Developed Dose-limiting Toxicities Research Articles

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.

Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS. The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15mg/m2 /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs). Ten patients (seven males and three females; median age=4.5 years [range: 0.2-14.4years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1weeks (range: 11.7-15weeks). Weekly temsirolimus at 15mg/m2 /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.

A phase I/II dose-escalation study of fractionated 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC) in patients with prior treatment with 177Lu-PSMA.

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .

Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study

AbstractWe report results of our prospective pilot trial evaluating safety/feasibility of peritransplantation ruxolitinib for myelofibrosis treatment. Primary objectives were to determine safety and maximum tolerated dose (MTD) of ruxolitinib. Ruxolitinib was administered at 2 dose levels (DLs) of 5 and 10 mg twice daily, with fludarabine/melphalan conditioning regimen and tacrolimus/sirolimus graft-versus-host disease (GVHD) prophylaxis. We enrolled 6 and 12 patients at DL1 and DL2, respectively. Median age at transplantation was 65 years (range, 25-73). Per Dynamic International Prognostic Scoring System, 4 patients were high and 14 intermediate risk. Peripheral blood stem cells were graft source from matched sibling (n = 5) or unrelated (n = 13) donor. At each DL, 1 patient developed dose-limiting toxicities (DLTs): grade 3 cardiac and gastrointestinal with grade 4 pulmonary DLTs in DL1, and grade 3 kidney injury in DL2. All patients achieved engraftment. Grade 2 to 4 and 3 to 4 acute GVHD cumulative incidence was 17% (95% confidence interval [CI], 6-47) and 11% (95% CI, 3-41), respectively. Cumulative incidence of 1-year chronic GVHD was 42% (95% CI, 24-74). With 22.6-month (range, 6.2-25.8) median follow-up in surviving patients, 1-year overall and progression-free survival were 77% (95% CI, 50-91) and 71% (95% CI, 44-87), respectively. Causes of death (n = 4) were cardiac arrest, GVHD, respiratory failure, and refractory GVHD of liver. Our results show peritransplantation ruxolitinib is safe and well tolerated at MTD of 10 mg twice daily and associated with dose-dependent pharmacokinetic and cytokine profile. Early efficacy data are highly promising in high-risk older patients with myelofibrosis. This trial was registered at www.clinicaltrials.gov as #NCT02917096.

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade > 3 heme toxicity or grade > 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had > 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

A Dose-finding Study Followed by a Phase II Randomized, Placebo-controlled Trial of Chemoradiotherapy With or Without Veliparib in Stage III Non–small-cell Lung Cancer: SWOG 1206 (8811)

BackgroundWe conducted a 2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non–small-cell lung cancer. Patients and MethodsIn the phase I part, patients were treated successively at 3 dose levels of veliparib (40, 80, and 120 mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin and paclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care. ResultsOf 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P = .20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively. ConclusionVeliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.

A phase I/II radiation dose escalation trial using simultaneous integrated boost technique with elective nodal irradiation and concurrent chemotherapy for unresectable esophageal Cancer

BackgroundTo investigate the safety and tolerability of simultaneous integrated boost (SIB) technique concurrent with elective nodal irradiation (ENI) and dual-drug chemotherapy for patients with unresectable esophageal cancer.MethodsIn phase I, the prophylactic PTV received a stable dose of 50.40Gy/1.80Gy/28f while the boost area was planned with 3 consecutive dose levels: the first dose level was 60.76Gy/2.17Gy/28f, and then escalated approximately every 2 Gy. ENI was incorporated in Clinical Target Volume (CTV), and paclitaxel and nedaplatin were given concurrently for at least 5 weeks. In phase II, enrolled patients were treated with Maximum Tolerated Dose (MTD) obtained in phase I and the compliance rate, survival results and toxicities were evaluated.ResultsFrom December 2014 to April 2017, 53 patients were enrolled. In phase I, 2 out of 6 patients developed Dose-Limiting Toxicity (DLT) at dose level 1. Due to excessive treatment-related toxicities, the escalation process was suspended and de-escalated to 59.92Gy /2.14Gy /28 f. Three patients were treated at this dose level, all of whom completed at least 5 weeks of chemotherapy and none of whom reached a DLT, determining the newly added dose level to be the MTD.In phase II, 44 patients were treated with MTD, 31 of them (70.0%) completed at least 5 weeks of chemotherapy. The most common Grade 3 or 4 toxicities in phase II included leukopenia (21%) and esophagitis (15%). With a median follow-up time of 16.9 months, 1-y OS, DFS and local failure-free survival were 76.9, 63.6 and 78.8% respectively.ConclusionThe SIB technique was feasible and safe at the MTD (95% PGTV/PTV 59.92/50.40Gy/28f) concurrent with ENI and dual-drug chemotherapy for patients with unresectable esophageal cancer.Trial registrationclinicaltrials.govNCT02429622. Retrospectively registered on April 24, 2015.

