Start Of Study Treatment Research Articles

METAPANC, intensified treatment in patients with oligometastatic pancreatic cancer: Multimodal surgical treatment versus systemic chemotherapy alone—A prospective randomized controlled multicenter phase III trial.

TPS4207 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal overall survival rate due to early metastasis and high therapy resistance. The successful introduction of intensified chemotherapeutic regimen such as FOLFIRINOX (FFX) has significantly increased response rates, disease control and overall survival. Current standards recommend systemic chemotherapy but no surgical approach in metastatic PDAC. FFX has the highest rates of response and overall survival and is a current standard of care in patients with metastatic PDAC and good performance status. Extensive surgical interventions with synchronous or metachronous metastasectomy is not recommended according to current guidelines. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from randomized clinical trials are not available. Methods: METAPANC is a prospective randomized controlled multicenter phase III trial evaluating survival and quality of life after multimodal therapy with perioperative modified FOLFIRINOX (mFFX) chemotherapy (two times 4 cycles prior to resection of the primary tumor and resection of the metastases), followed by 4 cycles of adjuvant mFFX chemotherapy (Arm A) vs. mFFX (without surgery), as standard of care first-line treatment (Arm B). Patients are eligible for randomization after 8 cycles of mFFX if they have at least stable disease on imaging according to RECIST V1.1 (Response Assessment I after 4 cycles and Response Assessment II after 8 cycles of mFFX). Patients with progressive disease will be excluded from the study. This clinical trial will focus on a well-defined patient collective with resectable PDAC and metastatic load limited to the liver with a maximum of three metastases. Patients with metachronous liver metastatic status can also be included, but must have completed adjuvant chemotherapy at least 6 months before start of study treatment. In patients randomized into Arm A with metastatic lesions located in the center of the liver local ablative techniques can be combined. In total 272 patients will be enrolled and will be randomized 1:1. The primary endpoint is overall survival, secondary endpoints are progression free survival, procedure related complications and mortality, quality of life, quality-adjusted time without symptoms and toxicity. METAPANC is accompanied by an exploratory biomarker analysis program of collecting biological and imaging samples to subsequently identify and evaluate molecular-based patient subgroups and biomarkers for identification of a potential target population which may benefit from the intensified multimodal treatment strategy. 22 German participating sites are selected. Further international sites are planned in the Netherlands, Norway, Finland and Sweden. Clinical trial information: 2023-503558-10-00.

Impact of hepatitis B virus (HBV) infection on efficacy and safety in the KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) for advanced biliary tract cancer (BTC).

4097 Background: In KEYNOTE-966, pembro + gem/cis significantly increased overall survival compared with placebo + gem/cis alone as first-line therapy for patients (pts) with advanced BTC (hazard ratio [HR] = 0.83, 95% confidence interval [CI] 0.72-0.95; P = 0.0034). Chronic HBV infection is a known risk factor for BTC and may impact the effectiveness of immunotherapy in patients with BTC. An exploratory analysis showed low incidence of HBV reactivation and no cases of HBV-associated hepatitis in HBV-positive pts from KEYNOTE-966. Here, we present a post hoc analysis from KEYNOTE-966 to assess whether patient HBV infection status is associated with differences in efficacy and safety outcomes. Methods: Pts were randomized 1:1 to pembro 200 mg IV or placebo IV Q3W for ≤35 cycles plus gem 1000 mg/m2 IV until disease progression and cis 25 mg/m2 IV for ≤8 cycles. HBV status was determined by anti-HBc (total and IgM), HBV DNA, and HBsAg. Pts with chronic HBV infection (HBsAg positive and/or detectable HBV DNA) and clinically resolved HBV infection (HBsAg negative and anti-HBc positive, and undetectable HBV DNA) at baseline were eligible and comprised the HBV-positive subgroup. Pts with chronic HBV infection needed to have begun antiviral therapy ≥4 weeks before, and HBV DNA <100 IU/mL prior to, starting study treatment. The data cutoff date for this analysis was November 14, 2023. Results: 1069 pts were enrolled in KEYNOTE-966. 329 (30.8%) were HBV positive (164 from pembro arm vs 165 from placebo arm) and 732 (68.5%) were HBV negative (366 from pembro arm vs 366 placebo arm); 8 had unknown HBV status at baseline. More pts in the HBV-positive subgroup were male (60.8% vs 47.4% in the HBV-negative group), ≥65 years old (53.2% vs 44.5%), and from Asia (76.9% vs 31.8%). In the HBV-positive subgroup, median OS was 12.3 mo (95% CI 9.5-14.5) for the pembro arm vs 10.9 mo (95% CI 9.7-13.2) for the placebo arm (HR = 0.87, 95% CI 0.69-1.10). For the HBV-negative subgroup, median OS was 12.8 mo (95% CI 11.4-13.9) for the pembro arm vs 10.7 mo (95% CI 9.4-11.7) for the placebo arm (HR = 0.85, 95% CI 0.73-0.99). Grade 3-5 treatment-related AE rates in the pembro arm vs the placebo arm were 69% vs 73% of pts in the HBV-positive subgroup and 72% vs 68% in the HBV-negative subgroup, respectively. Rates of discontinuation of any drug due to a treatment-related AE in the pembro arm vs the placebo arm were 14% vs 15% in the HBV-positive subgroup and 22% vs 16% in the HBV-negative subgroup. Conclusions: Efficacy and safety outcomes remained consistent between HBV-positive and HBV-negative subgroups from KEYNOTE-966. These data further support pembro + gem/cis as first-line therapy for advanced BTC regardless of HBV infection status. Clinical trial information: NCT04246177 .

A phase 1 study of mebendazole with bevacizumab and irinotecan in high-grade gliomas.

High-grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole is an anti-helminthic benzimidazole that has demonstrated efficacy in numerous in vitro cancer models, and is able to cross the blood-brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of mebendazole in combination with bevacizumab and irinotecan in children and young adults with HGG. To determine the maximally tolerated dose of mebendazole when given in combination with bevacizumab and irinotecan in children with HGG; to describe the progression-free survival (PFS) and overall survival (OS) for this group. Patients between 1 and 21years of age with HGG were enrolled in a 3+3 design to escalating doses of mebendazole in combination with bevacizumab (10mg/kg/dose) and irinotecan (150mg/m2 /dose). Subjects were eligible upfront after completion of radiation or at the time of progression. Mebendazole was taken orally twice per day continuously, and bevacizumab and irinotecan were given intravenously on Days 1 and 15 of 28-day cycles. Between 2015 and 2020, 10 subjects were enrolled at mebendazole doses of 50mg/kg/day (n=3), 100mg/kg/day (n=4), and 200mg/kg/day (n=3). One subject assigned to 100mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, one subject had anaplastic astrocytoma, and one subject had a spinal HGG. All subjects received radiation. There were no dose-limiting toxicities. The most frequent G3/4 adverse events were neutropenia (n=3) and lymphopenia (n=4). The overall response rate was 33%, with two subjects achieving a partial response and one subject achieving a complete response sustained for 10months. The mean PFS and OS from the start of study treatment were 4.7 and 11.4months, respectively. Mebendazole was safe and well tolerated when administered with bevacizumab and irinotecan at doses up to 200mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

