Patient Experienced Grade Research Articles

CTNI-03. DECREASED GROWTH VELOCITY IN A PHASE 1 TRIAL (PNOC014) OF TOVORAFENIB IN PATIENTS WITH RECURRENT OR PROGRESSIVE MAPK-ALTERED TUMORS

Abstract BACKGROUND The mechanisms by which MAPK-targeted agents affect children in active phases of neurocognitive and physical development are poorly understood and hence, may place them at risk, particularly for uncommon patient toxicities that may require longer monitoring or larger patient cohorts to understand the long-term implications. Decreased growth velocity was identified in our investigator-initiated phase 1 trial (NCT03429803) of tovorafenib in relapsed MAPK-altered tumors. METHODS Forty-four patients enrolled from February 2018-October 2021. Toxicity was assessed according to CTCAE version 5 term growth suppression (GS). Patients were also evaluated retrospectively based on age-specific growth velocity norms. Post-pubertal patients (n=14), those with pre-existing growth abnormalities (n=3), and those on drug less than 6 months (n=10) were excluded (total n=27; 61%). Growth velocities for each patient were calculated prior to, on, and after discontinuing treatment as available. RESULTS Our safety database included 17 reported events of GS. Sixteen patients experienced grade 3 GS, defined as growth velocity reduction ≥50% ideally measured over a year compared to baseline. One patient experienced grade 2 GS, defined as reduced growth velocity by 30-49% compared to baseline. Separate retrospective analysis using age-specific growth velocity norms further confirmed that all 17 patients (100%) demonstrated decreased growth velocity compared to age-specific norms following start of treatment regardless of dose (3, 5 and 9 patients at 280, 420 and 530 mg/m2/dose, respectively with a mean dose of 507 mg, range: 220-840 mg). Four of 9 patients on 530 mg/m2 were dose reduced for other reasons and hence treated at 420 mg/m2. In 14/15 patients off drug, growth rates recovered at near normal or normal rates within 12 months of discontinuation. CONCLUSIONS Patients on tovorafenib experience decreased growth velocity, which is recoverable off drug. Long-term monitoring of growth and further preclinical investigations to mitigate this toxicity and understand its effect are warranted.

HLX07 alone or combined with serplulimab, cisplatin and 5-fluorouracil for advanced esophageal squamous cell carcinoma: A phase 2 study.

The combination of anti-PD-1 antibody serplulimab and chemotherapy is considered standard first-line therapy for advanced esophageal squamous cell carcinoma (ESCC), but few later-line treatments are available. Here we evaluated the therapeutic efficacy of the recombinant, humanized anti-EGFR antibody HLX07 when used alone or together with serplulimab and chemotherapy against advanced ESCC. This open-label, non-randomized, two-cohort, phase 2 trial involved patients 18-75 years old with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients who had failed first-line immuno-chemotherapy or at least two lines of other systemic therapy received HLX07 monotherapy intravenously at a dose of 1,000 mg once every 2 weeks (Q2W). Patients with no prior systemic therapy received HLX07 (1,000 mg, day 1) and serplulimab (200 mg, day 1) intravenously Q2W for up to 2 years, concurrently with cisplatin (50 mg/m2, day 1) for up to 8 cycles and 5-fluorouracil (1,200 mg/m2, days 1-2) for up to 12 cycles intravenously Q2W. The primary endpoints were progression-free survival (PFS) and objective response rate (ORR). Overall, 50 patients were enrolled. In the HLX07 monotherapy group, ORR was 15.0% (3/20), and the median PFS was 1.5 months (95% confidence interval [CI], 1.3 to 3.7). The median duration of response was not reached, and the rate of patients showing an objective response lasting at least 6 months was 66.7% (95% CI, 5.4 to 94.5). Two (10.0%, 2/20) patients experienced grade 3-4 treatment-related adverse events (TRAEs), including hypomagnesemia, hypocalcemia, and fatigue. No patient experienced grade 5 TRAEs. In the HLX07 combination group, the ORR was 60.0% (18/30), and the median PFS was 7.8 months (95% CI, 3.3 to 9.1). Fourteen (46.7%, 14/30) patients experienced grade 3-4 TRAEs, and one (3.3%, 1/30) patient died due to serplulimab-related pneumonitis. HLX07 monotherapy and its combination with serplulimab and chemotherapy showed manageable toxicity and promising antitumor activity in patients with recurrent or metastatic ESCC. Randomized controlled trials are warranted to further establish the safety and efficacy of HLX07 against ESCC. This trial was registered at Clinicaltrials.gov (NCT05221658).

