NCI Common Toxicity Criteria Research Articles

Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of central nervous system.

30 Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.

Sequential GD2 Chimeric Antigen Receptor T Cell Therapy (4SCAR2.0-GD2) for the Treatment of Refractory/Relapsed Neuroblastoma

BACKGROUND: Neuroblastoma (NB) is one of the most common childhood malignancies and half of the patients are diagnosed with high-risk disease. Current multimodal treatment regimens only achieve long-term survival in 50-60% of the high-risk patients. In the past two decades, several new treatment strategies, including immunotherapy directed against the NB tumor-associated antigen GD2, have significantly improved the outcome for NB patients. However, many patients still suffer relapsed and refractory disease. The chimeric antigen receptor-modified T cells (CAR-Ts) have shown promising anti-tumor effects in B-cell malignancies. In an earlier trial using 4SCAR-GD2 T cells (NCT02992210), we evaluated 34 refractory/relapsed (R/R) NB patients for safety and long-term survival with a median follow-up of 27.5 months (ranged 2 to 53). We found low to no CAR-T-related toxicities (CRS grade 0-2), and no grade 3 or above CRS. The overall survival (OS) and progression-free survival (PFS) were 48.7±8.7% and 35.3±8.2%, respectively, at 3 years of follow-up. The 34 patients were divided into 2 groups according to their disease status at the time of CAR-T infusion: active disease (n=9) and stable disease (n=25). The PFS (p=0.006) and OS (p=0.017) were significantly worse among patients with active disease upon CAR-T therapy, indicating that patients with active disease did not benefit from the 4SCAR-GD2 therapy. This prompted a change of strategy in the patient enrollment criteria to improve clinical outcomes. In a revised 4SCAR2.0-GD2 study, we enrolled R/R NB patients with stable disease to receive sequential 4SCAR-GD2 T cell infusions and evaluated the anti-tumor effects and in vivo CAR-T persistency. METHODS: This report included 19 R/R NB patients, with stable disease and without high tumor burden or central nervous system involvement, who were enrolled in the 4SCAR2.0-GD2 study. If disease was stable and the CAR-T level in the blood was reduced below 0.5%, a booster GD2 CAR-T infusion was considered. Autologous T cells were collected and transduced with a safety-engineered lentiviral CAR (4SCAR) carrying the following intracellular signaling domains: CD28-CD27-CD3ζ-iCasp9. The patients received cyclophosphamide and fludarabine conditioning before the first infusion of an average of 2.93x106 CAR-T cells/kg. The toxicity was determined based on the NCI common toxicity criteria. The International NB Response Criteria were used to define response after CAR-T treatment. RESULTS: Total 19 patients who had refractory minimal residual disease in the bone marrow were included for evaluation. Besides bone marrow involvement, some had metastatic lesions in the bone or lymph nodes. After the first 4SCAR-GD2 infusion, 12 patients achieved CR in the bone marrow, and 7 did not achieve disease remission. After the CAR-T infusion, the levels of CAR-Ts in the peripheral blood were monitored by qPCR. Once the CAR-Ts were diminished, a booster CAR-T infusion was given. A rise in the CAR-T levels in the blood after the booster infusion is routinely observed; representative CAR-T kinetic graphs of five patients are shown (Figure). Total 10 of the 19 patients received a booster 4SCAR-GD2 infusion. After the booster infusion, seven of the ten patients remained stable, and three had disease progression. The median observation time after the initial CAR-T infusion is 13 months (ranged 7 to 22). The adverse effects observed after the 1st or the 2nd CAR-T infusions were grade 0, 1 or 2 CRS, thrombocytopenia, and localized pain in the peripheral nerve or tumor lesions. CONCLUSIONS: These results have demonstrated safety and anti-tumor effects of the new 4SCAR2.0-GD2 regimen in R/R NB patients with bone marrow disease. Expanded study is ongoing to address long-term clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hypnosis on patients treated with adjuvant chemotherapy for breast cancer: A feasibility study.

Acceptability and tolerance of chemotherapy on patients treated for breast cancer remain challenging. Complementary approaches such as hypnosis may have a favorable impact both at the time of announcing and during chemotherapy, due to the notorious anxiety, distress, and self-perceived dysfunction. The objective of the study was that the patients complied with at least four self-hypnosis sessions out of the six cycles of chemotherapy. This open, prospective longitudinal study assessed feasibility of compliance to self-hypnosis during chemotherapy in an outpatients setting. Training sessions were given by a hypnotherapist. Throughout each cycle of chemotherapy, the patient had to use self-hypnosis to better control her anxiety or any difficulties. Nurses could offer help to the patient. Chemotherapy-associated side effects were evaluated through the NCI-Common Toxicity Criteria for Adverse Events v 4.03; moreover, side effects as pain, nausea, vomiting, fatigue, and anxiety were also evaluated during chemotherapy using a visual analogic scale. Health-related quality of life, emotional distress (anxiety and depression), and cancer-related fatigue were assessed (at inclusion, end of chemotherapy and 3months later) using the EORTC QLQ-C30 and QLQ-BR23, HADS and MFI-20 questionnaires, respectively. The number of patients screened and actually included in the study was reported, as the reasons for refusal. Thirty-five patients were included with a median age of 55 years (35-78). All patients received a hypnosis training session. The overall compliance with self-hypnosis was 68.6% (95% CI: 50.7%-83.2%), meaning that more than two thirds of patients performed at least four sessions of self-hypnosis. According to NCI-CTCAE, Grade 2 nausea and vomiting was observed in 45.7% and 22.9%, respectively, Grade 2 fatigue in 62.9%. Based on the HADS questionnaire, anxiety increased at the end of the chemotherapy and returned to the initial value 3months later (p=.97) whereas depression significantly decrease 3months after the end of chemotherapy with respect to the inclusion (p=.003). Role, emotional, and cognitive functioning were slightly affected throughout the treatment, in contrast to dyspnea or physical functioning. Our study showed that self-hypnosis was feasible on patients newly diagnosed for breast cancer receiving chemotherapy.

