Slow Accrual Research Articles

Abstract P2-21-02: Longitudinal tumor-immune microenvironment changes in patients with clinical luminal A early breast cancer treated with neoadjuvant palbociclib and endocrine therapy: results from the Swedish randomized PREDIX Luminal A trial

Abstract Introduction: The use of preoperative CDK4/6 inhibitors combined with endocrine treatment remains investigational in breast cancer (BC), while their effect on tumor-immune microenvironment (TIME) in luminal BC is the subject of few published studies. The aim of this study was to characterize the treatment-induced changes of TIME at a spatial proteomic and bulk tumor transcriptomic level in clinical luminal A BC patients treated with neoadjuvant palbociclib and endocrine treatment. Methods: The PREDIX Luminal A phase II randomized clinical trial (NCT02592083) included patients with stage 2-3 BC and IHC-defined luminal A biology (ER+ and PR+, HER2-, low proliferation) treated with preoperative ET (tamoxifen or aromatase inhibitor) with or without the addition of CDK4/6i palbociclib, based on the early change of Ki67 levels. A core biopsy was obtained at baseline, after 10 weeks of treatment (on-treatment) and at surgery. The study was closed after the inclusion of 10 patients due to slow accrual. By using formalin-fixed paraffin-embedded tissue from all timepoints, we performed the GeoMx® Digital Spatial Profiling (DSP, NanoString, Seattle, WA, USA) for the spatial profiling of 27 immune cell and tumor markers (immune cell profiling core and pan-tumor panels) both at intra-epithelial and stromal tissue segments. Upon data normalization, a linear mixed model was adopted for differential marker expression assessment between the different timepoints and treatment arms, using the DSP Suite® software. RNA was also extracted from fresh-frozen biopsies and the nCounter® Breast Cancer 360™ panel (NanoString) was used for gene expression profiling of 776 targets and data analysis was performed using the nSolver® software. Results: A total of 7 patients received palbociclib + ET and 3 were treated with ET only. All patients experienced an on-treatment radiological partial response while no patient achieved pathological complete response. While ET suppressed the ER axis in both palbociclib-treated and untreated patients, treatment with palbociclib additionally led to cell-cycle arrest as evidenced by a decrease in proliferation and downregulation of cell-cycle gene pathways. Immune-related protein markers were enriched in the stroma segments and pan-tumor markers were enriched in the intra-epithelial segments at all timepoints. In palbociclib-treated patients, immune cell markers (e.g. CD45, CD68, CD20, CD4, HLA-DR) were significantly enriched in on-treatment samples (n=3) both in tumor and stromal segments, while these expression changes were reversed between on-treatment and surgery. In the ET-treated patients immune markers reflecting e.g. T-, B- and/or antigen-presenting-cells were significantly enriched at the operation samples (n=2), in the intra-epithelial but not in the stromal areas. This finding was confirmed also at the gene level, where immune-related pathways (e.g. chemokine and cytokine activity and receptor binding) were upregulated in the palbociclib-treated patients on-treatment but they were partially abrogated at surgery. The ET-only treated patients presented with enhanced immune activation gene sets at both on- and post-treatment timepoints Conclusion: The findings of this small hypothesis-generating study indicate an upregulation of immune function during treatment with palbociclib and ET and an altered tumor microenvironment. The prognostic and potential therapeutic implications of sensitizing tumors to subsequent chemotherapy and immunotherapy need to be further investigated in larger studies. Citation Format: Ioannis Zerdes, Dimitrios Salgkamis, Alexios Matikas, Lars Selander, Kang Wang, Evangelos Tzoras, Emmanouil Sifakis, Susanne Agartz, Xinsong Chen, Mats Hellström, Johan Hartman, Jonas Bergh, Theodoros Foukakis, Thomas Hatschek. Longitudinal tumor-immune microenvironment changes in patients with clinical luminal A early breast cancer treated with neoadjuvant palbociclib and endocrine therapy: results from the Swedish randomized PREDIX Luminal A trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-21-02.

A prospective randomized crossover trial of systemic chemotherapy in patients with low-grade mucinous appendiceal adenocarcinoma.