Abstract A001: An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer

Abstract Background: Approximately 92% of pancreatic ductal adenocarcinoma (PDAC) harbor activating mutations in the KRAS oncoprotein. Therapeutic targeting of key elements of the MAPK pathway, including RAF, MEK and ERK, have failed to yield clinical benefit in patients with metastatic PDAC. Autophagy is a putative mechanism of resistance to ERK MAPK inhibition. Hydroxychloroquine (HCQ) is an inhibitor of autophagy and functions by inhibiting acidification of lysosomes. LY3214996 is an inhibitor of ERK 1/2 and has shown anti-tumor activity in pre-clinical models of PDAC. In this study, we evaluate the clinical efficacy of LY3214996 alone and in combination with HCQ. Methods: Eligible patients had metastatic PDAC or poorly differentiated carcinoma of the pancreas. Patients had at least one, but no more than two prior lines of systemic therapy. Twelve patients were included in the safety lead-in. One patient experienced grade 3 acute kidney injury and another experienced grade 3 nausea, thus dose level -1 was chosen as the tolerable dose for combination therapy. Patients were randomized in a 1:1 fashion to receive either LY3214996 200mg PO daily + HCQ 600mg PO BID (Arm 1) or LY3214996 400mg PO daily (Arm 2). The primary endpoint was disease control rate (DCR), defined as the proportion of patients with complete responses (CR), partial responses (PR) or stable disease (SD) that persisted for at least 4 months. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). Point estimates and exact binomial 95% confidence interval (CI) were used for binary endpoints and the Kaplan Meier method was used for survival analysis. With 20 subjects in each treatment arm, there is 79% power using a one-sided alpha of 0.1 to differentiate between an unacceptable DCR of 5% and a desirable DCR of 20%. Results: A total of 39 patients met criteria for analysis (20 in Arm 1, 19 in Arm 2). The DCR rate in Arm 1 was 5% and 5.3% in Arm 2. One patient in each arm had SD. No patients achieved a CR or PR. The median PFS was 1.31 months in Arm 1 (95% CI 0.79-1.77) and 1.87 months in Arm 2 (95% CI 1.64-2.36). The median OS was 2.43 months in Arm 1 (95% CI 1.34-5.77) and 4.56 months in Arm 2 (95% CI 3.08-5.67). The most frequently observed toxicities in both arms included nausea, diarrhea, elevated creatine phosphokinase (CPK), anorexia and cytopenias. Exploratory analysis using patient-derived organoids did not show evidence of synergistic anti-tumor activity of LY3214996 in combination with chloroquine. Conclusion: LY3214996 alone or in combination with HCQ did not result in clinically meaningful activity in patients with metastatic pancreatic cancer. Further studies are needed to evaluate optimal strategies for autophagy inhibition, as well as combination strategies with other ERK MAPK targets (i.e., KRAS inhibitors) to fully elucidate the role of autophagy as a driver of resistance to ERK MAPK inhibition. Citation Format: Rishi Surana, Hui Zheng, Junning Wang, Micaela Morgado, Lauren K Brais, Kirsten L Bryant, Ashwin Somasundaram, Colin D Weekes, Bruno Bockorny, Mary Linton B Peters, Andrea J Bullock, Jessica A Zerillo, Ahmed A Rattani, Hanna K Sanoff, Jeffrey W Clark, Aparna R Parikh, Matthew B Yurgelun, Anuj Patel, Robert J Mayer, James M Cleary, Peter C Enzinger, Douglas A Rubinson, Nadine J McCleary, Andrea C Enzinger, Sarah E Slater, Kimmie Ng, Thomas A Abrams, Leah Biller, Srivatsan Raghavan, Joseph D Mancias, Jonathan O Nowak, Andrew J Aguirre, Channing J Der, Brian M Wolpin, Kimberley Perez. An open label, phase II trial of ERK inhibition alone and in combination with autophagy inhibition in patients with metastatic cancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A001.

Salvage stereotactic ablative body radiotherapy after thermal ablation of primary kidney cancer.

To evaluate the effectiveness and safety of salvage stereotactic ablative body radiotherapy (SABR) for recurrent renal cell carcinoma (RCC) after thermal ablation (TA). This study was a multi-institutional retrospective analysis of patients with recurrent RCC following TA who received SABR between 2016 and 2020. The primary study outcome was freedom from local failure, evaluated radiographically based on Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Distant failure, cancer-specific survival (CSS), overall survival (OS), treatment-related toxicity and renal function changes following SABR were the secondary outcomes. The Kaplan-Meier method was used to estimate freedom from local and distant failure, CSS and OS. Seventeen patients with 18 biopsy-confirmed RCCs were included, with a median (interquartile range [IQR]) age at time of SABR of 75.2 (72.6-68.7) years, a median (IQR) tumour size of 3.5 (1.9-4.1) cm and follow-up (reverse Kaplan-Meier method) of 3.36 (95% confidence interval [CI] 1.6-4.1) years. Six of the 17 patients had a solitary kidney. Five patients had failed repeat TA prior to SABR. The median (IQR) time from TA procedure to SABR was 3.03 (1.5-5.1) years. No patient experienced local progression, with a local control rate of 100%. Four patients, two with baseline metastatic disease, experienced distant progression. The distant progression-free survival, CSS and OS at 3 years were 72.1% (95% CI 51.9%-100%), 92.3% (95% CI 78.9%-100%) and 82.1% (95% CI 62.1%-100%), respectively. The median (IQR) glomerular filtration rate before SABR was 58 (40-71) mL/min, and at last follow-up, it was 48 (33-57) mL/min. No patient experienced grade 3+ toxicity or went on to develop end-stage renal disease. The results showed that SABR appears to be an effective and safe salvage strategy in patients with recurrent RCC following TA.

Mecapegfilgrastim for prophylaxis of febrile neutropenia in children and adolescents with rhabdomyosarcoma or Ewing sarcoma: a prospective, single-arm, pilot study