Low-dose dasatinib in older patients with chronic myeloid leukaemia in chronic phase (DAVLEC): a single-arm, multicentre, phase 2 trial

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are commonly initiated in older patients with chronic myeloid leukaemia in the chronic phase at standard doses. However, because of their safety profile in this population, appropriate therapy has not been established. We aimed to investigate whether a lower than standard dose of dasatinib was an appropriate therapy for older patients with chronic myeloid leukaemia in the chronic phase. DAsatinib, Very Low-dose, for Elderly CML-CP patients (DAVLEC) was a multicentre, single-arm, phase 2 trial done in 25 Japanese hospitals. We enrolled patients older than 70 years with newly diagnosed chronic myeloid leukaemia in the chronic phase, ECOG performance status 0-2, and no previous treatment for CML other than hydroxyurea within 4 weeks. Second-generation TKI dasatinib was given orally at a starting dose of 20% of the standard dose (20 mg/day). If the treatment was assessed as optimal response at 3 months, 6 months, and 9 months and adverse events were grade 2 or better (according to the NCI Common Toxicity Criteria v 4.0), the same dose was continued. If response was suboptimal and adverse events were grade 2 or better, the dose was increased by 20 mg/day. Once a dose reduction had been made because of a grade 3 or worse adverse event, there were no further dose increases. Treatment was discontinued if assessed as failure (disease progression to the accelerated phase or acute phase). The primary endpoint was the achievement of major molecular response at 12 months, assessed using a per-protocol analysis. This trial is registered at with the UMIN clinical trial registry, UMIN000024548, and has completed its planned observation period. Between Nov 1, 2016, and Oct 30, 2019, 52 patients received first-line dasatinib therapy at 20 mg/day. The median age at diagnosis was 77·5 years (73·5-83·0). 35 (67%) patients were male and 17 (33%) were female. 31 (60%) of 52 patients reached major molecular response at 12 months (one-sided 95% CI 48-71), with a median follow-up of 366 days (IQR 353-372). Grade 3-4 adverse events were reported in 12 (23%) patients. Neutropenia was the most frequent grade 3-4 adverse event, occurring in three (6%) patients. No treatment-related deaths were observed. Low-dose dasatinib at 20mg/day is worthy of consideration as a starting dose for older patients with newly diagnosed chronic myeloid leukaemia in the chronic phase. However, this dose needs to be further studied in a larger cohort and with a more ethnically diverse population. Bristol-Myers Squibb.

Chimeric Antigen Receptor 4SCAR-GD2-Modified T Cells Targeting High-Risk and Recurrent Neuroblastoma: A Phase II Multi-Center Trial in China

Background: Neuroblastoma (NB) is one of the most common childhood malignancies responsible for 15% of pediatric cancer deaths. 70% of children with NB present with high-risk features characterized by severe metastasis and poor long-term survival even if the multimodal intensive combination therapies are used. There is ongoing challenge for developing novel therapeutic strategies for NB. GD2 is a well-characterized tumor antigen in NB. Anti-GD2 antibodies and T cells genetically modified to express GD2-specific chimeric antigen receptor (GD2-CART) have demonstrated anti-cancer activity. Here we report the safety and efficacy of a new generation of GD2-CAR (4SCAR-GD2) targeting high-risk NB with a 1-year follow-up (NCI registrations: NCT02992210 and NCT02765243).Patients and Methods: Total 34 high-risk NB patients, after confirmation for GD2 expression, are enrolled from 5 hospitals in China. These patients had undergone a series of standard therapies, including surgery, chemo- and radio-therapy before CART treatment. CD3 positive cells were selected from apheresis lymphocytes and activated before lentiviral infection. The cells were transduced with a caspase 9-inducible, safety-engineered lentivector CAR containing multiple intracellular signaling domains: GD2-scFv/CD28/CD27/CD3ζ-iCasp9. Before CART infusion, patients received cyclophosphamide and fludarabine conditioning. The CART infusion dose was at average 1.1x10^6/kg. Toxicity was determined based on NCI common toxicity criteria. The International Neuroblastoma Response Criteria were used to define response after CART treatment. The total observation time for all patients is 1 year after infusion.Results: GD2 expression was scored 0 to 4 by immunohistochemical staining of tumor sections, and total 142 specimens were stained. The results showed that 9% of specimens were negative and more than 71% scored more than 2. Total 34 patients were infused with 4SCAR-GD2 T cells: 24% of them experienced no adverse reactions (per NCI-CTC v.4.0), 50% had grade 1 and 26% had grade 2 toxicity responses including fever, skin rash and peripheral nerve pain. No grade 3 or 4 toxicity was observed. CART expansion kinetics were monitored by quantitative PCR of CAR in peripheral blood. The 4SCAR-GD2 illustrated long term persistence with the highest level of copy number detected at 30% on day 180 after CART infusion. Marked tumor regression was observed in 2 patients. At 28 days after infusion, by ultrasound the mediastinal and peritoneal tumors in one patient were reduced by 94% and 99.5%, respectively. The other patient had progressive tumor located in retroperitoneum and PET-CT showed shrinking tumor two months after CART treatment; retroperitoneal SUV decreased from 2.5 to 1.5. At the one-year observation point, 38% of patients were in stable disease, 15% had partial response and 47% were in disease progression. The 1-year overall survival rate is 74%.Conclusion: This multicenter trial demonstrates that the 4SCAR-GD2 T cells are safe and effective for treating high-risk stage IV NB children. The correlations of GD2 expression in tumor, CART kinetics in blood and treatment responses could not be statistically established, suggesting a vast disease heterogeneity. Important therapeutic correlates require a large patient cohort and long-term follow-ups to elucidate. DisclosuresYu:H3 Biomedicine Inc.: Employment.

