Phase I Trial of Oral Yeast-Derived β-Glucan to Enhance Anti-GD2 Immunotherapy of Resistant High-Risk Neuroblastoma

Beta glucans, complex polysaccharides, prime leukocyte dectin-1 and CR3-receptors and enhance anti-tumor cytotoxicity of complement-activating monoclonal antibodies. We conducted a phase I study (clinicaltrials.gov NCT00492167) to determine the safety of the combination of yeast-derived beta glucan (BG) and anti-GD2 murine monoclonal antibody 3F8 in patients with relapsed or refractory high-risk neuroblastoma. Patients received intravenous 3F8 (fixed dose of 10 mg/m2/day × 10 days) and oral BG (dose-escalated from 10–200 mg/kg/day × 17 days in cohorts of 3–6 patients each). Forty-four patients completed 141 cycles. One patient developed DLT: transient self-limiting hepatic transaminase elevation 5 days after starting BG (120 mg/kg/day). Overall, 1, 3, 12 and 24 evaluable patients had complete response, partial response, stable and progressive disease, respectively, at the end of treatment. Positive human anti-mouse antibody response and dectin-1 rs3901533 polymorphism were associated with better overall survival. BG dose level and serum BG levels did not correlate with response. Progression-free and overall survival at 2 years were 28% and 61%, respectively. BG lacked major toxicity. Treatment with 3F8 plus BG was associated with anti-neuroblastoma responses in patients with resistant disease. Although the maximal tolerated dose for yeast BG was not reached, considering the large volume of oral BG, we recommended 40 mg/kg/day as the phase II dose.

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5-Azacytidine in 82 Low/Intermediate-1 IPSS Risk Myelodysplastic Syndromes: Results from the Italian Patient Named Program

Blood ◽

10.1182/blood.v112.11.2680.2680 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2680-2680

Author(s):

Pellegrino Musto ◽

Luca Maurillo ◽

Alessandra Spagnoli ◽

Antonella Gozzini ◽

Flavia Rivellini ◽

...

Keyword(s):

Overall Survival ◽

Myelodysplastic Syndromes ◽

Response Rate ◽

Previous Treatment ◽

Response Duration ◽

Complete Response ◽

Median Number ◽

Phase Iii ◽

Fixed Dose ◽

Female Ratio

Abstract 5-azacytidine (AZA) significantly prolonged overall survival in higher-risk patients with myelodysplastic syndromes (MDS) in a large, international, randomized, phase III trial (AZA-001). However, data about efficacy and safety of AZA in lower risk MDS are less consistent and only few small studies have addressed this topic. Among a total of 246 MDS treated with AZA in 31 different Italian Institutions since 2005 within to a national patient named program, we evaluated 82 patients scored as low/int-1 IPSS risk MDS. Median age was 68 years (range 34–85), male/female ratio 50/32. According to WHO classification, there were 21 RA/RARS, 4 5q-syndromes, 20 RCMD, 24 RAEB-1, 5 RAEB-2, 4 CMMoL, and 4 MDS unclassified. Median time from diagnosis was 27 months (range 1–132). Sixty-eight patients (82.9%) were transfusion-dependent, sixty (74%) had received a prior treatment, mostly with erythropoiesis stimulating agents. AZA was administered as single drug in 61 patients (74.4%), while in the remaining subjects it was variously combined with growth factors, valproic acid or other agents. Forty-eight patients (58.5%) received a “standard” AZA dose of 75 mg/sqm/d s.c., thirty-four (41.5%) a fixed dose of 100 mg/d s.c. Single cycle treatment duration was 7 days in 45 patients (54.9%), < 7 days in 32 patients (39%), > 7 days in 3 patients (3.7%), unknown in 2 patients (2.4%). The median number of monthly cycles was 6 (range 1–21), and 63 patients (76.8%) completed at least 4 cycles. The most relevant toxicities observed (grade 3–4) were represented by myelosuppression (22%) and infections (6%). According to 2006-updated IWG criteria, overall response rate was 39% (47.5% in patients who had completed at least 4 cycles). In particular, complete response, partial response and hematological improvement occurred in 12.2%, 8.5% and 18.3% of patients (15.8%, 11.1% and 20.6% in those who were treated with at least 4 cycles), respectively. Stable or progressive disease was observed in 29.3%/25.6% and 30.2%/22.2% of patients receiving less than or at least 4 cycles, respectively. Response duration ranged from 1 to +21 months. There were no significant differences in response rate according to dose and schedule employed, although a slight trend in favour of 75 mg/sqm vs 100 mg fixed dose was seen (45.8% vs 29.4%, respectively). There was also no difference in the percentages of response according to age, previous treatment and transfusion dependence. Overall survival at 2 years was 62%. A survival benefit emerged for responding patients, compared to non responders (82% vs 57%) (p=0.015). A favourable trend was also observed for transfusion-independent patients, while age, pre-treatment and AZA dose did not influence survival. These data indicate that AZA may be safe and effective for a subset of patients with low/int-1 IPSS risk MDS, resistant or not suitable for alternative treatments. The efficacy may improve if at least 4 cycles are administered.

