Patient Experienced Grade Research Articles

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

Limited Toxicity of Hypofractionated Intensity Modulated Radiation Therapy (H-IMRT) for Head and Neck Cancer

Hypofractionated intensity modulated radiation therapy (H-IMRT) is uncommonly used in head and neck cancers due to concern for toxicity. This study reviews our experience using H-IMRT for head and neck cancers and explores its tolerability and efficacy.This single institution IRB approved retrospective study includes patients with head and neck cancers treated with definitive or post-operative H-IMRT from 2011-2020. Patients treated with ≥50Gy in 20 fractions to the primary tumor site and/or neck with at least 3 months of follow up were included. Patients treated to a superficial target only without proximity to mucosal surfaces or coverage of the elective neck (e.g., scalp; skin only targets) were excluded. Patients undergoing re-irradiation were excluded. Toxicity was scored using CTCAE v4.0. Acute toxicity included events occurring within 90 days of H-IMRT completion. Late toxicities occurred any time thereafter. Multiple toxicities in the same patient were scored separately.Fifty-nine patients with a median follow up of 10.9 months (range 3.0-111.5) were included. The majority of patients were white (93%) and male (78%) with a median age of 79.1. The most common primary tumor sites were skin (42%), major salivary glands (22%), and oral cavity (9%). The most frequent histologies included squamous cell carcinoma (66%) followed by thyroid cancer (7%), melanoma (5%), and Merkel cell carcinoma (5%). Treatment was delivered post-operatively in 80% and definitively in 20% of patients. All patients were treated with ≥50 Gy in 20 fractions, with the most common dose being 50 Gy (53%) followed by 55 Gy (44%). In 64% of patients a secondary elective dose of 45-50 Gy was used. Site treated included primary tumor site/bed with unilateral neck (54%), primary tumor site/bed with bilateral neck (19%), primary tumor site/bed alone (14%), unilateral neck (8%), and bilateral neck (5%). Five patients (8%) experienced a locoregional failure at a median time of 5.4 months (range 2.8-13.9). There were no grade 4 or 5 toxicities. Ten patients (17%) experienced acute grade 3 toxicity including mucositis (12%) and dermatitis (5%). Forty-six patients (78%) had an acute grade 2 toxicity, most commonly dermatitis (41%), pain (32%), fatigue (32%), dysgeusia (31%) and xerostomia (22%). Five patients (8%) experienced grade 2 late complications including neck fibrosis in three patients and trismus, aspiration pneumonia, and osteoradionecrosis in one patient each. No patient experienced grade 3 or higher late toxicity. No patients required the placement of a feeding tube or tracheostomy.Hypofractionated IMRT in the definitive or post-operative treatment of head and neck cancers using ≥50Gy in 20 fractions appears safe and well tolerated with modest toxicity. Prospective studies comparing the safety and efficacy of H-IMRT to conventionally fractionated IMRT are warranted.

Is Inflammatory Bowel Disease a Contraindication for Pelvic XRT in Patients With Gynecologic Cancers? Efficacy and Toxicity Outcomes in the Modern Era

Pelvic radiation therapy (XRT) is an integral part of treatment for many patients with gynecologic malignancies to help decrease the risk of morbid recurrences and allow for organ preservation as an alternative to radical surgery. Historically, providers have been reluctant to offer pelvic XRT to inflammatory bowel disease (IBD) patients due to concerns over increased acute and late toxicities of treatment based on limited historical data, precluding many patients from receiving optimal therapy. This retrospective study investigated the use of pelvic XRT in patients with gynecologic cancers and IBD treated in the modern era to assess toxicity and efficacy.Patients with IBD and a gynecologic malignancy receiving pelvic XRT or chemo-XRT between January 2014 and June 2020 were included. Data abstracted included diagnosis, stage, XRT technique/dose, use of concurrent chemotherapy, and acute and late CTCAE v4.0 toxicity scores. Statistics were performed using statistical software.Six patients with IBD and FIGO stage I-III or recurrent cancer of the gynecological tract who received definitive or adjuvant XRT to the pelvis were identified. Median follow-up was 29 months (range 6-66 months). Four patients (66%) had Crohn's Disease and two (33%) had ulcerative colitis. Primary disease locations were uterus (2), vulva (1), vagina (2), and cervix (1). Four patients received concurrent platinum-based chemotherapy with pelvic XRT. Pelvic XRT was delivered using IMRT/VMAT in all patients with doses of 45-57.6 Gy in 25-32 fractions. 100% of patients completed treatment without treatment breaks. No patients received treatment for active IBD during XRT, but most (83%) were on loperamide at baseline. No patients experienced any acute 3 or greater toxicity; most common toxicities reported during treatment were grade 1-2 fatigue (100%), grade 1 diarrhea (50%), grade 1 nausea (66%), and grade 1-2 dermatitis (66%). One patient experienced grade 2 rectal proctitis 5 years out from treatment; no other patients experienced late GI toxicity at last recorded follow-up. Two patients (33%) developed distant disease within 6 months of completing XRT, one of whom died of disease. No patient developed locoregional recurrence and 66% of patients remain disease free at the time of last follow-up. 83% were able to avoid upfront radical surgery, including 3 patients who would have required total pelvic exenteration.In our single-institution series, pelvic XRT +/-chemotherapy is well-tolerated in patients with gynecologic malignancies and IBD. The use of pelvic XRT in this population led to excellent loco-regional control outcomes that allowed patients to avoid radical upfront surgeries and preserve organ function. Our small series represents the largest cohort of IBD patients with gynecologic cancers treated with pelvic XRT or chemo-XRT and suggests that strong consideration should be given to offering pelvic XRT to IBD patients diagnosed with gynecologic cancers.S.R. Amarnath: None.

