Median Dose Intensity Research Articles

Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

AbstractThe multicenter, prospective phase 2 Australasian Leukaemia & Lymphoma Group NHL29 trial was conducted to assess the addition of ibrutinib to R-mini-CHOP (dose attenuated R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients aged ≥75 years with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Treatment consisted of six 21-day cycles of ibrutinib–R-mini-CHOP followed by two 21-day cycles of R-ibrutinib. Coprimary end points were deliverability and 2-year overall survival (OS). The median average relative total dose and average relative dose intensity for the entire regimen were both 97% (interquartile range, 82-100 and 88-100, respectively). With a median follow-up of 35.5 months, the 2-year OS was 68% (95% confidence interval [CI], 55.6-77.4) with a 2-year progression-free survival (PFS) of 60.0% (95% CI, 47.7-70.3). Median OS and PFS were 72 months (95% CI, 35 to not reached) and 40 months (95% CI, 20.4 to not reached), respectively. The overall response rate was 76% (61/79) of patients, with a complete response rate of 71% (56/79). Deaths occurred in 34 of 79 patients (43%), including 17 from progressive disease and 5 treatment related. Overall, 67% patients experienced at least 1 serious adverse event. Most common adverse events were infections and diarrhea (the majority grade 1-2). In both health-related quality of life measures, there was an improvement in functional and symptom scales, median health state classification score, and median visual analogue scale in responders over time. In conclusion, this study showed that the addition of ibrutinib to R-mini-CHOP was both deliverable and efficacious in elderly DLBCL patients.

A lower initial dose of bosutinib for patients with chronic myeloid leukemia patients resistant and/or intolerant to prior therapy: a single-arm, multicenter, phase 2 trial (BOGI trial)

Although bosutinib is generally safe and effective, drug-related toxicities (DRTs) such as diarrhea or increased transaminase levels often lead to treatment discontinuation. To clarify whether a lower initial dose of bosutinib (i.e., starting at 200 mg) would reduce rates of discontinuation due to DRTs, we conducted a phase 2 study of BOsutinib Gradual Increase (BOGI trial, UMIN 000032282) as a second/third-line treatment for chronic myeloid leukemia (CML). Between February 4, 2019 and May 24, 2022, 35 patients were enrolled. The rate of bosutinib discontinuation at 12 months was 25.7% vs. 35.9% in a historical control study (Japanese phase 1/2 study) (p = 0.102). The rate of bosutinib discontinuation due to DRTs was significantly lower, at 11.4% vs. 28.2% (p = 0.015). The incidence of grade 3/4 transaminase elevation was 20% vs. 29% (p = 0.427), while the incidence of diarrhea was 3% vs. 25% (p = 0.009). The median dose intensity of bosutinib was higher (391.7 mg/day vs. 353.9 mg/day). Pharmacokinetic analysis of bosutinib showed that patients who achieved a major molecular response tended to have high trough concentrations. Thus, a low initial dose of bosutinib followed by dose escalation reduced discontinuation due to severe DRTs while maintaining high dose intensity and efficacy.

Sequential high-dose methotrexate and cytarabine administration improves outcomes in real-world patients with primary central nervous system lymphoma: A report from the Australasian Lymphoma Alliance.

Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined. We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) (n=94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) (n=19, 10%), HD-MTX/Ara-C (n=31, 16%), HD-MTX monotherapy (n=35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) (n=11, 6%). Cumulative median HD-MTX and Ara-C doses were 17g/m2 (range: 1-64g/m2) and 12g/m2 (0-32g/m2) respectively. Using 14g/m2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving>0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p=0.0001 and p=0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI>0.75 were associated with longer PFS and OS. Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Clinical prognostic factors to guide treatment strategy for HPV‑positive oropharyngeal cancer using treatment outcomes of induction chemotherapy: A real‑world experience.

The role of induction chemotherapy (IC) in locally advanced oropharyngeal cancer (OPC) remains debatable, and suitable candidates for de-escalation treatment in these patients have not been fully identified. Therefore, the present study aimed to identify high-risk candidates for human papillomavirus (HPV)-positive OPC by analyzing patients who underwent IC followed by chemoradiotherapy (CRT) to guide optimal treatment strategies. Patients diagnosed with stage III-IVA OPC and treated with a minimum of two cycles of IC followed by CRT, between 2004 and 2020, were retrospectively reviewed. All the patients were restaged according to the American Joint Committee on Cancer, 8th edition. The overall response rate and survival outcomes associated with clinical factors based on HPV status were analyzed using univariate and multivariate analyses. The present study analyzed 105 patients with a median age of 60 years (range, 40-76 years). Among 105 patients, 40 (38.1%) were HPV-negative and 65 (61.9%) HPV-positive. In all patients, survival outcomes were notably poorer in patients aged ≥60 years (P=0.006) and those who did not achieve complete response post-CRT (P<0.001), irrespective of the HPV status. The median relative dose intensity of IC was ≥80%, indicating adequate treatment, regardless of age. In contrast to patients with HPV-negative OPC, age ≥60 years (P=0.011) and T4 stage (P=0.019) emerged as substantial poor prognostic factors for survival outcomes in patients with HPV-positive OPC. Patients with HPV-positive OPC were categorized into three groups based on the number of clinical factors at diagnosis (such as age and T4 stage). The progression-free and overall survival showed significant stratification across each group as the number of high-risk factors increased despite IC and CRT. The findings indicated that patients with these high-risk factors require a cautious therapeutic strategy even when they are diagnosed with HPV-positive OPC, and the role of combined modality, including IC, will need to be investigated in a randomized trial to be routinely incorporated into clinical practice.