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The Addition of Gemtuzumab Ozogamicin to Low Dose Ara-C Improves Remission Rates but Not Survival: Results of the UK LRF AML14 and NCRI AML16 “Pick a Winner” Comparison

Blood ◽

10.1182/blood.v116.21.18.18 ◽

2010 ◽

Vol 116 (21) ◽

pp. 18-18 ◽

Cited By ~ 4

Author(s):

Alan Burnett ◽

Robert Hills ◽

Ann Elizabeth Hunter ◽

Donald Milligan ◽

William J. Kell ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Older Patients ◽

Low Dose ◽

Remission Rate ◽

Significant Proportion ◽

Gemtuzumab Ozogamicin ◽

Fixed Dose ◽

The Uk

Abstract Abstract 18 In a significant proportion of older patients with AML intensive chemotherapy is not considered a viable option[1]. Such patients may receive low-dose Ara-C (LDAC), best supportive care (BSC) with hydroxyurea or an experimental agent but outcomes are poor. We have shown that LDAC is superior to BSC [2], but only in patients who enter CR (fewer than 20%).[2]. There is therefore scope to improve outcomes in these patients, and a number of possible treatments have been evaluated in the randomised UK NCRI AML16 trial, one of which is gemtuzumab ozogamicin (GO), which we have shown to benefit the majority of younger patients when given in conjunction with standard chemotherapy[3]. In AML16 novel agents or combinations are tested in untreated older patients with AML or high risk MDS (marrow blasts >10%) using a “pick a winner” design. The design allows unpromising treatments to be identified early (typically after 50 or 100 patients per arm): only those arms which show promise will continue to a trial with OS and DFS as endpoints. The aim is to at least double the remission rate from 15% to 30%, and thus improve overall survival. We now report the results of LD Ara-C (20mg bd days 1–10 for 4 courses) versus LDAC combined with GO (at a fixed dose of 5mg on day 1 of each course for 4 courses at 6–8 week intervals). Patient Details: The comparison opened as part of the UK LRF AML14 trial and was carried forward to AML16 unchanged. Between June 2004 and June 2010, 495 patients were randomised, 249 to LDAC plus ATO, 246 to LDAC. The median age was 75 years (range 54–90); 83% of patients were aged over 70 years, and 61% were male. To be eligible patients’ LFTs had to be less than twice ULN. Treatment arms were balanced for age, gender, performance status, de novo/secondary AML/high risk MDS, presenting WBC and cytogenetic risk group. Follow-up is complete to 1st January 2010, with median follow up of 21 months. Survival and remission data is available on 412, 404 patients respectively. Treatment Results: The trial passed through both stopping hurdles based on CR/CRi rates and therefore continued to full accrual, with overall survival as primary outcome measure. The table shows the distribution of outcomes: there was no heterogeneity by recruitment period (AML14 vs AML16). The causes of death (316) were:- There were no significant interactions between treatment and any of the baseline variables on either remission or survival outcomes. Likewise there were no major toxicity implications, although resource usage tended to be higher in patients given GO. Discussion: While the addition of GO significantly improves CR rate, achieving the 30% response originally sought, this does not translate into survival. This is predominantly due to an increase in relapse, indicating that if GO is to have a role in this setting, it will require effective treatment to maintain remission. [1] Juliusson G et al. Blood 2009; 113: 4179 – 4187 [2] Burnett et al. Cancer 2007 109: 1114–1124 [3] Burnett et al. JCO 2010 to appear. Disclosures: Off Label Use: Mylotarg (gemtuzumab ozogamicin).

