Dose Escalation Approach Research Articles

Real-world dosing patterns of regorafenib for patients with metastatic colorectal cancer in Spain: the RE-SEARCH study.

To describe the dosing patterns of regorafenib in a real-world population of patients with metastatic colorectal cancer (mCRC) in a routine clinical practice setting in Spain, focusing on the starting dose of regorafenib. An observational, retrospective, multicenter study that included patients ≥ 18years old who had histologically documented mCRC and who had initiated treatment with regorafenib since January 2017. Post hoc categorization of dosing patterns revealed the following: initial dose < 160mg and dose escalation, initial dose < 160mg and maintenance, initial dose equal to 160mg and maintenance, and initial dose equal to 160mg and dose reduction. Most patients (152/241, 63.8%) initiated treatment with regorafenib at doses < 160mg. There was large variation in the starting dose of regorafenib over time: in 2017, most patients (59%) initiated regorafenib at a dose of 160mg, this proportion decreased to 6% in 2021. There were no significant differences in the median progression-free survival according to the regorafenib dose patterns during the first two cycles. The proportion of patients who reported at least one adverse event (AE), had a grade 3-4 AE or had an AE leading to dose reduction was greater in the group of patients who received an initial dose equal to 160 and reduction. Our results indicate that physicians in Spain have gradually adopted a dose-escalation approach during cycle 1, which is a common practice for starting treatment with a reduced dose (< 160mg/day), a strategy that seems to improve tolerability while maintaining efficacy. Not applicable.

NANO-GBM trial of AGuIX nanoparticles with radiotherapy and temozolomide in the treatment of newly diagnosed Glioblastoma: Phase 1b outcomes and MRI-based biodistribution

BackgroundIn glioblastoma (GBM), tumor progression occurs mainly within the irradiated tumor volume. To address this challenge, a radiosensitization strategy with intravenous gadolinium-based theranostic nanoparticles (AGuIX) is being explored in the NANO-GBM phase1b/2R trial (NCT04881032). Here, we present the results of the phase 1b part, which is the first-in-human use of these nanoparticles with radiotherapy and chemotherapy for the treatment of newly diagnosed GBM. Material and MethodsEligible patients were aged 18 to 75 years with newly diagnosed and histologically confirmed GBM, with incomplete resection (biopsy or partial surgery). The phase 1b part was a dose escalation approach (Time-to-event Continuous Reassessment Method) with three dose levels: 50, 75, and 100 mg/kg. Patients were treated with RT (60 Gy), and concomitant and adjuvant TMZ, and 4 injections of AGuIX (D-3/-7, D1, D8, and D15). Dose-limiting-toxicity (DLT) was defined as any grade 3–4 adverse event (CTCAE v5.0), excluding alopecia, nausea, and rapidly controlled vomiting. Pharmacokinetic (PK), and biodistribution based on MRI were evaluated. ResultsBetween March 2022 and March 2023, eight patients were enrolled: 1 at 50 mg/kg, 1 at 75 mg/kg, and 6 at 100 mg/kg. All patients received the four AGuIX injections. Only one patient experienced a DLT (at 100 mg/kg): a grade 3 lymphopenia (related to TMZ). The RP2D of AGuIX was determined as 100 mg/kg. AGuIX mean AUC increased with dose. Regions of GBM with moderate (36–123 µM), and high (123–291 µM) or very high (>291 µM) AGuIX concentrations accounted in average for 38.7 and 26.8 %, respectively. ConclusionThese results confirm the lack of AGuIX-related toxicity and the widespread dispersion of nanoparticles throughout GBM. This supports progression to the randomized phase 2 part, utilizing an RP2D of AGuIX of 100 mg/kg (4 injections).

Acute Toxicity and Early Prostate Specific Antigen Response After Two-Fraction Stereotactic Radiation Therapy for Localized Prostate Cancer Using Peri-Rectal Spacing – Initial Report of the SABR-Dual Trial

Purpose: SABR-Dual is a phase III trial with an initial phase-I safety cohort, of two-fraction stereotactic radiotherapy (SABR) with optional MRI-based focal boost, using peri-rectal spacing, for localized prostate cancer. This represents the initial report from the phase-I non-randomized cohort. Materials and methods: Subjects had favorable intermediate risk (FIR) or low risk (LR) prostate adenocarcinoma, and gland volume <80cc. All underwent radiopaque hydrogel spacer and fiducial marker placement prior to simulation (CT and 3-tesla T2 MRI). The clinical target volume included the entire prostate, and in FIR patients, 1-2cm of seminal vesicle (SV). A 2mm expansion was applied for planning target volume (PTV), and a dose of 27 Gy was prescribed to the PTV-prostate, 23 Gy to the PTV-SV, with an optional 30 Gy simultaneous boost (SIB) to an MRI-defined dominant lesion. Primary endpoint was 3-month patient-reported changes in quality of life based on the EPIC-26, IPSS, and SHIM questionnaires. Secondary endpoints were 6-month quality of life, acute toxicity (using CTCAEv5) and early PSA response. Results: Among the 20 patients in the phase-I cohort, 95% had FIR disease, and 50% received an SIB. At median follow-up of 8 months, a 3-month minimally clinically important change occurred in 1/20 (5%), 6/20 (30%), 2/20 (10%), 4/20 (20%), and 5/20 (25%) in urinary incontinence, urinary obstructive, bowel, sexual, and hormonal domains. There was a mean increase of 1±5.4 in IPSS and decrease of 1.8±6.5 in SHIM scores. Rates of grade 2 urinary and bowel toxicity 10% and 0%, respectively, with no grade ≥3 toxicities. Mean PSA decrease at last follow-up was 70.4%±17.7%. Conclusion: This generalizable protocol of two-fraction prostate SABR using peri-rectal spacing is a safe approach for ultra-hypofractionated dose-escalation, with minimal acute toxicity. Longer-term outcomes and direct comparison with standard 5-fraction SABR are being studied in the phase-III randomized portion of SABR-Dual.