A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (Guadecitabine), in children and adults with SDH-deficient GIST, pheochromocytoma, and paraganglioma, and HLRCC-associated kidney cancer.

11540 Background: Loss of activity of the Krebs cycle component succinate dehydrogenase (SDH) complex is a mechanism of tumorigenesis in SDH-deficient cancers. Accumulation of the metabolite succinate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation. Guadecitabine is a small molecule DNA methyltransferase inhibitor. We conducted a Phase II study to test the hypothesis that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Study Objectives: Our primary objective was to assess the clinical activity of guadecitabine in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Secondarily, we desired to evaluate the toxicities of patients on treatment with guadecitabine. Methods: We conducted a single site, open label, phase II study using a small optimal two-stage design to evaluate response in SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Patients >12 years of age received guadecitabine subcutaneously at 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity via imaging response was assessed utilizing RECISTv1.1. Toxicities were graded using version 4.0 of the NCI Common Toxicity Criteria. All patients were included in analysis. Results: We enrolled nine patients (6F:3M) with an age range of 18-57 years. Seven patients had SDH-deficient GIST (78%), one patient with paraganglioma (11%), and one with HLRCC-associated renal cell carcinoma (11%). No patients had a complete or partial response. Five patients came off study due to progression (56%) with one death due to disease progression in the patient with HLRCC-associated renal cell carcinoma (11%). Three patients (33%) withdrew due to lack of response with stable disease. One patient was withdrawn due to investigator’s discretion (11%). Toxicities possibly, probably, or definitely related to drug included grade 3 leukopenia (11%) febrile neutropenia (11%), grade 3-4 neutropenia (22%) requiring dose reductions, grade 3 hypertension (11%), grade 2 lung infection requiring hospitalization (11%). Conclusions: In this single site, open label, phase II study in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell cancer guadecitabine was tolerated by the majority of patients. No complete or partial responses were observed. Clinical trial information: NCT03165721 .

Safety and outcome of stereotactic body radiation therapy (SBRT) with rectal hydrogel spacer for prostate cancer.

76 Background: Ultra-hypofractionated radiotherapy delivered using stereotactic body radiotherapy (SBRT) is a cost-effective treatment for localized prostate cancer. Optimal dosing remains unclear, as commonly used 30-40Gy/5fx regimens appear to overestimate hypofractionation’s control benefits. Here, we report the largest experience of 45Gy/5Fx of SBRT for prostate cancer patients treated with hydrogel peri-rectal spacer (‘hydrogel’). Methods: An IRB-approved retrospective protocol was used to conduct a registry search identifying all patients with prostate cancer who received 45Gy/5Fx between 2015-2019 with hydrogel. Genitourinary (GU) and gastrointestinal (GI) toxicities were defined using the NCI Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0. The ASTRO-Phoenix failure definition of Nadir+2 ng/mL was used for biochemical failure. Results: We analyzed 250 low (9.2%), intermediate (85.2%), and high-risk (5.6%) prostate cancer patients with a median follow-up of 9.9 months (range: 0-45.7 months). Acute GU and GI grade ≥ II toxicities were noted in 15.2% and 7.2% of patients, respectively. Late GU grade II and III toxicities occurred in 24.0% and 1.2% of patients, respectively, while late GI grade II and III toxicities occurred in 4.0% and 0.4% of patients, respectively. In patients (N=44) with follow-up >2 years, late GU and GI grade III toxicities occurred in 4.55% and 2.27% of patients, respectively. A significant correlation was noted for acute GI and GU toxicity predicting the respective late GI and GU toxicity (p-value < 0.001 for both). Physician-reported Grade ≥ II new onset erectile dysfunction was 17.2%. A gradual decline in prostate-specific antigen with a mean nadir of 0.04 (95% CI: [0.018, 0.067]) at 36 months was noted. The actuarial freedom from biochemical failure was 96.33% at 3 years. Overall survival was 94.09% at 3 years with no deaths attributed to prostate cancer. Conclusions: SBRT treatment of 45Gy/5Fx with hydrogel is well tolerated with GU/GI toxicities comparable to those reported for conventional fractionation. Although short, the 3-year biochemical control rate is encouraging. Longer follow-up and prospective evaluation are warranted.

Multisession radiosurgery for intracranial meningioma treatment: study protocol of a single arm, monocenter, prospective trial

BackgroundSingle session radiosurgery represents a widely accepted treatment for intracranial meningiomas. However, this approach could involve a high risk of treatment-related complications when applied to large volume lesions. In these cases and for those not suitable for surgical resection, radiosurgery in multisession setting could represents a viable option. The literature results are reassuring in terms of correlated adverse events as well as in terms of tumor control. However, no prospective long-term results are available. In this scenario, we design a prospective monocentric phase II study, in order to verify the safety of a multisession radiosurgery schedule delivering 25 Gy in 5 daily fractions.MethodsPatients diagnosed with large and/or near to critical structures, intracranial meningiomas have been treated by means of multisession radiosurgery in both exclusive and postoperative settings. The primary study aim is safety that has been being prospectively scored based on international scales, including NCI Common Toxicity criteria, version 4.03, Barrow Neurological Institute pain intensity score, Barrow Neurological Institute facial numbness score and House-Brackmann Facial Nerve Grading System for qualitative analysis. Secondary aim is treatment efficacy in terms of local control that has been being assessed on volumetric analysis.DiscussionThis is the first prospective phase II trial on multisession radiosurgery for large and/or near to critical structures intracranial meningiomas. If positive results will be found, this study could represent the starting point for a phase III trial exploring the role of multisession radiosurgery in the exclusive and postoperative radiation therapy treatment of intracranial meningiomas.Trial registrationTrial registration: clinicaltrials.gov platform (Multisession Radiosurgery in Large Meningiomas –MuRaLM- identifier NCT02974127). Registered: November 28, 2016. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02974127?term=radiosurgery&cond=Intracranial+Meningioma&draw=2&rank=1