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Early Treatment of High Risk Chronic Lymphocytic Leukemia with Alemtuzumab, Rituximab, and PGG Beta Glucan: A Phase I Clinical Trial

Blood ◽

10.1182/blood.v120.21.1792.1792 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1792-1792

Author(s):

Clive S. Zent ◽

Betsy R. LaPlant ◽

Timothy G. Call ◽

Deborah A. Bowen ◽

Michael J. Conte ◽

...

Keyword(s):

High Risk ◽

Phase I ◽

Dose Level ◽

Research Funding ◽

Early Stage ◽

Lymphocytic Leukemia ◽

Cellular Cytotoxicity ◽

Beta Glucan ◽

Stage Disease ◽

Grade 3

Abstract Abstract 1792 High risk disease can be identified in patients with early stage chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) using biological prognostic markers. We have shown that early therapy of high risk CLL patients with alemtuzumab (ALM) and rituximab (RTX) is effective and could possibly delay first standard treatment (Cancer 2008;113:2110-8). Efficacy of unconjugated monoclonal antibody (mAb) therapy in these patients could be improved by enhancing mAb mediated cellular cytotoxicity. Preclinical studies show that yeast cell wall derived beta glucan, which increases complement receptor 3 (CR3) binding to the complement fragment iC3b on target cells, could increase mAb mediated cellular cytotoxicity. Both ALM and RTX activate complement resulting in deposition of iC3b on the cell membrane. In CLL cells that are not lysed by complement activation, these iC3b molecules are targets for the effector cells mediating cellular cytotoxicity. We hypothesized that PGG beta glucan (Imprime PPG®, Biothera, Eagan MN) an intravenous formulation of a 1,3/1,6 glucose polymer prepared from a strain of Saccharomyces cerevisiae, would improve the efficacy of therapy with ALM and RTX in patients with CLL by increasing CR3 binding to iC3b and thus enhancing macrophage, neutrophil, and NK cell mediated cytotoxicity. We report the results of a Phase I study of the combination of ALM, RTX and PPG beta glucan in patients with CLL. Methods: The primary aim of this IRB approved study (NCT01269385) was to determine the maximum tolerated dose (MTD) of PGG beta glucan that could be safely combined with ALM and RTX. The MTD was defined as the PGG beta glucan dose level below that which induced dose limiting toxicity in at least one third of patients, or the highest dose level tested if all levels were tolerated. Eligibility for the trial required a diagnosis of CLL by standard (IWCLL-NCI 2008) criteria, no prior treatment for CLL, high risk CLL based on molecular markers, absence of standard indications for initiation of therapy for CLL, and adequate performance status and organ function. High risk CLL was defined as at least one of the following: 17p13-; 11q22-; either unmutated (<2%) IGHV or use of VH3–21 as well as CD38+ and/or ZAP70+. Patients received standard premedication for mAb, antimicrobial and allopurinol prophylaxis and weekly PCR testing for CMV reactivation with treatment of viremia. The duration of treatment was 33 days. PGG beta glucan was administered IV on days 1, 5, 10, 17, 24, and 31 and the first dose was premedicated with hydrocortisone 100mg IV, oral acetaminophen 1000 mg and diphenhydramine 50 mg. The starting dose level of PGG beta glucan was 1 mg/kg, 2nd dose level was 2 mg/kg and the 3rd dose level 4 mg/kg. Subcutaneous ALM therapy started on day 3 with daily dose escalation (3 – 10 – 30 mg) and then 30 mg Mon-Wed-Friday for 4 weeks. Weekly RTX started on day 10 at 375 mg/m2 IV × 4 doses. Results: Thirteen patients were enrolled from February 2011 to April 2012. The 11 evaluable patients had a median age of 61 years (range 47 – 77), 73% were male, 3 had early stage disease (Rai 0) and 8 had intermediate stage disease (Rai I n = 7, Rai II n = 1). High-risk parameters were 17p- in 4 patients, 11q22- in 3 patients, and unmutated IGHV and expression of ZAP70 and/or CD38 in 4 patients. There were no dose limiting toxicities. One patient had grade 4 febrile neutropenia, with no grade 3–4 anemias or thrombocytopenias, and there were no grade 3–4 non-hematological toxicities. All patients responded to therapy with 7 CR, 1 CCR, 1 nPR, and 2 PR (IWCLL-NCI 2008 criteria). Median follow up was 6.9 months (2.3 – 13.2) and one patient progressed at 9.7 months. No patients have required treatment for progressive disease and there have been no patient deaths. Two patients were not evaluable: One developed neutropenia and therapy was not held per protocol, and the other developed a grade 2 skin reaction to ALM and treatment was stopped. Discussion: The combination of PGG beta glucan with ALM and RTX is well tolerated at a PGG beta glucan dose of 4 mg/kg. All patients responded to therapy with 64% achieving a CR. These data support continuation of this study in a phase II component. Acknowledgment: This study was funded by the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274) and Biothera. Disclosures: Zent: Biothera: Research Funding; Genzyme: Research Funding; Genentech: Research Funding; Novartis: Research Funding; GlaxoSmithKline: Research Funding. Off Label Use: Phase I study using PGG beta glucan in CLL.