BackgroundThe chemotherapy regimens recommended for both rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) patients are myelosuppressive and can reduce the absolute neutrophil count (ANC) and subsequently increase the risk of febrile neutropenia (FN). However, only a few studies have focused on the efficacy and safety of granulocyte-colony stimulating factor (G-CSF) drugs in pediatric and adolescent patients with RMS and ES. Our objective was to investigate the efficacy and safety of mecapegfilgrastim, a biosimilar of pegfilgrastim, in prophylaxis of FN for pediatric and adolescent patients with RMS or ES.MethodsIn this single-arm, single-center, prospective study, pediatric and adolescent patients with RMS or ES were enrolled to receive either VAC (vincristine, cyclophosphamide, dactinomycin) regimen or VDC (vincristine, cyclophosphamide, doxorubicin) regimen in a 3-week cycle, followed by treatment with mecapegfilgrastim (100 μg/kg, maximum 6 mg) given at 24 h after completing chemotherapy. The primary endpoint was the incidence rate of FN. Secondary endpoints included the incidence rate of grade 4 neutropenia, duration of ANC ≤ 0.5 × 109/L, incidence rate of chemotherapy delay or reduction, use of antibiotics, and safety profile.ResultsIn total, 2 of the 30 (6.7%, 95% CI: 0.82–22.07) patients experienced FN after the first cycle of chemotherapy. Eight (26.7%, 95% CI: 12.28–45.89) patients experienced grade 4 neutropenia after receiving prophylactic mecapegfilgrastim. Eight patients experienced ANC ≤ 0.5 × 109/L with a median duration of 4.5 days; among them, 6 patients reached the lowest point of their ANC level on day 7, and 5 of them recovered by day 10. No dose reductions, delays, or discontinuation of chemotherapy was reported. Twenty-one (70.0%) patients received antibiotics during the treatment period. No patient experienced FN in the 0–5 years and the 13–18 years groups, and 2 patients experienced FN in the 6–12 years group. Two patients, 6 patients, and no patient experienced grade 4 neutropenia in the 0–5 years, 6–12 years, and 13–18 years groups, respectively.ConclusionMecapegfilgrastim showed acceptable efficacy and safety profile in pediatric and adolescent patients with RMS or ES. Further randomized studies with large sample size are warranted.Trial registrationThis clinical trial was registered at Chictr.org.cn (No.ChiCTR1900022249). Registered on March 31, 2019.

The Safety of Intraoperative Photodynamic Diagnosis Using 5-Aminolevulinic Acid Combined with Talaporfin Sodium Photodynamic Therapy in Recurrent High-Grade Glioma

Intraoperative photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is a widely adopted technique to enhance the extent of resection during high-grade glioma (HGG) surgery. Recent updates to the package insert for 5-ALA in Japan now allow its use in combination with drugs that may induce photosensitivity, such as talaporfin sodium (TS). TS is employed in intraoperative photodynamic therapy (PDT) and has been shown to improve overall survival. The combination of 5-ALA with TS is expected to offer further benefits. However, the safety of this combination had not been established. This study reports on the safety of 5-ALA-PDD with TS-PDT in the treatment of recurrent HGG. 7 patients with recurrent HGG underwent tumor resection using a combination of 5-ALA-PDD and TS-PDT. The incidence of photosensitivity as an adverse effect associated with 5-ALA and TS was evaluated as described in the package insert. Adverse events were assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tumor-specific fluorescence intensity was strong in 4 cases and weak in 3. Photosensitivity occurred in only 1 patient (14.3%). Three patients exhibited CTCAE grade 1 or 2 abnormal liver function, and 1 patient experienced CTCAE grade 1 γ-GTP elevation. All abnormalities improved during follow-up. The combined use of 5-ALA-PDD and TS-PDT for HGG surgery did not increase the risk of serious adverse events in our study. Further investigations with a larger number of cases are needed for a more accurate assessment of its safety and efficacy.

Efficacy, safety, and cost-effectiveness of pegylated PEG-rhg-CSF in pediatric patients receiving high-intensity chemotherapy: results from a phase II study.

High-intensity chemotherapy can cause life-threatening complications in pediatric patients. Therefore, this study investigated safety and efficacy of long-acting pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF; Jinyouli®) in children undergoing high-intensity chemotherapy. Treatment-naive patients received post-chemotherapy PEG-rhG-CSF as primary prophylaxis for two cycles. The primary endpoints were drug-related adverse events (AEs) and bone pain scores. Secondary endpoints included grade 3-4 neutropenia, duration of neutropenia recovery, absolute neutrophil count changes, febrile neutropenia (FN), reduced chemotherapy intensity, antibiotic usage, and AE severity. The cost-effectiveness of PEG-rhG-CSF was compared with that of rhG-CSF (Ruibai®). Here, 307 and 288 patients underwent one and two PEG-rhG-CSF cycles, respectively. Ninety-one patients experienced drug-related AEs, primarily bone pain (12.7%). Moreover, Grade 3-4 neutropenia and FN were observed. Median FN durations were 3.0 days in both cycles. No drug-related delays were observed during chemotherapy. One patient experienced grade 4 neutropenia-induced reduction in chemotherapy intensity during cycle 2. In total, 138 patients received antibiotics. PEG-rhG-CSF exhibited superior cost-effectiveness compared to rhG-CSF. Our findings indicate that PEG-rhG-CSF is safe, efficient, and cost-effective in pediatric patients undergoing high-intensity chemotherapy, providing preliminary evidence warranting further randomized controlled trials.

CT-guided online adaptive stereotactic body radiotherapy for pancreas ductal adenocarcinoma: Dosimetric and initial clinical experience