A Phase II Trial of Escalated Dose Proton Radiotherapy With Elective Nodal Irradiation and Concomitant Chemotherapy for Patients with Unresectable, Borderline Resectable or Medically Inoperable Pancreatic Adenocarcinoma

To report outcomes of a phase II single-institution trial of escalated dose proton therapy with elective nodal irradiation and concomitant chemotherapy for patients with unresectable, borderline resectable, or medically inoperable pancreatic adenocarcinoma.Patients were treated to 40.5 GyE in 18 fractions to gross disease and elective nodal volumes with a 22.5 GyE in a 10-fraction boost to gross disease, for a total of 63 GyE. Oral capecitabine (1000mg orally twice a day) was given on radiation treatment days. The primary objective of this study was to achieve a 1-year overall survival rate of 75%. Secondary objectives included assessing gastrointestinal toxicity and patient quality of life during treatment, as well as evaluating the safety of subsequent surgical resection. The single-institution study was closed to accrual once opened as the multicenter PAN009-18 trial by the Proton Collaborative Group.At enrollment, 10 (67%) of patients were unresectable, 3 (20%) were borderline, and 2 (13%) refused surgery. Thirteen patients (87%) had previously received chemotherapy. All 15 patients successfully completed radiation therapy as prescribed. With regard to toxicity, a single patient experienced grade 3 nausea requiring cessation of capecitabine, which ultimately resolved at treatment completion. All other patients received concurrent capecitabine for the duration of their radiotherapy treatment. Radiation did not result in any other significant gastrointestinal toxicity during or after treatment. Median percentage weight loss during treatment was -3.0% (-9.6% - +12.0%). Two (13%) initially borderline patients ultimately underwent resection. Their total operating room times were 267 and 410 minutes; blood loss was 700mL and 400mL. Neither patient experienced intraoperative or postoperative complications. Both patients were discharged on postoperative day six. Median follow-up was 0.93 years (0.21-2.14). The 1-year overall survival rate was 47%. Three enrolled patients are currently alive: 2 with no evidence of disease and 1 with stable disease. One patient died of intercurrent disease. Of the remaining 11 patients who died following tumor recurrence, only 3 failed locally, with the remaining 8 failing distantly.Protocol therapy was well-tolerated. Patients undergoing surgery did not experience operative or perioperative complications - suggesting that patients with borderline resectable or even resectable disease may benefit from this regimen as neoadjuvant therapy. The Proton Collaborative Group will test this premise as patients accrue to the multicenter PAN009-18 trial.

Definitive Radiotherapy for Patients With Anal Squamous Cell Carcinoma: A Retrospective Cohort Study.

BackgroundAnal squamous cell carcinoma accounts for less than 2-3% of all digestive system carcinomas. The present study aimed to determine the clinical characteristics, treatment patterns, and treatment outcomes of patients at our institution.MethodologyWe reviewed the clinical data of all consecutive patients with anal squamous cell carcinoma who were treated with definitive radiotherapy in our department between July 2009 and July 2020. Radiotherapy was delivered in 1.8-2 Gy daily fractions to a whole pelvic dose ranging from 45 to 50 Gy, followed by boost radiotherapy of 10-15 Gy, resulting in a total dose of approximately 60 Gy. Concurrent chemotherapy with radiotherapy included 5-fluorouracil/mitomycin C or 5-fluorouracil/cisplatin.ResultsA total of 14 patients with a median age of 61.5 years (range: 45-85 years) were analyzed. There were nine women and five men. The clinical T stage was T1 in two patients, T2 in six patients, T3 in two patients, and T4 in four patients. The clinical N stage was N0 in four patients and N1 in 10 patients. Patients with clinical stage III disease comprised 79% of the entire study population. For the entire cohort, the five-year overall survival rate was 83.3% and the five-year progression-free survival rate was 48.5%. One patient experienced grade 3 fecal incontinence, and the others experienced no radiation-induced severe delayed adverse events.ConclusionsThe results of our study demonstrated that definitive radiotherapy with or without chemotherapy for patients with anal squamous cell carcinoma is an effective and feasible treatment.