711P - Phase Ib Trial of Nab-Paclitaxel Plus Gemcitabine, Capecitabine, and Cisplatin (Paxg Regimen) in Patients with Stage III Pancreatic Adenocarcinoma

ABSTRACT Aim: Gemcitabine (GEM) and nab-paclitaxel (nab-P) significantly improved overall survival over GEM in metastatic pancreatic adenocarcinoma (PA). Given the synergism of taxanes with platinum compounds and fluoropyrimidines, we determined the recommended phase 2 dose (RP2D) of nab-P in combination with cisplatin, capecitabine, and GEM (PAXG regimen) in a phase Ib trial in patients (pts) with stage III PA (NCT01730222). Methods: GEM, cisplatin and capecitabine were given at fixed dose (800, 30, and 1250 mg/m2, respectively) q 2 weeks. Doses of nab-P were escalated in cohorts of 3 to 6 pts from 100 (level 1), to 125 (level 2) and 150 mg/m2 (level 3) q 2 weeks. The maximum tolerated dose (MTD) was defined as the dose at which > 2 out of 3-6 pts developed dose-limiting toxicity (DLT) during the first month of therapy. DLT was defined as G ≥ 4 neutropenia lasting ≥ 7 days; G ≥ 3 febrile neutropenia, fever ≥38.5°C, thrombocytopenia, diarrhea, nausea or vomiting; G ≥ 2 neurological toxicity or failure to recover to grade ≤ 1 toxicity (except alopecia) or to baseline values after delaying the initiation of next cycle by > 2 weeks. Results: Between Dec 2012 and Mar 2014, 23 pts (16 males; median age 63 years) with unresectable (according to a surgical team performing >100 duodenocephalopancreasectomy/year) stage III PA, were enrolled at a single institution (3 at level 1, 5 at level 2, 15 at level 3). To date, 197 cycles of PAXG were administered. Therapy is ongoing in 5 pts at level 3. No DLT has occurred. Worse per patient toxicity was G3/4 neutropenia 29/29%; G3 fatigue 14%; G3 neuropathy, anemia, nausea, diarrhea 7%. After 123 cycles at 150 mg/m2 the nab-P dose-intensity was 90%. To date, a partial response (PR) was observed in 15 pts (65%) and stable disease (SD) in 8 pts; among 20 pts with positive PET scan a complete response was observed in 8 (40%), PR in 10 (50%), SD in 2; 19 pts had elevated basal CA19-9 which was reduced by >50% in 18 (95%); 15/16 (94%) pts with mature follow-up were progression-free at 6 months from therapy start. Conclusions: The RP2D of nab-P in the PAXG regimen was 150 mg/m2 every 2 weeks. Preliminary results are promising and a phase II randomized trial with this regimen is ongoing. Disclosure: M. Reni: Participation in an Advisory Board : Merck; Celgene; CLOVIS; Genentech; Boehringer L. Gianni: advisory board Celgene. All other authors have declared no conflicts of interest.

Phase I trial of sunitinib (S) and temsirolimus (T) in metastatic renal cell carcinoma (mRCC).