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Phase I study of capecitabine combined with weekly carboplatin and intensity modulated radiation therapy (IMRT) for treatment of locally advanced squamous cell carcinomas of the head and neck (HNSCC)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.15522 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 15522-15522

Author(s):

C. Y. Thomas ◽

P. Read ◽

K. Sheng ◽

D. Bliesner ◽

P. Levine ◽

...

Keyword(s):

Phase I ◽

Locally Advanced ◽

Intensity Modulated Radiation Therapy ◽

Complete Response ◽

Maximum Tolerated Dose ◽

Stage Iii ◽

Fixed Dose ◽

Parotid Sparing ◽

Grade 3 ◽

Carboplatin Auc

15522 Background: Chemoradiotherapy (CRT) programs for locally advanced HNSCC that reduce toxicity but maintain efficacy are needed. Methods: A two-step phase I trial to determine the maximum tolerated dose (MTD) of capecitabine combined with fixed dose carboplatin, given prior to and during concomitant IMRT. Start dose of capecitabine =1500 mg/m2/d p.o. BID days 1–14 and 22–35 with carboplatin AUC =2 IV weekly x 6. With IMRT, the doses were adjusted to 1000 mg/m2/d and AUC =1.5, respectively. Parotid-sparing IMRT = 50 and 45 Gy/25 fractions to gross disease (GD) and low risk nodes, respectively; 3D conformal boost of 20 Gy/10 fractions to GD. Dose limiting toxicity (DLT) defined as ANC <750, ≥ grade 3/4 thrombocytopenia or selected non-hematologic toxicities. Results: 11 patients (pts) with stage III/IV (T2–4,N1–2C) HNSCCs of the oropharynx (7), oral cavity (2), both (1), or hypopharynx (1) were studied. 10/9 pts evaluable for toxicity after induction/concomitant chemotherapy, respectively; 2 pts had early disease progression (d22 and 43). During radiation, the MTD for capecitabine established as 825 mg/m2/d. At start dose, 2/3 pts developed thrombocytopenia as DLT; CRT-related toxicities = grade 3 mucositis (3), dysphagia (3), fatigue (1), anemia (1), and dermatitis (1). For induction chemotherapy, DLTs seen in 0/3 pts at capecitabine =1750 mg/m2 and 1/6 at lower doses (grade 4 diarrhea; no other Gr3/4 drug-related toxicities). Response of primary (or neck) tumors to induction: CR 3 (3), PR 6 (3), SD 1 (3), and PD 2 (2). After CRT, 8/9 pts achieved CR and are alive without disease (mean follow-up 6 months). Conclusions: Capecitabine 825 mg/ m2/d and carboplatin AUC =1.5 weekly given on the described schedule and in combination with IMRT produce moderate toxicity and a high complete response rate in stage III/IV HNSCC pts that received the same drugs as induction therapy. The latter combination was also well tolerated and had anti-tumor activity (capecitabine Y=1500–1750 mg/m2/d). Additional studies are warranted to determine if these regimens provide an effective but less toxic alternative to cisplatin or taxane-based CRT programs. Supported in part by Bristol-Myers-Squibb. No significant financial relationships to disclose.

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Rituximab - Inmunotherapy Combined with Chemotherapy, CHOP for the Treatment of Patients with Difusse Large B - Cell Lymphoma (DLBCL).