Mitapivat Treatment Reduces Levels of Interference in Work/School Activity for Adult Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. It is associated with a range of acute and long-term complications and negatively impacts health-related quality of life. Patients (pts) with PK deficiency report daily social and physical limitations, which negatively impact various aspects of their lives, including the ability to perform at their full potential at work or school. Mitapivat is a first-in-class, oral, allosteric activator of PK, approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, and by the European Union European Medicines Agency and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. Mitapivat has shown sustained and clinically meaningful improvements in the disease impact of PK deficiency measured by two disease-specific patient-reported outcome (PRO) instruments, the PK Deficiency Impact Assessment (PKDIA) and the PK Deficiency Diary (PKDD), in the pivotal ACTIVATE trial (NCT03548220) and its long-term extension (LTE) study (NCT03853798) in adult pts with PK deficiency who were not receiving regular transfusions. In this post hoc analysis, new PRO data are reported from ACTIVATE and its LTE study focusing on the impact of PK deficiency on work or school performance and how treatment with mitapivat impacts this over time in these pts. Methods: In the global, phase 3, placebo (PBO)-controlled ACTIVATE trial, adult pts with PK deficiency who were not receiving regular transfusions were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 weeks (wks). Pts who completed ACTIVATE were eligible to continue in the open-label LTE study, where all pts received mitapivat (5/20/50 mg twice daily or dose at last visit of ACTIVATE). Pts from ACTIVATE who participated in the LTE study were categorized into either the mitapivat-to-mitapivat arm (M/M) or the PBO-to-mitapivat arm (P/M). In the PKDIA questionnaire, pts who worked or went to school over the 7 days prior to a scheduled visit were asked to rate how often their PK deficiency interfered with their ability to perform to their full potential at work or school, using an 11-point numeric rating scale (work/school interference score; ranging from 0 [none of the time] to 10 [all of the time]). Changes in the work or school interference score from baseline (BL; defined as the last complete assessment before start of study treatment in ACTIVATE) were summarized descriptively by treatment arm over the fixed-dose period of ACTIVATE (24 wks) and up to Wk 60 of the LTE study (84 wks overall). Results: Among the 80 randomized adult pts with PK deficiency who were not receiving regular transfusions in ACTIVATE, 54 (67.5%) attended work/school at BL (28 pts randomized to mitapivat, 26 pts to PBO), 3 pts found it too difficult to attend, 21 did not attend for reasons unrelated to PK deficiency, and data were unavailable for 2. The mean (SD) work/school interference score for the 54 pts at BL was 4.0 (2.49) and was similar for the mitapivat (4.2 [2.42]) and PBO (3.9 [2.61]) arms. At Wk 24, 37 pts worked or went to school (including 22 in the mitapivat arm and 15 in the PBO arm), 5 pts found it too difficult to attend, 32 pts did not attend for reasons unrelated to PK deficiency, and data were unavailable for 6 pts. Change from BL in work/school interference score was compared for the 33 pts who attended work/school at both BL and Wk 24. Pts treated with mitapivat (n=19) had a reduction in the work/school interference score (mean [SD] change: -1.5 [1.74]) while negligible change (0.1 [2.41]) was observed among PBO pts (n=14). Notably, this reduction in score was sustained among M/M pts up to Wk 60 of the LTE. Furthermore, P/M pts experienced a reduction in the work or school interference score after starting mitapivat treatment in the LTE period, which was consistent with the improvements seen in the M/M arm during the ACTIVATE trial (Figure). Conclusions: In this post hoc analysis, interference in work or school performance was observed in adult pts with PK deficiency who were not receiving regular transfusions. Treatment with mitapivat showed sustained improvements in work or school performance over time. These data continue to support the potential for mitapivat to provide long-term benefits and reduced interference in work or school performance in these pts.

Immune Checkpoint Inhibitors and the Risk of Cardiovascular Adverse Events: A Pooled Clinical Trial Database Analysis

Introduction Immune checkpoint inhibitors (ICIs) are a highly effective class of cancer immunotherapy, but their use has been limited by immune-related adverse events (irAEs) affecting various organ systems. Recent real-world studies have shown higher incidence rates of cardiovascular (CV) events in patients with cancer who are treated with ICIs compared to those treated with conventional chemotherapy (Laenens et al, J Clin Oncol 2022). Studies suggest that the underlying mechanism involves a pro-inflammatory response causing unintended vascular compromise, but there have been limited data on ICI-related cardiotoxicity across pooled datasets. Given that ICIs have been applied to lung cancer treatment in recent years, we use it as an example indication to study clinical trial (CT) patients with advanced non-small cell lung cancer (aNSCLC) randomized to either a first-line (1L) ICI-containing regimen or to 1L chemotherapy alone (chemo) to evaluate for potential differential rates of CV events. Methods We pooled patient-level, phase 3 CT data on aNSCLC patients treated with ICI or chemo from the Medidata Enterprise Data Store. Treatment assignment was the main variable of interest. The primary outcome was a composite CV event (acute coronary syndrome, heart failure, stroke, transient ischemic attack), occurring between the start of study treatment (index date) and 30 days following the last dose of study treatment. Incidence rates and the relative hazard of a CV event by treatment assignment were estimated. Additionally, the risk of CV event with non-CV death treated as a competing risk was estimated using the Fine-Gray model. In a post-hoc subgroup analysis we explored the impact of treatment assignment on overall survival (OS) among patients with and without baseline vascular disease. OS was defined as the time from the index date until the date of death (all-cause). Patients alive at the end of CT follow-up were censored. Results A total of 1862 patients were included in this analysis, with 1128 (60.6%) randomized to ICI and 734 (39.4%) to chemo. Baseline demographics and comorbidities were balanced across treatment groups. Forty-six (2.5%) patients experienced at least 1 CV event. The incidence rate of CV events was 2.48 times (95% CI: 1.10, 6.57) higher among patients treated with ICI compared to chemo. The unadjusted hazard of composite CV event, estimated using Kaplan-Meier, differed significantly by treatment assignment (p= 0.008) ( Figure 1). After adjusting for baseline demographics and comorbidities, the hazard of a composite CV event remained higher for patients treated with ICI compared to chemo (aHR 2.68, 95% CI: 1.19-6.06) ( Table 1). Baseline vascular disease history (N=359; 19.3%) was also associated with an increased hazard of a CV event (aHR: 2.40; 95% CI: 1.25-4.60). Similar results were found in the competing risk analysis. In the subgroup analysis, patients without baseline vascular disease history had a significant OS benefit from an ICI compared to chemo (aHR 0.84, 95% CI: 0.75-0.95), whereas patients with baseline vascular disease did not (aHR 1.00, 95% CI: 0.78-1.27). Conclusion Though ICIs enhance the body's immune responses against cancer, it is important to study the associated effect of irAEs on off-target tissues. These analyses of historical CT data suggest a positive association between 1L treatment of aNSCLC with ICI and subsequent composite CV events compared with chemo alone. Given the high prevalence of morbidity among patients with lung cancer, the use of concomitant cardioprotective therapies may be an important consideration when treating cancer populations with ICIs. Pooling CT data increases the power to detect clinically important differences in rare toxicities and may inform future research and patient-physician decision-making regarding the suitability of ICI use in aNSCLC treatment. Furthermore, this research highlights the potential clinical utility of drug repurposing: expanding the use of drugs approved to treat CV events and exploring their use in patients with vascular disease who are also being treated with ICIs. As cell-mediated immune responses play a key role in the potential CV effects of ICI treatments, future studies are needed to define the underlying mechanisms of ICI-related dysregulation of the immune system to better monitor patients and improve clinical outcomes in the context of immunotherapy for aNSCLC and other cancer types.