Preliminary safety, antitumor activity, and pharmacodynamics of intratumoral ABO2011 (IL-12 mRNA) in patients with advanced solid tumors.

e14583 Background: Interleukin (IL)-12 is a potent immunomodulatory cytokine demonstrating robust antitumor activity in multiple preclinical studies and potent immune-stimulating potential in humans. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. ABO2011 is a human IL-12 mRNA encapsulated in lipid nanoparticle and has been developed to be more effective and less toxic through the use of novel delivery technology and intratumoral injection. Methods: This phase I trial enrolled adults with advanced solid tumors who failed available standard treatments (NCT05392699). The trial was designed to primarily evaluate the safety of ABO2011 in single-dose cohorts and multiple-dose cohorts using “3+3” dose escalation approach. Patients (pts) would receive intratumoral ABO2011 at either a single dose, QW with 3 doses overall, every 3 weeks (Q3W) or QW followed by Q3W. Results: As of 09 December 2023, a total of 20 pts were enrolled and received at least one dose of ABO2011 at 4 μg single dose, 4 μg QW for 3 times, 12 μg single dose, 12 μg QW for 3 times followed by Q3W, 24 μg Q3W and 48 μg Q3W. Seventeen (85%) pts experienced treatment-related adverse events (TRAEs), and all were grade 1 or 2, including pyrexia (35%), pain (25%), and gamma-glutamyl transferase increased (25%). There were no dose-limiting toxicities or treatment-related SAEs reported and no TRAEs leading to treatment discontinuation. Of the 17 evaluable pts per RECISIT v1.1, 5 maintained stable disease, and the progression free survivals achieved 6.0 months, 5.6 months and 4.1 months for pts with colorectal cancer (6th line), non-small cell lung cancer (5th line) and pancreatic cancer (4th line), respectively. Peripheral blood IL-12 and IFN-γ levels increased and peaked at 24 hours and 48 hours after dosing, respectively, indicating expression of IL-12 and subsequent induction of IFN-γ after ABO2011 administration. Dose-dependent elevation of CXCL9, CXCL10, CXCL11 in peripheral blood was observed, consistent with the activation of downstream pathway of IFN-γ. CD8 T cells infiltration and PD-L1 expression were increased in tumor microenvironment (TME) at day 7, and further RNA sequencing analysis revealed increase of activated CD8 T cell and antigen processing and presentation after study treatment, suggesting the regulation of TME by ABO2011 and supporting the combination with PD-1(L1) inhibitor. Conclusions: Intratumoral ABO2011 was safe and well-tolerated in pts with advanced solid tumors. The pharmacodynamic changes were as expected. Promising preliminary antitumor activities of the single agent and the pharmacodynamic profiles support further investigation of ABO2011 in combination with immune checkpoint inhibitor. Clinical trial information: NCT05392699 .

Fludarabine, Cytarabine (ARA-C) and Pegylated Erwinase (PEGCRISANTASPASE) in Patients with Relapsed or Refractory Leukemia