Blood ◽

10.1182/blood.v106.11.4745.4745 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4745-4745

Author(s):

Jorge H. Milone ◽

Fernando Bezares ◽

Maria del Carmen Ardaiz ◽

Dardo Riveros ◽

Luis Palmer ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

B Cell Lymphoma ◽

Complete Response ◽

High Risk Group ◽

Hematologic Toxicity ◽

Gastric Bleeding ◽

Bulky Disease ◽

Free Survival

Abstract Several studies (GELA 98.5, MInT) have demonstrated the benefit of combination rituximab (R) with chemotherapy to improve event free and overall survival in patients with DLBCL. We analyzed retrospectively the safety of combination R-CHOP for 6 cycles (rituximab 375 mg/m2 day 1; cyclophosphamide 750 mg/m2 day 1; doxorrubicin 50 mg./m2 day 1; vincristine 1.4 mg/m2 day 1 and prednisone 100 mg/m2 day 1 to 5) the tolerance and adverse effects. We evaluated the response (R), event free survival (EFS) and the overall survival (OS). Between March to December 2004, 28 patients with DLBCL were evaluated, 17 men and 11 women, with a median age 57 years old (range 28 – 84). They were IPI low 21,4 %, low - intermediate 25%, high - intermediate 35,7 % and high risk 17,9 %. Elevated LDH was present en 14 patients, bulky disease > 7 cm in 50% of cases. During the treatment they presented hematologic toxicity grade III 21,4 % and grade IV 25% of cases; 1 patient had anaphilactic reaction; 2 patients pneumonia; 1 patient sepsis; 4 patients neutropenia and fever; and gastric bleeding 1 patient. Response was achieve in 71,4 %: complete response (CR) in 57,1%, parcial (PR) in 14.3 %, and there was no response in 8 patients (28.6%). With follow up of 10 months (range 2 to 18.5) 15 patients were in CR 53,6%, 8 patients died, 7 of then primary no responders. Analyzed by IPI, 60% of CR in intermediate high and high was obtained. The R-CHOP combination is a feasible and safe treatment in our hospitals, and 71,4 % of response was obtained in all patients and 60% of CR in high risk group.

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Myeloablative Timed Sequential Busulfan Is Safe in Older Patients

Blood ◽

10.1182/blood.v124.21.3859.3859 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3859-3859 ◽

Cited By ~ 2

Author(s):

Uday R. Popat ◽

Patricia S Fox ◽

Roland Bassett ◽

Julianne Chen ◽

Benigno C. Valdez ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Older Patients ◽

Disease Risk ◽

Risk Index ◽

Fixed Dose ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Antileukemic Effect ◽

Very High

Abstract Background: Reduced intensity conditioning regimen (RIC) extends allogeneic hematopoietic cell transplantation (HCT) to older patients and patients with comorbidities. Compared to myeloablative (MA) conditioning, RIC has higher rate of relapse but lower rate of non-relapse mortality (NRM), resulting in similar survival. BMT CTN is conducting a prospective study to compare these two approaches. To further improve survival for older patients, a MA regimen with low NRM is needed. Timed sequential therapy (TST), giving two courses of chemotherapy 1 week apart, has higher antileukemic effect in in-vitro and in-vivo in studies of patients with AML, including phase 3 studies. We hypothesized that MA dose of busulfan delivered per principles of TST enhances antileukemic effect without increasing toxicity. We therefore designed a study to test safety of two MA schedules of busulfan targeting busulfan exposure (AUC) of 16000 μmol.min and 20000 μmol.min. AUC of 20000 μmol.minis close to total average drug exposure achieved with IV busulfan fixed dose of 12.8mg/kg. Methods: Patients were randomized to receive total busulfan exposure of 16,000 μmol.min(16K) or 20,000 μmol.min( 20K). Patients received IV busulfan 80 mg/m2 per day on day -13 and -12 in outpatient clinic, fludarabine 40 mg/m2 day x 4 (day -6 to -3) and IV busulfanx 4 (day -6 to -3). Busulfan was dosed to achieve target AUC of 16K or 20K based on pharmacokinetic studies done on day -13 and day -6. GVHD prophylaxis was Tacrolimus (day -2 onwards) and mini dose methotrexate-5mg/m2 on day 1, 3, 6, and 11. Stem cells were infused on day 0. Primary endpoint of the study was to compare 100 day non-relapse mortality in two arms with stopping rules built in for safety. Patients with hematological malignancies were eligible for the study if they had adequate organ function and 8/8 matched related or unrelated donor. We enrolled patients on this study who were suitable for RIC. When the study began, upper age limit for eligibility was 70 years, but this was increased to 75 years during the course of the study as safety was established. Fisher’s exact test was used to compare toxicity and NRM rates between arms. Cox proportional hazards regression was used to estimate the effects of clinical variables on overall survival. Results: 97 patients were enrolled on the study until the DSMB stopped the randomization and permitted continued accrual onto the higher dose arm with busulfan AUC of 20,000 μmol.min. 49 were randomized to busulfan AUC of 16K and 48 to 20K. For all patients, median age was 60 (18-75) years. 3 (2%) patients were less than 40 years of age, 12 (12%) 40-49, 33 (34%) 50-59, 39 (40%) 60-69, and 10 (10%) 70-79 years. 53 patients had AML/MDS, 24 CML/MPD, 16 myeloma, and 4 lymphoid malignancies. Based on revised disease risk index, 3 had low risk, 53 intermediate risk, 35 high risk, and 6 very high risk disease. Donor was related for 43 and unrelated for 54. Comorbidity scores were 0 in 23, 1-2 in 24, and ≥ 3 in 50. With a median follow up of 9.2 months (range 1.8-24) in surviving patients, 100 day NRM was similar in two groups, 4% in 16K and 6% in 20K (p=0.68). Maximum toxicity per patient was not significantly different between arms (Table 1, p=0.37). The 1-year unadjusted survival rates (95% CI) in combined disease risk indexes low and intermediate vs high and very high were 67 (50-79)% and 38 (19-57)%, respectively for all 97 patients. Multivariable Cox regression analysis for overall survival showed increased risk of death for older age (HR 1.05; p=0.03), comorbidity 3 and higher (HR 1.89 p=0.08), and high or very high risk index (HR 2.04; p= 0.05). After also accounting for donor relation and cell type, Bu AUC of 20k showed improved overall survival and a 50% reduction in the risk of death (HR 0.50, P= 0.058). Table 1. Maximum grade of toxicity per patient, N (Row %) MaximumGrade per Patient AUC=16k AUC=20k Total p-value 5 7 (54%) 6 (46%) 13 0.37 4 6 (50%) 6 (50%) 12 3 23 (44%) 29 (56%) 52 2 11 (73%) 4 (27%) 15 1 2 (40%) 3 (60%) 5 Total Patients 49 48 97 Conclusion: Myeloablative timed sequential busulfan regimen is safe in older patients and patients with comorbidities. The regimen with busulfan AUC of 20,000 μmol.min appears promising and needs to be studied further. Disclosures Popat: Otsuka: Research Funding. Off Label Use: Busulfan.