Long-Term Remissions with MRD-Guided Acalabrutinib, Venetoclax and Obinutuzumab in Relapsed/Refractory CLL: Follow-up Efficacy and Circulating Tumor DNA Analysis of the CLL2-Baag Trial

Background The phase 2 CLL2-BAAG trial tested a triple combination of acalabrutinib (acala), venetoclax (ven) and obinutuzumab (obi) after an optional debulking with bendamustine in patients (pts) with relapsed/refractory (r/r) CLL. In its primary endpoint analysis, 75.6% of pts achieved undetectable MRD (uMRD) in peripheral blood (PB) at final restaging (RE) after approximately 6 months of the triplet (Cramer, Lancet Haematol. 2022). We now report efficacy data and circulating tumor DNA (ctDNA) analyses with additional follow-up. Methods In the induction phase, obi was started in cycle 1 (days 1, 8, 15) and given 4-weekly in cycles 2-6. Acala was added in cycle 2 and ven in cycle 3. Maintenance treatment with continuous acala and ven and 3-monthly obi was administered until achievement of a deep remission with uMRD <10 -4 in PB or for up to 24 months (mo). MRD was measured centrally by flow cytometry (FCM) in PB and by digital droplet PCR (ddPCR) of patient-specific VDJ rearrangements and CLL-related mutations in blood plasma. uMRD was defined as <1 CLL cell/10,000 leukocytes (<10 -4) and no detected ctDNA. Results In total, 46 pts were included in the trial, 1 pt had to be excluded from the analysis due to a retrospectively noted violation of exclusion criteria. The median number of previous treatments was 1 (range 1-4) and 18 pts (40%) had received a BTK inhibitor (BTKi) and/or ven (BTKi: 8, ven: 7, both: 3) prior to inclusion, 14/44 pts (31.8%) had del(17p) and/or TP53 mutations, 34 (75.6%) had unmutated IGHV. With a median observation time of 34.4 mo (range 12.0-39.2), all 45 pts are off study treatment. The median treatment duration was 14.7 mo (range 6.1-32.9), 2 pts (4.4%) discontinued treatment during the first 6 induction cycles, both due to adverse events (AEs). Following the MRD- and response-guided approach, 25 pts (55.6%) discontinued therapy according to confirmed uMRD and 9 pts (20.0%) completed the maximum of 8 maintenance cycles due to persisting MRD and/or lack of a complete response. As reported, the uMRD rate in PB at RE was 75.6% with 10 pts showing detectable MRD ≥10 -4. In the course of maintenance, 7 of these 10 pts (70%) achieved uMRD, 1 pt had a Richter's transformation (RT) and 2 pts still had detectable MRD after 8 cycles of maintenance ( Figure 1A). With all pts off-treatment, uMRD <10 -4 in PB was achieved in 42 of 45 pts (93.3%) at any time point,including 17 of 18 pts (94.4%) previously exposed to ven and/or a BTKi and 13 of 14 pts (92.9%) with TP53 aberrations. The median time to uMRD in PB was 5.4 months from the start of study treatment. Median progression-free survival (PFS) was not reached, the estimated 30-mo PFS rate for the whole analysis population was 88.2% ( Figure 1B). A similar PFS was shown for pts with TP53 aberrations (30-mo PFS 85.7%) and pts previously exposed to BTKi and/or ven (30-mo PFS 93.3%). The estimated overall survival at 30 mo was 100%. One patient died of COVID-19 18 mo after the end of study treatment. In total, 564 paired FCM/ctDNA samples were available. Overall, 17 MRD recurrences (after uMRD by both methods) occurred. Of these, 11 were first detected by ctDNA, and 3 by FCM (+3 with concordant detection, Figure 1C). Among those with earlier ctDNA detection, more pts appeared to have high-risk genetics (unmutated IGHV in 10/11 pts, complex karyotype in 4/8 evaluated pts), del(11q) and prior exposure to ven/BTKi compared to those with earlier detection by FCM, and MRD recurrences seemed to occur earlier (mean, 7.1 mo after end of treatment). Notably, in 2 of 3 CLL-type progressions (PD, both nodal with normal lymphocyte counts), ctDNA was detected 6 mo/14 mo before MRD by FCM and 7 mo/17 mo before clinical PD, in the third pt ctDNA and FCM MRD recurred at the same time. In a pt with RT (DLBCL), patient-specific VDJ ctDNA was detected at diagnosis while FCM MRD remained negative. At the time of the data cut (02/2023) 50 serious AEs (SAEs) were reported, 33 were of CTC G3, 6 of CTC G4 and 1 CTC G5. The most common SAEs were COVID-19 (n=8), other pneumonias (n=5), infusion-related reactions (n=5) and neutropenias (n=3). Conclusions Time-limited MRD-guided acala, ven and obi led to an estimated 30-mo PFS rate of 88.2% in pts with r/r CLL. Remissions deepen with ongoing maintenance and almost all pts achieve uMRD in PB including pts with TP53 aberrations and those treated with BTKi and/or ven in prior lines. The addition of ctDNA-based analyses to conventional MRD assessment by FCM seems to improve early detection of relapses.

First-line systemic treatment strategies in patients with initially unresectable colorectal cancer liver metastases (CAIRO5): an open-label, multicentre, randomised, controlled, phase 3 study from the Dutch Colorectal Cancer Group