Purpose/ObjectivesRetrospective analysis suggests that dose escalation to a biologically effective dose of more than 70 Gy may improve overall survival in patients with pancreatic ductal adenocarcinoma (PDAC), but such treatments in practice are limited by proximity of organs at risk (OARs). We hypothesized that CT-guided online adaptive radiotherapy (OART) can account for interfraction movement of OARs and allow for safe delivery of ablative doses. Materials/MethodsThis is a single institution retrospective analysis of patients with PDAC treated with OART on the Ethos platform (Varian Medical Systems, a Siemens Healthineers Company, Palo Alto). All patients were treated to 40 Gy in 5 fractions. PTV overlapping with a 5 mm planning risk volume expansion on the stomach, duodenum and bowel received 25 Gy. Initial treatment plans were created conventionally. For each fraction, PTV and OAR volumes were recontoured with AI assistance after initial cone beam CT (CBCT). The adapted plan was calculated, underwent QA, and then compared to the scheduled plan. A second CBCT was obtained prior to delivery of the selected plan. Total treatment time (first CBCT to end of radiation delivery) and active physician time (first to second CBCT) were recorded. PTV_4000 V95 %, PTV_2500 V9 5%, and D0.03 cc to stomach, duodenum and bowel were reported for scheduled (S) and adapted (A) plans. CTCAEv5.0 toxicities were recorded. Statistical analysis was performed using a two-sided T test and α of 0.05. Results21 patients with unresectable or locally-recurrent PDAC were analyzed, with a total of 105 fractions. Average total time was 29 min and 16 s (16:36–49:40) and average active physician time was 19:41 min (9:25–39:34). All fractions were treated with adapted plans. 97 % of adapted plans met PTV_4000 V95.0 % >95.0 % coverage goal and 100 % of adapted plans met OAR dose constraints. Median follow up was 6.6 months. Only 1 patient experienced acute grade 3+ toxicity directly attributable to radiation. Only 1 patient experienced late grade 3+ toxicity directly attributable to radiation. ConclusionsDaily CT-based OART was associated with significantly reduced dose OARs while achieving superior PTV coverage. Given the relatively quick total treatment time, radiation delivery was generally well tolerated and easily incorporated into the clinic workflow. Our initial clinical experience demonstrates OART allows for safe dose escalation in the treatment of PDAC.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

Feasibility and Safety of the “One-Week Breast Radiation Therapy” Program

AimsFAST-Forward and UK-FAST-trials have demonstrated the safety and efficacy of five-fraction breast adjuvant radiation therapy (RT) and have become the standard of care for selected early breast cancer patients. In response to the additional burden caused by the COVID-19 pandemic, we implemented “One-Week Breast RT,” an innovative program delivering five-fraction whole breast RT in a complete 5-day workflow. The primary objective of this study was to demonstrate the feasibility and safety of our program. The secondary objective was to evaluate cosmetic results. Material and methodsA total of 120 patients treated from February 2021 to March 2022, received whole breast RT without lymph node irradiation nor boost, with 26 Gy in five fractions over one week. Inverse planning with restricted optimization parameters offers systematic deep inspiration breath-hold aimed to provide treatment plans compliant with FAST-Forward recommendations. Toxicity and cosmetic evaluations were prospectively registered prior (pre-RT), at the end (end-RT), and 6 months after RT (6 months) based on Common Terminology Criteria for Adverse Events v. 4.03 and Harvard scale. ResultsWith a median age of 70 years (interquartile range (IQR): 66–74) and a median follow-up of 6 months (IQR: 6.01–6.25), most patients (93.3%) completed their RT in one week from baseline to the end of the treatment consultation. The most common acute toxicities (at end-RT) were skin-related: radio-dermatitis (72%), induration (35%), hyperpigmentation (8%), and breast edema (16%). The rate of radio-dermatitis decreased from end-RT to 6 months (71.7% vs 5.4%, P< 0.001). No patient experienced grade ≥3 toxicity. At 6 months, cosmetic results were generally good or excellent (94.1%). ConclusionThis study confirms the feasibility and acute safety of the “One-Week Breast RT” in real life. Favorable toxicity profiles and good cosmetic outcomes are in line with FAST-Forward results. A prospective national cohort, aimed at decreasing treatment burden, maintaining safety, efficacy, and improving RT workflow efficiency with longer follow-up is ongoing.

A study of a new mechanism: Intracellular retention allo-CART safety and efficacy for extranodal bulky B-NHL.

e19007 Background: Extranodal bulky lesions, a significant adverse prognostic factor in lymphoma, commonly denote a more aggressive disease course, mandating prompt and intensified treatment strategies. In response, we developed ThisCART19A, a non-genetic editing and off-the-shelf anti-CD19 CAR T-cell therapy incorporating intracellular retention of membrane proteins, representing a novel approach that downregulates surface expression of TCRαβ/CD3 complexes. ThisCART19 has exhibited a favorable safety profile and promising efficacy in patients with relapsed/refractory bulky B-cell Non-Hodgkin Lymphoma. Methods: This is an investigator-initiated trial employing an open-label, dose escalation, and expansion design to evaluate the safety and efficacy of ThisCART19A in patients with relapsed or refractory bulky B-cell non-Hodgkin lymphoma (B-NHL). Bulky disease was defined as the longest diameter of the mass &gt;5 cm at baseline. Results: Between June, 2021, and June, 2023, 13 extranodal bulky disease were enrolled in the studies and successfully received ThisCART19A. The median age was 56 (range, 37~67) years. All 13 patients had 3 median prior lines of therapy (range, 2-5). All patients received anti-CD20 and multi- agent chemotherapy. 8 (61.54%) patients had prior auto CART. mSPD was 48 (range, 16~162) cm². mTMTV was 114.9 (range, 14~483) ml. As of February 2024, The most common adverse events were CRS (100%) , infections (30.77%), ICANS (23.08%) and cytopenias(100%); This is no grade 3 or higher CRS occurred;only 1(7.69%)patient experienced grade 4 ICANS and relieved after intravenous dexamethasone treatment. This is no treatment-related deaths occurred. Among the 13 patients, 10 were evaluable, with an ORR and CR of 90% and 80%, respectively, at 28 days post-infusion. mPFS was 62 days (range, 28~227). The patient who achieved a PR received chemotherapy and radiotherapy as consolidation, As of February 5th, 2024, the patient has survived for 263 days and is still under follow-up. Additionally, two patients progressed after CR received sequential chemotherapy and BCL-2 Inhibitor, with an average OS of 326.5 days, still being under follow-up. In 13 evaluable patients, the mean C-max was 1043.13 cells/μL(range, 0.59~10045.4), and the mean AUC0-28d was 1542.23 cells/μL × day(range, 0.91~11724).In this cohort, two patients received low-dose infusions at 1×106 cells/kg and still achieved excellent expansion, the respective C-max were 726.432 cells/μL and 336.67 cells/μL. Conclusions: This CART19A exhibited favorable safety, remarkable expansion potential, and efficacy profiles in the treatment of r/r bulky lymphoma. Notably, it achieved a high ORR of 90%, providing a favorable window of opportunity for subsequent consolidation and intensification treatments. Moreover, this transition from a bulky to a non-bulky disease state reduces the intricacy of follow-up treatments. Clinical trial information: NCT04384393 .