Tolerability, dose intensity, and prescribing patterns of capecitabine by race.

e23278 Background: Capecitabine (cap) is approved for the treatment of breast and colorectal cancer and is used off-label to treat other solid malignancies. Approved dosing varies by indication and concurrent therapies, and the initial dose of cap may be modified empirically based on different patient characteristics. Race/ethnicity have been used by some providers as factors in prescribing patterns. However, the tolerability of cap among patients of different racial/ethnic backgrounds is unknown. Here, we present an updated analysis outlining the tolerability of cap among patients of different racial/ethnic groups. Methods: We performed a retrospective, multicenter study that included patients treated with cap monotherapy, concurrent with other chemotherapy, or concurrent with radiation at three sites in Massachusetts between 2017-2021. Patients were excluded if race/ethnicity data were not available. Data on cap dose, required dose reductions/treatment discontinuation, and adverse events (AE) were collected. Dose Intensity (DI) was calculated (Total administered cap dose during the treatment period (mg)/Recommended cap dose (mg/m2)*BSA (m2)). DI was compared across groups using non-parametric Kruskal-Wallis tests. The frequency of AE leading to dose reduction/discontinuation was compared across groups using chi-square tests. Results: 239 patients were included as outlined in Table 1. Median DI (IQR) for White patients was 0.95 (0.77,1.00), for Asian patients 1.00 (0.86,1.00), for Black/African American patients 0.88 (0.67,1.00), and for patients of other race 1.00 (0.79,1.00). There was no statistically significant difference across racial groups (p = 0.233). Median DI (IQR) for Hispanic/Latino patients was 0.84 (0.73,1.00) and for non-Hispanic/Latino patients 0.96 (0.77,1.00). There was no statistically significant difference between ethnicity groups (p = 0.562). The most commonly experienced AE included Hand Foot Syndrome, Fatigue, Diarrhea, and Nausea/Vomiting (Table 1). There was no statistically significant difference in AE frequency between groups. Conclusions: Our study shows no significant difference in the tolerability of cap between patients of different racial/ethnic groups, nor did we find any difference in the predominant AE. While this study is limited by the fact that it is retrospective and small, the results reinforce the importance of considering the entire clinical context when selecting a treatment dose and avoiding empiric dose reductions based on factors such as race/ethnicity. [Table: see text]

Effect of nivolumab combined with definitive chemoradiotherapy on response rate for esophageal cancer: An immune active intrinsic subtype could be its biomarker—The NOBEL trial.

4068 Background: The usefulness of combined therapy with immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) and its potential biomarker of treatment efficacy for esophageal cancer remains unclear. We investigated the safety, efficacy, and associated biomarkers of combined therapy with ICI and definitive CRT in operable and inoperable esophageal squamous cell carcinoma (ESCC). Methods: This prospective single-arm phase 2 trial was performed at five hospitals in Japan. Patients aged 20–75 years with histologically confirmed ESCC, an ECOG PS score of 0 or 1, and adequate organ and bone marrow functions were eligible. Inoperable patients did not have distant organ metastasis. Patients did not receive any chemotherapy or surgical resection as an initial therapy. Concurrent radiotherapy (50.4 Gy/28 fractions to the primary lesion and 41.4 Gy/23 fractions to the regional LN area) consisted of 4 courses of CF (cisplatin, 75 mg/m2/day, day 1; 5-fluorouracil, 1000 mg/m2/day, days 1–4) plus nivolumab (240 mg/m2/day, every 2 weeks for up to 1 year). The primary endpoint was safety. The incidence rates of nonhematological toxicity grade ≥ 4 and pneumonitis grade ≥ 3 were ≤10% and ≤15%, respectively. The secondary endpoints included overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and time to esophagectomy-free survival (EFS). Sixty patients were to be accrued, but the trial enrollment was terminated because of slow accrual. This trial was registered as jRCT1091220408. Results: Between January 2019 and September 2021, 42 patients were enrolled. Twenty-five patients had operable disease and 16 had inoperable disease. Two patients (4.8%) experienced grade 3 pneumonitis, suggesting that the primary endpoint was met. The median relative dose intensity of nivolumab was 92.4%. One-year OS, PFS, and EFS rates in all cases were 92.7%, 65.4%, and 78.0%, respectively. One-year OS, PFS, and EFS rates in operable and inoperable cases were 100%, 79.6%, and 84.0% and 81.3%, 43.8%, and 68.8%, respectively. The CR and objective response rates were 73.2% (95% confidence interval [CI]: 58.1%–84.3%) and 87.8% (95% CI: 74.5%–94.7%), respectively. The CR rates in operable and inoperable cases were 84% (95% CI: 65.3%–93.6%) and 56.3% (95% CI: 33.2%–76.9%), respectively. Immune high-active intrinsic subtype before treatment (n=4) with an expression score &gt; 80 of 51 immune-related genes showed a high CR rate (100%, n=4), whereas the immune low-active intrinsic subtype (n=37) with an expression score &lt; 80 showed a relatively high CR rate (70%). Conclusions: Nivolumab combined with definitive CRT provided encouraging efficacy and acceptable toxicity in patients with ESCC. Immune high-active intrinsic subtype before treatment has the potential to predict a high CR rate for this combination treatment. Clinical trial information: jRCT1091220408 .

Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin for locally advanced resectable esophageal squamous cell carcinoma: A prospective phase 2 study.

e16097 Background: Whether combined immunotherapy on the basis of neoadjuvant chemotherapy is beneficial for locally advanced esophageal squamous cell carcinoma (ESCC) remain to be inconclusive. This phase 2 study (ChineseClinical Trial Registry: ChiCTR2000041081) evaluate the efficacy and safety of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin in locally advanced ESCC. Methods: Patients with locally advanced ESCC (T2N+M0, T3N0-2M0, T4aN0-2M0, or no distant metastases, or viable or potentially viable) were enrolled and received 3 cycles of neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin. Surgery was scheduled within four to six weeks of completing the neoadjuvant treatment. Three additional cycles of adjuvant sintilimab monotherapy or sintilimab plus chemotherapy were scheduled after a multidisciplinary discussion. The primary endpoint was the MPR rate. Results: From November 2020 to November 2021, twenty-four patients (median age: 64.5 years, men: 21/24,lower segment tumor location12/24,stage IV disease 15/24) were included in this study. All patients completed three cycles of neoadjuvant treatment and surgery. The median dose intensities for sintilimab, carboplatin and albumin-bound paclitaxel were 100% (range, 66.7–105.0%), 98.4% (range, 64.1–104.0%), and 100% (range, 38.1–105.8%), respectively. The R0 resection rate was 100%. The pCR rate and MPR rate was 33.3% and 41.7%. Among the 10 patients with PD-L1 CPS of ≥1, the pCR and MPR rates were 40% and 50%. 20 (83.1%) had TNM downstaging. The median DFS and median OS had not been reached yet, 500 days DFS and OS rate was 85.3% (95%CI 85.4%-97.2%) and 94.1% (95%CI 94.8%-100.0%). PD-L1 protein expression showed a higher life expectancy trend in the post-neoadjuvant therapy esophageal tissue samples than in the pre-therapy samples. The most common grade 3-4 treatment-related adverse events were anemia (29.2%), increased gamma-glutamyl transferase level (4.2%) and hyponatremia (4.2%). Emergency reoperation and intensive care were not required, and there were no postoperative mortalities. Conclusions: Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin preliminarily demonstrate encouraging clinical benefits and acceptable safety. Preoperative immunotherapy combined with chemotherapy alters the immune microenvironment of locally advanced resectable ESCC. Clinical trial information: ChiCTR2000041081.

Association between albumin–bilirubin grade and plasma trough concentrations of regorafenib and its metabolites M-2 and M-5 at steady-state in Japanese patients

SummaryThe aim of the present study was to determine whether the trough plasma concentrations (C0) of regorafenib and its metabolites, the N-oxide metabolite (M-2) and the desmethyl N-oxide metabolite (M-5), in 21 patients receiving regorafenib therapy were affected by albumin-bilirubin (ALBI) grade. Regorafenib was administered at dosages ranging from 40 to 160 mg once daily on a 3-week-on, 1-week-off cycle. C0 values of regorafenib and its major metabolites were measured by high-performance liquid chromatography on day 8 after treatment initiation. The C0 values of regorafenib and metabolites M-2 and M-5 were significantly lower in patients with ALBI grade 2 as compared with grade 1 (P = 0.023, 0.003 and 0.017, respectively). The total C0 of regorafenib and its metabolites was significantly higher in ALBI grade 1 patients relative to grade 2 (3.489 μg/mL vs. 1.48 μg/mL; P = 0.009). The median relative dose intensity (RDI) of patients categorized as ALBI grade 2 was significantly lower than that of grade 1 patients (21.9% vs. 62.9%; P = 0.006). In 15 colorectal cancer patients among the total 21 patients, patients with ALBI grade 2 (n = 9) had a significantly shorter median overall survival time than patients with grade 1 (n = 6; P = 0.013). Administering a low dose of regorafenib to patients with ALBI grade 2 reduces the RDI of regorafenib and lowers treatment efficacy, as an appropriate C0 of regorafenib is not maintained. Monitoring the C0 of regorafenib regularly is necessary to guide dose adjustment.

The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia.

Polymorphisms in NUDT15 may result in differences in mercaptopurine-induced toxicity. This study aimed to identify the frequency of the NUDT15 (c.415C>T; rs116855232) polymorphism and investigate the effect of this polymorphism on mercaptopurine-induced toxicity in a population of Syrian patients with childhood acute lymphoblastic leukemia (ALL). This is a retrospective study that included children with ALL reaching at least 6 months of maintenance therapy. The NUDT15 genotyping was determined using standard targeted sequencing of polymerase chain reaction products. The odds ratio (OR) for the association between toxicity and genotype was evaluated. A total of 92 patients were enrolled. The majority of the patients in the study population were low-risk (63.04%), followed by intermediate-risk (25%), and high-risk (11.96%). There were 5 patients (5.4%) with NUDT15 (c.415C>T; rs116855232) CT genotype, and 1 patient (1.08%) with NUDT15 TT genotype, with allele frequencies of C=0.962 and T=0.038. The mercaptopurine median dose intensity was 100%, 54.69%, and 5% for the genotypes CC, CT, and TT, respectively (P=0.009). Early onset leukopenia was significantly associated with the NUDT15 polymorphism (OR: 6.16, 95% CI: 1.11-34.18, P=0.037). There was no association between the NUDT15 genotype and hepatotoxicity. Approximately 6.5% of the study population exhibited reduced NUDT15 activity. The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.