Prospective results of concurrent radiation therapy and weekly paclitaxel as salvage therapy for unresectable locoregionally recurrent breast cancer

PurposeTo investigate the efficacy and toxicity of concurrent radiation therapy (RT) and paclitaxel in the treatment of unresectable locoregionally recurrent breast cancer (RBC) after mastectomy as primary treatment.MethodsThis was a prospective monocentric study of 51 patients (pts) diagnosed with unresectable locoregionally RBC after mastectomy and treated between 2008 and 2012. Radiotherapy (RT) was delivered at 60 Gy in 30 treatment fractions to recurrent sites. Chemotherapy was weekly paclitaxel of 50 mg/m2 for 5 weeks. All pts. underwent clinical examination, CT or PET/CT every 3 months in first 2 years and then every 6 months. Tumor response was evaluated clinically and by CT using the RECIST criteria. Toxicity was assessed weekly during RT by the NCI common toxicity criteria (version 3.0).ResultsFifty-one pts. with 61 recurrent sites were studied. The median age was 49 years. Sites of RBC were chest wall in 20 patients (32.8%), supraclavicular in 19 (31.1%), axilla in 11 (18.0%), and internal mammary lymph nodes in the remaining 11 (18.0%). RBC presented as single in 25 pts., multiple in 20 pts. and diffuse growth in 6 pts. Clinical response was observed in 47 pts. (92.2%), with 36 (70.6%) complete and 11 (21.6%) partial responses. Two patients (3.9%) presented with stable disease and 2 progressive disease. The cumulative local progression-free survival rate was 62.8% at 2 year and 53.0% at 5 years after treatment. No grade 4 toxicity was observed. Grade 3 radiation dermatitis and leukocytopenia were observed in 10 (19.6%) and 12 (23.5%) pts., respectively. One patient experienced grade 2 pneumonitis.ConclusionsConcurrent RT and weekly paclitaxel could be an effective therapeutic option for unresectable locoregionally recurrent breast cancer after mastectomy with an acceptable toxicity profile.

Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders.

ObjectiveTo evaluate if short‐term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC.MethodsThis was a prospective, double‐blind randomized, placebo‐controlled two‐center phase II study. Participants diagnosed with TSC and age 6–21 years were treated with 4.5 mg/m2 per day of oral everolimus (n = 32) or matching placebo (n = 15) taken once daily for 6 months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3 months, and 6 months. For safety, adverse events recorded continuously via patient diary were categorized and graded per NCI Common Toxicity Criteria for Adverse Events, version 3.0 (CTCAE 3.0). Analyses were performed on the intention‐to‐treat population (n = 47).ResultsNearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6 months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (P = 0.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (P = 0.011) was observed. A total of 473 adverse events (AE) were reported. The average number of total AE per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious AE were rare.InterpretationWhile safe, oral everolimus administered once daily for 6 months did not significantly improve neurocognitive functioning or behavior in children with TSC.

Critically short telomeres and toxicity of chemotherapy in early breast cancer.

Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres (< 3 kilobases, CSTs), but not average telomere length by itself, accounts for limited tissue renewal and turnover capacity. The impact of this parameter (which can be modified with different therapies) in chemotherapy-derived toxicity has not been studied.Blood from 115 treatment-naive patients from a clinical trial in early HER2-negative breast cancer that received weekly paclitaxel (80 mg/m2 for 12 weeks) either alone or in combination with nintedanib and from 85 healthy controls was prospectively obtained and individual CSTs and average telomere lenght were determined by HT Q-FISH (high-throughput quantitative FISH). Toxicity was graded according to NCI common toxicity criteria for adverse events (NCI CTCAE V.4.0). The variable under study was “number of toxic episodes” during the 12 weeks of therapy.The percentage of CSTs ranged from 6.5%–49.4% and was directly associated with the number of toxic events (R2 = 0.333; P < 0.001). According to a linear regression model, each 18% increase in the percentage of CSTs was associated to one additional toxic episode during the paclitaxel cycles; this effect was independent of the age or treatment arm. Patients in the upper quartile (> 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.

B35 - Neo-adjuvant treatment in patients with pancreatic cancer with nab-paclitaxel and gemcitabine

Purpose: Pancreatic adenocarcinoma remains one of the deadliest forms of cancer. In this study, we analyzed the efficacy, and toxicity of neo-adjuvant chemotherapy in the treatment of for borderline resectable or unresectable locally advanced pancreatic cancer. Methods: Fifteen patients affected by locally advanced pancreatic cancer treated with nab-paclitaxel and gemcitabine chemotherapy were evaluate. Median age was 55 years (range 47-69 years). The most frequently ECOG performance status were 1 (65%). The majority of the patients has a borderline resectable disease. (65%). Acute toxicity was prospectively recorded weekly using RTOG and NCI common toxicity criteria.(65%). Results: Within a median follow-up of 16.5 months (range 4-21 months), the majority of the patients received 6-7 of the 9 scheduled cycles of nab-paclitaxel and gemcitabine:: dose reduction were necessary in the 70% of patients. One of patients (15%) achieved a complete response: this patient received also radiotherapy. Partial response were achieved in 15% of patients and stable disease in 75%. Conclusions: Despite the brief period of follow-up and the small number of patients, we conclude that nab-paclitaxel and gemcitabine chemotherapy (+/- radiotherapy) is a valid option in locally advanced pancreatic cancer.