433 Background: Anti-VEGF agents and mTOR inhibitors are mainstay therapies in mRCC. Pre-clinical data suggests synergistic anti-tumor effect when combining these 2 classes. A previous phase I trial using sunitinib (S) 25 mg/d 4 wks on, 2 wks off, and temsirolimus (T) 15 mg/wk was stopped after 2 of the first 3 pts developed dose limiting toxicity (DLT). Methods: Pts with any subtype mRCC (PS 0-1) were eligible. Each cycle consisted of daily S for 14 days on, 7 days off, and weekly T. The continuous reassessment method (CRM) was used. The primary objective was to find the maximum tolerated doses (MTD) of S and T. The total planned accrual was 60 pts. Results: Accrual was stopped after 20 pts received study drugs. Median age was 63.5 years; 13 pts received prior targeted therapy, 7 pts were treatment naïve; median number of prior treatments 1 (range 0-6). Treatment cohorts (#pts, S, T, dose in mg): 2 (S12.5,T6), 1 (S25,T12.5), 1 (S12.5,T8), 8 (S12.5alt25,T9), 2 (S25,T6), 2 (S25alt37.5,T6), 2 (S37.5,T6), 2 (S37.5,T8). Dose reduction was required in 6 of 20 pts; the most common DLT was mucositis in 3 of 20 pts, followed by thrombocytopenia in 2 of 20 pts. The mean number of cycles for all pts was 6.6±5.36, with mean time on study 159±120 days. One pt experienced DLT in cycle 1 and received no study related imaging, 1 had a partial response, 16 pts had stable disease, and 2 pts had progressive disease (PD) as best response. A total of 21 grade 3/4 adverse events (AEs) attributed to drug occurred in 11 of 20 pts. Reasons for study discontinuation were PD in 12 pts, toxicity in 6 pts, and pt preference in 2 pts. There were no treatment related deaths. Conclusions: The MTD of S and T using the CRM were not reached due to premature trial closure. However, we believe S 37.5 mg/d, 2 wks on, 1 wk off, and T 8-10 mg weekly may well be close to MTD. Clinical trial information: NCT01122615.

Phase Ib Study Of Combination Epigenetic Therapy With 5-Azacitidine and Vorinostat In Patients With Relapsed Or Refractory DLBCL

IntroductionPatients with chemorefractory DLBCL have a poor prognosis, rarely achieving durable responses to additional treatment with standard chemotherapy. Epigenetic dysregulation likely contributes to lymphomagenesis and chemoresistance. Distinct epigenetic signatures predicted response to the DNA methyltransferase inhibitor (MTI) azacitidine (Aza) and vorinostat (V), a histone deacytelase inhibitor (HDACi) in DLBCL cell lines. Preclinical studies suggested synergy between MTI and HDACi in chemoresistant DLBCL cell lines. We performed a phase Ib trial to evaluate the combination of Aza plus V in patients with relapsed or refractory DLBCL. MethodsSubjects with relapsed or refractory DLBCL ineligible for (due to chemorefractory state or comorbidities) or relapsed after autologous stem cell transplant were treated with Aza and V at four different dose levels (DL). DL 1 consisted of Aza 55mg SC x 5 days plus V 300mg PO x 7 days. DL 2 consisted of Aza 75mg SC x 5 days plus V 200mg PO x 7 days. DL 3 and 4 used the same Aza doses as DL1 and 2 respectively but V was administered for 14 days. Treatment was administered on 28-day cycles. Subjects remained on treatment for a maximum of 6 cycles. Up to 8 subjects could be enrolled into each DL, depending on the toxicity and activity profile. If 2 patients developed dose-limiting toxicities (DLT), enrolment to that dose level was closed. Cycle 1 DLT was defined as any of the following treatment-related adverse events: Grade 3-4 non-hematologic toxicity excluding alopecia, nausea, or fatigue responding to maximal treatment; grade 4 neutropenia lasting longer than 7 days or failing to recover to > 1000 cells/mm3 within 14 days; grade 4 thrombocytopenia of any duration; grade 4 febrile neutropenia. Primary endpoints were safety and tolerability as well as overall response rates (ORR). ResultsA total of 18 patients were enrolled. The median age was 66 years old (range 26-82). Subjects had received a median of 3 prior lines of treatment, including 3 that had undergone autologous stem cell transplantation. Thirteen patients were refractory to their previous treatment. Eight subjects were treated at DL1, 5 at DL2, 4 at DL3 and 1 at DL4. DL2 was closed early due to limited efficacy demonstrated with the 7-day course of V; only 1 out of 13 patients treated at DL1 and DL2 achieved an objective response. DL3 and DL4 were closed early after 2 patients at DL3 required dose reductions. The following grade 1-2 non-hematologic toxicities, independent of relation to study drugs, were experienced by at least 2 subjects: nausea (11), diarrhea (8), hypoglycemia (7), vomiting (5), renal impairment (5), raised ALP (5), fatigue (4), hyperglycemia (4), fever (3) and hyperbilirubinemia (3). One patient experienced grade 3 thromboembolism (DL1), 1 experienced grade 3 diarrhea (DL2), and 1 experienced grade 4 ALP increase (DL4). Grade 3-4 hematologic toxicity included thrombocytopenia (8), anemia (3) and neutropenia (2). A median of 2 cycles of study regimen was administered (range 1-6). One patient completed 6 cycles of treatment and 17 patients stopped treatment due to PD. There was 1 DLT at DL1. Only one subject had an objective response (PR at DL2) and 3 subjects had stable disease. The trial was stopped prematurely because of low clinical activity and poor tolerability. Interestingly, 7 patients (2 with relapsed disease and 5 with disease refractory to prior pre-study therapy) received treatment post-study. Retrospective review of these cases demonstrated that 2 had CR (PEP-C and R-DICE) and 3 others appeared to have had a significant clinical response (bendamustine, radioimmunotherapy, and brentuximab vedotin-PEP-C), 1 had PD (PEP-C), and 1 was not formally evaluated (bendamustine). The median OS of these 7 patients was 501 days following Aza-V. ConclusionsThe combination of Aza and V was poorly tolerated and had minimal clinical activity at the doses/schedules tested in this study of refractory DLBCL patients. However, we observed that several heavily pre-treated and refractory patients appeared to go on to achieve better than expected responses to the next treatment following the study regimen, perhaps consistent with a chemosensitization effect (i.e., epigenetic priming) of Aza and V. Epigenetic priming in DLBCL warrants further investigation in less refractory patients and in combination with other agents. Epigenetic profiling of patient samples derived from this trial is ongoing. Disclosures:Martin:Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees. Furman:Celgene: Research Funding.