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NRG-HN003: Phase I and Expansion Cohort Study of Adjuvant Pembrolizumab, Cisplatin and Radiation Therapy in Pathologically High-Risk Head and Neck Cancer

Cancers ◽

10.3390/cancers13122882 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2882

Author(s):

Julie E. Bauman ◽

Jonathan Harris ◽

Ravindra Uppaluri ◽

Min Yao ◽

Robert L. Ferris ◽

...

Keyword(s):

Radiation Therapy ◽

High Risk ◽

Phase I ◽

Head And Neck ◽

Positive Margin ◽

Fixed Dose ◽

Group Setting ◽

Grade 3 ◽

Expansion Cohort ◽

Further Development

The anti-PD1 monoclonal antibody pembrolizumab improves survival in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Patients with locoregional, pathologically high-risk HNSCC recur frequently despite adjuvant cisplatin–radiation therapy (CRT). Targeting PD1 may reverse immunosuppression induced by HNSCC and CRT. We conducted a phase I trial with an expansion cohort (n = 20) to determine the recommended phase II schedule (RP2S) for adding fixed-dose pembrolizumab to standard adjuvant CRT. Eligible patients had resected HPV-negative, stage III–IV oral cavity, pharynx, or larynx HNSCC with extracapsular nodal extension or positive margin. RP2S was declared if three or fewer dose-limiting toxicities (DLT) occurred in a cohort of 12. DLT was defined as grade 3 or higher non-hematologic adverse event (AE) related to pembrolizumab, immune-related AE requiring over 2 weeks of systemic steroids, or unacceptable RT delay. A total of 34 patients enrolled at 23 NRG institutions. During the first cohort, only one DLT was observed (fever), thus RP2S was declared as pembrolizumab 200 mg every 3 weeks for eight doses, starting one week before CRT. During expansion, three additional DLTs were observed (wound infection, diverticulitis, nausea). Of the 34 patients, 28 (82%) received five or more doses of pembrolizumab. This regimen was safe and feasible in a cooperative group setting. Further development is warranted.