Patients with initially unresectable colorectal cancer liver metastases might qualify for local treatment with curative intent after reducing the tumour size by induction systemic treatment. We aimed to compare the currently most active induction regimens. In this open-label, multicentre, randomised, phase 3 study (CAIRO5), patients aged 18 years or older with histologically confirmed colorectal cancer, known RAS/BRAFV600E mutation status, WHO performance status of 0-1, and initially unresectable colorectal cancer liver metastases were enrolled at 46 Dutch and one Belgian secondary and tertiary centres. Resectability or unresectability of colorectal cancer liver metastases was assessed centrally by an expert panel of liver surgeons and radiologists, at baseline and every 2 months thereafter by predefined criteria. Randomisation was done centrally with the minimisation technique via a masked web-based allocation procedure. Patients with right-sided primary tumour site or RAS or BRAFV600E mutated tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group A) or FOLFOXIRI plus bevacizumab (group B). Patients with left-sided and RAS and BRAFV600E wild-type tumours were randomly assigned (1:1) to receive FOLFOX or FOLFIRI plus bevacizumab (group C) or FOLFOX or FOLFIRI plus panitumumab (group D), every 14 days for up to 12 cycles. Patients were stratified by resectability of colorectal cancer liver metastases, serum lactate dehydrogenase concentration, choice of irinotecan versus oxaliplatin, and BRAFV600E mutation status (for groups A and B). Bevacizumab was administered intravenously at 5 mg/kg. Panitumumab was administered intravenously at 6 mg/kg. FOLFIRI consisted of intravenous infusion of irinotecan at 180 mg/m2 with folinic acid at 400 mg/m2, followed by bolus fluorouracil at 400 mg/m2 intravenously, followed by continuous infusion of fluorouracil at 2400 mg/m2. FOLFOX consisted of oxaliplatin at 85 mg/m2 intravenously together with the same schedule of folinic acid and fluorouracil as in FOLFIRI. FOLFOXIRI consisted of irinotecan at 165 mg/m2 intravenously, followed by intravenous infusion of oxaliplatin at 85 mg/m2 with folinic acid at 400 mg/m2, followed by continuous infusion of fluorouracil at 3200 mg/m2. Patients and investigators were not masked to treatment allocation. The primary outcome was progression-free survival, analysed on a modified intention-to-treat basis, excluding patients who withdrew consent before starting study treatment or violated major entry criteria (no metastatic colorectal cancer, or previous liver surgery for colorectal cancer liver metastases). The study is registered with ClinicalTrials.gov, NCT02162563, and accrual is complete. Between Nov 13, 2014, and Jan 31, 2022, 530 patients (327 [62%] male and 203 [38%] female; median age 62 years [IQR 54-69]) were randomly assigned: 148 (28%) patients to group A, 146 (28%) patients to group B, 118 (22%) patients to group C, and 118 (22%) patients to group D. Groups C and D were prematurely closed for futility. 521 patients were included in the modified intention-to-treat population (147 in group A, 144 in group B, 114 in group C, and 116 in group D). The median follow-up at the time of this analysis was 51·1 months (95% CI 47·7-53·1) in groups A and B and 49·9 months (44·5-52·5) in in groups C and D. Median progression-free survival was 9·0 months (95% CI 7·7-10·5) in group A versus 10·6 months (9·9-12·1) in group B (stratified hazard ratio [HR] 0·76 [95% CI 0·60-0·98]; p=0·032), and 10·8 months (95% CI 9·9-12·6) in group C versus 10·4 months (9·8-13·0) in group D (stratified HR 1·11 [95% CI 0·84-1·48]; p=0·46). The most frequent grade 3-4 events in groups A and B were neutropenia (19 [13%] patients in group A vs 57 [40%] in group B; p<0·0001), hypertension (21 [14%] vs 20 [14%]; p=1·00), and diarrhoea (five [3%] vs 28 [19%]; p<0·0001), and in groups C and D were neutropenia (29 [25%] vs 24 [21%]; p=0·44), skin toxicity (one [1%] vs 29 [25%]; p<0·0001), hypertension (20 [18%] vs eight [7%]; p=0·016), and diarrhoea (five [4%] vs 18 [16%]; p=0·0072). Serious adverse events occurred in 46 (31%) patients in group A, 75 (52%) patients in group B, 41 (36%) patients in group C, and 49 (42%) patients in group D. Seven treatment-related deaths were reported in group B (two due to multiorgan failure, and one each due to sepsis, pneumonia, portal vein thrombosis, septic shock and liver failure, and sudden death), one in group C (multiorgan failure), and three in group D (cardiac arrest, pulmonary embolism, and abdominal sepsis). In patients with initially unresectable colorectal cancer liver metastases, FOLFOXIRI-bevacizumab was the preferred treatment in patients with a right-sided or RAS or BRAFV600E mutated primary tumour. In patients with a left-sided and RAS and BRAFV600E wild-type tumour, the addition of panitumumab to FOLFOX or FOLFIRI showed no clinical benefit over bevacizumab, but was associated with more toxicity. Roche and Amgen.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: We previously reported promising efficacy for venetoclax (V) plus da-R-EPOCH (VR-EPOCH) for 26 patients (pts) with CLL who developed Richter Syndrome (RS), with a CR rate of 50% and median OS of 19.6 mo.; however, hematologic and infectious complications were common (Davids et al., Blood, 2022). We hypothesized that de-intensifying the chemoimmunotherapy backbone while keeping the venetoclax could potentially preserve efficacy while mitigating the toxicities observed with this approach. Here, we report for the first time on an ongoing study of VR-CHOP in RS. Methods: This is a single-arm, phase 2, investigator sponsored trial of VR-CHOP for RS (NCT03054896) open at 3 US sites. We treated pts with CLL and biopsy-confirmed DLBCL with R-CHOP for 1 cycle, then after count recovery with accelerated inpatient daily V ramp-up (20/50/100/200/400 mg), then VR-CHOP outpatient for up to 5 additional 21d cycles (V 400 mg qd, d1–10 of each cycle) with mandatory G-CSF support. Responders could then receive daily V 400 mg qd maintenance in 28d cycles or elect to come off study for alloHCT. Response was by Lugano criteria with PET/CT, toxicity by CTCAE v4.03. Results: As of 24 Feb 2023, 27 pts have started study treatment. Median age: 72 yrs (range 42–80), 37% had del(17p) or TP53 mut, 26% had NOTCH1 mut. Median # prior CLL treatments was 1 (range 1–9), including 44% post-BTKi and 17% post-V; 4 pts (15%) had prior treatment for RS. Median # of VR-CHOP cycles to date in this ongoing study is 4 (range 1–6). ≥Gr 3 heme toxicity included: neutropenia (36%), anemia (32%), thrombocytopenia (40%). Additional ≥Gr 3 toxicities in ≥10% of pts included: febrile neutropenia (32%) and peripheral neuropathy (12%). No TLS occurred with daily V ramp-up after 1 cycle of R-CHOP. Two pts on active treatment have not yet reached the first response eval. In the remaining 25 pts, ORR: 68% (17/25), CR: 48% (12/25). 7 pts have died: 4 due to PD (including 2 prior to starting V) and 3 due to infection (n = 2 sepsis, n = 1 COVID-19). 8 pts with initial CLL marrow involvement had re-staging marrows, and 88% (7/8) were uMRD for CLL by flow at 10–4. 7 pts in remission electively went to alloHCT. With a median follow-up of 6.1 mo (range 0.1–21.4), median PFS is 7.2 mo (Figure A), median OS is 19.5 mo (Figure B). The research was funded by: Genentech Keywords: Chemotherapy, Chronic Lymphocytic Leukemia (CLL), Combination Therapies Conflicts of interests pertinent to the abstract. M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biotechnologies, Ascentage Pharma, AstraZeneca, BeiGene, Bristol-Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Ono Pharmaceuticals, Secura Bio, Takeda, and TG Therapeutics Honoraria: Aptitude Health, AXIS Medical Education, BioAscend, Curio Science, Medscape Education, PeerView Institute for Medical Education, Physician’s Education Resource, PlatformQ Health Education, Plexus Communications, and Research to Practice Research funding: AbbVie, Ascentage Pharma, AstraZeneca, Genentech, Novartis, Secura Bio, and TG Therapeutics K. A. Rogers Consultant or advisory role: AbbVie, AstraZeneca, Genentech, Pharmacyclics, Janssen, Beigene, LOXO/Lilly Honoraria: AstraZeneca, Janssen Research funding: Genentech, AbbVie, Janssen, and Novartis Educational grants: AstraZeneca N. Jain Consultant or advisory role: Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, BMS, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma, Ipsen, CareDX, MingSight, Novalgen Research funding: Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, Mingsight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, TransThera Sciences, Novartis, Carna Biosciences, Sana Biotechnology, Kisoji Biotechnology J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics P. A. Thompson Consultant or advisory role: Janssen, AbbVie, Adaptive Biotechnologies, Beigene, Lilly, Genentech Research funding: AbbVie, Pharmacyclics, Lilly and Adaptive Biotechnologies

Feasibility, safety, and efficacy of stereotactic body radiotherapy combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination for non-progressive locally advanced pancreatic cancer, after induction chemotherapy with (modified)FOLFIRINOX – The LAPC-2 trial

Background and purposeIn this phase I/II trial, non-progressive locally advanced pancreatic cancer (LAPC) patients after (modified)FOLFIRINOX therapy were treated with stereotactic body radiotherapy (SBRT) combined with heat-killed mycobacterium (IMM-101) vaccinations. We aimed to assess safety, feasibility, and efficacy of this treatment approach. Materials and methodsOn five consecutive days, patients received a total of 40 Gray (Gy) of SBRT with a dose of 8 Gy per fraction. Starting two weeks prior to SBRT, they in addition received six bi-weekly intradermal vaccinations with one milligram of IMM-101. The primary outcomes were the number of grade 4 or higher adverse events and the one-year progression free-survival (PFS) rate. ResultsThirty-eight patients were included and started study treatment. Median follow-up was 28.4 months (95 %CI 24.3 – 32.6). We observed one grade 5, no grade 4 and thirteen grade 3 adverse events, none related to IMM-101. The one-year PFS rate was 47 %, the median PFS was 11.7 months (95 %CI 11.0 – 12.5) and the median overall survival was 19.0 months (95 %CI 16.2 – 21.9). Eight (21 %) tumors were resected, of which 6 (75 %) were R0 resections. Outcomes were comparable with the outcomes of the patients from the previous LAPC-1 trial, in which LAPC patients were treated with SBRT, without IMM-101. ConclusionCombination treatment with IMM-101 and SBRT was safe and feasible for non-progressive locally advanced pancreatic cancer patients after (modified)FOLFIRINOX. No improvement in the progression-free survival could be demonstrated by adding IMM-101 to SBRT.

TRIDENTE trial: A phase II study of rechallenge with encorafenib, binimetinib, and cetuximab in patients with RAS wild-type/BRAF V600E–mutant metastatic colorectal cancer.