Safety and Efficacy of Gemcitabine Plus Cisplatin Against Recurrent/Metastatic Nasopharyngeal Carcinoma: A Retrospective Study.

Although gemcitabine plus cisplatin (GC) prolongs survival in patients with recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) compared with fluorouracil plus cisplatin, no study has evaluated the efficacy and safety of GC in nonendemic regions, including Japan, yet. Therefore, we assessed the safety and efficacy of GC in Japanese patients with R/M NPC. We retrospectively reviewed patients with R/M NPC who received GC treatment at the Aichi Cancer Center Hospital from January 2017 to March 2020. The main eligibility criteria were histologically confirmed NPC, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-2, and locally recurrent disease unsuitable for local treatment or metastatic disease. The regimen was administered every 3 weeks (gemcitabine, 1,000 mg/m2 on days 1 and 8; cisplatin, 80 mg/m2 on day 1). Fourteen patients (median age, 58 years) were included in the study. Two patients had an ECOG PS of 2 and 11 exhibited nonkeratinizing histology. Of the eight patients with measurable lesions, one exhibited complete response and seven exhibited partial response, with an objective response rate of 75%. Median progression-free survival and overall survival were 7.7 and 24.2 months, respectively. Common grade 3 or 4 adverse events included neutropenia (64%), thrombocytopenia (14%), and febrile neutropenia (14%). The median relative dose intensity of gemcitabine and cisplatin was 62% and 60%, respectively. No treatment-related deaths occurred. The GC regimen demonstrates promising activity and is tolerable in Japanese patients with R/M NPC.

HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first line treatment.

647 Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs patient’s quality of life. In other gastrointestinal cancer, infusion pump free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen by its convenience. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for metastataic pancreatic cancer. Methods: HGCSG1803 study has conducted as a multicenter, non-randomized, single arm, phase II study in Japan. The chemotherapy-naïve patients with metastatic pancreatic cancer were eligible. S-1 (40 mg/m2) orally intake twice daily for 14-day followed by a 14-day rest, and intravenous 65 mg/m2 of L-OHP and 100 mg/m2 of IRI on day 1 and day 15 every four weeks were continued until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by RECIST ver1.1, with a threshold of 10% and an expected value of 30%. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. Results: Between Jan 2020 and May 2022, forty patients were enrolled and 39 patients were included in full analysis set (one patient were excluded because of consent withdrawal). Median age was 66 (range, 41-75), female/male were 16/23, ECOG PS 0/1; 32/7, UGT1A1 wild /heterozygous for *6 or *28 allele 27/12, liver/lung/peritoneal metastasis 28/9/11, respectively. The median relative dose intensities of S-1, irinotecan, and oxaliplatin were 76%, 72%, and 70%, respectively. Objective response rate and disease control rate were 43.6% (95%CI 27.8-60.4%) and 76.9% (95%CI 60.4-89.1%), respectively. In the median follow-up time was 13.7 months, median progression free survival and overall survival were 4.3 months (95%CI 2.5-6.2 months) and 11.1 months (95%CI 7.2-14.9 months), respectively. Four patients discontinued protocol therapy due to adverse events (AE) without disease progression. Grade 3 or higher AE that occurred in more than 5% of patients were leucopenia (21%), hypokalemia (21%), neutropenia (18%), anemia (15%), hyponatremia (15%), ALT elevation (10%), anorexia (8%), nausea (5%), and febrile neutropenia (5%). One patient died due to protocol therapy (drug induced pneumonitis). Conclusions: OX-IRIS showed high response rate with manageable safety, and the primary endpoint was met. This new triplet regimen could be a useful first line treatment option for patients with metastatic pancreatic cancer. Clinical trial information: jRCTs011190008 .

Niraparib in Japanese patients with heavily pretreated, homologous recombination-deficient ovarian cancer: final results of a multicenter phase 2 study.

To evaluate the long-term efficacy and safety of niraparib in Japanese women with heavily pretreated ovarian cancer. This was the follow-up analysis of a phase 2, multicenter, open-label, single-arm study in Japanese women with homologous recombination-deficient, platinum-sensitive, relapsed, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed 3-4 lines of chemotherapy and were poly(ADP-ribose) polymerase inhibitor naïve. Participants received niraparib (starting dose, 300 mg) once daily in continuous 28-day cycles until objective disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was confirmed objective response rate (ORR), as assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Safety evaluations included treatment-emergent adverse events (TEAEs). 20 patients were enrolled in the study and included in both efficacy and safety analyses. Median total study duration was 759.5 days. Median dose intensity was 201.3 mg/day. Confirmed ORR was 60.0% (90% confidence interval [CI]=39.4-78.3); 2 patients had complete response and 10 patients had partial response. Median duration of response was 9.9 months (95% CI=3.9-26.9) and the disease control rate was 90.0% (95% CI=68.3-98.8). The most common TEAEs were anemia (n=15), nausea (n=12), and decreased platelet count (n=11). TEAEs leading to study drug dose reduction, interruption, or discontinuation were reported in 16 (80.0%), 15 (75.0%), and 2 patients (10.0%), respectively. The long-term efficacy and safety profile of niraparib was consistent with previous findings in the equivalent population in non-Japanese patients. No new safety signals were identified. ClinicalTrials.gov Identifier: NCT03759600.