Retrospective study of ivosidenib for patients with recurrent IDH mutant gliomas.

2040 Background: IDH mutant gliomas are the most common primary malignant brain tumors in adults under the age of 50 and accounts for approximately 12% of all glioma diagnoses each year. While lower grade gliomas (LGG) encompassing WHO grades II and III are less aggressive than their higher-grade counterparts, treatment is not curative, and most patients develop tumor recurrence in which there are a paucity of effective treatment options. Mutations in IDH1/ 2 occur upwards of 80% of patients with LGG and drive specific epigenetic programs to dysregulate and impair differentiation leading to tumorigenesis. As such, pharmacologic blockage of IDH mutant enzymes is being actively investigated as potential treatment option. Ivosidenib (AG-120), a second-generation IDH inhibitor, is an FDA approved medication for treatment of IDH-mutated acute myeloid leukemia and has demonstrated safety and clinical activity in patients with progressive IDH mutant gliomas. We explored the efficacy of Ivosidenib in IDH mutant gliomas. Methods: We retrospectively analyzed patients with IDHm gliomas treated with ivosidenib in our institution. We included patients with an IDH1 mutation who received at least one cycle of ivosidenib. Data collected included patient demographics, tumor histology, tumor location, grade, 1p/19q co-deletion, MGMT, CDKN2A, TERT, EGFR, P53, PTEN mutational status, prior treatment history, duration of treatment, toxicities, radiographic response, PFS, and OS. Descriptive statistics were used to summarize patients' characteristics. The distribution of mPFS was estimated by the Kaplan-Meier method. Results: Between April 2010 and December 2023, we identified 33 patients that received ivosidenib. 7 patients received ivosidenib in combination with bevacizumab, 3 patients received ivosidenib in combination with radiation, and 1 patient received ivosidenib and nivolumab. The median age was 52 (range 31-81). 21 (63%) were male. The median lines of medical therapy and radiation/surgery prior to starting ivosidenib were 3.03(range 0-6) and 1.5(range 0-4), respectively. 27(81%) were grade 2, 5(15%) were grade 3, and 1(3%) were grade 4. 19(57%) had 1p/19q co-deletion. As of 12/31/2023, 48%(16) patients were alive. The median PFS was 7.52 months (1-26) and median OS 12.7 months (3-25). 11(33%) patients experienced partial response (PR), 20(60%) experienced stable disease (SD) and 2(6%) demonstrated progressive disease (PD) at 12-week assessment. Nine patients experienced adverse events: grade 1 fatigue (3), grade 1 diarrhea (1), grade 2 fever (1), grade 2 weakness (1), and grade 3 confusion (1). One patient experienced grade 4 lobar hemorrhage thought to be related to concurrent bevacizumab use. Conclusions: Treatment with Ivosidenib therapy was associated with a manageable safety profile. In a subset of patients, there was disease stabilization in heavily pre-treated recurrent IDH mutant gliomas.

Abstract PO1-06-12: Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer

Abstract Background: The combination of a PD-(L)1 inhibitor plus chemotherapy demonstrated promising anti-tumor activity as first-line therapy for patients (pts) with locally recurrent inoperable or metastatic PD-L1 positive triple-negative breast cancer (TNBC). However, for pts without PD-L1 expression and for those who have failed prior lines of treatment, therapeutic options are still limited. This multi-cohort, phase II trial aimed to evaluate the safety and antitumor activity of 70 mg (cohort A) or 100 mg (cohort B) sitravatinib plus tislelizumab in pts with locally recurrent or metastatic TNBC, and their combination (70 mg sitravatinib plus tislelizumab) with nab-paclitaxel in untreated locally recurrent inoperable or metastatic TNBC pts (cohort C). The efficacy of sitravatinib plus tislelizumab in cohort A and B has been reported with objective response rate (ORR) of 38.1% and 45.0%, respectively. Herein, the preliminary results of cohort C and updated results of cohort A and B were reported. Methods: Pts with untreated locally inoperable or metastatic TNBC were included in cohort C and received 70 mg sitravatinib orally once daily plus 200 mg tislelizumab intravenously on day 1 and 100mg/m2 nab-paclitaxel on days 1 and 8 every three weeks until disease progression or intolerable toxicity. The primary endpoint was ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival (OS) rate and safety/tolerability. Based on Simon’s two-stage design, &amp;gt; 9 responders were need in stage 1 (n=18) for the study to continue, and &amp;gt;19 responders were needed by the end of study (n=35) to demonstrate statistical superiority with sitravatinib plus tislelizumab and nab-paclitaxel (assumed to be around 65%) to a historical control of 46% (1-sided alpha of 0.1, power of 80%). Updated analyses were provided for cohort A (Simon’s 2 stage design) and B (Bayesian optimal phase II design). Results: Among the 18 pts in stage 1 of cohort C, 12 of them achieved confirmed response, and therefore the study proceeded to the enrollment in stage 2. As of April 30, 2023, a total of 32 pts were enrolled, with a median age of 51 years. Among the 23 efficacy evaluable pts, unconfirmed ORR was 87.0% (95% CI 66.4-97.2) (including 3 CRs and 17 PRs), with 7 pts not reaching next tumor assessment after reaching CR/PR, and confirmed ORR was 52.2% (95% CI 30.6-73.2). DCR was 95.7%. Any grade of treatment-related adverse events (TRAEs) occurred in 31 (96.9%) pts, and grade ≥3 TRAEs occurred in 5 (15.6%) pts. One (3.1%) patient experienced grade ≥3 immune-related adverse events. SAEs were reported in 3 (9.4%) pts. At the data cut-off date, the median follow-up duration for cohort A and B was 20.4 (range 1.3–24.3) months and 13.3 (range 5.1-19.1) months, respectively. The median PFS in cohort A was 8.2 (95% CI 2.8-12.4) months, and in cohort B was 5.4 (95% CI 4.2-10.9) months. Median OS was not reached in both cohorts. RNA-seq analysis showed that the suppression of immune regulatory pathways and the activation of metabolic pathways promoted early progression. Besides, baseline angiogenesis associated pathway held the potential to predict the favorable response to tislelizumab plus sitravatinib. Conclusion: In the first-line treatment of locally recurrent or metastatic TNBC, preliminary analysis of cohort C showed that sitravatinib combined with tislelizumab and nab-paclitaxel had promising anti-tumor activity with a high ORR, and the combination was generally well tolerated. In TNBC pts with less than three lines of therapy, the chemotherapy-free regimen with sitravatinib plus tislelizumab demonstrated promising PFS after a longer follow-up duration. Citation Format: Lei Fan, Xiyu Liu, Ying Xu, Xinyi Sui, Wenjuan Zhang, Linxiaoxi Ma, Xi Jin, Song-Yang Wu, Han Wang, Yi Xiao, Li Chen, Jiong Wu, Ke-da Yu, Guangyu Liu, Xin Hu, Zhonghua Wang, Yi-Zhou Jiang, Zhi-Ming Shao. Phase II study of sitravatinib plus tislelizumab with or without nab-paclitaxel in patients with locally recurrent or metastatic triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-06-12.