TPS264 Background: The BEACON CRC trial demonstrated survival benefit of combination therapy with encorafenib (ENCO) + cetuximab (CET) +/- binimetinib (BINI) in patients with RAS wild-type (WT)/ BRAF V600E mutant metastatic colorectal cancer (mCRC). However, prognosis of those patients still be poor after the refractoriness to the BEACON combination therapy. One of resistant mechanisms to BRAF inhibitor has been reported as MAPK alterations including RAS mutation, similar to those for anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC. Promising results of rechallenge therapy with anti-EGFR antibody in patients with RAS/ BRAF V600E WT mCRC and with combination of BRAF inhibitor + MEK inhibitor in patients with BRAF V600 mutant melanoma suggest the treatment strategy of rechallenge therapy with the BEACON triplet therapy in patients with RAS WT/ BRAF V600E mutant mCRC. Methods: TRIDENTE trial is a multicenter phase II trial to assess efficacy and safety of rechallenge therapy with ENCO + BINI + CET in patients with RAS WT/ BRAF V600E mutant mCRC after the refractoriness to either the BEACON doublet or triplet therapy. Key eligibility criteria includes RAS WT/ BRAF V600E mutant mCRC; ≥ 20 years old; ECOG PS 0-1; refractory or intolerant to at least one fluoropyrimidine-based regimen (including irinotecan or oxaliplatin); refractory or intolerant to anti-PD-1 antibody if patients with MSI-high; history of previous combination therapy containing ENCO + CET with at least partial response by RECIST v1.1; confirmed disease progression within 4 weeks after last administration of previous ENCO; ≥ 4 months of period between the last administration of previous ENCO and the start of study treatment. Enrolled patients receive the combination therapy with ENCO (300 mg, QD), BINI (45 mg, BID), and CET (initially 400 mg/m2, and subsequently 250 mg/m2, QW) as the study treatment. Primary endpoint is the objective response rate (ORR) by investigators’ assessment in patients receiving at least one dose of study treatment. A target sample size is calculated to be 21 on the hypothesis that the threshold ORR is 3% and expected ORR is 20%, with a significant level of 5% (one-sided) and power of 80%. Secondary endpoint includes progression-free and overall survivals, disease control rate, and safety. Exploratory molecular analysis is performed using targeted next-generation sequencing in circulating-tumor DNA at the timepoints of baseline and discontinuation of study treatment. As of September 19, 2022, 8 patients have been enrolled. Clinical trial information: jRCTs031210511 .

732. Microbiologic and clinical outcome concordance in the global phase 3 ATTACK trial: Sulbactam-durlobactam (SUL-DUR) versus colistin therapy in patients with Acinetobacter baumannii-calcoaceticus complex (ABC) infections

Abstract Background SUL-DUR is a β-lactam/β-lactamase inhibitor combination in development for the treatment of ABC, which is a cause of severe infections with substantial mortality. ATTACK evaluated the efficacy and safety of SUL-DUR versus colistin (COL) in patients with serious ABC infections. Methods Part A was a randomized, blinded non-inferiority study (SUL-DUR versus COL) in ABC pneumonia or bacteremia; Part B was an open label study (SUL-DUR only) that enrolled patients with ABC infections who did not tolerate COL or whose pathogens were resistant to COL (COL-R). All subjects received imipenem/cilastatin as background therapy. Primary endpoint included 28-day all-cause mortality (ACM) in Part A patients with carbapenem-resistant ABC at baseline (CRABC m-MITT). Clinical and microbiologic outcomes were measured at the End of Therapy (EOT), Test of Cure (TOC) and Late Follow-up (LFU) visits in CRABC m-MITT patients. In this study, COL-R was defined as MIC ≥ 4 µg/ml and SUL-DUR-non-susceptible (NS) was defined as MIC ≥ 8 µg/ml. Results SUL-DUR was non-inferior to COL in 28-day ACM; 19.0% SUL-DUR versus 32.3% in the COL group (Table 1). SUL-DUR therapy resulted in statistically significant higher clinical cures at EOT and TOC. Similarly, a significant treatment difference in microbiological favorable assessment was observed at EOT and TOC (24.4% and 26.3%, respectively, in Part A). Similar mortality differences were observed in subgroups including infection type, severity of illness, mechanical ventilation, and duration of stay of at least 5 days in the ICU prior to starting study treatment (Table 2). All 149 baseline ABC isolates from CRABC m-MITT patients were multi-drug resistant; the SUL-DUR MIC50/90 was 2/4 µg/ml (range of 0.25 – 8 µg/ml). At baseline 33% of ABC infections were polymicrobial. Conclusion In ATTACK, patients treated with SUL-DUR had lower mortality, higher clinical cure rates and significantly greater microbiologically favorable outcomes than those treated with COL. The correlation between clinical and microbiologic outcomes provides additional evidence that, if approved, SUL-DUR could be an important therapeutic option for Acinetobacter infections including carbapenem-resistant and multidrug-resistant strains. Disclosures David Altarac, MD, MPA, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Alita Miller, PhD, Entasis Therapeutics: Employee Sarah McLeod, PhD, Entasis Therapeutics: Employee Adam B. Shapiro, Ph.D, Entasis Therapeutics: Employee|Entasis Therapeutics: Stocks/Bonds Khurram Rana, PharmD, Entasis Therapeutics: Employee|Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Drew Lewis, MD, MTM&amp;H, Entasis Therapeutics: employee|Entasis Therapeutics: employee|Entasis Therapeutics: Stocks/Bonds|Entasis Therapeutics: Stocks/Bonds Gabrielle Poirier, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds Daria Chabas, BS, Entasis Therapeutics: Ownership Interest|Entasis Therapeutics: Stocks/Bonds.

Siremadlin Monotherapy and in Combination with Donor Lymphocyte Infusion for Patients with Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation Who Are in Complete Remission but at High Risk for Relapse