464P - A Phase I Study of Daily Afatinib, an Irreversible Erbb Family Blocker, Combined With Weekly Paclitaxel and 2-Weekly Bevacizumab in Patients with Advanced Solid Tumours

ABSTRACT Background The clinical efficacy of cytotoxic agents can be enhanced both by ErbB inhibition and by bevacizumab (Bev). The primary objective of this study was to determine the maximum tolerated dose (MTD) of afatinib (A), an oral, irreversible ErbB Family Blocker, in combination with paclitaxel (P) and Bev. Afatinib (mg/day) Paclitaxel (mg/m2 Days 1, 8, 15) Bevacizumab (mg/kg Days 1, 15) All pts/Evaluable pts/Pts with DLT DLT (all Grade 3) 40 80 5 7/6/2 Fatigue/diarrhoea; fatigue 30 80 5 5/5/2 Diarrhoea; paronychia 20 80 5 3/3/0 20 80 7.5 6/6/1 Mucositis (recommended dose) 20 80 10 8/6/1 Dysphonia (MTD) Overall, the most frequent (any grade) adverse events (AEs) included diarrhoea (86%), fatigue (86%), rash (69%), mucositis (59%), and nausea (59%). Partial responses were confirmed in pts with non-small cell lung (n = 2) and cervical (n = 1) cancer. Eleven pts completed at least 6 treatment cycles of combination therapy. Methods A Phase I open-label 3 + 3 design dose-escalation trial was undertaken to determine safety, pharmacokinetics (PK), and antitumour efficacy of A combined with P (fixed dose 80 mg/m2 on Days 1, 8 and 15 of a 4-week cycle), and Bev (5 mg/kg starting dose to be escalated to 10 mg/kg) administered on Days 1 and 15 in patients (pts) with advanced solid tumours. After at least 6 cycles of triplet combination therapy, pts benefiting and tolerating treatment were eligible to continue treatment with A and Bev. The PK data of P and Bev (± A), as well as the steady state PK of A combined with P and Bev will be presented. Results Twenty-nine pts were enrolled (12 male; median age: 58 years [range: 21–73]; ECOG PS 0/1: 3/26). The MTD dose previously established for A (40 mg/day) in combination with P only (above schedule; Spicer et al. ESMO 2008) had to be de-escalated to 30 mg and then to 20 mg after 2/6 pts developed dose-limiting toxicities (DLTs) at 40 mg A and 2/5 at 30 mg A when combined with P and Bev 5 mg/kg. Conclusions Promising antitumour activity was seen with the combination of A at 20 mg/day with weekly P 80 mg/m2 and 2-weekly Bev 7.5 mg/kg, the recommended dose for a Phase II study. At this dose, AEs of A combined with P and Bev were generally mild to moderate and manageable. Disclosure M. Uttenreuther-Fischer: Employee of Boehringer-Ingelheim. K. Pemberton: Employee of Boehringer Ingelheim. K. Pelling: Employee of Boehringer Ingelheim. D. Schnell: Employee of SocraMetrics/Boehringer Ingelheim. J.S. de Bono: I have served as a paid consultant for Boehringer Ingelheim. J. Spicer: Honoraria from Boehringer Ingelheim. All other authors have declared no conflicts of interest.