163 Background: Appendiceal adenocarcinoma is both a rare and heterogenous tumor, with marked contrast in the natural history of low-grade and high-grade tumors (5-year OS 68% for low-grade vs. 7% for high-grade). While low-grade appendiceal adenocarcinoma is primarily treated with surgical resection sometimes followed by hyperthermic intraperitoneal chemotherapy (HIPEC), many inoperable candidates are treated with systemic chemotherapy although there is no prospective data supporting this practice. The purpose of our study was to objectively evaluate the effectiveness of systemic chemotherapy in low-grade mucinous appendiceal adenocarcinoma. Methods: A randomized crossover trial of surgically unresectable low-grade (well differentiated) mucinous appendiceal adenocarcinoma was performed with patients randomized to either 6 months observation followed by 6 months of chemotherapy (physician’s choice), or initial chemotherapy followed by observation. In this way each patient would serve as their own control. Enrollment of 30 patients was planned to have complete 6- and 12-month tumor measurements for 24 patients, providing 80% power at 0.05 significance level to detect a 5.0% difference in change in tumor size as measured by peritoneal RECIST in observation vs. treatment periods. Results: The trial closed early due to slow accrual. A total of 24 patients were enrolled. The majority of patients were treated with either 5FU or capecitabine (n = 15, 63%), bevacizumab was added for 3 (13%), and 3 were treated with doublet chemotherapy (FOLFOX/FOLFIRI). 15 patients who completed both treatment and observation periods were available for the primary analysis, the mean difference in tumor size was -4.5% (95% CI: -12.6, 3.7), indicating a slight trend towards faster growth on treatment than observation. This difference was not statistically or clinically significant (8.4% growth on treatment vs. 4.0% observation, p=0.26). Of the 18 patients who received any chemotherapy during the study period, zero achieved an objective response, 14 (77.8%) had stable disease during the entire year of follow up, and 4 (12.2%) had progression on study. Patient reported quality of life metrics identified that fatigue (p=0.02), peripheral neuropathy (p=0.014), and financial difficulty (p=0.0013) were all significantly worse while on treatment. There was not a significant difference in rate of bowel obstruction between the treatment first vs. observation first arms (12.5%, (n=3) vs 8.3%, (n=2)). Conclusions: These data from a prospective, randomized crossover trial indicate that patients with low-grade mucinous appendiceal adenocarcinoma do not derive benefit from 5FU based chemotherapy but do incur toxicity. These data further highlight the unique biology of low-grade appendiceal cancer and demonstrates the need to identify novel systemic therapies for this patient population. Clinical trial information: NCT01946854 .

HCRN GI16-288: A phase II trial of perioperative CV301 vaccination in combination with nivolumab and systemic chemotherapy for resectable hepatic-limited metastatic colorectal cancer—Preliminary efficacy and correlative results.

103 Background: Novel strategies to improve the efficacy of immune checkpoint inhibitors in microsatellite stable (MSS) mCRC are needed. CV301 is a vector-based vaccine that expresses carcinoembryonic antigen (CEA) and mucin 1 (MUC1), and in a phase II study in resected hepatic limited mCRC significantly improved OS compared with unvaccinated contemporary controls. Methods: In this multi-center randomized phase II study, patients with previously untreated resectable hepatic-limited mCRC were randomized to perioperative nivolumab + mFOLFOX +/- CV301 (Arm B) with a primary endpoint of 3-year OS. Treatment included mFOLFOX-nivo (+/- CV) x 4 cycles followed by resection, then 8 more cycles of mFOLFOX-nivo followed by maintenance nivo monthly for two years in both arms, and CV boosters concurrently with mFOLFOX, and then every 3 months for two years in arm B. Secondary endpoints of ORR (following induction pre-resection), PRR, and safety were determined. Correlative analyses included immune cell quantification using Immunoscore and T-cell clonality. Results: 17 patients were enrolled prior to premature closure for slow accrual (8 arm A, 9 arm B). At the time of data cutoff, 5 patients remained on treatment and no deaths had occurred. One patient was removed from study due to protocol non-compliance. The median age was 61, majority were male (59% vs 41%), and ECOG PS 0-1 (71% 0, 17% 1). All patients had complete surgical resection. Four patients (24%) experienced a SAE related to drug. The TRAE rate was 40.3%,. No AEs delayed/prevented surgical resection. The ORR in arm A was 50% (including 4 CR) and 87.5% in arm B (including 7 CR) (p=0.129, NS). There was no significant difference in pathologic response (p=0.9047). Correlative analyses demonstrated the Immunoscore CD3/CD8 predicted response to mFOLFOX + nivolumab, but did not correlate with response to CV301, though CV301 may induce a shift to predominantly cytotoxic CD8+ T cells. While there was no significant difference in T cell repertoire, clonality, fraction (TCFr) or richness, patients in arm B had significant decreases in blood TCFr and increase in tumor TCFr with treatment; those with CR had higher TCFr and clonality. Conclusions: The addition of CV301 to perioperative nivolumab and mFOLFOX was safe, did not delay or prevent surgical resection, and gave a higher response (p=ns due to sample size). Changes in T cells suggest a vaccine response. Clinical trial information: NCT03547999 . [Table: see text]

18F-FDG-PET guided vs whole tumour radiotherapy dose escalation in patients with locally advanced non-small cell lung cancer (PET-Boost): Results from a randomised clinical trial

Background and purposeWe aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer. Materials and methodsPatients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions.The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II ‘pick-the-winner’ design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. ClinicalTrials.gov:NCT01024829. Results150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91–100) in whole tumour group, and 91 % (95 %CI 82–100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group. ConclusionBoth strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