Background: Asparaginase, which depletes serum asparagine by breaking it down into asparagine, is part of the standard of care along with chemotherapy, in adolescent and young adult patients with acute lymphoblastic leukemia (ALL). Leukemic blasts require asparagine for survival, therefore serving as an important therapeutic target; among the mechanisms of resistance includes the upregulation of expression of asparagine synthetase (AS) (gene located in chromosome 7). Depletion of asparagine and more recently glutamine may also have an important role in the treatment of acute myelogenous leukemia, either alone or in combination with chemotherapy. Pegcristaspase (PegC) is a long-acting pegylated asparaginase derived from Erwinia that also has a glutaminase activity. We hypothesize that the combination of chemotherapy and PegC might overcome resistance and provide therapeutic benefit pts with relapsed and/or refractory leukemias. Methods: This is a phase Ib study of fludarabine, cytarabine (ara-c), and PegC in patients with relapsed or refractory leukemia (NCT 04526795). Pts received induction cycle (C) (defined as 5 weeks) with PegC on day (D) 1 and 15 as single agent. Fludarabine (30mg/m 2/D) and 4 hours later Cytarabine (1.5g/m 2/D) are given D 8 to D 11. A 3+3 dose-escalation approach was implemented to evaluate 3 different dose levels for pegcrisantaspase (level -2: 350 IU/m 2; level -1: 500 IU/m 2; and level 1: 750UI/m 2). Once the MTD is established, an expansion cohort to further evaluate safety and efficacy was opened. Endpoints included safety, overall response rate (complete remission [CR], CR with incomplete count recovery [CRi], partial remission [PR], or morphologic leukemia free state [MLFS] ) of fludarabine, araC, and pegcrisantaspase in patients with relapsed and refractory leukemias. Response was denoted as per the ELN 2017 criteria. Results: From April 2021, 15 pts have been treated on the trial, 12 (80%) pts with AML, 2 pts (13%) with ALL (one patient was Ph+ ALL), and 1 patient with isolated myeloid sarcoma. The median age was 46 years (range, 22-61), median bone marrow blasts were 37% (1-90) . 9/15 (60%) patients had complex karyotype. Patient characteristics are summarized in Table 1. The median lines of prior therapy was 4 (range, 1-9). Six pts were treated at dose level -1 and then at dose level 1. There were no dose limiting toxicities to proceed to the expansion cohort. From the 15 treated pts, 2 patients from the dose level -1 died from sepsis related to disease progression within the first 4 weeks. Overall, 3 pts (20%) responded to treatment (2CRp and 1 CRi). The patient with Ph+ B-ALL achieved CRp, proceeded to SCT, and remains alive in remission. The 2 other patients (both with AML) relapsed after 6 weeks and 4 months, respectively. The median overall survival was 2.6 months. (Figure 1) A total of 29 adverse events (AE) were noted in 13/15 patients. The most common AEs was grade ≥ grade 3 neutropenic fever (10 pts, 67%; including 2 grade 5 events). The only possibly related AE was tumor lysis syndrome in one patient, grade 3, and was successfully managed per institutional guidelines. Conclusion: In this high-risk, heavily treated population, the combination of fludarabine, cytarabine, and PegC is feasible. Responding patients included 2 AML and 1 ALL. Further exploratory analysis about the relation between response and asparagine depletion as well as specific sensitive subsets could clarify which patients might benefit the most from this combination.

Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

AML arising from HMA-treated myeloid disorders, also known as “treated-secondary AML” (ts-AML) is associated with an adverse prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-10 months). E-selectin, a marker of cell survival and resistance to chemotherapy, is highly expressed in the leukemic microenvironment. Exposure of leukemic blasts to HMAs has been shown to increase its expression. Uproleselan is an e-selectin antagonist that has demonstrated antileukemic activity in AML. We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance. This Phase Ib/II clinical trial (NCT04848974) evaluate the safety, tolerability, and efficacy of Uproleselan added to Cladribine and LDAC. A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at fixed dose of 800mg intravenously [IV]). Induction and reinduction if required, included IV uproleselan twice a day from day 1-12; consolidation was given same days but once a day if patients(pts) achieved response (complete response[CR] with incomplete hematological recovery [CRi] or morphologic leukemia-free state [MLFS]). CLAD was IV for 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1 respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1 respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles, pts aged ≥18 years with a diagnosis of ts-AML with adequate organ function, who have not received therapy for their AML were enrolled. ts-AML is defined as AML arising from previously treated myeloid neoplasm. Presence of the e-selectin was assessed as exploratory analysis. 20 pts have been treated, 18 pts evaluable: 14 (70%) male, median age was 72 yrs (range, 58-86); at the start of therapy, the median bone marrow blasts were 26.5% (20-82%), median WBC was 2.1x10 9/L (0.6-26.4), and median platelets were 26x10 9/L (4-667). Pts had received a median of 1 (1-6) treatments prior to AML transformation. Prior diagnoses were: Chronic Myelomonocytic Leukemia (CMML), MDS, and MDS/MPN in 3 (25%), 14 (70%), and 1 (5%) respectively; all had received HMA, 11 (55%) additionally had received Ven, and 5 (25%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable cytogenetics by ELN 2022. The most frequent mutations were: TET2, TP53, RUNX1 and SRSF2 in 9 (45%), 7 (35%), 6 (30%) and 6 (30%) pts respectively. 18 pts were evaluable for e-selectin; median plasmatic concentration was 26.2ng/mL (15.3-131 ng/mL). Most common AEs were grade(gr) ≥3 neutropenic fever (13 pts, 65%; including 2 gr 5 events), gr 3 bleeding (10%) and gr 2 thrombosis (5%). There were no dose-limiting toxicities observed on dose levels -1 or 1. The chosen dose level was 1 as described above. 2/3 pts who received dose level -1 died during the study follow-up due to sepsis in the first 4-week after induction. Median time to 0.5x10 9/L neutrophil and 50x10 9/L platelets recovery was 30 (17-52) and 38 (20-69) days, respectively. The response rates were 2 (11%) CRi, 1 (6%) CRp, and 4 (22%) MLFS. There was a reduction in BM blasts in 13 pts (72%) (Figure 1). The ORR was 50%(5/10) ( p=0.60) and 20% (1/5) ( p=0.06) among pts who had prior Ven exposure or prior SCT, respectively. The median cycles received was 1.5 (1-4), median cycles at which the best response was achieved was 1 (1-2). 12 pts were taken off protocol due to progression, 3 for death, 3 for allogeneic SCT and 1 continued in remission. The pt who achieved negative MRD-negative by flow cytometry underwent SCT and is still alive. The median follow-up is 8.1 months. Median OS and EFS were 5.3 and 1.4 months respectively; 4-month RFS (CRi, CRp and MLFS) was 30% (Fig 2). In the univariate analysis by Cox regression for plasmatic E-selectin concentration the HR for OS was 1.016 (95% CI 1.002-1.031). Ts-AML, progressing from previously treated antecedent myeloid disorders, is associated with low rates of remission and poor OS. Uproleselan combined with Cladribine + LDAC was well-tolerated with minimal therapy-related AEs - allowing a safe approach to marrow blast reduction and disease control in preparation for a potential allogeneic SCT. We are currently determining the relationship of plasmatic e-selectin concentration and response to treatment.