A Phase I Study of ENMD-2076 In Patients with Relapsed or Refractory Leukemia

AbstractAbstract 3307 Background:ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase and FLT3, as well as multiple receptor tyrosine kinases that drive tumor vascularization, including VEGFR2 (KDR), PDGFR and FGFR. A phase I study was conducted to determine the maximum tolerated dose (MTD) and toxicities of ENMD-2076 in patients with refractory hematological malignancies. Methods.Patients (cohorts of 6 evaluable patients per dose level) received escalating doses of ENMD-2076 administered orally daily [225 mg (n=7), 375 mg (n=6), 325 mg (n=9), or 275 mg (n=5)]. Plasma levels of ENMD-2076 were measured on Days 1, 8, & 29 of cycle 1 and at the end of study. Peripheral blood and/or bone marrow were obtained at baseline for ex vivo drug sensitivity testing, and on Days 8 & 29 of cycle 1 for pharmacodynamic (PD) monitoring to assess the effects of ENMD-2076 on cell signaling pathways. The latter flow cytometry-based assay used combined pERK, pAkt, pSTAT5, and pS6 labelling, and tested the effects of acute stimulation with SCF and FLT3 ligands in the presence or absence of pathway inhibitors, including ENMD-2076. Results.Twenty-seven patients have been treated to date (26 AML; 1 CMML-2). Median age is 69 years (range, 43–84 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (89%) had received prior therapy (median, 2 regimens; range, 0 to 6 regimens); 2 had received a prior allogeneic stem cell transplant. A total of 42 cycles have been administered, with a median of 1 cycle (range, 0 to 8 cycles); 10 patients (37%) have received 2 or more cycles of therapy. The most common nonhematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Two of 6 patients treated at the 375 mg/day dose level developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue. The dose was therefore decreased to 325 mg/day; one patient on this dose level developed a DLT with grade 3 fatigue. However, as 2 additional patients subsequently developed grade 2 or 3 fatigue (during cycles 1 and 2, respectively), the 325 mg/day dose was not believed to be tolerable for chronic administration in this patient population. The dose was therefore decreased to 275 mg/day; 2 patients subsequently developed DLTs consisting of grade 3 typhilitis and grade 3 syncope, respectively. Overall, no patient experienced grade 4 toxicities or death from ENMD-2076. Of the 20 evaluable patients, one patient achieved a CRi (transfusion-independent with platelets <100 × 109/L), three a morphologic leukemia-free state (MLFS) with a major HI-P and/or HI-E, and 4 other patients had an 11%, 14%, 23%, and 65% reduction in marrow blast count, respectively. Ex vivo studies showed that pre-incubation with ENMD-2076 in concentrations in the range of 0.5–2 mM suppressed growth factor stimulation in the blast cells of most patients tested to date. Decreases in the stimulation of ERK, Akt, STAT5, and S6 were seen in the Day 8 & 29 samples, including a striking inhibition of cell signaling in one patient who achieved a CRi. Conclusions.Single agent ENMD-2076 has activity in a heavily pretreated group of AML patients that may correlate with inhibition of ERK, Akt, STAT5, and S6 activity. The recommended phase two dose (RPTD) is 225 mg/day. Enrollment, as well as PK and PD monitoring of this study, is ongoing. Disclosures:Off Label Use: Clinical trial investigating ENMD-2076 in patients with relapsed or refractory leukemia. Sidor:EntreMed, Inc.: Employment. Fletcher:EntreMed, Inc.: Employment. Arnott:EntreMed, Inc.: Employment. Bray:EntreMed, Inc.: Employment.

A Phase I Study of Lenalidomide in Combination with Fludarabine-Rituximab in Previously Untreated CLL/SLL.