Feasibility of S-1 adjuvant chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202

IntroductionMajor hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. Materials and methodsOf the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. ResultsIn the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 104/mm3, p < 0.0001) and lower serum albumin level (3.5 vs. 3.8 g/dL, p < 0.0001). The treatment completion proportion tended to be lower for MH than for NMH (59.5 % vs. 75.8 %; risk ratio, 0.786 [95 % confidence interval, 0.603–1.023], p = 0.0733), and the median dose intensity was lower as well (88.7 % vs. 99.6 %, p = 0.0358). The major reasons for discontinuation were biliary tract infections and gastrointestinal disorders after MH. The frequency of grade 3–4 biliary tract infection was 19.0 % in MH vs. 4.2 % in NMH. ConclusionThe treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.

Safety of Elranatamab in Patients with Triple-Class Refractory Relapsed/Refractory Multiple Myeloma (RRMM) in Magnetismm-17, a North American Expanded Access Protocol

BACKGROUND In the phase 2, registrational MagnetisMM-3 (NCT04649359) trial, patients with RRMM who had not previously received a B cell maturation antigen (BCMA)-directed therapy (n=123) achieved an objective response rate of 61% with single-agent elranatamab (ELRA), a BCMA-CD3 bispecific antibody. Common treatment-emergent adverse events (TEAEs) included infections (70%; 40% grade [G] 3/4) and CRS (58%; all G1/2). Here we report on the safety of ELRA in the MagnetisMM-17 (MM-17; NCT05462639) trial, a North American Expanded Access Protocol (EAP). METHODS MM-17 is an ongoing, single-arm, open-label study for patients with triple-class refractory RRMM (refractory to ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody), and who had no prior BCMA-directed therapy. Patients must be ≥18 years of age and have a confirmed diagnosis of MM, measurable disease by IMWG criteria, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, adequate organ function, and no active, uncontrolled infection. The study is being conducted in the US and Canada. The primary objective is to provide access to ELRA for patients with RRMM and no access to comparable/alternative therapy. The secondary objective is to evaluate the safety and tolerability of ELRA. Patients received subcutaneous ELRA 76 mg once every week on a 28-day cycle after step-up doses of 12 and 32 mg during week 1. Dose frequency was reduced to once every 2 weeks (Q2W) after ≥6 cycles in patients with persistent response (≥partial response), and then from Q2W to Q4W after ≥6 Q2W cycles. Patients received ELRA until disease progression, unacceptable toxicity, withdrawal of consent, study termination, or ELRA becomes commercially available. TEAEs were graded by NCI CTCAE v5.0, except cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded according to the American Society for Transplantation and Cellular Therapy criteria (ASTCT). RESULTS As of April 28, 2023, 20 patients had enrolled in the trial. Median patient age was 72.5 years (range 53-82); 50% male, 85% white, and 15% Black/African American. At baseline, most patients had an ECOG PS of 1 (95%), and 40% had R-ISS disease stage III. Patients had a median of 4 prior lines of therapy (range 2-8); 95% and 35% of patients had triple-class and penta-drug refractory disease, respectively. At the time of data cut-off, 2 patients had discontinued due to progressive disease. Median treatment duration was 0.95 months (range 0.26-2.83); median relative dose intensity was 98.3% (range 48-105). TEAEs were reported in all 20 patients, with G3 or G4 events reported in 13 (65%). There were no G5 events. Thirteen (65%) patients developed CRS, all events were G1 (50%) or G2 (15%); no events G ≥3 were reported. After the first step-up dose, 11 (55%) patients had a CRS event. CRS events occurred in 3 patients (15%) and 1 patient (5%) after the second step-up dose and first treatment dose, respectively. The median time to onset was 2 days (range 1-4), and the median time to resolution was 3 days (range 1-5). ICANS occurred in 2 of the 20 patients (10%), both events were G1, with 1 occurring after the first step-up dose and the other after the second step-up dose. The median time to onset was 3 days (range 3-3) and the median time to resolution was 2.5 days (range 2-3). Four (20%) patients had infections, including 1 event each of G1 sinusitis, G2 acute sinusitis, G2 folliculitis, G2 upper respiratory tract infection and G3 bacterial conjunctivitis. Cytopenias were reported in 11 (55%) patients. The most common (occurring in ≥3 [15%] patients) cytopenias were neutropenia (30%; G3/4 25%), lymphopenia (20%; G3/4 15%), and thrombocytopenia (15%; G3/4 10%). CONCLUSIONS Early safety data (median treatment duration &amp;lt;1 month) from this ongoing expanded access protocol of elranatamab in patients with RRMM are consistent with results from the phase 2, registrational MagnetisMM-3 trial, with no new safety signal identified.