Abstract 3920: Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations

Abstract Radiotherapy-induced skin toxicity is one of the critical quality of life issues in breast cancer patients receiving adjuvant radiation therapy (RT). Finding a biomarker which can predict the development of acute RT-induced toxicity prior to RT is critical to improve precision medicine in radiation oncology. This study evaluated the association of single nucleotide polymorphisms (SNPs) in DNA-repair genes in 268 breast cancer undergoing adjuvant RT. We analyzed 3,747 polymorphisms in 119 DNA repair-related genes; 15 genes in base excision repair (BER), 11 in mismatch repair (MMR), 26 in nucleotide excision repair (NER), 15 in homologous recombination, 5 in non-homologous end-joining (NHEJ), 15 in DNA polymerases, and 47 in other DNA repair-related pathways. Skin toxicity was assessed at post-RT using the modified NCI's Common Toxicity Criteria for Adverse Events (CTCAE) and multiple logistic regression analyses were conducted to assess the associations between SNPs and grade ≥ 4 skin toxicity n = 115). After controlling for covariates, 221 SNPs were significant at p &amp;lt;0.05 and 34 at p &amp;lt; 0.01. Significant associations (p&amp;lt;0.01) were found in 7 SNPs in PAPD5 gene, 1 in POLD1, POLE, and POLI in DNA polymerase; 5 in RAD51L1 and 1 in RAD54L in HR; 4 in MMS19 in NER; 2 in MSH4 and 1 in PMS1 in MMR; 2 in RPA3 in BER; 2 in RAD18, and 1 in UBE2V2 in Rad6 pathway; 2 in CHEK2 in DNA damage response pathway; 1 in MGMT in direct reversal of DNA damage; and 1 in BLM in diseases associated with sensitivity to DNA damaging agents pathways. Among these, most significant association was found in BLM variant (s16944918) which showed that carrying at least one minor T allele was associated with increased risk of RT-induced skin toxicity (odds ratio [OR] = 3.36; 95% confidence interval (CI) = 1.62-6.97, p = 0.001). For RPA3 (rs11978293), carriers with at least one minor G allele were more likely to develop RT-induced skin toxicity (OR = 2.17, 95% CI = 1.34-3.52, p = 0.002). The current study suggests that genetic variations in multiple DNA-repair genes/pathways may contribute to inter-individual variation in RT-induced normal tissue toxicity in breast cancer patients and suggests the possibility of potential predictive values of genetic polymorphisms in RT sensitivity. Further validation studies with larger sample size are warranted. Citation Format: Sung Yong Eum, Eunkyung Lee, Jean L. Wright, Christiane Takita, Eden R, Martin, Susan Slifer, Jennifer J. Hu. Polymorphisms of DNA-repair pathways and its association with radiotherapy-induced acute skin toxicity among tri-racial breast cancer populations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3920.

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program.

BackgroundOnartuzumab, a recombinant humanized monovalent monoclonal antibody directed against MET, the receptor for the hepatocyte growth factor, has been investigated for the treatment of solid tumors. This publication describes the safety profile of onartuzumab in patients with solid tumors using data from the global onartuzumab clinical development program.MethodsAdverse event (AE) and laboratory data from onartuzumab phase II/III studies were analyzed and coded into standardized terms according to industry standards. The severity of AEs was assessed using the NCI Common Toxicity Criteria, Version 4. Medical Dictionary for Regulatory Activities (MedDRA) AEs were grouped using the standardized MedDRA queries (SMQs) “gastrointestinal (GI) perforation”, “embolic and thrombotic events, venous (VTE)”, and “embolic and thrombotic events, arterial (ATE)”, and the Adverse Event Group Term (AEGT) “edema.” The safety evaluable populations (patients who received at least one dose of study treatment) for each study were included in this analysis.ResultsA total of 773 onartuzumab-treated patients from seven studies (phase II, n = 6; phase III, n = 1) were included. Edema and VTEs were reported in onartuzumab-treated patients in all seven studies. Edema events in onartuzumab arms were generally grade 1–2 in severity, observed more frequently than in control arms and at incidences ranging from 25.4−65.7% for all grades and from 1.2−14.1% for grade 3. Hypoalbuminemia was also more frequent in onartuzumab arms and observed at frequencies between 77.8% and 98.3%. The highest frequencies of all grade and grade ≥3 VTE events were 30.3% and 17.2%, respectively in onartuzumab arms. The cumulative incidence of all grade ATE events ranged from 0−5.6% (grade ≥3, 0−5.1%) in onartuzumab arms. The frequency of GI perforation was below 10% in all studies; the highest estimates were observed in studies with onartuzumab plus bevacizumab for all grades (0−6.2%) and grade ≥3 (0−6.2%).ConclusionsThe frequencies of VTE, ATE, GI perforation, hypoalbuminemia, and edema in clinical studies were higher in patients receiving onartuzumab than in control arms; these are considered to be expected events in patients receiving onartuzumab.