Abstract 3426Poster Board III-314Lenalidomide is an immunomodulatory drug recently reported to have an objective response rate (ORR) of 35-53% in relapsed/refractory CLL, even with poor risk features. Initial therapy of CLL currently includes chemoimmunotherapy combinations like FCR, which have high response rates and improved PFS, but at the cost of myelosuppression and infection. Given the high ORR reported with lenalidomide and its potential to spare immune function, we undertook this Phase I study to explore the safety and tolerability of lenalidomide in combination with fludarabine and rituximab. Eligibility criteria included a confirmed diagnosis of CLL/SLL, previously untreated with systemic therapy with an indication for therapy by NCI-WG 1996 criteria; ANC > 1000, platelets > 50K, and adequate organ function. Six dose levels were planned, beginning with fludarabine 25 mg/m2 days 1-3, rituximab 375 mg/m2 day 1, and lenalidomide 2.5 mg administered on days 1-21 of a 28-day cycle. The study used a standard 3+3 dose escalation design, with dose limiting toxicity (DLT) assessed in the first 28 days and defined as grade 3 or greater non-hematologic toxicity, grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or a >2-week delay in initiating the second cycle. Nine patients were enrolled on this study, 7 males and 2 females, with a median age of 59 yrs (range 37-66). The median time from diagnosis to study entry was 66.1 months (range 11.7-82.8 months). The median WBC at study entry was 99.6 (range 11.1-325.7). Six patients had Rai 3-4 disease, and three patients had bulky lymphadenopathy (>5 cm) on physical exam. Median beta-2 microglobulin level at study entry was 3.8 mg/L (range 2.5-7.7). The first cohort enrolled four patients, of whom two developed DLTs (grade 4 neutropenia persisting through day 50; febrile syndrome with grade 3 rash, myalgias and grade 4 CPK elevation). The study then proceeded to enroll five patients at dose level -1, with the same dosing of rituximab and fludarabine, but reduced lenalidomide dosing of 2.5 mg every other day for 21 of 28 days. Only two of five patients on dose level -1 completed the planned six cycles of therapy. The other three patients discontinued after 3 cycles due to toxicity: persistent grade 2 thrombocytopenia preventing further therapy; recurrent grade 3-4 neutropenia and thrombocytopenia, despite growth factor support, dose reduction and holding lenalidomide; and intermittent recurrent grade 3 tumor flare, rash and hand-foot syndrome, along with recurrent grade 3 neutropenia despite similar measures as above. At that point the study was closed to enrollment due to the significant myelotoxicity and idiosyncratic tumor flare, resulting in only two of nine patients completing the planned therapy. The median number of cycles completed for all patients was three. Six of the nine enrolled patients were evaluable for response, with five of nine having objective responses (56%, 90% CI 25-83%). No significant difference was observed in IgG and IgM levels between baseline and two months on study, although a trend toward a decrease in IgA levels (p=0.05) was observed. Baseline CD4 counts were variable (median 1139, range 529-2687), but showed significant declines of 574 cells by week 4 (p=0.003) and 707 cells by post-treatment (p=0.002). Analysis of alterations in serum cytokines is ongoing. We conclude that administering lenalidomide concurrently with fludarabine and rituximab is difficult, does not appear to preserve immune function, and limits the ability to deliver adequate therapy with either drug. Other trials currently in progress are exploring alternative schedules of lenalidomide administration with fludarabine and other standard CLL chemotherapy regimens; our data would favor a sequential schedule. DisclosuresBrown:Celgene: Honoraria, Provided funding for this investigator-initiated study; Genzyme: Research Funding; Genentech: Consultancy; Calistoga: Consultancy. Off Label Use: Lenalidomide for CLL. Hochberg:Enzon: Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau.

Toxicity of concurrent chemoradiotherapy and consolidation chemotherapy with docetaxel and cisplatin in stage III non-small cell lung cancer:a phase I trial