Dexamethasone to prevent everolimus-induced stomatitis (Alliance MIST Trial: A221701)

mTOR inhibitors such as everolimus may cause oral stomatitis, often a dose-limiting toxicity. Prior clinical research has suggested that a dexamethasone mouth rinse might help prevent and/or treat this. Alliance A221701 was a randomized phase III trial of patients initiating 10 mg daily oral everolimus that compared dexamethasone mouthwash taken preventively (initial dexamethasone group) versus therapeutically (initial placebo group) to assess two coprimary endpoints: the incidence of mTOR inhibitor-associated stomatitis (mIAS), and the area under the curve (AUC) of mIAS-associated pain over an 8-week treatment period. A Fisher's exact test was used to compare the incidences while a Wilcoxon rank-sum test was used to compare the AUCs. In addition, we performed an exploratory analysis of the association of everolimus trough concentrations and toxicity using a Mann-Whitney U test. Due to slow accrual, this study closed after 39 patients were randomized (19 to upfront placebo and 20 to upfront dexamethasone). There were no significant differences between groups seen in either of the coprimary endpoints; furthermore, we found no association between whole blood everolimus trough concentrations and toxicity. Although limited by poor enrollment, the results of this study do not suggest that prophylactic dexamethasone mouthwash is superior to therapeutic dexamethasone mouthwash (initiated at the first sign of mouth pain) for reducing the incidence or severity of mIAS from everolimus.

BRACHY: A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy

Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power. A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P=.84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P=.49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P=.03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups. Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms.

Gimema ALL2418: Interim Analysis of a Phase Iia Study of Feasibility and Effectiveness of Inotuzumab Ozogamicin in Adult Patients with B-Cell Acute Lymphoblastic Leukemia with Positive Minimal Residual Disease before Any Hematopoietic Stem Cell Transplantation

Background: Persistence of minimal residual disease (MRD) is associated with a high rate of treatment failure, relapse, and death in B-cell acute lymphoblastic leukemia (B-ALL). Particularly, patients who remain MRD positive before an allogeneic hematopoietic stem cell transplant (HSCT) have an expected disease-related death rate due to the disease of about 60%. The T cell-engager CD19-directed therapy blinatumomab demonstrated considerable efficacy in this setting, however resistant or unsuitable patients have no alternative therapy. Inotuzumab Ozogamicin (IO) is a CD22-directed antibody-drug conjugate with remarkable efficacy in B-ALL with overt disease. Furthermore, IO does not need a high effective immune system to exert activity. Methods: In this multicenter phase 2 trial (NCT03610438), we are investigating the efficacy of IO in obtaining MRD negativity in two cohorts of 38 Ph+ and 38 Ph- B-ALL patients. IO was administered at the dose of 0.5 mg/sqm on days 1, 8, and 15 of a 28-days cycle. Patients who did not obtain MRD negativity after the 1st IO cycle had the option to receive the 2nd IO cycle maintaining the same dosage. Responding Ph- patients received short-term maintenance with low-dose chemotherapy (alternating vincristine, cyclophosphamide, prednisone, methotrexate, and 6-mercaptopurine), responding PH+ patients received tyrosine kinase inhibitor (TKI) for up to 12 weeks, allowing proper IO washout before HSCT. HSCT ineligible patients entered into low-dose chemotherapy or TKI maintenance for up to 2 years. For the primary endpoint, MRD was centrally assessed at baseline, after course 1, after course 2, and eventually before transplant with high sensitive molecular methods for BCR-ABL1 or V(d)J fusion transcripts. Here, we present the results of an unplanned interim analysis that was generated to evaluate the continuation of the study considering the slow accrual due to the Sars-COV2 pandemic. Results: To date, 51 patients underwent screening procedures, and 43 were considered eligible. We report data from the first 39 patients treated in the study. Nineteen out of 39 patients had Ph- B-ALL and 20/39 Ph+ B-ALL. Eighteen out of 39 (46%) patients were male. The median age was 55 years (22-84), 15/39 patients (38%) were older than 65 years. Demographics were comparable between Ph+ and Ph- patients. Within Ph+, ALL 39% of patients harbored p190 and 61% p210 fusion transcript. Within Ph- B-ALL, 1 patient harbored ALL1/AF4 and 1 patient harbored ALL1/ENL fusion transcript. Most of the patients received 1 (16/39, 42%) or 2 (19/39, 50%) previous lines of therapy; 5 patients (13%) were resistant to blinatumomab, and all of them had Ph- B-ALL. Twelve out of 19 (63%) Ph- B-ALL patients received only 1 IO cycle, 7/19 (37%) received 2 cycles; 5/20(25%) Ph+ B-ALL received only 1 IO cycle, and 15/20 (75%) received 2 cycles. To date, central MRD monitoring is available for 20 patients (12 Ph- and 8 Ph+ B-ALL, ongoing for the remaining cases). Overall, MRD negativity was obtained in 7/20 patients (35%); Particularly, in Ph- B-ALL cohort 5/12 (42%) patients achieved MRD negativity, 4/12 (38%) achieved disease reduction at low level MRD positivity (<10-4); in Ph+ B-ALL cohort, 2/8 (25%) patients achieved MRD negativity. One out of 5 (20%) blinatumomab pre-treated patients obtained MRD negative response. IO was an effective bridge to HSCT for 10/39 patients (26%; in patients <65 years old, 9/24 patients, 37%); Specifically, all 7 patients who obtained MRD negativity after IO, a patient with low-positive MRD and 2 patients with non yet available MRD data were bridged to HSCT. Accordingly, with the caveat of a short median follow-up (2.8 months, range 0.6-20.0 months), overall survival in the study population seems promising (figure 1, median OS not reached). Overall, adverse events collected during the study were limited in number and grading. Also, myelotoxicity was manageable. Out of 39 patients, we documented 1 veno-occlusive disease (2.5%) that occurred within 20 days from the last IO dose and before any HSCT. Conclusions: IO administration demonstrated activity with a good safety profile in the setting of MRD positive B-ALL, including blinatumomab resistant patients. Importantly, IO was capable to bridge 37% of eligible patients to HSCT, augmenting the chance to achieve a cure. The continuation of the study will deliver mature efficacy and survival data for a proper evaluation of this promising strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Canadian Cancer Trials Group (CCTG) LY.17: A Randomized Phase II Study Evaluating Novel Salvage Therapy Pre-Autologous Stem Cell Transplant (ASCT) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (RR-DLBCL) - Outcome of Rituximab-Dose-Intensive Cyclophosphamide, Etoposide, Cisplatin (R-DICEP) Versus R-GDP