Efficacy, Safety, and Survival Findings after Long-Term Follow-up from ZGJAK002, a Phase 2 Study Comparing Jaktinib 100 Mg Twice Daily with 200 Mg Once Daily for Myelofibrosis (MF)

Background: Jaktinib, a novel Janus kinase (JAK) and ACVR1 inhibitor, demonstrated promising clinical benefit with good tolerability, not only efficiently shrinking the spleen and reducing symptom burdens, but also improving anemia, in JAK-inhibitor naïve, ruxolitinib-intolerant or -resistant MF patients. We conducted a phase 2 study (the ZGJAK002 trial) to evaluate the effectiveness and safety of jaktinib at doses of 100 mg BID and 200 mg QD in JAK-inhibitor naïve patients with intermediate or high risk MF. Herein we present long-term data with a median follow-up time of 30.7 months. Methods: Patients who completed the 24 weeks of study treatment, tolerated the drug well, and had evidence of clinically significant improvement were allowed to enter an extension phase. Dose modifications were permitted according to the platelet count and neutrophil count. Duration of spleen response (from the first spleen volume reduction of ≥35% [SVR35] to an increase of 25% or more from the nadir), overall survival (OS), and leukemia-free survival (LFS) were evaluated in an intent-to-treat analysis using a Cox proportional hazard model that estimated the treatment effect. Results: A total of 118 patients were enrolled and treated with either jaktinib 100 mg BID (n=66) or 200 mg QD (n=52). The majority of patients remained on treatment after 48 weeks (100 mg BID group: 74.2%; 200 mg QD group: 65.4%). At the data cutoff of June 30, 2022, treatment was continued in 35 (29.7%) patients (30.3% in BID; 28.8% in QD). The best spleen response, defined as SVR35 at any time, was achieved by 59.3% (95% confidence interval [CI]: 49.9%-68.3%) of patients. The 100 mg BID group demonstrated a greater best spleen response (69.7% [95% CI: 57.1%-80.4%]) compared to the 200 mg QD group (46.2% [95% CI: 32.2%-60.5%]). The median maximum reduction from baseline in spleen volume was 49.7%. The median duration of spleen response was not reached, with 51.9% (95% CI: 36.0%-65.7%) of patients from 100 mg BID and 66.5% (95% CI: 41.4%-82.8%) from 200 mg QD maintaining a spleen response for over 108 weeks (Figure 1). The proportion of patients who achieved an improvement of ≥50% in the TSS (TSS50) was 69.6% (95% CI: 55.9%-81.2%) at week 24 and 74.2% (95% CI: 55.4%-88.1%) at week 108 in the 100 mg BID group. The proportion of patients who achieved TSS50 was 57.5% (95% CI: 40.9%-73.0%) at week 24 and 66.7% (95% CI: 44.7%-84.4%) at week 108 in the 200 mg QD group. As of the data cutoff, 25 (21.2%) deaths were reported (12 [18.2%] of 66 in the 100 mg BID group and 13 [25.0%] of 52 patients in the 200 mg QD group). Median OS was not reached, with 12, 24, and 36-month survival rates of 92.3%, 85.8%, and 78.2% in the 100 mg BID and 92.3%, 78.0%, and 73.6% in 200 mg QD groups. Median LFS was not reached, with 12, 24, and 36-month LFS rates of 94.8%, 90.6%, and 84.1% in the 100 mg BID and 95.5%, 85.7%, and 85.7% in 200 mg QD groups. The 100 mg BID induced more increase from baseline in hemoglobin concentration over 144 weeks with a range of 2.18-10.17 g/L compared to -1.74-1.96 g/L with 200 mg QD. The median (range) duration of jaktinib exposure was 672.0 (14-1262) days in the 100 mg BID group and 588.5 (42-1175) days in the 200 mg QD group. The median relative dose intensity for jaktinib was 97.5% (98.1% in BID; 96.3% in QD). There was no unexpected increased incidence of adverse events (AEs) with longer exposure. The most common grade ≥3 adverse drug reactions were anemia (15.2% vs. 21.2%), thrombocytopenia (15.2% vs. 11.5%), and infectious pneumonia (10.6% vs. 1.9%) in the 100 mg BID and 200 mg QD groups, respectively. Notably, infectious pneumonia (10.6%), thrombocytopenia (4.5%), and peripheral neuropathy (3.0%) were the most common drug-related serious AEs. AEs leading to treatment discontinuation occurred in 14 patients (11.9%), with higher rate in the 100 mg BID group compared to the 200 mg QD group (15.2% vs. 7.7%). AEs resulted in death in seven (5.9%) patients, with similar rates in both groups (6.1% in BID; 5.8% in QD). Conclusions: With over 30-month follow-up, jaktinib at doses of 100 mg BID and 200 mg QD demonstrated durable high effective rates and improved survival rates without new safety issue. The long-term data further supports the recommendation of 100 mg BID over 200 mg QD administration. It also concluded that jaktinib remains the treatment strategy that offers excellent chances for improving survival in MF patients.