Objective To investigate the maximal tolerated dose (MTD) of docetaxel and cisplatin (DC) combined with concurrent radiation therapy (RT), and the appropriate interval between consolidation chemotherapy and concurrent chemoradiotherapy (CCRT) in patients with stage Ⅲ non-small cell lung canc-er (NSCLC). Methods A total dose of 60 -70 Gy was delivered to the primary tumor and positive lymph node regions in 30-35 fractions by three dimensional conformal RT. Chemotherapy regimen consisted of do-cetaxel and cisplatin, which were administered at the same dose. MTD was defined as the dose level at which ≥2/6 patients developed dose-limiting toxicity (DLT). Concurrent chemotherapy was administered on day 1 and day 28 of RT. The initial dose level was 55 mg/m 2 , then increased by 10 mg/m 2 each time until to 75 mg/m 2 . Consolidation chemotherapy at the same dose level was given 21 days per cycle for two cycles, which started 4, 5 or 6 weeks after RT. If ≥2/6 patients developed DLT during the consolidation chemo-therapy, The second cycle would be postponed for 1 week. Results All of the 12 patients who enrolled in the trial completed CCRT. Among them, 6 patients successfully received 2 cycles consolidation chemothera-py 4 weeks after the completion of RT. No DLTs occurred until the dose level reached 75 mg/m 2 . Two of three patients experienced DLT at the level of 75 mg/m 2 . Neutropenia was the main adverse effect. Conclu-sions In the treatment of stage Ⅲ NSCLC, a dose level of 65 mg/m 2 was recommended for phase Ⅱ study of CCRT and consolidation chemotherapy with docetaxei and cisplatin. Concurrent chemotherapy should be repeated every 4 weeks. Consolidation chemotherapy can be started 4 weeks after the completion of radiation and repeated every 3 weeks for 2 cycles. Key words: Neoplasm; non-small cell lung/radiotherapy; Neoplasm; non-small cell lung/chem-otherapy; Combined modality therapy; Clinical trial of Phase Ⅰ

Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies

3540 Background: D is a small molecule inhibitor of several kinases, including SRC. SRC can potentiate Epidermal Growth Factor Receptor (EGFR) signaling and is implicated in resistance to EGFR inhibitors. Combined inhibition of EGFR and SRC may lead to improved therapeutic effect. We evaluated the combination of D and C, a chimeric IgG1 monoclonal anti-EGFR antibody. Methods: Eligible pts had advanced solid malignancies treated with any number of prior regimens but without EGFR or SRC inhibitors, ECOG performance status 0–2, QTc interval on baseline EKG &lt;450 msec, and adequate laboratory parameters. C was administered i.v as a loading dose of 400 mg/m2 on cycle 1, day 1 and then weekly at 250 mg/m2 on days 1, 8 and 15. D was administered orally, once daily, on a continuous schedule, on days 1–21. We used a standard up-and-down dose escalation scheme to assign pts on 3 dose levels (DL): 1- 100 mg QD, 2- 150 mg, 3- 200 mg. PK studies of D were performed on days 0 (prior to starting C) and 15 of cycle 1. Results: 25 pts (DL 1, 3 pts; DL 2; 19 pts; DL 3; 3 pts) were enrolled; 15 male; median age 62; median prior regimens: 2 (range: 0–5). Pts received a median of 2 cycles of D plus C (range: 1–15). 3 pts developed dose-limiting toxicities (DLT): 1 at DL 2 (headache; HA) and 2 at DL 3 (HA and nausea). Thus, MTD was reached at DL 2. DL 2 was expanded by an additional 12 pts to obtain further clinical and PK data. PK parameters (AUC and T-1/2) of D were comparable when given alone or in combination with C. Grade 3–4 toxicities in &gt; 2 pts included: dyspnea (4), vomiting (4), nausea (3), allergic reactions (3), HA (3) and anemia (3). 21 pts developed HA (grade 1, 8 pts; grade 2, 10 pts). HA occurred after the loading of C, and took a median of 2 days to resolve. Pleural effusion developed in 4 pts (grade 2, 3 pts; grade 3, 1 pt) after 2–5 months of treatment. In 17 evaluable pts, there were no objective responses; 9 pts had stable disease: salivary gland cancer (3), thyroid (2), sarcoma (1), unknown primary (1), esophagus (1), and NSCLC (1). Conclusions: D 150 mg plus C was well tolerated, but early-onset HA was frequent. C administration did not affect D PK. We plan to treat 6 additional pts starting D 3 days after the C loading dose in an attempt to ameliorate early-onset HA. A phase II trial of C plus D in head and neck cancer is planned. [Table: see text]

Phase I dose escalation study of docetaxel with a fixed dose of S-1 in combination chemotherapy for advanced gastric cancer