Introduction: The CCTG LY.12 trial established rituximab combined with gemcitabine, dexamethasone and cisplatin (R-GDP) as a standard salvage chemotherapy option prior to ASCT for patients (pts) with relapsed/refractory (RR) DLBCL (Crump JCO 2014). CCTG LY.17 is an ongoing multi-arm randomized phase II "pick a winner" trial evaluating novel salvage therapy compared with R-GDP in ASCT-eligible RR-DLBCL pts. Methods: The primary endpoint of the study is overall response rate (ORR) using CT imaging. According to the protocol futility rule, any treatment arm with an ORR lower than the R-GDP control arm at the first interim analysis (n = 16), or less than 10% higher at the second interim analysis (n=32) would not continue to full target accrual of 64 pts per treatment arm. Encouraging results could then be pursued in a larger phase III trial designed to detect differences in progression-free survival (PFS). This report involves the component of the trial that randomly allocated pts to either 1 cycle of inpatient R-DICEP (Rituximab 375mg/m2 IV or 1400mg sc days 1 and 5 plus dose-intensive Cyclophosphamide 5.25g/m2, Etoposide 1050mg/m2, Cisplatin 105mg/m2 divided over days 2-4, with daily filgrastim starting day 15 until apheresis of blood stem cells approximately between days 20-22) or to 3 cycles of outpatient R-GDP. This report is the result of the protocol-specified second interim analysis. Results: A total of 67 pts were randomized to R-DICEP (n=32) or to R-GDP (n=35) between April 2016 and April 2021. Table 1 lists baseline pt characteristics. Four pts (R-DICEP=2, R-GDP=2) were not evaluable for response. The ORR was 65.6% for R-DICEP (70.0% for evaluable pts), which was 17% greater than the ORR of 48.6% for R-GDP (51.5% for evaluable pts). Additionally, only 1 (3.1%) R-DICEP pts versus (vs) 11 (31.4%) R-GDP pts experienced progressive disease as best response to salvage therapy. Of interest, the ORR to salvage was 40% (14/35) for pts primary refractory to RCHOP (no response to RCHOP or progressive disease during or <3mo post RCHOP) vs 75% (24/32) for those who relapsed >3mo post RCHOP (p=0.006), with ORR to R-DICEP of 50% vs 81.3% and ORR to R-GDP of 31.6% vs 68.8% for primary refractory vs relapse >3mo, respectively. The ORR based on PET-CT scan was 50.0% vs 31.4% for the R-DICEP (n=26) vs R-GDP (n=25) arms, respectively. Overall, 23 (71.9%) R-DICEP pts and 19 (54.3%) R-GDP pts underwent ASCT. In total, 26 out of 27 (96.3%) R-DICEP, and 18 out of 20 (90%) R-GDP pts underwent successful autologous blood stem cell collection (requiring >1 attempt in 0 R-DICEP and 2 R-GDP pts). The median time to neutrophil engraftment post-ASCT was 13 (1-32) and 12 (1-22) days, and to platelet engraftment was 12 (1-50) and 16 (7-22) days for R-DICEP and R-GDP pts, respectively. Regarding adverse events (AEs) of salvage therapy and subsequent ASCT, R-DICEP pts had higher rates of culture positive infection (84% vs 40%), platelet (96.6% vs 60.0%) and red cell (75.0% vs 42.9%) transfusions, diarrhea (44% vs 14%), serious adverse events (50% vs 34.3%), and treatment-related mortality (3.1% vs 0%) but similar rates of other AEs including arrhythmia (6% vs 9%), bleeding (0 vs 0), fungal infections (0 vs 0) and pneumonitis (0 vs 0). At a median duration of follow-up of 26.9 months (R-DICEP 26.4 months and R-GDP 27.4 months), the 1-year PFS rate was 42% for R-DICEP and 32% for R-GDP (HR 0.59, 95%CI: 0.32-1.09, logrank p=0.09), and 1-year OS rate was 65% for R-DICEP and 55% for R-GDP (HR 0.675, 95%CI: 0.333-1.369, logrank p=0.27). Conclusions: Although the 17% improvement in ORR for R-DICEP vs R-GDP in the second interim analysis exceeded the pre-specified 10% threshold required proceed to full accrual of 64 pts in the R-DICEP arm, we decided to stop accrual to the R-DICEP arm of the LY.17 trial due to slow accrual, higher AE rates, and greater utilization of healthcare resources including hospitalization needed to administer treatment, which limits feasibility of R-DICEP at several Canadian centres. The LY.17 trial continues testing other salvage regimens. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lenalidomide-Rituximab or Lenalidomide-Rituximab-Bendamustine in Patients with Relapsed/Refractory Follicular Lymphoma: Priimary Analysis of the Randomized Phase II HOVON110/Rebel Trial