Background: Relapse post allogeneic stem cell transplantation (SCT) remains the main cause of treatment failure (~40%) for patients (pts) with acute myeloid leukemia (AML). Many pts who ultimately relapse post SCT do so within the first year post transplant, and earlier relapse is associated with poorer survival. Therapeutics that prevent early relapse for these pts are urgently needed. Early cellular or pharmacologic intervention or maintenance strategies that enhance the graft-versus-leukemia (GvL) effect after SCT are of renewed interest as they have the potential to reduce relapse risk post SCT. Siremadlin (HDM201) is a novel investigational MDM2 inhibitor with single-agent, anti-AML activity. MDM2 inhibitors, including siremadlin, possess potent immunomodulatory effects in murine solid tumor and AML models. MDM2 inhibition has been shown to synergize with the allogeneic immune response, increase the vulnerability of AML cells to allogeneic donor T cells, and promote the cytotoxicity and longevity of allogeneic donor T cells in murine models. As such, the post-SCT setting is ideal for investigating the immunomodulatory effects of MDM2 inhibition on enhancing the GvL effect (Ho et al. Blood. 2022). Here we describe the design of a Phase Ib/II, open-label study of siremadlin as monotherapy and in combination with donor lymphocyte infusion (DLI) in pts with AML post SCT who are in complete remission (CR) but at high risk for relapse based on the presence of pre-SCT risk factors (NCT05447663). Study Design: The trial is not yet recruiting but aims to enroll ~38 adult pts with AML who underwent first SCT and are currently between Day 60-120 post SCT. Prior to a patient's SCT, they must have a risk factor that puts them at high risk for relapse, including AML in first CR with adverse risk genetics per 2017 European LeukemiaNet risk stratification, therapy-related AML, or secondary AML; or AML in second or greater CR. The SCT must be from an 8/8 human leukocyte antigen (HLA) matched related or unrelated donor at HLA-A, -B, -C, -DRB1 loci using unmanipulated/T-cell replete bone marrow or peripheral blood stem cells as a stem cell source. Post SCT, pts must have achieved CR or CR with incomplete hematologic recovery (CRi) with no evidence of hematologic relapse. Exclusion criteria include prior exposure to an MDM inhibitor, active graft-vs-host disease (GvHD), past history of grade ≥III acute GvHD (aGvHD) or moderate/severe chronic GvHD (cGVHD), recipient of SCT from a haploidentical family donor or cord blood transplant, and prior systemic AML-directed treatments given at any time after SCT (including DLI). This study contains 2 parts, Part 1 is a dose confirmation of siremadlin monotherapy and will enroll ~12 pts. Siremadlin will be tested at a maximum of 3 dose levels with a starting dose of 30 mg/d on Days 1-5 of a 28-day cycle, dose level +1 at 40 mg/d and dose level -1 at 20 mg/d. The safety and tolerability of these dose levels will be assessed to determine the siremadlin recommended dose (RD) for Part 2. Pts in Part 1 of the study will receive siremadlin monotherapy for the entire duration of the treatment and will not receive DLI. Subsequently, ~26 pts will be enrolled in Part 2 and proceed through a priming phase with siremadlin monotherapy at the RD, followed by a combination phase of siremadlin + DLI, and subsequently a maintenance phase with siremadlin monotherapy (Figure). Primary safety endpoints of the study are incidence of dose-limiting toxicities (DLTs) in Part 1 and time to DLT in Part 2. The primary efficacy endpoint is the proportion of pts in Part 2 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment. Secondary endpoints include number of pts in Part 1 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment at the RD for Part 2, time to first documented hematologic relapse or death, incidence of relapse at 1 year and 2 years post study treatment, safety, GvHD-free/relapse-free survival, incidence of and time to treatment-emergent grade ≥III aGvHD or moderate/severe cGvHD, and pharmacokinetics. Conclusions: This Phase Ib/II study investigates siremadlin monotherapy and siremadlin in combination with DLI in pts with AML in remission but at high risk of relapse post SCT. The study will evaluate the unique immunomodulatory potential of siremadlin to reduce risk of relapse in this population with high unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Improvements in Patient-Reported Outcomes in Patients with Pyruvate Kinase Deficiency Treated with Mitapivat

Background: Pyruvate kinase (PK) deficiency is a rare, hereditary hemolytic anemia caused by a single gene defect encoding the red blood cell (RBC)-specific form of PK. This condition is associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea, that have a profound, wide-ranging impact on health-related quality of life (HRQoL). Patients (pts) report physical limitations, negatively impacted social functioning, reduced self-esteem, and concerns for the future. Mitapivat, a first-in-class, oral, allosteric activator of PK, has demonstrated improvement in hemoglobin, hemolysis, and transfusion burden in pts with PK deficiency, and is approved by the US Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency. In addition, improvements in patient-reported outcomes (PROs) (measured by disease-specific PRO instruments: the PK deficiency diary [PKDD] and the PK deficiency impact assessment [PKDIA]) were observed in two global, phase 3 clinicals trials among adults with PK deficiency treated with mitapivat who were not regularly (ACTIVATE; NCT03548220) or regularly transfused (ACTIVATE-T; NCT03559699). Here, we describe PKDD and PKDIA outcomes up to Week (Wk) 84 of the long-term extension (LTE) study (NCT03853798) of mitapivat in pts with PK deficiency previously enrolled in ACTIVATE and ACTIVATE-T. Methods: In the placebo (PBO)-controlled ACTIVATE trial, pts were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 wks. In the open-label, single-arm ACTIVATE-T trial, pts were treated with mitapivat for 40 wks. Pts who completed either trial were eligible to continue in the LTE, where all pts received mitapivat. Pts from ACTIVATE were categorized into either the mitapivat-to-mitapivat arm (M/M) or the PBO-to-mitapivat arm (P/M). Pts from ACTIVATE-T continued to receive mitapivat (M). Two PK deficiency-specific PRO instruments were used: the PKDD is a 7-item measure of the core signs and symptoms of PK deficiency, and the PKDIA is a 14-item measure of the impacts of PK deficiency on pts' HRQoL. In the ACTIVATE/LTE and ACTIVATE-T/LTE analyses, changes from baseline (BL; defined as the last complete assessment before start of study treatment in ACTIVATE/ACTIVATE-T) in PKDD and PKDIA mean scores were assessed at scheduled visits up to Wk 84 of the LTE for each of the 3 treatment arms. For both PRO instruments, a lower score represents a lower disease burden, and the minimal clinically important change is defined as a reduction of 4.2 and 5.5 in PKDD and PKDIA scores, respectively. Changes in PKDD and PKDIA scores were summarized descriptively using mean and SD. Results: In total, 80 pts were included in the ACTIVATE/LTE analysis (M/M=40; P/M=40) and 27 pts were included in the ACTIVATE-T/LTE analysis. At Wk 84 of the LTE study (ie, Wk 108 for ACTIVATE pts; Wk 124 for ACTIVATE-T pts), mean (SD) change from BL in PKDD score was ‒7.19 (6.740) for M/M pts, ‒4.58 (5.758) for P/M pts, and ‒3.94 (14.087) for M pts; mean (SD) change from BL in PKDIA score was ‒6.3 (7.12) for M/M pts, ‒6.3 (9.09) for P/M pts, and ‒11.5 (11.53) for M pts. Notably, P/M pts experienced improvements in PKDD and PKDIA mean scores after starting mitapivat in the LTE that were consistent with initial improvements seen in the mitapivat-treated group in the ACTIVATE trial. Across both PRO instruments, improvements among mitapivat-treated pts were sustained over time in the LTE (Figures 1A and 1B). Conclusions: Treatment with mitapivat was associated with long-term, durable, and clinically meaningful improvements in signs, symptoms, and functional impacts based on disease-specific PRO instruments, irrespective of transfusion status. These results suggest that by improving HRQoL, treatment with mitapivat may provide meaningful pt-centric benefits. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High-Dose Chemotherapy and Autologous Stem Cell Transplant in Elderly and Fit Primary CNS Lymphoma Patients - a Multicenter Study By the Cooperative PCNSL Study Group (MARTA study)

