Treatment of childhood glial tumors with cisplatin and irinotecan

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10062-10062
Author(s):  
J. Mora ◽  
O. Cruz ◽  
A. Parareda ◽  
A. Guillen ◽  
R. Puy ◽  
...  
Keyword(s):  
Clinical Symptoms ◽  
Objective Response ◽  
Prospective Trial ◽  
Glial Tumors ◽  
Clinical Responses ◽  
Grade 3 ◽  
Extent Of Surgical Resection ◽  
Objective Functional

10062 Background: Childhood glial tumors are heterogeneous neoplasias for which non-surgical management is controversial. After a pilot study suggesting that irinotecan/cisplatin (I/C) may be effective in children (Mora et al, Neuro Oncol 2007), we initiated a phase II prospective trial with the aim of avoiding radiation therapy for low grade's (LG) and improve outcome for high grade's (HG). Methods: The indication for adjuvant therapy was based upon histology, the extent of surgical resection, and the presence of clinical or neuroradiological signs of progression. Weekly Irinotecan (50 mg/m2 and 65 mg/m2 the last 2 cycles) and Cisplatin (30 mg/m2) for four consecutive weeks (1 cycle), and a total of 4 cycles was used. Results: From January 2004 to December 2007, 30 children aged 6 months to 17 years were treated, 21 at diagnosis, 7 at progression and 2 at relapse. Fourteen tumors were WHO grades I-II gliomas (LGG), 10 grade III (6 gliomas, 2 anaplastic ependymomas and 2 AT/RT), and 6 had no biopsy (3 brainstem (BST) and 3 optic-pathway tumors (OPT)). Two patients had type-1 neurofibromatosis and OPT. Primary sites included: 4 supratentorial, 8 BST, 9 OPT, 2 cerebellar, and 7 spinal. Prior to the I/C regimen, gross total resection was performed in 7 and biopsy in 14 tumors; 9 patients received chemotherapy and 5 radiotherapy. All but 6 patients, 2 because of C allergy and 4 BST because of progression, completed the protocol, with no grade 3–4 side effects. Vomiting was the main side effect. Twenty (90%) of 22 patients with evaluable clinical symptoms had a complete and rapid response, with objective functional recovery. With a median follow-up of 25 months, 14 (47%) patients had a complete/partial response (7 out of 10 HG), 10 (40%) had stable disease (8 out of 14 LG), and 6 (20%) progressed (all BST). Five patients died of disease, all BST. Twenty-five (83%) patients remain progression-free, median 27 months from protocol entry. Conclusions: Seventy percent objective response rate for HG and avoidance of radiotherapy for 93% of LG was obtained using the I/C regimen. Remarkable fast clinical responses and functional recoveries occurred. No significant financial relationships to disclose.

A single institution experience of EGFR inhibitors in patients with advanced squamous cell anal carcinomas (SCAC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 623-623
Author(s):  
Dae Won Kim ◽  
Jennifer Elizabeth Byer ◽  
Nishi Kothari ◽  
Amit Mahipal ◽  
Richard D. Kim
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Prospective Trial ◽  
Egfr Inhibitors ◽  
Egfr Mutations ◽  
Egfr Inhibitor ◽  
Potential Efficacy ◽  
Cancer Tumor ◽  
Grade 3

623 Background: Although SCAC are relatively rare, their incidence has been increasing steadily. Because of limited data, treatment of metastatic disease is a major therapeutic challenge. Recent data has demonstrated a low rate of KRAS and EGFR mutations, suggesting a potential target of EGFR inhibitors. In this study, we report the safety and efficacy of EGFR inhibitors in patients (pts) with advanced SCAC. Methods: A retrospective analysis was conducted using the Moffitt Cancer tumor registry from 1/2009 to 1/2014. Eligible pts had advanced SCAC and received an EGFR inhibitor as part of their treatment. Results: 13 pts were identified for analysis. Median age was 59 years (range: 41-68). All pts received concurrent chemoradiation (Nigro regimen) as initial treatment and subsequently had recurrence. Upon diagnosis of recurrent disease, 5 pts received 2 lines of systemic chemotherapy, 5 pts received 1 line and 3 did not receive any treatment prior to receiving EGFR inhibitors. 5 pts received single agent cetuximab (4) or panitumumab (1) and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. Pts received a median EGFR inhibitor dose of 8 (range: 2-45). Objective response rates were 30.8% (1 CR, 3 PR) and disease control rates were 46.2%. 1 pt with CR was on single agent cetuximab as second line therapy and 3 pts with PR were on cetuximab plus chemotherapy as front-line. With a median follow-up of 9.6 months (mo), the median PFS and median OS were 4.4 mo (95% confidence interval (CI) 2.99-5.81) and 11.4 mo (95% CI 7.93-14.87), respectively. No KRAS mutation was detected in 8 pts and KRAS testing was not done on 5 other pts. Grade 3 toxicities included anemia (n = 2), fatigue (n = 1), depression (n = 1), dyspnea (n = 1), anorexia (n = 1), nausea (n = 1) and diarrhea (n = 1). No grade 4 toxicities were observed. Conclusions: Our analysis suggests that EFGF inhibitors have potential efficacy and are reasonably well tolerated in patients with SCAC. These findings warrant further evaluation in a large prospective trial.