Introduction The R2 regimen (lenalidomide-rituximab) is effective in treatment-naive and relapsed/refractory follicular lymphoma (R/R FL). Combining R2 with bendamustine (R2B) is feasible (Stevens WBC et al., Hemasphere 2020) and hypothesized to deepen remission and prolong event-free survival (EFS) compared to historic controls. We performed a randomized phase II trial of R2 and R2B, aiming at identifying the most promising arm to take forward to a randomized phase III trial. Methods In the multicenter, prospective, randomized, non-comparative phase II part of the HOVON110/ReBeL study (Dutch Clinical Trial Register NTR3028), patients (pts) with FL relapsed after ≤5 prior therapies were randomized 1:1 to R2 (Arm A) or R2B (Arm B). Stratification factors used were FLIPI score (0-2 vs 3-5), number of prior treatments (1 vs 2-5), prior bendamustine use and relapse during rituximab maintenance (RM). Arm A pts received 6 cycles of R2 q28 days (lenalidomide 20 mg day 1-21, rituximab 375 mg/m2 day 1); Arm B pts received 6 cycles of R2B q28 days (lenalidomide 20 mg day 3-21, rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 day 1,2). In both arms, pts with partial or complete remission (PR/CR) received 2 years of RM treatment, once every three months. Subcutaneous rituximab was allowed. Thrombosis prophylaxis was advised during induction; antimicrobial prophylaxis with valaciclovir and cotrimoxazole was mandatory in arm B. Arms A and B were separately evaluated for efficacy and toxicity. Co-primary endpoints were CT-based CR rate according to Cheson 2007 criteria at end of induction (EOI) and incidence of severe toxicities (ST), defined as grade ≥ 3 non-hematological toxicity, specified grade 4 hematologic toxicity (neutropenia lasting ≥ 7 days despite GCSF, febrile neutropenia, thrombocytopenia) or non-lymphoma related death. An event for event-free survival was defined as induction failure, progression, relapse or death from any cause. PET-CT was performed before and after induction. Central pathology and blinded central PET-CT review (Lugano classification) were performed. Results Between 2014 and 2019, 92 of 150 planned pts were randomized. The trial was stopped early because of slow accrual. Two pts (1 in each arm) were ineligible. Baseline characteristics were comparable between Arms A/B in terms of gender and median age (64/62 years). Most pts had stage III/IV disease (85%/80%), an intermediate/high risk FLIPI score (78%/89%) and had undergone 1 prior treatment (75%/76%; range 1-5). For pts in arms A/B, 80%/76% completed all 6 induction cycles and 41%/43% completed 8 cycles of RM. Main reasons for discontinuation during induction were progressive disease (PD) (n=4 per arm) and toxicity or other reasons in 5/7 patients. Severe toxicity (ST) occurred in 3 pts in arm A (6.8%; 2 fatal pneumonia cases) and in 6 pts in arm B (13.0%; no fatalities), while 43%/66% of pts experienced any grade 3-4 AE (2%/7% grade 4). These comprised mainly skin toxicity, infections and gastrointestinal toxicity. In the R2B arm, 1 pt had Pneumocystis carinii pneumonia during RM. Based on intention to treat (ITT) and local CT assessment (efficacy co-primary endpoint), 16% of R2 and 22% of R2B treated pts achieved a CR at EOI; the overall response rate (ORR) was 70% and 72%, respectively. The complete metabolic remission rate (CMR) by central PET-CT review at EOI was 48% and 54%. At a median follow-up of 48 months (mo), EFS was 39% and 61%; median EFS was 24.6 mo and not reached (NR). Importantly, median time to next treatment (TTnT) was 9.2 mo and NR. There were 7 second primary malignancies (SPM) in 5 pts in Arm A) and 5 SPM in 4 pts in Arm B). Overall survival was excellent in both arms with 72% and 91% of pts alive at 48 months. Causes of death during the study were progression of FL (n=8) and toxicity (n=3) in Arm A; FL (n=3), toxicity (n=1) and suicide (n=1) in Arm B. Conclusions This randomized non-comparative phase II trial of R2 and R2B in R/R FL patients showed high CT-based OR rates and PET-CT CMR rates, but low CT-based CR rates for both treatments. At a median FU of 48 months, 39% of R2 treated patients and 61% of R2B treated patients were still alive and in remission; this compares favorably with historic real world controls (Batlevi et al, Blood Cancer J 2020). Both regimens were associated with less severe toxicity than expected (pre-set acceptability threshold of 20% ST), supporting further investigation of R2 combinations in randomized phase III trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