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MBCL-29. PHASE I/II STUDY OF SEQUENTIAL HIGH-DOSE CHEMOTHERAPY WITH STEM CELL SUPPORT IN CHILDREN YOUNGER THAN 5 YEARS OF AGE WITH HIGH-RISK MEDULLOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.505 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii394-iii395

Author(s):

Christelle Dufour ◽

Julien Masliah-Planchon ◽

Marie-Bernadette Delisle ◽

Anne Geoffray ◽

Rachid Abbas ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Phase I ◽

Complete Response ◽

Multicenter Trial ◽

High Dose Chemotherapy ◽

Craniospinal Irradiation ◽

High Dose ◽

Stem Cell Rescue

Abstract PURPOSE To assess the 3-year EFS rate of children younger than 5 years of age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5. PATIENTS AND METHODS After surgery, all children received 2 cycles of Etoposide- Carboplatine. If partial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell rescue. For patients in CR after high-dose chemotherapy, they received one course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part). The others patients (not in PR after induction or in CR after thiotepa) were treated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted craniospinal irradiation and maintenance treatment. RESULTS 28 children (2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were most common (57%). The response rate to Etoposide-Carboplatine was 60.7%. Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them, 9 patients (45%) are alive in CR without craniospinal irradiation (median follow-up 5 years). Among 15 patients treated with radiotherapy, 8 patients are alive (median follow-up 3.8 years). The study was prematurely stopped for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1). The 3-year EFS and OS were 42.3% [25.9 - 60.6] and 71.3% [52.7 - 84.7], respectively. CONCLUSIONS This risk-adapted strategy did not improve EFS in young children with high-risk MB. However, the study shows that good responders to chemotherapy can be cured without recourse to irradiation.

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Emerging Role of Adoptive T Cell Therapy for EBV Induced Nasopharyngeal Carcinoma (NPC) - a Systematic Review

Blood ◽

10.1182/blood-2020-137139 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Muhammad Saad Farooqi ◽

Unaiza Faizan ◽

Saad Ur Rahman ◽

Hassaan Imtiaz ◽

Muhammed Hamza Arshad ◽

...

Keyword(s):