The outcome of seven patients with hereditary tyrosinemia type 1

2016 ◽  
Vol 29 (10) ◽  
Author(s):  
Songul Gokay ◽  
Pembe Soylu Ustkoyuncu ◽  
Fatih Kardas ◽  
Mustafa Kendirci
Keyword(s):  
Clinical Symptoms ◽  
Age At Onset ◽  
Nodule Formation ◽  
First Year ◽  
Tyrosine Metabolism ◽  
Tyrosinemia Type 1 ◽  
Hereditary Tyrosinemia ◽  
Biochemical Imaging

AbstractBackground:Hereditary tyrosinemia type 1 (HT1) is a rare, inborn error of tyrosine metabolism. It is a fatal disorder without treatment. Early treatment may prevent acute liver failure, renal dysfunction, liver cirrhosis, hepatocellular carcinoma (HCC) and improves survival. The aim of the present study is to describe the clinical, biochemical, imaging and follow-up of seven patients with HT1 and to define the consequences of the late and interrupted treatment.Methods:A retrospective study was carried out with seven HT1 patients.Results:The median age at onset of clinical symptoms was 11.2 months (range, 3–28 months) and the median age at diagnosis was 22 months (range, 6–58 months). Liver enzymes and coagulation parameters were back to normal in all symptomatic patients in about 2 weeks. Alfa-fetoprotein (AFP) levels were normalized within the first year of therapy. Hypoechoic nodule formation was detected in two of the seven patients despite drug treatment without an increase of AFP and any dysplastic changes in the biopsies. One patient died due to metastatic HCC because of the late diagnosis and the poor compliance of the follow-up.Conclusions:This study showed once again that adherence to the treatment and a follow-up schedule of the patients are very important. Also it should not be forgotten that nodule formation can occur despite nitisinone treatment without an increase of AFP. Despite nitisinone treatment, HT1 patients still carry the risk of HCC. HCC must be detected before metastasis to other organs otherwise, patients may lose the chance for liver transplantation.

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16184-e16184
Author(s):  
Jeffrey Sum Lung Wong ◽  
Gin Wai Kwok ◽  
Vikki Tang ◽  
Bryan Li ◽  
Roland Ching-Yu Leung ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Median Number ◽  
Refractory Ascites ◽  
Time To Progression ◽  
Advanced Hcc ◽  
Grade 3 ◽  
Experienced Grade ◽  
Systemic Therapies

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.

First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9000-9000
Author(s):  
Martin Reck ◽  
Tudor-Eliade Ciuleanu ◽  
Manuel Cobo ◽  
Michael Schenker ◽  
Bogdan Zurawski ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Performance Status ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Expression Level ◽  
First Line ◽  
Ecog Performance Status ◽  
Grade 3

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

scholarly journals Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3320-3320
Author(s):  
Amy E. DeZern ◽  
Marianna Zahurak ◽  
Javier Bolanos-Meade ◽  
Richard J. Jones
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Stopping Rules ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

Could Enzyme Replacement Therapy for Long Time Normalize Chitotriosidase Activity in Type 1 Gaucher Disease?.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3802-3802
Author(s):  
Pilar Giraldo ◽  
Pilar Alfonso ◽  
Juan Perez-Calvo ◽  
Manuel Giralt
Keyword(s):  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Bone Disease ◽  
Clinical Symptoms ◽  
Analytical Data ◽  
Enzyme Replacement ◽  
Group A ◽  
Group B