LUSTRE: A Phase III Randomized Trial of Stereotactic Body Radiotherapy (SBRT) vs. Conventionally Hypofractionated Radiotherapy (CRT) for Medically Inoperable Stage I Non-Small Cell Lung Cancer (NSCLC)

Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02

AimsTo evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. Materials and methodsLARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. ResultsBetween November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1–2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. ConclusionThe addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.

Phase III Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection for Colon Cancer: An Intergroup Trial of the ECOG-ACRIN Cancer Research Group (E1292)

BackgroundStudies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer.Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy.ResultsFrom August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

ISABR: Safety and Efficacy Results from a Phase II Study of SABR in Combination with Durvalumab for Early-Stage Medically Inoperable NSCLC

<h3>Purpose/Objective(s)</h3> SABR is standard for medically inoperable early-stage NSCLC and results in excellent outcomes. However, rate of regional and distant failures is significant. Addition of immune check point inhibitors improve disease control and overall survival in stage III and IV NSCLC and may improve outcomes in early-stage NSCLC. We report safety and efficacy results of a phase II study of SABR with durvalumab (durva) in early-stage inoperable NSCLC. <h3>Materials/Methods</h3> Eligible patients had newly diagnosed, biopsy proven clinical stage I or IIA NSCLC defined by AJCC 7^th edition. Patient had to be medically inoperable or refused surgery. There was a 15-patient safety lead-in cohort with pre-specified stopping rules based on incidence of grade 3 or 4 treatment-related toxicity. Patients were treated with one cycle of durva at the time of CT simulation, followed by SABR (54 Gy in 3, 50 Gy in 4, or 65 Gy in 10), then up to 4 cycles of durva (1500 mg Q4 wk). No stopping rules were met, but due to slow accrual, the study terminated prematurely in the randomized Phase II portion (1:1; SABR/durva: SABR). A total of 20 patients were enrolled from October 2017 - March 2020. Eighteen patients received SABR/durva and thus form the cohort for analysis. Local control (LC), progression-free survival (PFS), overall survival (OS), and lung cancer specific survival (LCSS) were assessed using the Kaplan Meier method. Incidences of acute (≤ 90 days) and late (> 90 days) treatment-related grade 3+ pulmonary, cardiac, and GI toxicities were tabulated. <h3>Results</h3> Median age was 78.6 years-old with 61% male. Median follow-up time was 2.6 years. Seventy-two percent of the patients had T1 tumor and remaining had T2. Eighty-three percent of the patients had adenocarcinoma histology and remaining had squamous cell. Eighty-nine percent of the patients were former/current smokers. Seventy-eight percent of patients received all 5 cycles of durva, 1 patient received 3 cycles, and 2 patients received 1 cycle. The 1-, 2- year LC rates were 100% and 93.8%, PFS rates were 94.4% and 83.3%, and OS rates were 94.4% and 88.9%. The 2-year cumulative incidence for LCSS was 94.4%. At 2-years, stratified by median gross tumor volume (GTV), OS was 100% (GTV ≤ 7.9 mL) vs. 77.8% (GTV > 7.9 mL), p=0.07. Acute and late grade 3+ treatment-related toxicities were pulmonary (n=3, 16.7%; n=3, 16.7%), cardiac (none; n=3, 16.7%), and GI (none). There was one case of grade 4 pneumonitis. One patient retrospectively identified as having probably fibrotic lung disease at baseline died of respiratory failure, which was conservatively assessed as possibly related to study treatment. <h3>Conclusion</h3> For early-stage NSCLC, SABR/durva resulted in excellent disease specific outcomes, including survival. Safety was promising, but this study underscored the importance of excluding patients with any fibrotic lung disease for safety and optimal interpretation of adverse event data. Results support ongoing phase III trials determining the benefit of SABR/durva in these patients.