The Role of Physical Therapy Following CAR T-Cell Therapy: A Case Report

Background: Diffuse large B-cell lymphoma (DLBCL) affects 7 out of 100 000 people in the United States every year. Chimeric antigen receptor (CAR) T-cell therapy is approved by the Food and Drug Administration to treat patients with relapsed/refractory DLBCL who have not responded to 2 prior lines of therapy. CAR T-cell therapy can lead to debilitating side effects necessitating rehabilitation intervention. Case Description: This case report details a 38-year-old woman with refractory DLBCL who received CAR T-cell therapy. The patient experienced grade 2 cytokine release syndrome and grade 4 immune effector cell-associated neurotoxicity syndrome, which resulted in, among other symptoms, lower extremity paraplegia. Upon medical stabilization, the patient was referred to physical therapy. Outcomes: The patient participated in acute care rehabilitation for 8 weeks and progressed significantly toward her prior level of function before being discharged to an inpatient rehabilitation facility. Upon discharge, the patient was able to ambulate with a rolling walker, a knee orthosis, and supervision for safety and had initiated stair training. Discussion/Conclusion: Physical therapists need to understand and recognize the range of side effects that can occur following CAR T-cell therapy. As more patients receive CAR T-cell therapy to treat malignancies, acute care oncology units will undoubtedly be challenged with patients exhibiting severe side effects. Physical therapists are well trained to address physical impairments resulting from CAR T-cell therapy's side effects and will play a vital role in these patients' interdisciplinary care.

A Prospective Observational Study on the Efficacy and Safety of Infliximab-Biosimilar (CT-P13) in Patients With Takayasu Arteritis (TAKASIM).

Objectives: Infliximab (IFX) is widely used in patients with refractory Takayasu arteritis (TAK). Recently, the IFX-biosimilar CT-P13 has been introduced for the treatment of inflammatory diseases. The aim of this study was to assess the efficacy and safety of CT-P13 in patients with refractory TAK.Methods: In this prospective, open-label, single-center trial, TAK patients either already on treatment with IFX-originator (switch group) or never treated with IFX (naïve group) received CT-P13 for 52 weeks. The primary outcomes of the study were: (i) number of patients with active disease at month 6; (ii) incidence of treatment-emergent adverse events at month 12. Disease activity was assessed at month 6 and month 12 by clinical evaluation (ITAS-2020, ITAS-ESR, and ITAS-CRP scores) and imaging assessment [magnetic resonance angiography (MRA) and (18F)-FDG-PET].Results: 23 patients were recruited (21 switch, 2 naïve). At baseline, 7 patients (32%) were classified as active. At month 6, one patient voluntarily dropped out and 7 patients were still active (30%), including one patient started on a different bDMARD at month 2 due to poor disease control. Mean daily dose of prednisone equivalent was significantly lower than baseline (4.2 ± 1.9 mg vs. 4.8 ± 2.1 mg, p = 0.009). At month 12, another patient was excluded because of pregnancy desire. Five patients were classified as active (24%), including two patients started on a different bDMARD at month 2 and month 6. Mean daily dose of prednisone equivalent was significantly lower than baseline (3.3 ± 2.6, p = 0.034). No patient experienced side effects during CT-P13 infusion. Overall, one patient experienced grade 1 adverse event and 9 patients experienced grade 2 adverse events. In no case hospitalization was required. CT-P13 retention rate was 90.9% at month 6 and 90.4% at month 12.Conclusion: In this study, the use of IFX-biosimilar CT-P13 in patients with refractory TAK showed satisfying efficacy and safety profile.

Prospective Study Testing a Simplified Paclitaxel Premedication Regimen in Patients with Early Breast Cancer.

BackgroundIn early trials, hypersensitivity reactions (HSRs) to paclitaxel were common, thus prompting the administration of antihistamines and corticosteroids before every paclitaxel dose. We tested the safety of omitting corticosteroids after cycle 2 during the paclitaxel portion of the dose‐dense (DD) doxorubicin‐cyclophosphamide (AC)–paclitaxel regimen.Patients, Materials, and MethodsIn this prospective, single‐arm study, patients who completed four cycles of DD‐AC for stage I–III breast cancer received paclitaxel 175 mg/m2 every 2 weeks for four cycles. Patients received a standard premedication protocol containing dexamethasone, diphenhydramine, and a histamine H2 blocker prior to the first two paclitaxel cycles. Dexamethasone was omitted in cycles three and four if there were no HSRs in previous cycles. We estimated the rate of grade 3–4 HSRs.ResultsAmong 127 patients enrolled, 125 received more than one dose of protocol therapy and are included in the analysis. Fourteen (11.2%; 90% confidence interval, 6.9%–20.0%) patients had any‐grade HSRs, for a total of 22 (4.5%; 3.1%–6.4%) HSRs over 486 paclitaxel cycles. Any‐grade HSRs occurred in 1.6% (0.3%–5.0%), 6.5% (3.3%–11.3%), 7.4% (3.9%–12.5%), and 2.6% (0.7%–6.6%) of patients after paclitaxel cycles 1, 2, 3, and 4, respectively. Dexamethasone use was decreased by 92.8% in cycles 3 and 4. Only one patient experienced grade 3 HSR in cycles 3 or 4, for a rate of grade 3/4 HSR 0.4% (0.02%–2.0%) (1/237 paclitaxel infusions). That patient had grade 2 HSR during cycle 2, and the subsequent grade 3 event occurred despite usual dexamethasone premedication. A sensitivity analysis restricted to patients not known to have received dexamethasone in cycles 3 and 4 found that any‐grade HSRs occurred in 2.7% (3/111; 0.7%–6.8%) and 0.9% (1/109; 0.05%–4.3%) of patients in cycle 3 and 4, respectively.ConclusionCorticosteroid premedication can be safely omitted in cycles 3 and 4 of dose‐dense paclitaxel if HSRs are not observed during cycles 1 and 2.Implications for PracticeBecause of the potential for hypersensitivity reactions (HSRs) to paclitaxel, corticosteroids are routinely prescribed prior to each dose, on an indefinite basis. This prospective study, including 125 patients treated with 486 paclitaxel cycles, demonstrates that corticosteroids can be safely omitted in future cycles if HSRs did not occur during cycles 1 and 2 of paclitaxel and that this strategy reduces the use of corticosteroids in cycles 3 and 4 by 92.8% relative to current standard of care.