Abstract P5-15-07: Association of patient preference for adjuvant chemotherapy (chemo) at baseline (BL) with toxicity, mental health, function, quality of life (QoL) and survival in older women with early stage breast cancer (ESBC) [CALGB 49907 Alliance

Abstract Background: In CALGB-49907 (NEJM 2009;360:2055), older patients (pts) with ESBC were randomized to standard adjuvant chemo (AC or CMF versus capecitabine). The objective of this secondary QoL analysis is to assess if pts’ BL chemo preference (CP, defined as high or low), is associated with the following during and after completion of chemo: self and professional-reported toxicity, changes in mental health, function, QoL, recurrence-free (RFS) and overall (OS) survival. Patients and Methods: Of 633 trial pts 350 participated in the QoL substudy; 145/350 pts completed the BL assessment regarding CP. CP was measured by asking the amount of benefit women would require to choose adjuvant chemo in a hypothetical situation, irrespective of chemo agents. Women who chose chemo for an increase in OS of ≤12 months (mo) were designated as high chemo preference (HCP) and those who chose &amp;gt;12 mo were designated low chemo preference (LCP). CP associations were evaluated with: BL perception of self-health and perceived QoL on chemo; patient reported outcomes (PROs), changes in function and QoL (based on EORTC-QLQ-C30); anxiety and depression (Hospital Anxiety and Depression Scale); observed grade 3-5 adverse events (AEs) by NCI common toxicity criteria (CTC v2.0). Pts were assessed at midtreatment and at 1, 12, 18 and 24 mo post-treatment. Chi-square tests, t-tests, and Cox models were used for categorical, continuous, and time-to-event variables, respectively. Results: The demographic and tumor characteristics of women (median age 71) who provided CP at BL were not different from women in the QoL subset or from non-QoL pts. 68/145 (47%) women had a HCP. CP groups did not differ based on age, surgery type, tumor and nodal stage, hormone receptor status, performance status, chemo assignment, education, marital or employment status except the LCP group had a higher proportion of white women (95% vs. 78%, p=0.004). At BL, there were no differences in perception of self-health based on CP but women with LCP predicted QoL on chemo to be worse than women with HCP (p=0.006) and reported greater nausea/vomiting. Mid-treatment, LCP pts reported worse nausea/vomiting, financial worries, and cancer symptoms. Post-treatment, LCP pts had worse constipation (at 1 mo) and financial worries (at 24 mo). There were no differences based on CP for dyspnea, pain, fatigue, insomnia, anxiety or depression at any timepoint. Mid-treatment, LCP women reported lower QoL and worse social, emotional and physical function compared to HCP women. These scores were not significantly different after treatment completion. LCP women had significantly higher rates of grade 3-5 AEs (53 vs. 34%, p=0.02) during treatment but these did not persist post-therapy. CP was not significantly associated with OS (HR =0.75, p=0.36) or RFS (HR=0.94, p=0.84). Conclusions: LCP at BL was associated with lower QoL, worse physical symptoms, AEs and function mid-therapy, but not mental health. Mid-therapy declines in women with LCP largely reversed post-therapy. This information may be useful for oncology professionals to counsel older ESBC pts with LCP receiving adjuvant chemo. Citation Format: Ajeet Gajra, Linda McCall, Hyman B Muss, Harvey J Cohen, Aminah Jatoi, Karla V Ballman, Ann H Partridge, Linda Sutton, Barbara A Parker, Gustav Magrinat, Jaqueline M Lafky, Arti Hurria. Association of patient preference for adjuvant chemotherapy (chemo) at baseline (BL) with toxicity, mental health, function, quality of life (QoL) and survival in older women with early stage breast cancer (ESBC) [CALGB 49907 Alliance] [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-07.

Toxicity and efficacy of salvage paclitaxel chemotherapy in Royal Marsden (RM) oesophagogastric adenocarcinoma (OGA) patients (pts).

188 Background: Paclitaxel is a standard global salvage therapy for pts with advanced refractory OGA. Western pts may differ from Asian pts with respect to chemotherapy metabolism and cancer behaviour, and the benefits associated with paclitaxel in this setting have not been assessed outside of Asia. We examined the efficacy and toxicity associated with salvage paclitaxel for advanced OGA at RM over a 3 year period. Methods: This was a retrospective observational study. We identified all pts with OGA treated with salvage weekly paclitaxel from 01/06/2011 to 21/02/2014 from the electronic pt record at RM. The following data was collected: demographics, metastatic sites, resection status, response/duration of response to prior chemotherapy, ECOG PS, haemoglobin, albumin, alkaline phosphatase (ALP), neutrophil/lymphocyte ratio, CEA, CA19.9, RM prognostic score, CT response and date of progression, death or last follow up. Toxicity was collected as per NCI Common Toxicity Criteria (v4.0). Overall and progression free survival (OS/PFS) were estimated using the Kaplan-Meier method. Multivariate Cox regression analysis examined the association between clinical and laboratory variables with survival. Results: 57 pts were identified. Pts were 74% male; median age 64y; 66% PS 0-1; 91% 2nd line. Median number cycles 3 (range 1-8). Median follow up 13.6m. Response rate was 18.4% in evaluable pts. OS and PFS were 5.8m (95% CI: 4.8 – 6.8m) and 2.6m (95% CI: 1.9 – 3.2m). 2y and 3y survival from start of 1st line treatment were 26% and 13%. In multivariate analyses PS ≥2 [HR 2.28, p = 0.018], and ALP ≥100 U/L, [HR=2.01, p= 0.033] were independent negative prognostic factors for OS. ≥ Grade 3 nausea, diarrhea and neuropathy were uncommon (&lt;2% each), rate of ≥ grade 3 fatigue was 11%. Grade 3-4 neutropenia, leucopenia and thrombocytopenia occurred in 12%, 11% and 2% pts. Conclusions: Advanced OGA pts treated at RM with salvage paclitaxel have an OS equivalent to pts in clinical trials with less hematological toxicity than seen in Asian patients. This may be due to regional pharmacogenetic profiles. As a significant proportion of pts now survive 2-3y with limited toxicity, therapeutic nihilism is unwarranted.