A Dietary Model of Partial Meat Replacement with Walnuts Demonstrates Changes in the Nutrient Profile and Quality of the United States Population's Diet.

The purpose of the study is to assess the impact of partial meat replacement with walnuts using a dose-escalation approach on nutrient intake and diet quality in the usual US diet. Food modeling was implemented using the nationally representative 2015-2018 National Health and Examination Survey (NHANES), with a focus on non-nut consumers, which included 2707 children and adolescents and 5190 adults. Walnuts replaced meat in a dose-escalating manner (0.5, 1, 1.5, and 2 oz walnuts per day replaced 1, 2, 3, and 4 oz meat, respectively). Diet quality was estimated using the population ratio method of the 2015 Healthy Eating Index. The usual intake of nutrients was estimated using the National Cancer Institute method. Significant differences were determined using non-overlapping 95% confidence intervals. The partial replacement of meat with walnuts demonstrated significant increases in the mean intake of fiber, magnesium, and omega-3 fatty acids and significant decreases in cholesterol and vitamin B12 in the modeled diets for children, adolescents, and adults. Additionally, the partial replacement of meat with walnuts improved overall diet quality. Walnut consumption at 1-2 oz as a replacement for some meat may improve nutrient intake and diet quality across age groups.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

P17.03.A MAGIC-G1: A PHASE 1 DOSE-ESCALATION TRIAL OF WEEKLY INTRATUMORAL ADMINISTRATION OF THE SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (RGBM)

Abstract BACKGROUND One of the biggest challenges in treating rGBM is achieving high local drug concentration. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming the blood-brain barrier, while also limiting systemic toxicity. MTX110 (Midatech Ltd), a water-soluble formulation of panobinostat, has demonstrated cytotoxic activity in GBM cell lines, as well as safety and efficacy in two pediatric diffuse pontine glioma trials. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumor, thus avoiding systemic administration and therefore toxicity. MATERIAL AND METHODS Eligibility includes adult rGBM patients with a single enhancing lesion ≤3cm in maximal diameter; ≥4 weeks after chemotherapy, bevacizumab, or study drug; adequate organ function; and KPS ≥60%. MTX110 is continuously infused over 48hrs weekly at a rate of 0.5mL/h, via a CED catheter implanted into the enhancing disease recurrence connected to a fully internalized pump system. After safety of a single patient treated at 60μM has been established, 3-6 patients will be treated with MTX110 at 90μM as a single agent (Cohort 1). Patients in cohort 2 will receive MTX110 in combination with lomustine at a starting MTX110 dose of 60 μM and following the same dose-escalation approach. RESULTS As of March 30, 2023, the 1st patient was treated in monotherapy at 60μM and has received 12 weekly infusions of MTX110. No dose-limiting toxicities were observed. Observed study related adverse events (AEs) included: grade 1 cognitive disturbance, headache, and seizure; grade 2 candida wound infection, erythema of the scalp, bruising, and hemiparesis; and grade 3 abdominal seroma at pump insertion site. Enrolment is ongoing and the next patient will receive the 90 μM dose. CONCLUSION Weekly intratumoral administration of MTX110 via a fully internally implanted CED pump system is feasible. Updated results will be presented.

To Boost or Not to Boost: Pooled Analyses From 2-Fraction SABR Trials for Localized Prostate Cancer

Focal boost to dominant intraprostatic lesion (DIL) is an approach for dose escalation in prostate radiation therapy. In this study, we aimed to report the outcomes of 2-fraction SABR ± DIL boost. We included 60 patients with low- to intermediate-risk prostate cancer enrolled in 2 phase 2 trials (30 patients in each trial). In the 2STAR trial (NCT02031328), 26 Gy (equivalent dose in 2-Gy fractions=105.4 Gy) was delivered to the prostate. In the 2SMART trial (NCT03588819), 26 Gy was delivered to the prostate, with up to 32 Gy boost to magnetic resonance imaging-defined DIL (equivalent dose in 2-Gy fractions=156.4 Gy). The reported outcomes included prostate-specific antigen (PSA) response (ie, <0.4 ng/mL) at 4 years (4yrPSARR), biochemical failure (BF), acute and late toxicities, and quality of life (QOL). In 2SMART, median DIL D99% of 32.3 Gy was delivered. Median follow-up was 72.7 months (range, 69.1-75.) in 2STAR and 43.6 months (range, 38.7-49.5) in 2SMART. The 4yrPSARR was 57% (17/30) in 2STAR and 63% (15/24) in 2SMART (P=0.7). The 4-year cumulative BF was 0% in 2STAR and 8.3% in 2SMART (P=0.1). The 6-year BF in 2STAR was 3.5%. For genitourinary toxicities, there were differences in grade ≥1 urinary urgency in the acute (0% vs 47%; P < .001) and late settings (10% vs 67%; P < .001) favoring 2STAR. For urinary QOL, no difference was observed in the acute setting, but lower proportion in 2STAR had minimal clinically important changes in urinary QOL score in the late setting (21% vs 50%; P=.03). There were no significant differences in gastrointestinal and sexual toxicities and QOL in both acute and late settings between the 2 trials. This study presents the first prospective data comparing 2-fraction prostate SABR ± DIL boost. The addition of DIL boost resulted in similar medium-term efficacy (in 4yrPSARR and BF), with impact on late urinary QOL outcomes.