A Propensity-Matched Analysis of Survival of Clinically Diagnosed Early-Stage Lung Cancer and Biopsy-Proven Early-Stage Non-Small Cell Lung Cancer Following Stereotactic Ablative Radiotherapy.

PurposeStereotactic body radiotherapy (SBRT) has been increasingly regarded as a reasonable option for early-stage lung cancer patients without pretreatment pathologic results, but the efficacy and safety in a Chinese population remains unclear. The aim of this study was to compare survival outcomes and toxicities between patients with clinically diagnosed early-stage lung cancer or biopsy-proven early-stage non-small cell lung cancer and to demonstrate the rationality of this treatment.Material and MethodsFrom May 2012 to December 2018, 56 patients with clinically diagnosed early-stage lung cancer and 60 patients with early-stage biopsy-proven were selected into non-pathological group and pathological group, respectively. Propensity score matching (PSM) was performed to reduce patient selection bias. Survival analysis with log-rank test was used to assess the differences of treatment outcomes, which included local control (LC), progression-free survival (PFS), and overall survival (OS).ResultsThe median age was 76 (range 47–93) years, and the median follow-up time was 58.3 (range 4.3–95.1) months in the cohort without pathologic results. The median age was 74 (range 57–88) years, and the median follow-up time was 56.3 (range 2.6–94) months in the cohort with pathologic results. 45 matched-pair were analyzed. The 5-year LC, PFS, and OS rates in matched-pair patients with or without pathologic biopsy were 85.5% and 89.8%, 40.6% and 70.9%, and 63.2% and 76.1%, respectively. On Kaplan-Meier survival analysis after PSM analysis, there was no significant difference between patients with pathologic results versus patients with no pathologic results in terms of LC (P= 0.498) and OS (P=0.141). Of the matched-pair patients treated with SBRT, only 1 patient experienced grade 3 or above radiation pneumonitis.ConclusionFor early-stage lung cancer patients with medically inoperable or not suitable for invasive diagnosis, SBRT may be a good local treatment.

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer.

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome‐encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients.In this exploratory first‐in‐man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2‐week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy.Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1–2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter‐related urosepsis). No infusion‐related adverse events occurred. One patient had upsloping glucose levels ≤9.1 mmol/L. Trough plasma concentrations of liposomal‐ and free dexamethasone were below the lower limit of quantification (LLOQ) in part A, and above LLOQ in three patients in part B (t 1/2 ~50 h for liposomal dexamethasone), trough concentrations of liposomal‐ and free dexamethasone increased toward the end of the study. In seven of nine patients (78%) patients, stable disease was observed in bone and/or CT scans at follow‐up, and in one (part B) of these seven patients a >50% PSA biochemical response was observed.Bi‐ and once weekly administrations of IV liposomal dexamethasone were well‐tolerated. Weekly dosing enabled trough concentrations of liposomal‐ and free dexamethasone >LLOQ. The data presented support further clinical investigation in well‐powered studies.Clinical trial registration: ISRCTN 10011715.

Study of 89Zr-Pembrolizumab PET/CT in Patients With Advanced-Stage Non-Small Cell Lung Cancer.