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (&amp;gt;5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL). Recent clinical studies have evaluated the safety and efficacy of fixed-duration regimens with venetoclax and cBTKi. While these combinations are effective, their use may be limited by toxicity. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has shown promising safety and efficacy in heavily pretreated relapsed or refractory (R/R) CLL patients (pts). Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts with R/R CLL were eligible for pirtobrutinib combined with venetoclax ± rituximab in the phase 1b portion of the multicenter phase 1/2 BRUIN study (NCT03740529). Prior cBTKi therapy was allowed, but not prior venetoclax. Pts were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. Pirtobrutinib 200 mg QD was started on cycle 1 day 1, and venetoclax was started on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg QD target dose. PV was given for up to 24 cycles; each cycle was 28 days. For the PVR cohort, rituximab was given at 375 mg/m 2 on cycle 1 day 1 and then 500 mg/m 2 on day 1 of cycles 2-6. The primary endpoint was safety as assessed by treatment-emergent adverse events (TEAEs) graded according to CTCAE v5.0. Other key endpoints included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10,000 nucleated cells (&amp;lt;1x10 -4) in peripheral blood by ClonoSEQ® assay (Adaptive Biotechnologies, Seattle, WA). A data cut of May 5, 2023, was utilized. Results: Fifteen pts received PV, and 10 received PVR. Median age was 66 years (range, 49-77) for those who received PV and 69 (range, 39-78) for those who received PVR. Median prior lines of therapy was 1 (range, 1-2) for the PV cohort and 2 (range 1-4) for the PVR cohort. Most pts had received prior chemotherapy (PV=53%; PVR=60%), CD20 monoclonal antibody (73%; 70%), and cBTKi (73%; 60%). The majority of pts had IGHV unmutated CLL (PV=73%; PVR=89%). ORR was 93.3% (95% CI, 68.1-99.8) for the 15 pts receiving PV and 100% (95% CI, 69.2-100.0) for the 10 pts receiving PVR, with 10 complete responses (PV=7; PVR=3). Median duration of follow-up for PFS was 22.1 months (IQR, 20.1-25.7) for PV and 22.1 months (IQR, 20.7-22.1) for PVR; PFS at 18 months was 92.9% (95% CI, 59.1-99.0) for the 15 pts receiving PV and 80.0% (95% CI, 40.9-94.6) for the 10 pts receiving PVR. The overall uMRD rate at cycle 13 was 70.8% (PV=10; PVR=7) for the 24 evaluable pts, with 87.5% (PV=12; PVR=9) of pts achieving uMRD at some time during the trial and all but one pt sustaining uMRD during subsequent MRD assessments ( Figure). Twenty-two pts discontinued treatment (PV=14; PVR=8); of these, 14 completed all 24 cycles of therapy (PV=9; PVR=5) and 8 discontinued early because of progressive disease (PV=2), adverse events (PVR=2), protocol noncompliance (PV=1), death unrelated to treatment (PVR=1), or other reasons (PV=2). Three pts (PV=1; PVR=2) continue to receive treatment. The median relative dose intensity was similar in both cohorts (PV=97.9%; PVR=98.6%). The most common TEAE of any grade included nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%). The most common grade ≥3 TEAE was neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome occurred during venetoclax dose escalation (PV=2), including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids. Treatment-related adverse events led to dose reductions in three pts (PV=1; PVR=2) and treatment discontinuation in two pts (PVR=2). Conclusions: Fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and demonstrated sufficiently promising efficacy to warrant further investigation in pts with R/R CLL. The BRUIN CLL-322 phase 3 trial comparing PVR vs VR in previously treated CLL is currently enrolling pts (NCT04965493).

Golcadomide (GOLCA; CC-99282), a Novel CELMoD Agent, Plus R-CHOP in Patients (pts) with Previously Untreated Aggressive B-Cell Lymphoma (a-BCL): Safety and Efficacy Results from Phase 1b Dose Expansion

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was &amp;gt; 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Golidocitinib in Treating Refractory or Relapsed Peripheral T- Cell Lymphoma: Full Analysis of the Multinational Pivotal Study Results (JACKPOT8)

Introduction: Golidocitinib is the first JAK1 selective inhibitor to enter into pivotal clinical development for the treatment of relapsed/refractory peripheral T cell lymphoma (r/r PTCL). Preliminary analysis of the JACKPOT8 study (NCT04105010) has shown promising antitumor efficacy and a manageable safety profile of golidocitinib. Here we reported the full analysis of the phase 2 multinational pivotal study JACKPOT8 Part B. Methods: This study enrolled r/r PTCL patients who had undergone at least one line of systemic therapies. All patients received golidocitinib at 150 mg once daily (QD) until disease progression or pre-defined discontinuation criteria were met. The primary endpoint was a CT-based objective response rate (ORR) assessed by an independent review committee (IRC) per Lugano 2014 criteria. Other efficacy endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). The efficacy analysis set included patients whose pathological diagnosis of PTCL has been retrospectively confirmed by a central laboratory and who had at least one measurable lesion at the baseline assessed by IRC. The safety analysis set included all dosed patients. Results: A total of 88 efficacy evaluable patients with r/r PTCL were included in the analysis. The median age was 57.5 years, and the majority (64.8%) were male. The major pathological subtypes included PTCL NOS (56.8%), AITL (18.2%), and ALCL (11.4%). At the baseline, 54.5% of patients had ECOG PS of 1, 52.3% had elevated LDH levels, and 21.6% had bone marrow involvement. The median prior lines of therapies were two. All patients had been treated with chemotherapies, 50% had been treated with histone deacetylase inhibitors, and 10.2% had received CD30 targeted therapy. Per IRC assessment based on CT imaging, 39 patients achieved tumor response, with an ORR of 44.3% (95% CI: 33.7%, 55.3%), and 26 patients (29.5%) achieved complete response. The primary endpoint met the pre-defined target with statistical significance ( p &amp;lt; 0.0001). Tumor response was observed in various subtypes, irrespective of age, gender, baseline bone marrow involvement, and ECOG PS. With a median follow-up time of 10.4 months for DoR, 59% of responders were still event-free. The median DoR has not been reached, with an estimated 12-month DoR rate of 70.2%. With a median follow-up time of 9.6 months for PFS, the median PFS was 5.6 months. The longest PFS was 20 months, and the patient was still responding. Per investigator assessment, 34 patients achieved tumor response (ORR: 38.6%). The DoR and PFS by investigator assessment were similar to that of IRC assessed results. With a median follow-up time of 15.1 months for OS, approximately 60% of patients were still alive, with an estimated median OS of 19.2 months. A total of 112 patients were included in the safety analysis set. The median relative dose intensity was 100%. A total of 62 patients (55.4%) reported ≥ grade 3 treatment-emergent adverse events (TEAEs). The most common drug-related ≥ grade 3 TEAEs were hematological adverse events in nature, including neutropenia (25%), leukopenia (23.2%), and lymphopenia (18.8%). The majority of TEAEs were reversible and clinically manageable. Treatment-related AEs leading to dose interruption, reduction, and discontinuation were reported in 36.6%, 7.1%, and 8% of patients, respectively. Conclusions: This pivotal study met its primary objective, suggesting golidocitinib can be an effective treatment option with a manageable safety profile for patients with r/r PTCL. The updated data will be presented at the conference.