Stereotactic Body Radiation Therapy in Prostate Cancer: Where Do We Stand?

Stereotactic body radiotherapy (SBRT) is an important option for prostate cancer treatment. It involves the delivery of a high dose of radiation to the malignant tissue without affecting the neighboring healthy tissue to achieve a high therapeutic index. As the cells of prostate cancer are radiobiologically similar to a late-responding tissue with a low 𝛼/𝛽 ratio, the dose escalation approach has a better disease control probability than conventional dose fractionation. Therefore, considering the availability of intensity-modulated RT and possibility of dose escalation (&gt;70 Gy), ultrahypofractionated SBRT is now being recommended in select patients with prostate cancers of low and intermediate risk. Although adverse events following SBRT are a concern, acute toxicity can be limited to a certain extent by adjusting the overall length of treatment time by spacing out RT over multiple fractions. Modern radiation planning and delivery methods used in conjunction with cutting-edge imaging techniques have led to the increased adoption of SBRT in prostate cancer. Thus, from a practical standpoint, it is noninvasive and effective for treating prostate cancer, leading to increased access and higher patient satisfaction.

Two-fraction stereotactic MRI-guided ablative radiotherapy with simultaneous boost to dominant intraprostatic lesion: Results from the 2SMART phase 2 trial.

349 Background: Prostate stereotactic ablative radiotherapy (SABR) for localised prostate cancer is commonly delivered over 5 fractions. Focal boost to the dominant intraprostatic lesion (DIL) seen on multiparametric magnetic resonance imaging (mpMRI) is an approach for dose-escalation in prostate SABR. This is the first report of the outcomes of the 2SMART trial, a phase 2 single-arm study using 2-fraction prostate SABR with DIL boost. Methods: Men with low to intermediate risk prostate cancer were enrolled in the study. Three gold fiducial markers were inserted for image guidance. The clinical target volume (CTV) included the prostate gland, and the planning target volume (PTV) was a 2mm expansion antero-posterior and laterally, and 2.5mm supero-inferiorly. The DIL was contoured on fused mpMRI. The prescribed dose was 26Gy in 2 fractions (EQD2 110Gy, α/β of 1.4) to the CTV, and up to 32Gy in 2 fractions (EQD2 164Gy) to the DIL as long as the dose constraints for the organs at risks were not exceeded. Each fraction was delivered 1 week apart. Daily image guidance with cone-beam computed tomography was used pre- and post-treatment. The primary endpoint was acute (≤3 months) changes in quality of life (QOL), assessed using the EPIC questionnaire. Minimal clinically important change (MCIC) in QOL was defined as an EPIC score decrease of &gt;0.5 standard deviation of the baseline EPIC score for each domain. Secondary endpoints were acute and late toxicities (assessed using CTCAEv4), and biochemical failure (based on Phoenix criteria). Results: 30 men were enrolled in the study, of which 2 (7%) had low risk and 28 (93%) had intermediate risk prostate cancer. The median follow-up was 44 months (range: 39-49 months). The median PSA nadir was 0.2ng/mL, with median time to nadir of 37 months. One patient (3%) had biochemical failure at 44 months post-treatment. 1 (3%) and 17 (57%) had acute Grade 2 GU and GI toxicities, while 3 (10%) and 15 (50%) had late (&gt;6 months) Grade 2 GU and GI toxicities. No acute or late Grade ≥3 GU or GI was reported. 10 (33%), 6 (20%), and 3 (10%) men had acute MCIC in urinary, bowel and sexual domains respectively. 15 (50%), 9 (30%) and 13 (43%) had late MCIC in urinary, bowel and sexual domain respectively. Conclusions: Two-fraction prostate SABR with DIL boost is a safe approach for dose-escalation for localised prostate cancer, with minimal impact on acute QOL, and no grade 3-4 toxicities. Clinical trial information: NCT03588819 .

