have opened S1823. 3 Canadian centers have enrolled >10 patients (range 11-51). 17 USA institutions have enrolled >10 patients (range 11-112). In North America, 9 of the 12-storied GCM clinical research programs have had robust participation. The leading accruing organization was the Kaiser Permanente system where 112 patients have been enrolled. In Canada, all population centers contributed proportionally. In the USA, the dominant enrollment comes from the west coast and mid-west. Proportional enrollments have been seen in Hispanic and Asian populations. The entire study provides rich opportunities for a variety of secondary use and patterns of care projects that will begin to roll out over the next year. Clinical trial information: NCT03067181 . [Table: see text]

Plasma 25-Hydroxyvitamin D Levels and Survival in Stage III Colon Cancer: Findings from CALGB/SWOG 80702 (Alliance).

Abstract: PURPOSE To assess whether higher plasma 25-hydroxyvitamin D [25(OH)D] is associated with improved outcomes in colon cancer and whether circulating inflammatory cytokines mediate such association. EXPERIMENTAL DESIGN Plasma samples were collected from 1,437 patients with stage III colon cancer enrolled in a phase III randomized clinical trial (CALGB/SWOG 80702) from 2010 to 2015, who were followed until 2020. Cox regressions were used to examine associations between plasma 25(OH)D and disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). Mediation analysis was performed for circulating inflammatory biomarkers of C-reactive protein (CRP), IL6, and soluble TNF receptor 2 (sTNF-R2). RESULTS Vitamin D deficiency [25(OH)D <12 ng/mL] was present in 13% of total patients at baseline and in 32% of Black patients. Compared with deficiency, nondeficient vitamin D status (≥12 ng/mL) was significantly associated with improved DFS, OS, and TTR (all Plog-rank<0.05), with multivariable-adjusted HRs of 0.68 (95% confidence interval, 0.51-0.92) for DFS, 0.57 (0.40-0.80) for OS, and 0.71 (0.52-0.98) for TTR. A U-shaped dose-response pattern was observed for DFS and OS (both Pnonlinearity<0.05). The proportion of the association with survival that was mediated by sTNF-R2 was 10.6% (Pmediation = 0.04) for DFS and 11.8% (Pmediation = 0.05) for OS, whereas CRP and IL6 were not shown to be mediators. Plasma 25(OH)D was not associated with the occurrence of ≥ grade 2 adverse events. CONCLUSIONS Nondeficient vitamin D is associated with improved outcomes in patients with stage III colon cancer, largely independent of circulation inflammations. A randomized trial is warranted to elucidate whether adjuvant vitamin D supplementation improves patient outcomes.