The tumor programmed death ligand 1 (PD-L1) proportion score is the current method for selecting non-small cell lung cancer (NSCLC) patients for single-agent treatment with pembrolizumab, a programmed cell death 1 (PD-1) monoclonal antibody. However, not all patients respond to therapy. Better understanding of invivo drug behavior may help in the selection of patients who will benefit the most. Methods: NSCLC patients eligible for pembrolizumab monotherapy as first- or later-line therapy were enrolled. Patients received 2 injections of 89Zr-pembrolizumab, 1 without a preceding dose of pembrolizumab and 1 with a preceding dose of 200 mg of pembrolizumab, directly before tracer injection. Up to 4 PET/CT scans were obtained after tracer injection. After imaging acquisition, patients were treated with 200 mg of pembrolizumab every 3 wk. Tumor uptake and tracer biodistribution were visually assessed and quantified as the SUV. Tumor tracer uptake was correlated with PD-1 and PD-L1 expression and response to pembrolizumab treatment. Results: Twelve NSCLC patients were included. One patient experienced grade 3 myalgia after tracer injection. 89Zr-pembrolizumab was observed in the blood pool, liver, and spleen. Tracer uptake was visualized in 47.2% of 72 tumor lesions measuring ΒΧΡ20 mm in the long-axis diameter, and substantial uptake heterogeneity was observed within and between patients. Uptake was higher in patients with a response to pembrolizumab treatment (n = 3) than in patients without a response (n = 9), although this finding was not statistically significant (median SUVpeak, 11.4 vs. 5.7; P = 0.066). No significant correlations were found with PD-L1 or PD-1 immunohistochemistry. Conclusion:89Zr-pembrolizumab injection was safe, with only 1 grade 3 adverse event-possibly immune-related-in 12 patients. 89Zr-pembrolizumab tumor uptake was higher in patients with a response to pembrolizumab treatment but did not correlate with PD-L1 or PD-1 immunohistochemistry.

Radiation therapy for nonmetastatic medically inoperable upper-tract urothelial carcinoma.

BackgroundThe standard management for upper urinary tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU). However, some patients cannot undergo this procedure for several reasons, such as unresectable disease, old age, and multiple comorbidities. Our study explored the potential safety and effectiveness of radiotherapy as a curative treatment for UTUC patients unfit for surgery.MethodsThe data of patients treated with radiotherapy between December 2017 and November 2019 were retrospectively reviewed. For the literature review, computerized PubMed Medline, Index Medicus, and Web of Science databases and reference lists from the identified publications of interest were used. And “upper-tract urothelial carcinoma” and “radiotherapy” were used as key words in the search.ResultsWe describe 8 patients with UTUC who were treated with radiotherapy. The median follow-up time was 13.5 months (range, 8.6–30.9 months). Local tumor control was achieved in all patients. However, distant metastases were observed in 2 patients with T3-4/N+ status. One patient had T4 status and the other had N2+ status. The patients died of tumor progression at 15.0 and 17.7 months. In addition, the other 6 patients who were still alive had relatively early-stage tumors without nodal involvement. Regarding acute toxicity, according to the CTCAE v5.0, mild side effects were noted, including grade 1 nausea and diarrhea. Four patients developed mild anemia, generally of grade 1–2. One patient experienced grade 3 anemia, but it was manageable and improved with symptomatic support. In addition, no grade 4 acute or late toxicities were observed. No significant long-term impairment of renal function occurred.ConclusionsFor patients with nonmetastatic UTUC who are not suitable for surgery, radiotherapy is a safe treatment and can achieve good local tumor control.

Weekly Dosing of Bortezomib in RVD Achieves Minimal Toxicity with No Reduction in Efficacy in a Diverse Cohort of Multiple Myeloma Patients