Laparoscopic Treatment of Bulky Nodes in Primary and Recurrent Ovarian Cancer: Surgical Technique and Outcomes from Two Specialized Italian Centers.

(1) Background: Minimally invasive surgery (MIS) represents a feasible approach in early-stage ovarian cancer, while this question is still unsolved for advanced and recurrent disease. (2) Methods: In this retrospective, multicenter study, we present a series of 21 patients who underwent MIS for primitive or recurrent epithelial ovarian cancer (EOC) with bulky nodal metastasis and discuss surgical technique and outcomes in relation to the current literature. (3) Results: Complete cytoreduction at primary debulking surgery was obtained in 86% of cases. No complication occurred in our patients intraoperatively and only 11.1% of our patients experienced grade 2 and 3 postoperative complications. Notably, all the patients with isolated lymph nodal recurrence (ILNR) were successfully treated with a minimally invasive approach with no intra- or postoperative complications. (4) Conclusions: The results of our study are consistent with those reported in the literature, demonstrating that MIS may represent a safe approach in advanced and recurrent EOC with nodal metastasis if performed on selected patients by expert surgeons with an adequate setting and appropriate technique.

Abstract CT257: Hyperprogressive disease following bintrafusp alfa and DNA damaging chemotherapy in relapsed small cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. Current therapies have limited efficacy in SCLC, and despite a highly mutated genome, SCLC is largely unresponsive to immunotherapy. We sought to leverage the immune surveillance triggered by DNA damage in patients with relapsed SCLC using bintrafusp alfa, a bifunctional fusion protein targeting both PD-L1 and TGF-beta. Hyperprogressive disease (HPD), characterized by the rapid acceleration of tumor growth, has been reported in approximately 13% of patients treated with immune checkpoint inhibitors. However, the mechanistic basis is poorly understood. Methods: This is a safety run-in and phase II clinical trial. Cohort 1 enrolled patients with relapsed SCLC across Arms A (bintrafusp alfa 2400 mg q3 wks), B (bintrafusp alfa 2400 mg on D1 plus topotecan 1 mg/m2/day on D1-5 q3 wks), and C (bintrafusp alfa 1200 mg on D1 q2 wks plus temozolomide 200 mg/m2/day on D1-5 q4 wks). The primary endpoint was objective response rate (ORR). Results: Thirty-seven patients enrolled. Grade 3 treatment-related adverse events (TRAE) included transaminitis (27.0%), anemia (24.4%), lymphopenia (10.8%), and maculopapular rash (5.4%). Grade 4 TRAE included thrombocytopenia (8.1%), lymphopenia (5.4%) and transaminitis (5.4%). One patient experienced grade 5 tumor hemorrhage. By RECIST 1.1, partial responses were observed in 5 (13.5%), stable disease in 11 (29.7%), and progressive disease in 21 (56.8%) patients. Importantly, 13 (35.1%) patients developed HPD (≥ 2x increase in tumor growth rate from pre-trial vs on-trial, time to treatment failure ≤ 2 months, and ≥ 50% increase tumor burden). Changes in circulating cell-free DNA (n=20) tumor fraction using DELFI-TF, a mutation-independent, low-coverage whole genome sequencing approach, correlated with treatment responses. Pre-treatment serum from HPD (n=10 vs. 9 non-HPD) patients showed significantly lower levels of inflammatory cytokines (CXCL10, CCL13, CCL8, CCL19, TRAIL) and Granzyme H, and higher levels of anti-inflammatory cytokine IL10. Consistently, pre-treatment tumor transcriptomes of HPD (n=5 vs. 7 non-HPD) patients revealed suppression of IFN-gamma response, allograft rejection, and inflammatory response pathways. Conclusions: Concomitant TGF-beta and PD-L1 blockade is associated with a high frequency of HPD in SCLC patients. cfDNA could be critical for monitoring HPD. Tumor and blood immune signatures may inform the likelihood of HPD, with immune excluded tumors more likely to develop HPD. NCT Number: NCT03554473 Bintrafusp alfa was provided by EMD Serono (CrossRef Funder ID: 10.13039/100004755) Citation Format: Brett Schroeder, Nobuyuki Takahashi, Howard Yang, Renee Donahue, Zachary Skidmore, Alissa Konicki, Michael Nirula, Max Greenberg, George Chrisafis, Yang Zhang, Yo-Ting Tsai, Linda Sciuto, Samantha Nichols, Melissa Abel, Parth Desai, Rajesh Kumar, Christopher Schultz, Danielle Pinkiert, Chante Graham, Ajit Sharma, Justin Malin, Manan Krishnamurthy, Sophie Zhuang, Maxwell Lee, Lorenzo Rinaldi, Jeffrey Schlom, Lalage Wakefield, Anish Thomas. Hyperprogressive disease following bintrafusp alfa and DNA damaging chemotherapy in relapsed small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT257.