30-Minute Infusion of Isatuximab in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Results of a Phase 1b Study

Introduction: The anti-CD38 antibody isatuximab (Isa) is approved in various countries with pomalidomide-dexamethasone for relapsed/refractory multiple myeloma (RRMM) patients (pts) with ≥2 prior therapies including lenalidomide and a proteasome inhibitor, based on the ICARIA-MM study, and with carfilzomib-dexamethasone for RRMM pts with ≥1 prior therapy, based on the IKEMA study. To enhance convenience of intravenous (IV) Isa administration, a shorter IV infusion over 30 minutes (30-min) was assessed in pts with NDMM not eligible/with no immediate intent for autologous stem cell transplantation (ASCT) still on maintenance therapy in a Phase 1b trial (NCT02513186). Results previously reported from this study showed efficacy of treatment with Isa in combination with bortezomib-cyclophosphamide-dexamethasone (VCd) or bortezomib-lenalidomide-dexamethasone (VRd), with manageable safety profiles. The rates of very good partial response or better and of minimal residual disease negativity (at 10 -5 sensitivity) were 80% and 53.3% with Isa-VCd, and 92.9% and 50.7%, respectively, with Isa-VRd [Ocio EM et al. HemaSphere 2023;7(2):e829; Ocio EM et al. Leukemia 2023;37(7):1521-1529]. Preliminary results with the new 30-min Isa administration method are presented here. Methods: Pts still receiving maintenance treatment were to be switched to the 30-min infusion with Isa at 10 mg/kg diluted in a 250 mL infusion bag of 0.9% sodium chloride. The infusion rate of the first infusion was 250 mL/hr; in the absence of infusion reactions (IRs), subsequent infusions were to be administered at an infusion rate of 500 mL/hr. The objective was to evaluate safety in terms of incidence and severity of IRs during the first 2 full 30-min infusions. The initial, recommended premedication to be given at the time of the switch consisted of dexamethasone 20 mg orally (PO) (or equivalent [eq.]), acetaminophen (paracetamol) 650 to 1000 mg PO; ranitidine 50 mg IV (or eq.), diphenhydramine 25 to 50 mg IV (or eq.), and montelukast 10 mg PO (or eq.). Prior to switching, pts received weight-based Isa infusion in the VCd cohorts and initially in the VRd Part A cohort, followed by fixed-volume Isa infusion in both VRd Parts A and B (in Part B, at 200 mL/hr from 3 rd infusion, ~75 min with no IRs/interruptions). Results: As of 19 May 2023, 29.4% of pts in Isa-VCd, 48.1% in Isa-VRd Part A, and 60.9% in Isa-VRd Part B were still on treatment. The median follow-up for all pts was 71.1, 55.1, and 38.1 months for the Isa-VCd, Isa-VRd Part A, and Isa-VRd Part B cohorts, with a median duration of exposure of 63.5, 54.1, and 40.8 months, respectively. A total of 45 pts received 142 infusions between Jan 2023 and May 2023: 45 first infusions with intermediate rate and 97 30-min infusions across cohorts, with a median of 3 cycles started by pts (range, 1-5) (44 pts received at least 2 infusions) and a median relative Isa dose intensity of 99.4% (range, 73.7-105.5%). Switching occurred at a median of 46 cycles (range, 38-88) for all treated pts. The median duration of Isa infusion in all treated pts was 32 min, 33 min, and 33 min at the 2 nd, 3 rd, and subsequent infusions, respectively ( Table). 30-min infusion of Isa was well tolerated, with no IRs and no infusion interruptions across cohorts. Conclusions: These preliminary results show that 30-min infusion of Isa is a feasible, well-tolerated, and convenient administration method for pts with multiple myeloma on Isa treatment for several months. The 30-min Isa infusion is currently being assessed from day 1 of cycle 2 in the ongoing Phase 1-2 UMBRELLA trial of Isa with or without dexamethasone in combination with novel agents, conducted in pts with RRMM (NCT04643002). Clinical trial registration: NCT02513186. Funding: Sanofi.