Introduction: High-dose methotrexate (HD-MTX) based induction chemo-immunotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) has been shown to be feasible and effective in younger and in selected elderly PCNSL patients. We aimed to investigate this treatment approach in patients > 65 years with newly diagnosed PCNSL in a multicentre study. Methods: This open-label, multicentre, single arm phase II study was conducted at 15 German centres (DRKS 00011932). Main eligibility criteria included newly diagnosed PCNSL, immunocompetence, age > 65 years, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤ 2, and adequate organ function. Induction treatment consisted of two 21-day cycles of HD-MTX 3.5 g/m² (day 1), cytarabine 2 g/m² twice daily (days 2, 3) and rituximab 375 mg/m² before and after each chemotherapy with stem cell harvest after the 1st cycle. Patients not suffering disease progression subsequently received consolidation treatment with HCT-ASCT with rituximab 375 mg/m² (day -8), busulfan 3.2 mg/kg (days -7, -6), thiotepa 5 mg/kg/d (days -5, -4) and reinfusion of stem cells (day 0). Primary endpoint was progression-free survival (PFS) at 1 year by intention-to-treat (ITT). Secondary endpoints included overall survival (OS), treatment response and toxicities. Results: Between Nov 2017 and Sept 2020, we registered 57 patients. Five patients were excluded because of systemic lymphoma manifestation, absence of measurable radiologic lesion(s), inadequate renal function, ECOG PS >2 and deterioration before the start of study treatment. Finally, 52 eligible patients were included in the ITT population. Mean age was 72 years (range 65-80 years), 27/52 (51.9%) patients initially presented with an ECOG PS > 1. All patients started induction chemo-immunotherapy, 45 of 52 (86.5%) patients completed induction treatment. Thirty-seven of 52 (71.2%) patients proceeded to HCT-ASCT. Most common serious adverse events were infections, renal failure and (cerebro)vascular events, which mainly occurred during induction treatment. Overall, 22 (42.3%) patients died, 12 of whom (23.1%) without evidence of disease progression or relapse. Three (5.8%) patients died because of treatment-related complications, all of them during induction treatment. An additional patient died within 30 days after HCT-ASCT due to fatal viral pneumonia, main other non treatment-related causes of deaths were late infections and (cerebro)vascular events. Forty-one of 52 (78.8%) patients responded to induction treatment; 23 (44.2%) patients achieved a (unconfirmed) complete response and 11 (21.2%) patients a partial response 30 days after HCT-ASCT. After an estimated median follow-up of 23 months, PFS at 12 and 24 months was 57.7% (95% CI 43.2-69.7%) and 54.8% (40-67.4%), respectively; median PFS was 41.1 months (95% CI 6.7 to not calculable). Overall survival at 12 and 24 months was 63.1% (95% CI 48.4-74.7%) and 60.5% (95% CI 45.5-72.5%), respectively; median OS was 41.1 months (95% CI 10.3 to not calculable). Of those 37 patients undergoing HCT-ASCT, 2-year PFS and OS rates were 71.7% (95% CI 53.4-83.8%) and 80.8% (95% CI 63.8-90.3%), respectively. Conclusions: Feasibility and efficacy of HCT-ASCT in selected elderly patients with newly diagnosed PCNSL are confirmed in a multicenter setting with survival rates comparable to those of younger cohorts. Nevertheless, non-relapse mortality remains a major challenge in this vulnerable patient population emphasizing that standardized assessment of eligibility for intensive treatment is of utmost importance. This will be addressed in the upcoming randomized phase III PRIMA-CNS trial (DRKS00022768). Final data analysis is currently ongoing and will be presented in detail at the meeting.

Phase 2 Study of Oral Decitabine/Cedazuridine in Combination with Magrolimab for Previously Untreated Subjects with Intermediate to Very High-Risk Myelodysplastic Syndromes (MDS)

Rationale Hypomethylating agents (HMAs) are approved for higher risk MDS (azacitidine, decitabine, oral decitabine/cedazuridine US package insert). Parenteral therapy (subcutaneous or intravenous) is required 5-7 days each month, often resulting in hospital or clinic visits on a chronic basis and represents a substantial burden for this primarily elderly population and their caregivers. Not surprisingly, patients with higher risk MDS are often not started and/or have low compliance with parenteral HMAs, with patients preferring oral medications (Zeidan et al., CLML 2022). Magrolimab has demonstrated encouraging preliminary data in the higher-risk MDS population in combination with azacitidine and is currently being evaluated in a randomized Phase 3 study (ENHANCE, NCT04313881), comparing the efficacy and safety of magrolimab plus azacitidine with that of azacitidine plus placebo in previously untreated patients with higher-risk MDS. This phase 2 study examines the possibility of using an oral HMA (oral decitabine/cedazuridine) in combination with magrolimab which may provide the benefits without the burden of significant parenteral therapy (4-6 additional clinic days each month). Study Design ASTX727-10 is a phase 2, international, single-arm, open-label study investigating the safety and efficacy of combination oral decitabine/cedazuridine and magrolimab treatment in intermediate to very high-risk MDS, based on the MDS International Prognostic Scoring System - Revised (IPSS-R). Secondary objectives include evaluating the pharmacokinetic profiles of oral decitabine/cedazuridine and magrolimab, other clinical efficacy of the combination, and safety and efficacy in prespecified subgroups (e.g. IPSS-Molecular, p53 mutant status). To be eligible, subjects with ECOG Performance Status ≤2 must have previously untreated MDS per WHO 2016 classification with < 20% bone marrow blasts and be willing to undergo red blood cell transfusions to achieve a hemoglobin >9 gm/dl at the start of study treatment. Subjects must also be willing to undergo blood transfusions as per the parameters of the protocol and as clinically necessary. Key exclusion criteria include significant medical issues (including uncontrolled diabetes and New York Heart Association Class III-IV heart failure), creatinine clearance < 50 ml/min, immediate eligibility for hematopoietic stem cell transplant, secondary MDS, or MDS / (myeloproliferative neoplasm) overlap syndromes. As part of the study, tolerability of the combination regimen will be confirmed in the first 6-18 subjects. Dose and/or dosing decreases identified during this dose limiting toxicity assessment will be applied to the entire study. Approximately 100 subjects will be enrolled. Anticipated study opening is November 2022.

EPCT-02. A Phase 1 Study of Mebendazole with Bevacizumab and Irinotecan in High Grade Gliomas

Abstract BACKGROUND: High grade gliomas (HGG) have a dismal prognosis despite multimodal therapy. Mebendazole (MBZ) is an anti-helminthic benzimidazole. In vitro, MBZ has efficacy in numerous cancer models and is able to cross the blood brain barrier. We conducted a phase 1 trial (NCT01837862) to evaluate the safety of MBZ in combination with bevacizumab (BVCZ) and irinotecan (CPT-11). OBJECTIVE: To determine the maximally tolerated dose of MBZ when given in combination with BVCZ and CPT-11 in children with high-grade gliomas; to describe the progression-free survival (PFS) and overall survival (OS) for this group. METHODS: Patients between 1 and 21 years of age with HGG were enrolled in a 3 + 3 design to escalating doses of MBZ in combination with BVCZ 10mg/kg/dose and CPT-11 150mg/m2/dose. Subjects were eligible upfront after completion of radiation or at the time of progression. MBZ was taken orally twice per day continuously and BVCZ and CPT-11 were given intravenously on days 1 and 15 of 28-day cycles. RESULTS: Between 2015 and 2020, 10 subjects were enrolled at MBZ 50mg/kg/day (n=3), 100mg/kg/day (n=4), and 200mg/kg/day (n=3). One subject assigned to 100mg/kg/day was not evaluable. Seven subjects had a diagnosis of diffuse midline glioma, 1 subject had anaplastic astrocytoma, and 1 subject had a spinal HGG. All subjects received radiation. There were no dose limiting toxicities. The most frequent G3/G4 adverse events were neutropenia (n=3), and lymphopenia (n= 4). The overall response rate was 33% with 2 subjects achieving a partial response and 1 subject achieving a complete response sustained for 10 months. The PFS and OS from the start of study treatment were 4.7 months and 11.4 months, respectively. CONCLUSION: MBZ was safe and well tolerated when administered with BVCZ and CPT-11 at doses up to 200mg/kg/day. Further studies are needed to determine the efficacy of this treatment.

EO2401, a novel microbiome-derived therapeutic vaccine for patients with adrenocortical carcinoma (ACC): Preliminary results of the SPENCER study.