Introduction: Lenalidomide, bortezomib, and dexamethasone is a standard of care in the treatment of fit multiple myeloma patients due to high efficacy, with ORR exceeding 90% in the first-line setting (Richardson et al. 2010). The initial RVD regimen utilized a 21-day cycle with bortezomib administered IV 1.3 mg/m2 days 1, 4, 8, and 11; lenalidomide 25 mg administered days 1-14; and dexamethasone administered 160 to 320 mg per cycle. However, toxicity may be treatment-limiting, with bortezomib-induced neuropathy affecting up to 80% of patients. Modifications to RVD to optimize tolerance include reducing the bortezomib dose to a weekly schedule (1.6 mg/m2 IV or 1.3 mg/m2SC) and extending the cycle to 28 or 35 days (Broijl et al. 2016; O'Donnell et al. 2014). Notably, those regimens were studied in transplant-ineligible or relapsed/refractory patients. Based on regimens like CyBorD (which utilize weekly SC administration of bortezomib, are well-tolerated and are efficacious), we modified the standard 21-day RVD regimen to include 3 doses of weekly bortezomib in an attempt to preserve efficacy while minimizing toxicity. We present a retrospective analysis of both fit and transplant-ineligible patients treated at our institution using “Louisville RVD.”Methods: We identified the charts of patients who received RVD over a 21-day cycle at the following starting doses: lenalidomide 25 mg orally days 1-14; bortezomib 1.5 mg/m2 SC days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, and 15. Autologous stem cell harvest took place after 4 cycles of lenalidomide-based therapy when feasible, in appropriate candidates. We noted demographic factors, ISS stage, performance status, cytogenetic risk stratification, line of therapy (initial, later-line, and consolidation), history of autologous transplant, degree of response (PD, SD, PR, VGPR, and CR based on International Myeloma Working Group criteria), EFS, OS, and toxicities.Results: We identified 23 patients who received Louisville RVD between 2009 and 2017. Median age was 59 years (range 37-77) at treatment start; 9 (39%) were 65 or older; 12 (52%) were male; 11 (48%) were African-American; ISS stages were I in 6 (26%), II in 7 (30%), III in 9 (39%), and missing in 1 patient; ECOG status was 0 in 7 (30%), 1 in 11 (48%), and 2 in 5 (21%). Line of therapy was 1 in 13 (56%) and 2 or later in 10 (44%); RVD was used as post-transplant consolidation in 4 (14%). Line of therapy ranged from 1 to 8. 16 patients (57%) were treated with intent to transplant. The median number of cycles given was 4 (range 1-64). Dose reductions and discontinuation occurred in 5 (22%) patients and 1 (4%) patient after 1 cycle, respectively. Response was assessable in 22 patients. 21 (95%) of patients achieved PR or better; 3 patients (14%) achieved CR, 7 (32%) VGPR; and 11 (50%) PR. OS and EFS at 1 year were 90% and 60%, respectively; median duration of follow-up was 15.5 months (range 1.2-95.1); follow-up time was limited for a significant fraction of our patients. There was no association of relapse with ISS stage (p=0.357), ECOG score (p=0.088), or cytogenetic risk (p=1.00). Treatment-related toxicities were reported for 11 patients. Treatment-emergent neuropathy was seen in 5 patients (22%); 4 patients experienced grade 1 neuropathy (17%), and 1 patient experienced grade 3 neuropathy (4%). 1 patient underwent dose-reduction of bortezomib to 1.3 mg/m2 after 18 cycles. 6 patients had treatment related cytopenias (26%), of which 1 (4%) was grade 3.Conclusions: Retrospective analysis of 21-day “Louisville RVD” with weekly subcutaneous bortezomib demonstrates efficacy comparable to previously published RVD regimens. Toxicity, especially peripheral neuropathy, favors the weekly SC administration schedule. Dose reductions were uncommon and treatment discontinuations were rare. Patients may ultimately achieve superior bortezomib dosing due to rarity of dose reductions. Our cohort was well-balanced with regard to ethnicity, gender, age, and performance status. Treatment was efficacious and well-tolerated in both transplant and non-transplant candidates. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Single Institution Comparison of Mitoxantrone, Etoposide and Cytarabine (MEC) Vs High-Dose Cytarabine and Mitoxantrone (Ara-C Couplets) for Treatment of Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background:Relapsed or refractory acute myeloid leukemia (R/R AML) is a common occurrence and remains a therapeutic challenge due to its poor prognosis. Hematopoietic cell transplantation (HCT) is the only curative approach for R/R AML, and while chemotherapy regimens are generally used as a bridge to HCT, the ideal second-line therapy is unknown. For decades cytarabine (Ara-C) has been the backbone of a number of regimens that are frequently used in this R/R setting. At our academic institution patients who can tolerate aggressive therapy are treated with either MEC (mitoxantrone 8 mg/m2 IV, etoposide 80 mg/m2 IV and intermediate dose cytarabine 1 g/m2 daily for 5 days) or Ara-C couplets (mitoxantrone 30 mg/m2 x 1 and high dose cytarabine (2 g/m2) twice daily, on days 1 and 5). MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol . 1991). The Ara-C couplets regimen has been shown to have a similar overall response rate of 55%, in a single study (Larson et al., Leukemia & Lymphoma . 2012). Currently, there are no studies that have directly compared these two treatments. The objective of this single institution retrospective analysis is to assess the efficacy and toxicity of MEC and Ara-C couplets therapy.Methods:R/R AML patients treated from January 1998 through May 2015 were identified using our hospital and pharmacy billing records. From a review of 118 patient charts a total of 51 R/R AML adult patients were identified who had received either MEC or Ara-C couplets, and all were included in this analysis. The efficacy and toxicity of the two regimens were compared by assessing the rates of CR, progression free survival (PFS), overall survival (OS), the duration of hospitalization, hematologic and non-hematologic toxicities and success in proceeding to HCT.Results:Fifteen patients, ages 20-64, were treated with MEC, and 36 patients, ages 22-75, were treated with Ara-C couplets. Baseline characteristics, including gender, race, and Charlson Comorbidity Index (CCI) were well balanced. Within the MEC group, there were an equal number of White, Black and Hispanic patients (n=4), and 3 patients who identified as other. Amongst the Ara-C couplets patients, 14 were White, 11 Black, 7 Hispanic, and 4 identified as other. Six of the MEC patients (9%) and 9 of the Ara-C couplets patients (25%) had unfavorable cytogenetics. The time from initial diagnosis to relapse or refractory disease was similar between the 2 groups, 253 days (MEC) and 244 days, respectively (p=0.38)CR was achieved in 64% of the MEC patients and 57% of the Ara-C couplets patients (p=0.75). OS was 6.5 months and 8 months respectively (p=0.35). PFS was 5.2 months in the MEC group and 4 months in the Ara-C couplets group (p=0.86). In both groups, 47% of patients (7 in MEC, 17 in Ara-C couplets) underwent HCT. Within the MEC group, the median number of days to ANC and platelet recovery was 45 days and 65 days respectively, and was similar within the Ara-C couplets group, 40 days and 55 days, respectively. The median duration of hospitalization for patients receiving MEC was 34 days while the median for those receiving Ara-C couplets was 31 days (p=0.2).The most common adverse event was febrile neutropenia, occurring in 100% of the MEC and 89% of the Ara-C couplets patients (p=0.3). Non-hematologic toxicities were minimal and there were no significant differences between groups in terms of pulmonary, liver or gastrointestinal toxicities. Within the Ara-C couplets group, one patient experienced grade 3, and another grade 4 cardiac toxicity (CHF).Conclusions:This is the first study that directly compares MEC and Ara-C couplets regimens in R/R AML patients; two salvage therapies commonly used at our institution. We show that both therapies are equally effective as second-line regimens with equivalent toxicities in a racially diverse population (n= 51). Our data suggests either regimen can be considered in those able to tolerate aggressive therapy and can serve as a bridge to HCT. A significant portion of patients with AML relapse, and, surprisingly, very few comparative studies have been performed in this population. In the future, large multi-center studies should be performed in order to establish the optimal chemotherapy regimen for these patients. DisclosuresPatel:Celgene: Consultancy, Honoraria. Khan:Takeda: Research Funding; Gilead: Consultancy; Teva: Speakers Bureau.