Abstract Background: Extreme elevations of plasma chitotriosidase (CT) are observed in Gaucher’s disease (GD) patients. This enzyme has been considered as a response marker to enzyme replacement therapy (ERT). It has been previously described the normalization of enzymatic activity only in patients who have been treated by bone marrow transplantation (Young E et al, 1997). It is widely accepted that GD subjects receiving ERT show improvements in clinical symptoms and regression of signs of disease, such as disappearance or reduction of visceral enlargement, normalized haematological parameters and skeletal improvement and also reduce the CT activity values, but these do not actually reach a normal range. Surprisingly, in the follow-up of patients included in the Spanish Gaucher Registry, some cases showed normalization of their CT activity after several years under therapy. The purpose of this study is to analyze the clinical, analytical and genotype characteristics of type 1 GD patients that have normalized their CT activity and to compare with the rest of patients under ERT for same period of follow-up. Patients and Methods: We have studied a cohort of 64 type 1 GD patients receiving ERT. We observed 20 GD patients who reach a normal CT activity range (CT activity < 200 nmol/mL.h) under therapy 2–7 years (group A) and 44 GD patients whose CT activity maintained increased under therapy 2–10 years (group B). Clinical and analytical data have been obtained from Spanish GD registry. Assessment of response included serial measurement of haemoglobin (Hb), platelet count, liver and spleen sizes and CT activity. Plasma CT activity was measured with the fluorogenic substrate 4-methylumbelliferyl-β-D-N, N′, N″ triacetylchitotrioside. Determination of the 24-bp duplication in the CT gene was performed by PCR followed by electrophoresis of the amplified fragments. For statistical analysis we used the StatView database (version 4.5). Results: At baseline characteristics of both groups were as indicated in tables. Patients of group B had worse indicators of disease severity at baseline. SSI, percentages of bone disease and spleen removal were higher in group B than group A. In addition we found twice more heterozygous patients for 24 bp duplication of the CT gene in group A compared to group B Nevertheless, as the table shows, patients of group B received higher doses of ERT and for a longer time. Conclusion: The normalization of CT activity is infrequent in GD patients under ERT. It is influenced by CT genotype and probably by severity of disease. Clinical data Age at diagnosis Male/Female SSI Spleen removal(%) Bone disease (%) N370S Homozygous/N370S Heterozygous N: number, SSI: severity score system Analytical data Group A (n=20) 32 ± 15.0 7/13 7.6 ± 2.55 5 55 0/20 Group B (n=44) 29 ± 15.9 19/25 8.4 ± 3.15 27 66 5/39 Analytical data Hb (g/dL) Platelets x 109/L CT activity(nmol/mL.h) Heterozygous CT genotype(%) ERT Dose (Units/2 weeks) N: number; Hb: Haemoglobin; CT: chitotriosidase; ERT: Enzyme replacement theraphy Group A (n=20) 12.3 ± 1.85 72.8 ± 31.27 7,489 ± 3,751 65 34.3 ± 10.33 Group B (n=44) 11.9 ± 1.84 107.5 ± 83.85 8,459 ± 3,563 32 41.4 ± 15.08

Proton radiotherapy for rhabomyosarcoma: Preliminary results from a multicenter prospective study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9585-9585
Author(s):  
Torunn I. Yock ◽  
Jackie Szymonifka ◽  
Alison M. Friedmann ◽  
Anita Mahajan ◽  
Beow Yong Yeap ◽  
...  
Keyword(s):  
Late Effects ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Stage I ◽  
Entire Group ◽  
Early Results ◽  
Group I ◽  
Oral Pain ◽  
Grade 3