Overall Survival ◽

Nasopharyngeal Carcinoma ◽

Cell Therapy ◽

Phase I ◽

Adoptive Immunotherapy ◽

Research Funding ◽

Adoptive Cell Therapy ◽

Complete Response ◽

Barr Virus

Introduction: Nasopharyngeal carcinoma (NPC) is defined as the cancer of squamous epithelium lining nasopharynx. The single most common culprit of undifferentiated NPC is the Epstein-Barr virus (EBV). Recurrent local-regional or metastatic NPC cannot be treated with repeated chemo-radiotherapy because of poor overall survival and profound effect of these therapies on quality of life. One safer approach is immunotherapy with autologous EBV specific cytotoxic T lymphocytes (EBV-CTLS) targeted to the EBV antigens EBNA1, latent membrane protein LMP1, and LMP2 expressed by most NPC tumors. This study aims to review the efficacy and toxicity of adoptive immunotherapy with EBV-CTLS in patients with EBV induced NPC. Methods: A systematic search of PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in EBV induced NPC patients from inception to May 28, 2020. Out of 604 studies, 07 phase I and II clinical trials were selected for the systematic review. Results: A total of 134 patients (pts) were evaluated out of 157 pts. 56 had a locoregional disease, 63 had distant metastasis, 15 had both locoregional disease as well as distant metastasis, 8 were in remission and disease status was unknown in 5 pts. Li et al. (2015) in their phase I clinical trial on 20 NPC pts with ECOG performance status of <3 after chemoradiotherapy (CCRT) showed overall response rate (ORR) of 95% with complete response (CR) in 19 patients. One patient showed progressive disease (PD). Median progression-free survival (PFS) was observed to be 16 months. Eighteen (90%) pts showed disease-free survival of greater than 12 months after adoptive cell therapy (ACT). Grade (G) ≥3 adverse events (AEs) included leukopenia (5%) and neutropenia (5%). Phase I/II dose-escalation trial by Louis et al. (2010) on 23 pts showed ORR of 48.7% (20% CR, 13.3% undetermined complete response [Cru], 15.4% PR) among pts with active disease. Eight pts remained in remission while 10 had metastatic disease at the time of infusion. PD was 21.7%, Stable Disease (SD) 13%, and 3 pts (13%) had recurrent disease. The median time to progression was 1059 days with PFS of 65% and 52% at 1 and 2 years respectively while the (Overall Survival) OS was 87% and 70% at 1 year and 2 years respectively. There was a higher risk of disease progression (HR: 3.91, P= 0.015) and decreased overall survival (HR: 5.55, P=0.022) in metastatic disease as compared to locoregional disease. Huang J. et al (2017) conducted a phase I/ II trial in 21 pts with a mean waiting period of 71 days after chemotherapy. Two CTL infusions were given 2 weeks apart. Two pts (9.5%) maintained SD but all other pts (85%) showed PD after 8 weeks follow- up. One patient achieved CR (4.8%). Hence, ORR was 4.8% while median PFS and OS were of 2.2 months and 16.7 months respectively. In a phase II trial, 24 patients completed 6 EBV- CTL therapy cycles after receiving chemotherapy cycles of Gemcitabine and Carboplatin. ORR was observed to be 42.9% (CR 5.7%, PR 31.7%). SD was 20% while PD was 31.4%. Median OS was 29.9 months (95% CI 20.8-39.3) with 1, 2, and 3-year rates being 77.1%, 62.9%, and 37.1 % respectively. Median PFS was 7.6 months (95% CI 7.4-8.4). All G≥3 AE occurred during chemotherapy. (Chia et al, 2014) Secondino et al. (2011) conducted a phase I/II study in 11 NPC patients who also received chemotherapy consisting of cyclophosphamide and fludarabine. After a mean follow-up of 4 weeks, ORR was 27% (PR 18%, Minor Response [MR] 9%). PD was reported to be 45% and SD 27%. Median PFS at 6 months was 54% (6/11 pts). Only G≥3 AE reported was neutropenia (36%). Phase I/II trial by Comoli et al. (2005) evaluated 10 EBV-related stage IV NPC in progression after CCRT. After receiving two to twenty-three EBV-specific CTLs infusions, 2 patients showed PR (20%), 40% of pts maintained SD and all others showed evidence of PD (40%) at 1-2 months follow up. Median PFS was 6.5 months. Smith et al (2012) in their phase I trial on 14 patients with locoregional and metastatic NPC reported SD 71.4% and PD 28.6% of patients at a median follow up of 1 month. Median OS and PFS were 17.4 months and 4.5 months respectively. No G≥3 AEs were reported. Conclusion : Adoptive Immunotherapy with EBV-CTLS has shown impressive efficacy with improvement in median PFS and OS and a favorable safety profile. Key Words: Adoptive cell therapy, Cytotoxic T lymphocytes, nasopharyngeal carcinoma, Phase I/II clinical trials, Epstein-Barr virus. Disclosures Anwer: Celgene: Research Funding; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding.

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A phase I/II multi-center study of nivolumab and carboplatin/paclitaxel with radiation therapy (RT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC).

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.tps199 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. TPS199-TPS199

Author(s):

Iulia Giuroiu ◽

Geoffrey Yuyat Ku ◽

Lawrence P. Leichman ◽

Kevin Lee Du ◽

Philmo Oh ◽

...

Keyword(s):

Overall Survival ◽

Phase I ◽

Clin Oncol ◽

Phase Ii ◽

Locally Advanced ◽

Pathologic Complete Response ◽

Progression Free Survival ◽

Standard Of Care ◽

Complete Response ◽

Multi Center Study

TPS199 Background: ESCC comprises 80% of esophageal cancers worldwide. Preoperative chemoRT is a standard-of-care based on the CROSS trial ( N Engl J Med 2012;366:2074-2084), which reported encouraging pathologic complete response (pCR) and overall survival (OS). Surgery is often deferred in patients with clinical CR (cCR) based on lack of overall survival (OS) benefit ( J Clin Oncol 2005;23:2310-2317, J Clin Oncol 2007;25:1160-1168). Nivolumab has activity in advanced ESCC ( Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes. ESCC has a high somatic mutation rate and treatment with chemoRT may augment the abscopal effect. Methods: Our trial aims to establish the safety and tolerability (phase I), as well as the efficacy (phase II) of nivolumab added to a standard chemoRT backbone for patients with TanyN1-3 or T3-4N0M0 ESCC. Phase I will enroll up to 12 patients and phase II, up to 44, per an optimal two-stage design. The phase I primary endpoint is unacceptable toxicity at 28 days after the last dose of chemotherapy. Phase II primary endpoints are cCR (endoscopy + PET/CT), pCR for patients undergoing surgery, and median progression-free survival and OS, which will be estimated via Kaplan Meier curves. Extensive tumor and blood immune correlative studies are planned. Clinical trial information: NCT03278626. [Table: see text]

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