Combination therapy of capecitabine, irinotecan, oxaliplatin, and bevacizumab as a first\u2010line treatment for metastatic colorectal cancer: Safety lead\u2010in results from the QUATTRO-II study

SummaryBackground FOLFOXIRI plus bevacizumab is the first-line treatment for metastatic colorectal cancer (mCRC) but demonstrates high neutropenia incidence among Asian patients. Hence, we conducted the randomized phase II QUATTRO-II study (ClinicalTrials.gov identifier: NCT04097444; Japan Registry of Clinical Trials identifier: jRTCs041190072) to evaluate the safety and efficacy of capecitabine, oxaliplatin, and irinotecan (CAPOXIRI) combination plus bevacizumab versus FOLFOXIRI plus bevacizumab, expecting a lower incidence of neutropenia without compromising the efficacy. Methods We investigated the recommended doses (RD) of oxaliplatin and irinotecan as a safety lead-in portion of Step 1 before initiating the randomized portion as Step 2. Four dose levels of CAPOXIRI (fixed dose of capecitabine, 1600 mg/m2; escalated/de-escalated doses of oxaliplatin and irinotecan) plus bevacizumab (7.5 mg/kg) were investigated in a 3 + 3 manner. A dose level of ≤ 2/6 of dose-limiting toxicity (DLT) cases was expected as the RD. Results In Step 1, we included nine patients (three and six in levels 0 and + 1, respectively). Level 0 (irinotecan, 200 mg/m2; oxaliplatin, 100 mg/m2) did not demonstrate DLTs. In level + 1 (irinotecan, 200 mg/m2; oxaliplatin, 130 mg/m2), although one patient experienced grade 4 febrile neutropenia, no further safety concerns were observed. As a preliminary efficacy result, the objective response rate in all nine patients was 89 % (100 and 83 % in levels 0 and + 1, respectively). Conclusions The RD of CAPOXIRI plus bevacizumab was 200, 130, and 1600 mg/m2 for irinotecan, oxaliplatin, and capecitabine, respectively, and 7.5 mg/kg for bevacizumab. The randomized portion is still ongoing.

Afatinib and pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma (ALPHA Study): A phase II study with biomarker analysis.

6024 Background: Epidermal growth factor receptor (EGFR) pathway inhibition may synergize with anti-PD1 activity by inhibiting macrophage function, increasing antigen presentation, and augmenting T cell responses. Afatinib, an irreversible EGFR tyrosine kinase inhibitor (TKI), has been shown to enhance anti-PD1 activity in in vitro and animal studies. We thus hypothesized that adding afatinib to pembrolizumab may improve the treatment outcomes for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Methods: The ALPHA study (NCT03695510) is a single-arm, phase II study with a Simon 2-stage design. Patients with platinum-refractory, recurrent, or metastatic HNSCC are eligible for the study. Afatinib (40mg, oral, daily) and pembrolizumab (200mg, every 3 weeks) are administered to eligible patients. The primary endpoint is the objective response rate (ORR). PD-L1 IHC testing (22C3), comprehensive genomic profiling (CGP, Roche Foundation Medicine One CDx), and targeted multiplexed gene expression profiling (Nanostring nCounter PanCancer Immune Profiling Panel) were applied for biomarker analysis. Results: From JAN 2019 to MAR 2020, 29 patients were enrolled in the study. Age: mean = 53.4 years old; M/F = 27/2. Tumor type: oral cavity: 19; oropharynx: 6, hypopharynx: 2, larynx: 2. PD-L1 TPS > = 50: 7/29 (24.1%), CPS > = 20: 8/29 (27.6%), TMB > 10: 0/25 (0%). The common treatment-related adverse events (AEs; all grades, grade > = 3) were skin rash (22/29, 4/29), diarrhea (17/29, 3/29), paronychia (13/29, 0/29), mucositis (9/29, 1/29), and weight loss (2/29, 0/29). One patient experienced grade 2 pneumonitis. Twelve patients had partial responses to the treatment (12/29, ORR: 41.4%). The data cut-off date was 11FEB2021. The median progression free survival (PFS) was 4.1 (95% confidence interval [CI], 1.9-6.3) months. The median overall survival (OS) was 8.4 (95% CI, 4.1-10.8) months. Patients with high PD-L1 expression had a higher response rate (TPS > = 50: ORR = 0.71, CPS > = 20: ORR = 0.63). EGFR amplification might also predict a higher response rate (ORR: 3/3, 100%). MTAP loss or mutation may predict a poor response to the treatment (ORR: 0/5, 0%), shorter PFS (HR: 4.21, [95% CI: 1.34-13.24], p = 0.014), and shorter OS (HR: 4.20 [95% CI: 1.32-13.41], p = 0.015). Nine patients underwent paired pre-treatment and post-treatment biopsies for gene expression analysis. The mRNA of HLA-A, HLA-B, CXCL13, CXCL9, and CD8A were elevated in the post-treatment biopsies. Three patients underwent post-progression biopsies for CGP study. One patient had a new MTAP mutation. Conclusions: Afatinib can modify tumor microenvironment and increase the clinical response rate in pembrolizumab-based therapy in HNSCC patients. PD-L1, EGFR amplification, and MTAP loss/mutation could be biomarkers for cancer immunotherapy. Clinical trial information: NCT03695510.