4596 Background: In advanced ACC, no significant progress has been made since introduction of mitotane and cisplatin-based therapy. EO2401 (EO) was designed to activate existing commensal memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in ACC, IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This Phase 1/2 trial (NCT04187404) investigated EO + nivolumab (N) (EO + N = EN) in pts with ACC. Cohort 1 lead-in established safety of EN. Cohort 2 includes pts with metastatic ACC, with (C2a), or without (C2b) prior systemic therapy. EN was given 4 times q2 w, followed by boosters q4 w until PD (iRECIST). Results: 33 pts with ACC started study treatment: C2a 26 pts (58% 1; 42% 2 prior lines), C2b 7 pts. Median age 47; 24% men; ECOG 0/52%, 1/42%, 2/6%; 61% ≥2 organs involved by metastases (61% liver, 76% lung). EN was well tolerated. The combination safety profile was consistent with the profile of N monotherapy except for higher local administration site reactions (any erythema/pain/induration in 35% of pts). Overall (n = 33), best RECIST response was PR 12%, SD 24%, PD 45%, NE 18%; median PFS was 1.9 mo (range 0.4-7.6+); median survival not reached, and survival rate at 6-mo 63% (median FU 4.9 mo, range 0.9-12.0). Strong CD8 T cell ELISPOT responses against the vaccine peptides (9/9 pts) and cross-reactivity against targeted TAAs (8/8 evaluable pts) was observed. Tetramer staining of specific CD8 cells for all 3 peptides was detected in 7/8 tested. When investigated, positive staining against BIRC5 was detected as early as 4 w after the first vaccination. In C2a, a group of pts (n = 10) with SD at the first CT (incl. 4 pts with PR) seemed to fare well; all investigated tumor samples in this group showed a low level of TMB, low MSI, and low PDL1 expression. In contrast, 10 pts had PD &lt; 2mo and died &lt; 6mo. There was no correlation between clinical benefit and a large panel of cytokines/chemokines. However, post-hoc analysis identified several clinical factors (prior mitotane, ECOG ≤ 1, ACC 1st diagnosis &gt; 9 mo, max lesion ≤125 mm, ≤3 organs involved, lymphocytes ≤ grade 1) that excluded 90% of pts without benefit to EN. In the post-hoc selected group (n = 14) with median FU 6.9 mo (12 pts censored) the DCR was 64% (4 PR, 5 SD), 6-mo PFS was 42% and 6-mo survival rate 93%. Conclusions: EO2401 in combination with nivolumab was well tolerated and induced a specific immune response in all tested pts. In addition, efficacy was seen in a subpopulation of pts with ACC defined by clinical parameters in a post-hoc analysis. A randomized phase 2 study based on the findings of Cohort 2a is being planned. Clinical trial information: NCT04187404.

ETCTN 10437: A single-arm phase II study of bone-targeted sn-117m-DTPA in symptomatic castration-resistant prostate cancer with skeletal metastases.

TPS5095 Background: Most patients with metastatic castration resistant prostate cancer (mCRPC) develop bone metastases with debilitating pain that is itself associated with shorter survival. Several bone-seeking radionuclides have been developed for palliation of metastatic bone pain. To date, radium-223 dichloride is the first and only approved targeted alpha therapy for mCRPC; the major dose limitation is bone marrow toxicity with modest pain relief. Sn-117m-diethylenetriaminepentaacetic acid (DPTA), is a complex of a radioisotope of tin with DTPA. It emits a low-energy conversion electron and also yields a gamma emission. Sn-117m-DPTA localizes selectively in bone, and the limited range (0.2-0.3 mm) of its conversion electrons resulting in deeper tissue penetration with less radiation effects on bone marrow as compared to radium-223 dichloride. Srivastava et al. (1998) reported in a phase I/II study of patients with painful bone metastases from a variety of solid tumors, 45% of patients obtained reduction of pain by at least 50%, and 30% had complete relief of pain for more than two weeks after one injection. Thus, Sn-117m-DTPA has high palliative efficacy with little significant toxicity. Additional evaluation of this agent in mCRPC patients is urgently required. Methods: The study is a phase 2 single-arm clinical trial of Sn-117m-DPTA (20 mCi/70Kg or 0.28 mCi/kg) intravenously every 8 weeks for two injections for patients with mCRPC metastatic to at least two bone sites with at least one clinically meaningful pain site at baseline. Re-treatment with additional two cycles is allowed if patients meet re-treatment criteria. Key eligibility criteria include 1) refractory mCRPC patients who progressed on any lines of therapies 2) self-reported bone pain (≥4 on an 11-point pain intensity scale), and 3) must be on either regular pain medication or have undergone palliative radiation for bone pain within 12 weeks prior to starting study treatment. Key exclusion criteria include 1) visceral metastases and 2) malignant lymphadenopathy exceeding 3cm in short-axis diameter. Twenty-five patients will be enrolled with a primary objective to assess the efficacy of Sn-117m-DTPA on sustained pain response; defined as 1) achieving pain index ≤3 index within a 12-week period and 2) maintaining pain index ≤3 over a 16-week period. Secondary endpoints include patient reported outcomes, adverse events, progression-free survival and overall survival. Correlative aims include assessing blood (systemic inflammatory markers) and tissue biomarkers (gene sequencing and polo-like kinase-1) for association with clinical benefit. An interim analysis will be performed to assess efficacy after 10 patients become evaluable. The study began enrolling patients in December 2021 and is ongoing. Clinical trial information: NCT04616547.

Efficacy of a New Commercial Ocular Spray Containing Oftasecur Citrus Extract for Reducing Microbial Load in the Conjunctiva of Patients Receiving Intravitreal Injections.

IntroductionThe control of conjunctival microbial load is crucial for patients receiving intravitreal injections (IVTs) in order to reduce the risk of endophthalmitis. The purpose of this work was to assess the antimicrobial activity of a new commercial ocular spray containing Biosecur citrus extract (Oftasecur®, Off Health, Florence, Italy).MethodsThis prospective cross-sectional pilot study included patients receiving IVTs who were instructed to apply Oftasecur spray onto the eye to be injected four times daily starting 4 days before surgery. The contralateral eye was considered the control. A conjunctival swab for microbiological analysis was performed in both eyes before starting study treatment and at the time of the injection. The Brief Ocular Discomfort Inventory (BODI) questionnaire was administered to patients based on an 11-point scale (0 for no discomfort and 10 for maximum discomfort).ResultsThirty patients (15 male, 15 female; mean age 64.7 ± 11.6 [standard deviation, SD] years) were included. Before starting treatment, 53.3% of the total eyes tested positive during the microbiological analysis. After the treatment period, only 20% of the eyes tested positive at the time of injection, showing a significant reduction in the microbial load (p < 0.01). Moreover, in the treated arm, the positive swabs before and after the prophylactic treatment with Oftasecur ocular spray showed a significant reduction (from 70.4% to 29.6%; p = 0.003, McNemar’s test). Oftasecur ocular spray was well tolerated, with an average BODI score of 1.2 (± 0.70 SD).ConclusionOftasecur ocular spray showed antimicrobial activity that significantly reduced the microbial load in patients receiving intravitreal injections. Therefore, it may have a role in the prophylaxis of infection in the setting of IVTs.

Impact of Precision Medicine on Clinical Outcomes: A Single-Institution Retrospective Study.

PurposeThe strategy of precision medicine has been widely adopted in the practice of oncology, although the efficacy remains unclear. This study assesses clinical outcomes in patients with an actionable alteration found during FoundationOne CDx™ (F1CDx) testing and who received a targeted therapy based on the results.Materials and MethodsThis is a retrospective cohort study of patients with tumors that underwent F1CDx from September 2012 to July 2018. F1CDx provided actionable alterations for patients to select appropriate therapies. The primary objective was to estimate the objective response rate (ORR) at 3 months from the start of study treatment. The secondary objectives were to estimate progression-free survival (PFS) and overall survival (OS).ResultsOne thousand patients underwent F1CDx testing. Six hundred fifty-two patients were identified as having actionable mutations. Thirty-eight patients (18 males and 20 females) received targeted therapy and were included in the study. The most common alterations were PD-1/PDL-1, high-TMB, P13K, and HER2/ERBB2. Patients received various treatments including nivolumab, pembrolizumab, trastuzumab, and everolimus. Eight (23.5%) and six (17.7%) patients achieved partial response (PR) and stable disease (SD), respectively; 20 (58.8%) had progression of disease (PD). The disease control rate was 41.2% (95% CI: 24.7% to 59.3%). The median PFS was 2.7 months (95% CI: 2.3 to 5.4 months), and median OS was 9.9 months (95% CI: 4.5 to 33.7 months).ConclusionOur results demonstrate promising data in precision medicine in real community oncology practice. It warrants further large and prospective studies in patients with actionable alterations.