Upfront Advanced Radiotherapy and New Drugs for NSCLC Patients with Synchronous Brain Metastases: Is the Juice Worth the Squeeze? A Real-World Analysis from Lombardy, Italy

Healthcare administrative databases represent a valuable source for real-life data analysis. The primary aim of this study is to compare effectiveness and cost profile in non-small-cell lung cancer (NSCLC) patients harboring synchronous brain metastases (BMs) who received non-chemo first-line systemic therapy with or without advanced radiotherapy (aRT). Diagnostic ICD-9-CM codes were used for identifying all patients with a new diagnosis of lung cancer between 2012 and 2019. Among these, patients who had started a first-line systemic treatment with either TKIs or pembrolizumab, alone or in combination with intensity-modulated or stereotactic RT, were selected. Clinical outcomes investigated included overall survival (OS), progression-free survival (PFS), and time-to-treatment failure (TTF). The cost outcome was defined as the average per capita cumulative healthcare direct costs of the treatment, including all inpatient and outpatient costs. The final cohort included 177 patients, of whom 58 were treated with systemic treatment plus aRT (STRT) and 119 with systemic treatment alone. The addition of aRT to systemic treatment was associated with a significantly better OS (p = 0.020) and PFS (p = 0.041) than systemic therapy alone. The ICER (incremental cost-effectiveness ratio) value indicated an average cost of €3792 for each month of survival after STRT treatment and confirmed clinical effectiveness but higher healthcare costs. This real-world study suggests that upfront aRT for NCLSC patients with synchronous BMs represents a valid treatment strategy, boosting the efficacy of novel and emerging drug classes with sustainable costs for the health service. The present real-world study reports that the use of upfront advanced radiotherapyaRT and new-generation systemic agents, such as TKIs and pembrolizumab, may have higher oncological control and an improved cost-effectiveness profile than the use of new-generation systemic agents alone in NCLSC patients with synchronous brain metastases. Acquired evidence can also be used to inform policymakers that adding advanced radiotherapy results is a sustainable cost for the health service. Since approximately 50% of patients do not meet RCT inclusion criteria, a significant proportion of them is receiving treatment that is not evidence-informed; therefore, these results warrant further studies to identify the best radiotherapy timing and possible dose escalation approaches to improving treatment efficacy in patient subgroups not typically represented in randomized controlled trials.

Two-fraction stereotactic ablative radiotherapy with simultaneous boost to MRI-defined dominant intra-prostatic lesion – Results from the 2SMART phase 2 trial

PurposeThis is the first report of the 2SMART Phase II trial evaluating the safety of two-fraction stereotactic ablative radiotherapy (SABR) with focal boost to magnetic resonance imaging (MRI) defined dominant intra-prostatic lesion (DIL) for localised prostate cancer. Materials and methodsMen with low or intermediate risk prostate cancer were eligible for the study. The gross tumour volume (GTV) was MRI-defined DIL, and the clinical target volume (CTV) was entire prostate gland. The planning target volume (PTV) was a 2 mm expansion anteroposterior and lateral, and 2.5 mm superoinferior. The prescribed dose was 32 Gy to GTV, and 26 Gy to CTV. Primary endpoint was minimal clinically important change (MCIC) in quality of life (QOL) within 3-months of SABR, assessed using the EPIC-26 questionnaire. Secondary endpoints were acute and late toxicities (assessed using CTCAEv4), PSA nadir, and biochemical failure (based on Phoenix criteria). ResultsThirty men were enrolled in the study – 2 (7%) had low-risk and 28 (93%) had intermediate risk prostate cancer. The median follow-up was 44 months (range:39–49 months). The median PSA nadir was 0.25 ng/mL, with median time to nadir of 37 months. One patient (3%) had biochemical failure at 44 months post-treatment. Ten (33%), six (20%), and three (10%) men had acute MCIC in urinary, bowel, and sexual QOL domains respectively. No acute or late grade ≥ 3 urinary or bowel toxicities were observed. ConclusionThis novel protocol of two-fraction prostate SABR with MRI-defined DIL boost is a safe approach for dose-escalation, with minimal impact on acute QOL and no grade ≥ 3 toxicities.

Dose Escalation for Pancreas SBRT: Potential and Limitations of using Daily Online Adaptive Radiation Therapy and an Iterative Isotoxicity Automated Planning Approach

To determine the dosimetric limitations of daily online adaptive pancreas stereotactic body radiation treatment by using an automated dose escalation approach. We collected 108 planning and daily computed tomography (CT) scans from 18 patients (18 patients×6 CT scans) who received 5-fraction pancreas stereotactic body radiation treatment at MD Anderson Cancer Center. Dose metrics from the original non-dose-escalated clinical plan (non-DE), the dose-escalated plan created on the original planning CT (DE-ORI), and the dose-escalated plan created on daily adaptive radiation therapy CT (DE-ART) were analyzed. We developed a dose-escalation planning algorithm within the radiation treatment planning system to automate the dose-escalation planning process for efficiency and consistency. In this algorithm, the prescription dose of the dose-escalation plan was escalated before violating any organ-at-risk (OAR) dose constraint. Dose metrics for 3 targets (gross target volume [GTV], tumor vessel interface [TVI], and dose-escalated planning target volume [DE-PTV]) and 9 OARs (duodenum, large bowel, small bowel, stomach, spinal cord, kidneys, liver, and skin) for the 3 plans were compared. Furthermore, we evaluated the effectiveness of the online adaptive dose-escalation planning process by quantifying the effect of the interfractional dose distribution variations among the DE-ART plans. The median D95% dose to the GTV/TVI/DE-PTV was 33.1/36.2/32.4 Gy, 48.5/50.9/40.4 Gy, and 53.7/58.2/44.8 Gy for non-DE, DE-ORI, and DE-ART, respectively. Most OAR dose constraints were not violated for the non-DE and DE-ART plans, while OAR constraints were violated for the majority of the DE-ORI patients due to interfractional motion and lack of adaptation. The maximum difference per fraction in D95%, due to interfractional motion, was 2.5 ± 2.7 Gy, 3.0 ± 2.9 Gy, and 2.0 ± 1.8 Gy for the TVI, GTV, and DE-PTV, respectively. Most patients require daily adaptation of the radiation planning process to maximally escalate delivered dose to the pancreatic tumor without exceeding OAR constraints. Using our automated approach, patients can receive higher target dose than standard of care without violating OAR constraints.