Prospective, Observational Study to Assess the Safety of Rituximab(R) in Combination with Chemotherapy in Patients with Previously-Untreated or Relapsed or Refractory B Cell-Lineage Chronic Lymphocytic Leukaemia (B-CLL): Final Results

Aim and Background: MABERYC non-interventional study was designed to characterize the type, severity and frequency of all adverse events (AEs)/serious-AEs (SAEs) occurring on-treatment and in the year following rituximab infusion. Secondary objectives included response rate (CR/PR) and to evaluate the clinical utility and the validity of a specific comorbidity scale (CoLLECT scale) for B-CLL patients, planned to recognize patients who may benefit from some special pharmacological approach.Methods: Between November 2010 and February 2012, data were collected prospectively from B-CLL patients, in 47 Spanish hospitals, starting a new treatment with an R-based chemotherapeutic scheme in accordance with normal clinical practice at the time of enrollment. Safety analyses were conducted by closely monitoring patients throughout the study. AEs and SAEs were tabulated by NCI-Common Toxicity Criteria (NCI-CTC), v4.0. In order to validate the CoLLECT scale, specifically designed for this study, assessment of comorbidity was planned at baseline and 12 months following treatment finalization, using three subscales (low [0-3], moderate [4-7] and high [>7]) with ten different indexes. Changes were categorized in improvement (reduction ≥2), no changes (variation <2) and worsening (increase ≥2).Results: A total of 218 patients have been enrolled, 108 and 110 pts in the first-line and pre-treated arm, respectively. The median age (range) of the whole series was 69 (r: 39–87) years. ECOG status varied across the two groups, with a ≤1 ECOG status score of 99%, and 84% of first-line and pre-treated patients, respectively. The baseline characteristics on both arms are shown in Table 1. [Display omitted] 1448 AEs were reported on treatment, 50% of them considered as drug-related. The most frequently related-AE in first-line and pre-treated arm included: neutropenia (34/30%); fever (18/12%); nausea (15/11%); thrombocytopenia (10/17%), febrile neutropenia (FN) (10/9%), and anemia (7/16%). Overall, the treatment was well tolerated and the toxicity profile differed according to the treatment arm (Table 2). Treatment discontinuations due to related-AEs in the first-line and pre-treated arm was of 9 and 11% on-treatment, fatal AEs occurred in 3% and 4%, respectively. [Display omitted] In the overall population by IWG response criteria, the best response on treatment was CR in 28% and PR in 30% of patients (nPR in 4% of patients). Although, based on fairly different number of patients by scheme that preclude a completely valid statistical comparison, the complete and partial response rate (CR/PR) in the first-line arm was as follows: BR (50/31%), FCR (43/25%), R+others (29/43%) and ClbR cohort (23/46%), while in the pre-treated arm the response rate was higher in the BR (20/16%), followed by FCR (19/24%), R+others (5/52%) and ClbR cohort (15/40%).Mean CoLLECT score was higher in older patient, higher ECOG, previously treated and those receiving less aggressive treatments. Changes in CoLLECT showed CR could be associated to improvement in comorbidity. CR was reached by 53% of patients with COLLECT improvement, 47% without changes, and 32% worsening.Conclusion: In this unselected group of B-CLL patients taken from normal clinical practice, the AEs frequency was related to immunochemotherapy scheme as well as the stage of treatment. Rituximab seems an effective and relatively safe option when added to any chemotherapy regimen. With the help of the CoLLECT scale, which is related with patient´s profile, treatment regimen prescribed, CR and AEs, patient’s co-morbidity can be assessed and assist on decision-making about the intensity of the inmmunochemotherapy regimen to be prescribed. DisclosuresNo relevant conflicts of interest to declare.

Genetic Variation in NFATC2 Is Associated with a Higher Risk of Asparaginase Allergy