Recording and reporting of recruitment strategies in trial protocols, registries, and publications was nonexistent

ObjectivesTo investigate how trialists record and report their recruitment strategies and the recruiter details in trial protocols, registries, and publications. Study Design and SettingA retrospective study of ovarian cancer (OC) trials between 2010 and 2021. We reviewed 154 trial publications, 30 protocols, 105 registry entries, and 26 trial websites associated with 88 phase III OC trials. ResultsNone of the 88 trials reviewed published a recruitment strategy or made reference to an available recruitment strategy for the trial. Only 31% (n = 28) made reference to the recruiter but this was reported only in the protocol so we have no evidence these named recruiters performed the task. None of the trials reviewed which closed early or extended recruitment timelines due to slow accrual, reported measures taken to improve recruitment rates before stoppages or changes took place. There were disparities in the reported target recruitment numbers between the protocol, the publication, and the registry. ConclusionRecruitment strategies exist, and we are sure most trial centers use recruitment strategies, but they need to be recorded and reported, as part of the supplementary material if not the main publication, so we can evaluate their effectiveness.

Impact of a mobile application (reminder app) on acute toxicity during radiotherapy of head-and-neck cancer – results of a randomized phase III trial (RAREST-02)

BackgroundRadiotherapy of head-and-neck cancer (SCCHN) is often associated with acute toxicity. In a previous trial, daily reminders by staff members to perform skin care resulted in less dermatitis. This randomized trial investigated whether a mobile application can replace these reminders.MethodsPatients were stratified according to tumor site, treatment and center. Fifty-three patients were eligible for per-protocol-set (25 with, 28 without app). Primary endpoint was grade ≥ 2 dermatitis until 60 Gy. Secondary endpoints included dermatitis grade ≥ 2 until end of radiotherapy (EOT), dermatitis grade ≥ 3, and mucositis grade ≥ 2 and ≥ 3.ResultsAfter an interim analysis, the study was terminated (delayed and slow accrual). Until 60 Gy, grade ≥ 2 dermatitis rates were 72% with vs. 82% without app (p = 0.38), grade ≥ 3 dermatitis rates 20% vs. 11% (p = 0.45). Until EOT, grade ≥ 2 and ≥ 3 dermatitis rates were 72% vs. 86% (p = 0.22) and 24% vs. 18% (p = 0.58). Until 60 Gy, grade ≥ 2 and ≥ 3 mucositis rates were 76% vs. 82% (p = 0.58) and 20% vs. 36% (p = 0.20). Until EOT, corresponding mucositis rates were 76% vs. 82% (p = 0.58) and 28% vs. 43% (p = 0.26).ConclusionGiven the limitations of this trial, the reminder app led to non-significant reduction of grade ≥ 2 dermatitis, grade ≥ 2 mucositis and ≥ 3 mucositis. Additional studies are required to define the value of reminder apps during radiotherapy for SCCHN.

Phase 1 Randomized Trial of Stereotactic Body Radiation Therapy Followed by Nivolumab plus Ipilimumab or Nivolumab Alone in Advanced/Unresectable Hepatocellular Carcinoma

Immunotherapy has emerged as a promising therapeutic option for advanced or unresectable hepatocellular carcinoma (HCC). However, survival remains poor with only a subset of patients deriving benefit. This trial investigated the safety and efficacy of stereotactic body radiation therapy (SBRT) with immunotherapy in HCC. In this multicenter phase 1 randomized trial, patients with advanced or unresectable HCC received liver SBRT (40 Gy in 5 fractions) followed by either nivolumab alone or nivolumab plus ipilimumab. The primary endpoint was dose-limiting toxicity occurring within 6 months of SBRT. Secondary endpoints included overall response rate, progression-free survival, overall survival (OS), distant disease control, and local control of the irradiated tumor. Disease status and response endpoints were assessed radiographically every 8 weeks until progression or initiation of nonprotocol therapy. Response was determined using both RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 and iRECIST. Fourteen patients were enrolled across 3 centers. Thirteen patients were evaluated for study endpoints. The study was closed early because of slow accrual. The median follow-up time was 42.7 months. Dose-limiting toxicities within 6 months occurred in 2 (15.4%) of 13 patients: 1 of 6 patients in the nivolumab arm (16.7%; 90% confidence interval [CI], 0.9%-58.2%) and 1 of 7 patients in the nivolumab plus ipilimumab arm (14.3%; 90% CI, 0.7%-52.1%). Grade 3 adverse events occurred in 8 (61.6%), 5 (71.4%), and 3 (50.0%) patients in the overall nivolumab plus ipilimumab and nivolumab cohorts. Grade 3 hepatotoxicity occurred in 4 (30.8%), 3 (42.9%), and 1 (16.7%) patients in the respective cohorts. Clinical outcomes favored the nivolumab plus ipilimumab arm compared with nivolumab alone, including an overall response rate of 57% (4 of 7 patients; 90% CI, 23%-87%) versus 0% (0 of 6 patients; 90% CI, 0%-39%), median progression-free survival of 11.6 months (90% CI, 4.5 months to not reached) versus 2.7 months (90% CI, 1.3-4.7 months), and median OS of 41.6 months (90% CI, 4.5 months to not reached) versus 4.7 months (90% CI, 2.0-16.2 months) (all P < .05). With combination immunotherapy, 3-year OS was 57% (90% CI, 23%-81%), with 2 patients alive after 42.7 months without progression and negative PET. In this first prospective trial investigating the combination of SBRT and immunotherapy for HCC, multimodal therapy demonstrated acceptable safety. SBRT with nivolumab plus ipilimumab compared favorably to outcomes of immunotherapy alone and warrants further investigation.