9585 Background: Pediatric rhabdomyosarcoma (RMS) is commonly cured with chemotherapy and radiation. However, late effects of radiotherapy (RT) can be disabling. Proton RT irradiates less normal tissue, which should result in fewer late side effects of treatment. The purpose of this study was to describe the disease control and side effect profile of proton RT in RMS patients (pts). Methods: Eligible pts included those with localized disease and metastatic embryonal RMS if age 2-10. All pts were treated with VAC (vincristine, actinomycin, cyclophosphamide) based chemotherapy and proton RT, median dose 50.4 Gy (36-50.4 GyRBE). Concurrent enrollment in COG protocols was allowed. All pathology/imaging was reviewed at the treating institution. Results: 47 pts with RMS were prospectively enrolled from January 2005 to June 2011 and evaluable for analysis. Median age was 3.1 yrs, (range 0.6-15.6 years; M/F ratio 23:24). There were 1, 7, 37, and 2 Group I, II, III and IV and 14, 12, 19 and 2, Stage I-IV pts respectively, and 33 with embryonal 14 with alveolar/other. Most common sites included PM (48.9%), orbital (23.4%) bladder/prostate (6.4%), H&N non-PM (6.4%), extremities (4.3%), trunk/abdomen 2.1%), perineal/anal region (2.1%) and other (6.4%). Median follow-up is 15.2 months. One/two-year overall survival (OS) and progression-free survival (PFS) for the entire group is 94/81% (OS) and 79/73% (PFS). 2-year OS for stage I,II/III,IV pts is 91/66% (OS, p=0.114) and two-year PFS for these pts is 86/57%, respectively, (p=0.083. 16 (34%) had grade 3/4 acute toxicities attributable to the radiation during treatment, the most common of which was mucositis/oral pain (12.8%), anorexia (4.3%), and erythema (4.3%). Among the 24 pts analyzable for late toxicities with at least 2 yrs of follow up, there were no grade 3 or 4 late toxicities attributable to radiation. Conclusions: Early results of this prospective trial demonstrate comparable disease outcomes and thus far limited late effects in a young pediatric RMS population. However, additional follow up is needed to determine if protons truly reduce rates and severity of late effects compared with photon cohorts published in the literature.

Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9507-9507 ◽  
Author(s):  
Hussein Abdul-Hassan Tawbi ◽  
Peter A. J. Forsyth ◽  
Alain Patrick Algazi ◽  
Omid Hamid ◽  
F. Stephen Hodi ◽  
...  
Keyword(s):  
Objective Response ◽  
Complete Response ◽  
Median Number ◽  
Disease Assessment ◽  
Response Data ◽  
Grade 3 ◽  
Favorable Safety ◽  
The Brain ◽  
Clinical Trial Information

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]

First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9530-9530 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Jeffrey Russell ◽  
Jessica Cecile Hassel ◽  
Celeste Lebbe ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Safety Profile ◽  
Response Rate ◽  
Objective Response ◽  
Durable Response ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Related Reaction ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

First-line avelumab + axitinib in patients with advanced hepatocellular carcinoma: Results from a phase 1b trial (VEGF Liver 100).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4072-4072 ◽  
Author(s):  
Masatoshi Kudo ◽  
Kenta Motomura ◽  
Yoshiyuki Wada ◽  
Yoshitaka Inaba ◽  
Yasunari Sakamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Study Data ◽  
Clinical Activity ◽  
Advanced Hepatocellular Carcinoma ◽  
Data Set ◽  
Phase 1B ◽  
Grade 3

4072 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of advanced/metastatic (a/m) hepatocellular carcinoma (HCC). Avelumab is a human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib is a tyrosine kinase inhibitor selective for VEGF receptors 1/2/3. VEGF Liver 100 (NCT03289533) is a phase 1b study evaluating safety and efficacy of avelumab + axitinib in treatment-naive patients (pts) with HCC; interim results are reported here. Methods: Eligible pts had confirmed a/m HCC, ≥1 measurable lesion, a fresh or archival tumor specimen, ECOG PS ≤1, and Child-Pugh class A. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety and objective response (RECIST v1.1; modified [m] RECIST for HCC). Results: Interim assessment was performed after a minimum follow up of 6 months based on the released study data set (clinical cut-off date: Aug 1, 2018). As of the cut-off date, 22 pts (median age: 68.5 y) were treated with avelumab (median: 20.0 wk) and axitinib (median: 19.9 wk). The most common grade 3 treatment-related adverse events (TRAEs) (≥10% of patients) were hypertension (50.0%) and hand-foot syndrome (22.7%); no grade 4/5 TRAEs were reported. Immune-related AEs (irAEs) (≥10% of pts) were hypothyroidism (31.8%) and hyperthyroidism (13.6%). No grade ≥3 irAEs were reported; no pts discontinued treatment due to TRAEs or irAEs. Based on Waterfall plot calculations, tumor shrinkage was observed in 15 (68.2%) and 16 (72.7%) pts by RECIST and mRECIST, respectively. ORR was 13.6% (95% CI, 2.9%-34.9%) and 31.8% (95% CI, 13.9%-54.9%) by RECIST and mRECIST, respectively. OS data were immature at data cutoff. Conclusions: The preliminary safety of avelumab + axitinib in HCC is manageable and consistent with the known safety profiles of avelumab and axitinib when administered as monotherapies. This study demonstrates antitumor activity of the combination in HCC. Follow-up is ongoing. Clinical trial information: NCT03289533. [Table: see text]

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