Uproleselan Added to Cladribine Plus Low Dose Cytarabine (LDAC) in Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Background Treated secondary AML (TS-AML), arising after prior HMA-treated MDS, is associated with very poor prognosis (Complete Remission [CR] rates 15-30% and median Overall Survival [OS] 6-8 months). E-selectin ligand is highly expressed on AML blasts in the leukemic microenvironment and may be a marker of cell survival and resistance to chemotherapy. Exposure of leukemic blasts to HMAs has been shown to increase their expression of E-selectin ligand. Uproleselan is an E-selectin antagonist that overcomes resistance to chemotherapy in AML (Barbier, Nat Commun 2020). We sought to study the combination of low-intensity chemotherapy with Cladribine + LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance and improve outcomes in this difficult subset. Methods This is Phase Ib/II clinical trial (NCT04848974) to evaluate the safety, tolerability, and explore the efficacy of Uproleselan added to Cladribine and LDAC. A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at a fixed dose of 800mg intravenously [IV]) added to IV CLAD 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1, respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1, respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles. Pts aged ≥18 years with a diagnosis of TS-AML with adequate organ function, who have not received therapy for their AML were enrolled. TS-AML is defined as AML arising from a previously treated myeloid neoplasm. Presence of the E-selectin ligand was assessed using Flow Cytometry (FC). Results 10 pts have been treated, with 9 pts currently evaluable: 6 (67%) were male and the median age was 68 years (range, 58-80); at the start of therapy, the median bone marrow blasts were 33% (1-78%), median WBC was 2.2x109/L (0.6-20.1), median platelets were 18x109/L (4-305), and median creatinine was 0.98mg/dL (0.67-1.52). Pts had received a median of 1 (1-2) treatments prior to AML transformation. Prior diagnoses were: therapy-related Myelodysplastic Syndrome (t-MDS), Chronic Myelomonocytic Leukemia (CMML), MDS and MDS/MPN in 3 (33%), 3 (33%), 2 (22%) and 1 (11%) respectively; all had received HMA, 5 (56%) additionally had Ven and 3 (33%) had stem cell transplantation (SCT) prior to enrolling. All pts had unfavorable features by ELN 2017. The most frequent mutations were:SXL1, TP53 and TET2 in 4 pts each (44%), SRSF2 and NRAS in 3 patients each (33%) and SETBP1, RUNX1 and EZH2 in 2 patients each (22%). 6 pts were evaluable for E-selectin ligand expression; the median expression was 59% (42%-95%) and median MFI was 20.5 (13-262). The most common SAEs were ≥ grade 3 neutropenic fever (70%), (including 2 grade 5 events), grade 3 bleeding (10%), and grade 2 thrombosis (5%) (Table 1). There were no dose-limiting toxicities observed on dose levels -1 or 1. Two pts treated on dose level -1 die during the study follow-up due to sepsis within the first 4-weeks during induction. Median time to 0.5x109/L neutrophil and 50x109/L platelets recovery was 29 (17-39) and 38 (33-48) days respectively. The median follow-up is 4+ months. 8 pts were evaluable for response at the time of analysis. The ORR was 62% (5/8), including 2 (25%) PR, 1 (13%) CRi, 1 (13%) CRp and 1 (13%) MLFS. There was a reduction in BM blasts in 6 pts (75%) (Figure 1). 5 pts were taken off protocol due to progression, 2 for death, 1 for allogeneic SCT and 1 continued onto maintenance in remission. The one pt who achieved negative MRD, underwent SCT and is still alive. Median OS and EFS were 4.7 and 1.3 months respectively; 4-month RFS (CRi, CRp, and MLFS) was 67%. The median cycles received was 1 (1-3), median cycles at which the best response was achieved was 1 (1-2). The 4-month OS were 100% and 60% among responders vs. non-responders, respectively (p=0.27), and the 4-month EFS were 50% and 0% respectively (p=0.01). The ORR was 40% (2/5) (p=0.85) and 33% (1/3) (p=0.85) among pts who had prior Ven exposure or prior SCT, respectively. Conclusions The combination of Cladribine + LDAC with Uproleselan was overall well tolerated with few treatment-related AEs. The combination produced an ORR of 62% in a high-risk, refractory population whose prognosis is very dismal. The relationship of E-selectin ligand expression, response to treatment, and outcomes is being analyzed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

PurposeThe purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methodsPatients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. ResultsThere were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand–foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0–13.7) months in arm A, 8.6 (IQR 3.8–13.4) in arm B, and 7.1 (IQR 4.4–12.4) in arm C. ConclusionsThe alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifierNCT02835924.