Nelarabine, etoposide, and cyclophosphamide in relapsed pediatric T-acute lymphoblastic leukemia and T-lymphoblastic lymphoma (study T2008-002 NECTAR).

Children with relapse of T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have a dismal prognosis, largely due to difficulty attaining second remission. We hypothesized that adding etoposide and cyclophosphamide to the nucleoside analog nelarabine could improve response rates over single-agent nelarabine for relapsed T-ALL and T-LBL. This phase I dose-escalation trial's primary objective was to evaluate the dose and safety of nelarabine given in combination with etoposide at 100mg/m2 /day and cyclophosphamide at 330-400mg/m2 /day, each for 5 consecutive days in children with either T-ALL (13 patients) or T-LBL (10 patients). Twenty-three patients were treated at three dose levels; 21 were evaluable for dose-limiting toxicities (DLT) and response. The recommended phase II doses (RP2D) for this regimen, when given daily ×5 every 3weeks, were nelarabine 650mg/m2 /day, etoposide 100mg/m2 /day, and cyclophosphamide 400mg/m2 /day. DLTs included peripheral motor and sensory neuropathies. An expansion cohort to evaluate responses at the RP2D was terminated early due to slow accrual. The overall best response rate was 38% (8/21), with 33% (4/12) responses in the T-ALL cohort and 44% (4/9) responses in the T-LBL cohort. These response rates are comparable to those seen with single-agent nelarabine in this setting. These data suggest that the addition of cyclophosphamide and etoposide to nelarabine does not increase the incidence of neurologic toxicities or the response rate beyond that obtained with single-agent nelarabine in children with first relapse of T-ALL and T-LBL.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study

Background Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). Methods Patients with stages T2–4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57–58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41–43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. Results Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3–4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. Conclusion Tetramodal therapy of T2–T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

IntroductionPrevious studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC).Materials and methodsTreatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity.ResultsBetween April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity.ConclusionIntercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

TUXEDO: A phase I/II trial of cetuximab with chemoradiotherapy in muscle-invasive bladder cancer.

To assess feasibility and preliminary efficacy of adding cetuximab to standard chemoradiotherapy for muscle-invasive bladder cancer. TUXEDO was a prospective, single-arm, open-label, phase I/II trial conducted in six UK hospitals. Cetuximab was administered with an initial loading dose of 400mg/m2 on day 1 of week -1, and then 7-weekly doses of 250mg/m2 . Radiotherapy schedule was 64Gy/32F with day 1 mitomycin C (12g/m2 ) and 5-fluorouracil (500mg/m2 /day) over days 1-5 and 22-26. Patients with T2-4aN0M0 urothelial cancer and a performance status (PS) of 0-1 were eligible. Prior neoadjuvant therapy was permitted. The phase I primary outcome was impact on radiotherapy treatment completion and toxicity experienced during treatment. The phase II primary outcome was local control at three-months post-treatment. ISRCTN identifier: 80733590. Between Sept-2012 and Oct-2016, 33 patients were recruited; 7 in phase I, 26 in phase II. Three patients in phase II were subsequently deemed ineligible and received no trial therapy. Eight patients discontinued cetuximab due to adverse effects. Median age of patients was 70.1 years (range 60.6-75.1), 20 were PS 0, 27 male and 26 had already received neoadjuvant chemotherapy. In phase I, all patients completed planned radiotherapy, with no delays or dose reductions. Of the 30 evaluable patients in phase II, 25 had confirmed local control 3-months post treatment (77%, 95% CI: 58-90). During the trial there were 18 serious adverse events. The study was halted due to slow accrual. Phase I data demonstrate it is feasible and safe to add cetuximab to chemoradiotherapy. Exploratory analysis of phase II data provides evidence to consider further clinical evaluation of cetuximab in this setting.