Abstract CT142: Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML)

Abstract Background: The novel small-molecule inhibitor and degrader, BPI-23314, targeting of the bromodomain and extra-terminal domain (BET) family proteins, BPI-23314, has been showndemonstrated promising preclinical efficacy in hematologic malignancies. This Phase 1 study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of BPI-23314 monotherapy in patients with relapsed or refractory acute myeloid leukemia (R/R AML). Methods: This ongoing phase 1 study of BPI-23314 enrolled adult patients with R/R AML. Dose escalation was conducted using a standard 3+3 design, followed by additional expansion cohorts to further assess safety and preliminary efficacy. BPI-23314 tablets were administered orally once daily (QD) or twice daily (BID) in consecutive 21-day cycles. The key endpoints included determining the recommended Phase 2 dose (RP2D), safety, pharmacokinetics, and preliminary efficacy. Results: As of July 31, 2022, a total of 22 patients diagnosed with R/R AML were treated with BPI-23314 at seven different dose levels, ranging from 5 to 60 mg QD or 40 to 50 mg BID. The median age of the patients was 48 years (range: 19-68 years), and the median treatment duration was 6 weeks (range: 2-9 weeks). The median number of prior therapy lines was 3 (range: 1-4), with 15 (68.2%) being refractory to last line of therapy. Due to the high incidence of grade≥3 anemia, thrombocytopenia, and neutropenia among the patients at baseline, most treatment-emergent adverse events (TEAE) of hematologic toxicities were mainly correlated with disease progression. Only one patient experienced grade 3 treatment-related adverse events (TRAE) comprising anemia (4.5%) and neutropenia (4.5%). Non-hematologic TRAEs were predominantly of grade 1-2. The most common TRAEs (≥10%) were gastrointestinal reactions (10/22, 45.5%), hypertriglyceridemia (6/22, 27.3%), hyperbilirubinemia (4/22, 18.2%), elevated alanine aminotransferase levels (3/22, 13.6%), and increased gamma-glutamyl transferase levels (3/22, 13.6%). Gastrointestinal reactions characterized by nausea and/or diarrhea were the most commonly reported toxicities. The most common TEAEs associated with disease progression were infection and bleeding. No dose-limiting toxicity or treatment-related deaths were reported during the study period, and the maximum tolerated dose was not reached. Among the evaluable responses in all dose levels for R/R AML patients (n=21), one patient achieved complete response (CR) at a dosage of 40 mg BID while three patients maintained stable disease (SD) across various dosages, including QD at 60 mg and BID at both 40 mg and 50 mg. Furthermore, BPI-23314 demonstrated moderate elimination kinetics, with a plasma half-life ranging from 8.6 to 23.3 hours, while exhibiting dose-proportional exposure. Conclusion: BPI-23314 monotherapy exhibited preliminary clinical efficacy with manageable adverse events in patients with R/R AML. The study is ongoing. The satisfactory pharmacokinetic attribute and outstanding safety profile of BPI-23314 provide compelling rationales for further exploration of its therapeutic potential. Citation Format: Mingyuan Sun, Xiangyu Jin, Jing Guo, Xiaoyun Liu, Yan Xu, Hong Lan, Jiabing Wang, Jiangnan Zhen, Jing Yang, Lieming Ding, Junyuan Qi. Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT142.

Intradermal Naked DNA Vaccination by DNA Tattooing for Mounting Tumor-Specific Immunity in Stage IV Melanoma Patients: A Phase I Clinical Trial

Introduction: Naked DNA vaccination could be a powerful and safe strategy to mount antigen-specific cellular immunity. We designed a phase I clinical trial to investigate the toxicity of naked DNA vaccines encoding CD8+ T-cell epitope from tumor-associated antigen MART-1 in patients with advanced melanoma. Methods: This dose escalating phase Ia clinical trial investigates the toxicity and immunological response upon naked DNA vaccines encoding a CD8+ T-cell epitope from the tumor-associated antigen MART-1, genetically linked to the gene encoding domain 1 of subunit-tetanus toxin fragment C in patients with advanced melanoma (inoperable stage IIIC-IV, AJCC 7th edition). The vaccine was administrated via intradermal application using a permanent make-up or tattoo device. Safety was monitored according to CTCAE v.3.0 and skin biopsies and blood samples were obtained for immunologic monitoring. Results: Nine pretreated, HLA-A*0201-positive patients with advanced melanoma expressing MART-1 and MHC class I, with a good performance status, and adequate organ function, were included. With a median follow-up of 5.9 months, DNA vaccination was safe, without treatment-related deaths. Common treatment-emergent adverse events of any grade were dermatologic reactions at the vaccination site (100%) and pain (56%). One patient experienced grade 4 toxicity, most likely related to tumor progression. One patient (11%) achieved stable disease, lasting 353 days. Immune analysis showed no increase in vaccine-induced T cell response in peripheral blood of 5 patients, but did show a MART-1 specific CD8+ T cell response at the tattoo administration site. The maximum dose administered was 2 mg due to lack of clinical activity. Conclusion: We showed that the developed DNA vaccine, applied using a novel intradermal application strategy, can be administered safely. Further research with improved vaccine formats is required to show possible clinical benefit of DNA vaccination.