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

Radiation-induced brain injury in patients with meningioma treated with proton or photon therapy

Radiation therapy is often used to treat meningioma with adverse features or when unresectable. Proton therapy has advantages over photon therapy in reducing integral dose to the brain. This study compared the incidence of radiological and clinical adverse events after photon versus proton therapy in the treatment of meningioma. A retrospective review was conducted on patients with meningioma treated with proton or photon therapy at two high-volume tertiary cancer centers. Patients with a history of prior radiation therapy (RT) or less than 3months of follow-up were excluded. Post-RT imaging changes were categorized into abnormal T2 signal intensities (T2 changes) or abnormal T1 post-contrast and T2 signal intensities (T1c+T2 changes) on magnetic resonance imaging (MRI). Clinical outcomes of adverse events and survival were compared between the proton and photon therapies. Among the total of 77 patients, 38 patients received proton therapy and 39 patients received photon therapy. The median age at diagnosis was 55years and median follow-up was 2.2years. No significant differences in symptomatic adverse events were observed between the two groups: grade ≥ 2 adverse events were seen in 4 (10.5%) patients in the proton group and 3 (7.7%) patients in the photon group (p = 0.67). The 2-year cumulative incidences of T2 changes were 38.3% after proton therapy and 47.7% after photon therapy (p = 0.53) and the 2-year cumulative incidences of T1c+T2 changes were 26.8% after proton therapy and 5.3% after photon therapy (p = 0.02). One patient experienced grade ≥ 4 adverse event in each group (p = 0.99). Estimated 2-year progression-free survival was 79.5% (proton therapy 76.0% vs. photon therapy 81.3%, p = 0.66) and 2-year overall survival was 89.7% (proton therapy 86.6% vs. photon therapy 89.3%, p = 0.65). Following RT, high rates of T2 changes were seen in meningioma patients regardless of treatment modality. Proton therapy was associated with significantly higher rates of T1c+T2 changes compared with photon therapy, but severe adverse events were uncommon in both groups and survival outcomes were comparable between the two groups. Future studies will aim at correlating the MRI changes with models that can be incorporated into RT planning to avoid toxicity.

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancer.

The aim of the study was to investigate the safety of combining preoperative stereotactic body radiotherapy (SBRT) with robotic radical prostatectomy (RP) for high risk prostate cancer (HRCaP). Many patients with HRCaP will require adjuvant or salvage radiotherapy after RP. The addition of preoperative SBRT before RP may spare patients from subsequent prolonged courses of RT. Eligible patients had NCC N HRCaP and received a total of 25 Gy or 30 Gy in five daily fractions of SBRT to the prostate and seminal vesicles followed by robotic RP with pelvic lymphadenectomy 31-45 days later. The primary endpoint was prevalence of acute genitourinary (GU) and gastrointestinal (GI) toxicity. Secondary endpoints were patient-reported quality of life (QOL) and biochemical recurrence (BcR). Three patients received preoperative SBRT to 25 Gy and four received 30 Gy. Median follow-up was 18 months. Highest toxicity was grade 2 and 3 in six (85.7%) and one (14.3%) patients, respectively. All patients developed grade 2 erectile dysfunction and 4 of 7 (57%) developed grade 2 urinary incontinence (UI) within a month after surgery. One patient developed acute grade 3 UI, but there was no grade ≥ 4 toxicity. One patient experienced acute grade 2 hemorrhoidal bleeding. On QOL, acute GU complaints were common and peaked within 3 months. Bowel symptoms were mild. Two patients with pN+ experienced BcR. Preoperative SBRT before robotic RP in HRCaP is feasible and safe. The severity of acute GU toxicity with preoperative SBRT may be worse than RP alone, while bowel toxicity was mild.

Normal Tissue Injury Induced by Photon and Proton Therapies: Gaps and Opportunities.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.