Asparaginase is an important drug for the treatment of acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions to asparaginase can lead to suboptimal asparaginase exposure and to a higher risk of disease recurrence. Factors influencing the frequency of asparaginase hypersensitivity include asparaginase formulation, the schedule of asparaginase administration, and concurrent chemotherapy. In addition, using a candidate gene approach, our group previously identified a genetic association between HLA-DRB1*07:01 and asparaginase hypersensitivity in patients of European ancestry.[PMID 24970932] The objective of our current study was to use a genome-wide approach to identify additional genetic loci associated with hypersensitivity and to assess the relative importance of HLA-DRB1 as a genetic risk factor.Asparaginase hypersensitivity was assessed in children with ALL enrolled on SJCRH protocols Total XIIIA (n = 154), Total XV (n = 498) and Total XVI (n = 271) or Children’s Oncology Group (COG) protocols POG 9906 (n = 222) and AALL0232 (n = 2,163). Patients enrolled on protocols Total XIIIA, Total XV and POG 9906 received native E. coli asparaginase during treatment, whereas patients on Total XVI and AALL0232 received PEGylated E. coli asparaginase. Hypersensitivities were graded according to the NCI common toxicity criteria, and reactions of grade 2 and above were considered cases. Germline DNA was genotyped using the Affymetrix 500K, Affymetrix 6.0, or the Illumina Exome Beadchip array. Univariate analysis of risk factors associated with asparaginase hypersensitivity using the combined cohort of patients (n = 3,308) identified a significant positive association with treatment arm (P < 2.2x10-16; highest risk in patients enrolled on Total XV), native E coli asparaginase formulation (P < 2.2x10-16), age < 10 years (P = 3.3x10-4), male gender (P = 0.06), and racial ancestry (P = 2.1x10-4; highest risk among African ancestry). In multivariate analysis, treatment arm (P < 2.2x10-16), gender (P = 0.04), racial ancestry (P = 0.07), and ALL lineage (P = 0.003) remained significant risk factors.A multivariate logistic regression model adjusted for treatment arm, racial ancestry, gender, age, and ALL lineage was used to identify genomic variants associated with asparaginase hypersensitivity in the combined patient cohort. The minor allele of an intronic polymorphism in NFATC2 (rs6021191) was associated with hypersensitivity at the genome-wide significance threshold (P = 2.6x10-8, OR = 3.17). The minor allele frequency (MAF) for the NFATC2 high-risk variant was highest in non-European ancestries (MAFEuropean = 0.001, MAFAfrican = 0.142, MAFHispanic = 0.043, MAFAsian = 0.151, MAFOther = 0.034). Using RNA-seq data available from the ALL tumor samples of 65 SJCRH patients, we found that patients carrying the variant had higher expression of NFATC2 compared to non-carriers (P = 1.0x10-3). NFATC2 is known to play a critical role in inducing T-cell gene transcription during immune responses.The strongest association detected using SNPs from the Illumina Exome array was found in HLA-DRB1 (rs17885382, P = 4.0x10-6, OR = 1.65), and the SNP is in near complete linkage disequilibrium with the HLA-DRB1*07:01 allele, which we previously found associated with asparaginase hypersensitivity. A gene-level analysis was performed using SNP-set Kernel Association Test (SKAT), and the gene with the strongest association with hypersensitivity was PPT2, located in the HLA class III region on chromosome 6 (P = 3.70x10-6). To determine potential biological pathways differentially represented by the genes identified by our analysis, we used Ingenuity Pathway Analysis on the top 1% of genes associated with hypersensitivity as identified by our single SNP (68 genes) and gene level analysis (18 genes). We found an enrichment of genes (8 out of 21 genes, P = 2.6x10-5) within the top network involved in humoral immunity, suggesting that other genes regulating immune responses may also contribute to the risk of developing asparaginase hypersensitivity.In conclusion, the top inherited genetic loci (NFATC2, HLA-DRB1*0701, PPT2) associated with asparaginase hypersensitivity are directly involved in human immune response, and pathway analysis suggests that inherited variations in other genes involved in humoral immunity likely play a role in the development of asparaginase hypersensitivity. DisclosuresEvans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.

Abstract 2882: p53MVA therapy in patients with refractory gastrointestinal malignancies primes robust CD8+ T cell responses

Abstract PURPOSE: To conduct a Phase I safety trial of a Modified Vaccinia Ankara vaccine delivering wild type human p53 (p53MVA) in patients with refractory gastrointestinal malignancies. EXPERIMENTAL DESIGN: Three patients were vaccinated with 108 pfu p53MVA followed by nine patients at 5.6 x 108 pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre vaccine and post vaccination for immunophenotyping and assessment of p53MVA induced immune response. RESULTS: p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. Induction of strong T cell and antibody responses to the MVA backbone were apparent. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T cell compartment (p=0.03). However in most patients this did not expand further with the second and third immunization. Some patients exhibited a decline in myeloid-derived suppressor cells post vaccine, but this was not statistically significant. The frequency of PD-1+ T cells detectable in patients PBMC was significantly higher than healthy controls. Furthermore, the frequency of PD-1+ CD8+ T cells showed an inverse correlation with the peak CD8+ T cell response to p53 (p=0.02). CONCLUSION: p53MVA was well tolerated and induced robust CD8+ T cell responses. Combination of p53MVA with immune checkpoint inhibition could improve sustained immune responses and lead to clinical benefit. Citation Format: Nicola Hardwick, Mary Carroll, Teodora Kaltcheva, Dajun Qian, Jonathan Espenschied, Lucille Leong, Peiguo Chu, Joseph Kim, Joseph Chao, Marwan Fakih, Joshua Ellenhorn, Don Diamond, Vincent Chung. p53MVA therapy in patients with refractory gastrointestinal malignancies primes robust CD8+ T cell responses. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2882. doi:10.1158/1538-7445.AM2014-2882

P53MVA Therapy in Patients with Refractory Gastrointestinal Malignancies Elevates p53-Specific CD8+ T-cell Responses

To conduct a phase I trial of a modified vaccinia Ankara (MVA) vaccine delivering wild-type human p53 (p53MVA) in patients with refractory gastrointestinal cancers. Three patients were vaccinated with 1.0×10(8) plaque-forming unit (pfu) p53MVA followed by nine patients at 5.6×10(8) pfu. Toxicity was classified using the NCI Common Toxicity Criteria and clinical responses were assessed by CT scan. Peripheral blood samples were collected pre- and post-immunization for immunophenotyping, monitoring of p53MVA-induced immune response, and examination of PD1 checkpoint inhibition in vitro. p53MVA immunization was well tolerated at both doses, with no adverse events above grade 2. CD4+ and CD8+ T cells showing enhanced recognition of a p53 overlapping peptide library were detectable after the first immunization, particularly in the CD8+ T-cell compartment (P=0.03). However, in most patients, this did not expand further with the second and third immunization. The frequency of PD1+ T cells detectable in patients' peripheral blood mononuclear cells (PBMC) was significantly higher than in healthy controls. Furthermore, the frequency of PD1+ CD8+ T cells showed an inverse correlation with the peak CD8+ p53 response (P=0.02) and antibody blockade of PD1 in vitro increased the p53 immune responses detected after the second or third immunizations. Induction of strong T-cell and antibody responses to the MVA backbone were also apparent. p53MVA was well tolerated and induced robust CD8+ T-cell responses. Combination of p53MVA with immune checkpoint inhibition could help sustain immune responses and lead to enhanced clinical benefit.