Safety and Efficacy of Moderate-Intensity Stereotactic Body Radiation Therapy for Ultra-Central Lung Tumor.

Background and Objectives: Ultra-central (UC) lung tumors are defined as those abutting the proximal bronchial tree. Stereotactic body radiation therapy (SBRT) for UC tumors is difficult because of concerns about severe toxicities. Therefore, we report the safety and efficacy of moderate-intensity SBRT for UC tumors at our institution. Materials and Methods: From January 2017 to May 2021, we treated 20 patients with UC tumors with SBRT at a dose of 45-60 Gy in 10 fractions. The primary endpoints were local control (LC) and overall survival (OS). Results: The median follow-up time was 15.8 months (range: 2.7-53.8 months). Ten of the 20 patients (50.0%) showed a complete response, five (25.0%) had a partial response, two (10.0%) had stable disease, and three (15.0%) showed progressive disease (PD). The response and disease control rates were 75.0% and 85.0%, respectively. Patients with PD showed local progression at median 8.3 months (range: 6.8-19.1 months) after SBRT. One-year and 2-year OS rates were 79.4% and 62.4%, respectively. One-year and 2-year LC rates are 87.1% and 76.2%, respectively. Eight patients died due to a non-radiation therapy related cause. One patient experienced grade 5 massive hemoptysis 6 months after SBRT, resulting in death. One patient experienced grade 2 esophageal pain and two experienced grade 2 radiation pneumonitis. Otherwise, no grade 3 or higher toxicities were reported. Conclusions: Moderate-intensity SBRT offers effective control of UC tumors and is a well-tolerated treatment for such tumors.

CD19-CAR-DNT cells (RJMty19) in patients with relapsed or refractory large B-cell lymphoma: a phase 1, first-in-human study

Current approved chimeric antigen receptor (CAR) T-cell products are autologous cell therapies that are costly and poorly accessible to patients. We aimed to evaluate the safety and antitumor activity of a novel off-the-shelf anti-CD19 CAR-engineered allogeneic double-negative T cells (RJMty19) in patients with relapsed/refractory large B-cell lymphoma. We report the results from a first-in-human, open-label, single-dose, phase 1 study of allogeneic CD19-specific CAR double-negative T (CAR-DNT) cells. Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior immunochemotherapy, and an ECOG score of 0-1. We evaluated four dose levels (DL) of RJMty19 in a 3+3 dose-escalation scheme: 1×106, 3×106, 9×106 and 2×107 CAR-DNT cells per kilogram of body weight. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoints were dose-limiting toxicities (DLTs), incidence of adverse events (AEs), and clinically significant laboratory abnormalities. Secondary endpoints included evaluation of standard cellular pharmacokinetic parameters, immunogenicity, objective response rates (ORR), and disease control rate (DCR) per Lugano 2014 criteria. A total of 12 patients were enrolled between 22 July 2022 and 27 July 2023. Among these patients, 66% were classified as stage IV, 75% had an IPI score of 3 or higher, representing an intermediate risk or worse. The maximum tolerated dose was not reached because no DLT was observed. Four patient experienced grade 1 or 2 cytokine release syndrome and dizziness. The most common AEs were hematologic toxicities, including neutropenia (N=12, 100%), leukopenia (N=12, 100%), lymphopenia (N=10, 83%), thrombocytopenia (N=6, 50%), febrile neutropenia (N=3, 25%), and anemia (N=3, 25%). Seven subjects died till the cut-off date, five of them died of disease progression and two of them died of COVID 19. In all patients (N=12), the ORR was 25% and CRR was 8.3%. DL1 and DL2 patients benefited less from the therapy (ORR: 17%, N=1; DCR: 33%, N=2). However, all DL3 patients achieved disease control (N=3, 100%), and all DL4 patients achieved objective response (N=3, 100%). Our results demonstrate that CD19-CAR-DNT cells appear to be well tolerated with promising antitumor activity in LBCL patients. Further study of this product with a larger sample size is warranted. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). Wyze Biotech. Co., Ltd.

A new, potential and safe neoadjuvant therapy strategy in epidermal growth factor receptor mutation-positive resectable non-small-cell lung cancer-targeted therapy: a retrospective study.

Studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resectable non-small-cell lung cancer (NSCLC) have been conducted. The purpose of our study was to evaluate the benefits of osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC. This retrospective study evaluated patients with EGFR mutations in exon 19 or 21 who received targeted therapy with osimertinib (80 mg per day) before surgery between January 2019 and October 2023 in Henan Cancer Hospital. Twenty patients were evaluated, all of whom underwent surgery. The rate of R0 resection was 100% (20/20). The objective response rate was 80% (16/20), and the disease control rate was 95% (19/20). Postoperative pathological analysis showed a 25% (5/20) major pathological response rate and 15% (3/20) pathological complete response rate. In total, 25% (5/20) developed adverse events (AEs), and the rate of grades 3-4 AEs was 10% (2/20). One patient experienced a grade 3 skin rash, and 1 patient experienced grade 3 diarrhea. Osimertinib as neoadjuvant therapy for resectable EGFR-mutated NSCLC is safe and well tolerated. Osimertinib has the potential to improve the radical resection rate and prognosis.