Immunogenicity of biologics used in the treatment of inflammatory bowel disease.

Here we critically evaluate the literature on immunotherapy failure in inflammatory bowel disease patients. In particular anti-drug antibody production, and subsequently loss of response as the primary cause of immunotherapy failure in IBD patients. The benefits of shifting from the "standard" empirical dose escalation approach to therapeutic drug monitoring with anti-TNFα therapy is explored. The American Gastroenterology Association and British Society of Gastroenterology both currently recommend the use of reactive therapeutic drug monitoring to guide treatment, following loss of response in inflammatory bowel disease patients with active disease. However, further research is required to prove the efficacy of a proactive therapeutic drug monitoring approach alone in remitted IBD patients. A combination of personalised monitoring approach for anti-drug antibodies and therapeutic drug monitoring could provide beneficial treatment outcome for people with inflammatory bowel disease by predicting drug failure prior to clinical symptoms and allowing timely switching to an alternative drug.

Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients [PIRATES]: A Phase I safety and feasibility trial of MRI-guided adaptive particle radiotherapy

IntroductionRadiation dose-escalation for head and neck cancer (HNC) patients aiming to improve cure rates is challenging due to the increased risk of unacceptable treatment-induced toxicities. With “Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients” (PIRATES), we present a novel treatment approach that is designed to facilitate dose-escalation while minimizing the risk of dose-limiting toxicities for locally advanced HPV-negative HNC patients. The aim of this Phase I trial is to assess the safety & feasibility of PIRATES approach. MethodsThe PIRATES protocol employs a multi-faceted dose-escalation approach to minimize the risk of dose-limiting toxicities (DLTs): 1) sparing surrounding normal tissue from extraneous dose with intensity-modulated proton therapy, 2) mid-treatment hybrid hyper-fractionation for radiobiologic normal tissue sparing; 3) Magnetic Resonance Imaging (MRI) guided mid-treatment boost volume adaptation, and 4) iso-effective restricted organ-at-risk dosing to mucosa and bone tissues.The time-to-event Bayesian optimal interval (TITE-BOIN) design is employed to address the challenge of the long DLT window of 6 months and find the maximum tolerated dose. The primary endpoint is unacceptable radiation-induced toxicities (Grade 4, mucositis, dermatitis, or Grade 3 myelopathy, osteoradionecrosis) occurring within 6 months following radiotherapy. The second endpoint is any grade 3 toxicity occurring in 3–6 months after radiation. DiscussionThe PIRATES dose-escalation approach is designed to provide a safe avenue to intensify local treatment for HNC patients for whom therapy with conventional radiation dose levels is likely to fail. PIRATES aims to minimize the radiation damage to the tissue surrounding the tumor volume with the combination of proton therapy and adaptive radiotherapy and within the high dose tumor volume with hybrid hyper-fractionation and not boosting mucosal and bone tissues. Ultimately, if successful, PIRATES has the potential to safety increase local control rates in HNC patients with high loco-regional failure risk.Trial registration: ClinicalTrials.gov ID: NCT04870840; Registration date: May 4, 2021.Netherlands Trial Register ID: NL9603; Registration date: July 15, 2021.

A novel approach for radiotherapy dose escalation in rectal cancer using online MR-guidance and rectal ultrasound gel filling – Rationale and first in human

IntroductionDose escalated radiotherapy has previously been investigated as a strategy to increase complete response rates in rectal cancer. However large safety margins are required using cone-beam computed tomography guided radiotherapy leading to high doses to organs at risk or insufficient target volume coverage in order to keep dose constraints. We herein present the first clinical application of a new technique for dose escalation in rectal cancer using online magnetic resonance (MR)-guidance and rectal ultrasound gel filling. MethodsA 73-year-old patient with distal cT3a cN0 cM0 rectal cancer was referred for definitive radiochemotherapy with the goal of organ preservation after multidisciplinary discussion. A dose of 45 Gy in 25 fractions with a stereotactic integrated boost to the primary tumor of 50 Gy with concomitant 5-fluorouracil was prescribed. Furthermore, a boost to the primary tumor with 3 Gy per fraction using the adapt-to-shape workflow on a 1.5 T MR-Linac was planned once weekly. For the boost fractions 100 cc of ultrasound gel was applied rectally in order to improve tumor visibility and distancing of uninvolved rectal mucosa. In order to determine the required planning target volume margin diagnostic scans of ten rectal cancer patients conducted with rectal ultrasound gel filling were studied. ResultsBased on the ten diagnostic scans an average isotropic margin of 4 mm was found to be sufficient to cover 95% of the target volume during an online adaptive workflow. Three boost fractions were applied, mean treatment duration was 22:34 min. Treatment was well tolerated by the patient with no more than PRO-CTCAE grade I° toxicity of any kind. The rectal ultrasound gel filling resulted in superior visibility of the tumor and reduced the dose to the involved mucosa especially in the high dose range compared with a boost plan calculated without any filling. A considerable tumor shrinkage was observed during treatment from 17.43 cc at baseline to 4 cc in week four. ConclusionThis novel method appears to be a simple but effective strategy for dose escalated radiotherapy in rectal cancer. Based on the encouraging observation, a prospective trial is currently under preparation.