The primary objectives of this study were to estimate the maximum-tolerated dose (MTD) of docetaxel in combination with a fixed dose of S-1 and to determine the recommended dose (RD). Patients with histologically proven gastric carcinoma with metastatic or locally advanced inoperable disease were eligible. Patients received intravenous docetaxel starting at 40 mg/m(2) (dose level 1), and stepwise dose increases to 50, 60, and 70 mg/m(2) were planned for successive patient cohorts (dose levels 2, 3, and 4, respectively) over 1 h on day 1 and oral S-1 administered at a fixed dose of 40 mg/m(2) twice daily on days 1-14, both drugs every 21 days. A total of 13 patients were enrolled into this trial. All three patients at dose level 3 developed dose-limiting toxicities (DLT), and this level was declared to be the MTD. Hence, level 2 (docetaxel 50 mg/m(2)) was declared to be the RD for the next study. As 9 of the 13 enrolled patients responded to treatment, the overall objective response rate was 69.2% (95% CI, 44.1-94.3%). The median time to progression was 8.38 months (range 1.44-8.51) and the overall survival duration was 9.9 months (range 0.62-11.57). The most common grade 3/4 toxicity of docetaxel plus S-1 was neutropenia, which was tolerable and manageable. This regimen showed encouraging activity and a manageable safety profile in advanced gastric carcinoma and could be used in further randomized studies.

A phase I study of pegylated liposomal doxorubicin + gemcitabine in a fixed dose-rate infusion for the treatment of patients with recurrent ovarian cancer

5579 Background: Pegylated liposomal doxorubicin (PLD) constitutes the reference treatment for platinum-resistant (PR) ovarian cancer (OC). The combination of gemcitabine (G) + PLD seems to have additive activity in OC; however, it also has additive haematological toxicity, precluding administration of optimal dose of both drugs. Fixed dose-rate infusion (FDRI) of G improves haematological tolerance. Methods: We present data of a phase I trial using the combination of these two drugs, including G in this FDRI to ascertain whether we can enhance the therapeutic index of this combination. Inclusion criteria were: recurrent OC with a platinum-free interval <1 year, primary or secondary treatment with platinum, age < 80 years, Karnosky >60 and with normal organ function. The starting dose of G was 1500 mg/m2, 10 mg/m2 minute, q 2 weeks (± 250 mg G titration depending on toxicity) followed by PLD 35 mg/m2 q 4 weeks. Pharmacokinetic analyses were performed on days 1 and 15 of the first cycle. Results: From December 2005 to July 2007, 20 patients (pts) were enrolled. 5 were non-evaluable for toxicity due to early progression. In the first step, 4 (pts) were treated and 2 developed dose-limiting toxicity (DLT) consisting on grade 4 neutropenia and grade 3 stomatitis. In the next step G1250/PLD35, 5 pts have been included, 2 developed late grade 3 stomatitis and dermatitis. Heavily-pretreated pts (>6 cycles) and/or >70 years (frail pts) were treated with G1000/PLD35; to date 1 of 6 has presented grade 3 stomatitis. PLD did not affect the pharmacokinetic of G or its metabolites. Conclusions: In conclusion, the recommended dose for a phase II study in recurrent OC is G1250/PLD35, although dose reduction may be necessary due to late toxicity (being stomatitis and dermatitis the most common DLT). For frail pts, the recommended dose is G1000/PLD35. The study is ongoing in order to have more solid long-term toxicity data. Activity appears to be promising: 30.7% (4/13) objective response in PR OC (platinum-free interval < 6 months) and 85.8% (6/7) in pts with a platinum-free interval between 6–12 months. No significant financial relationships to disclose.

A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat.Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days.Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated.Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

Final Results of a Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Patients with Advanced Multiple Myeloma.

Background: The histone deacetylase inhibitor vorinostat was approved by the United States FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Vorinostat has also demonstrated promising preclinical activity in multiple myeloma.Patients and Methods: A Phase I trial of oral vorinostat 200, 250 or 300 mg bid for 5 days each week of a 4 week cycle or 200, 300, or 400 mg bid for 14 days/3 week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed and/or refractory multiple myeloma with adequate hematologic, hepatic, and renal function were eligible. The objectives were to determine the maximum tolerated dose (MTD) on each of the schedules and assess activity and safety.Results: Thirteen patients (median age, 63 years; median 7 prior systemic therapies) were enrolled. The MTDs were not determined due to early termination of the study due to the decision of the sponsor. One patient (250 mg bid 5 days/week) developed dose-limiting toxicity (DLT) of grade 3 fatigue. There were no other DLTs and the maximum administered doses were 250 mg bid for 5 days each week of a 4-week cycle and 200 mg bid for 14 days/3-week cycle. Common drug-related adverse experiences included fatigue (69%), anorexia (62%), dehydration (46%), diarrhea (46%), and nausea (38%) and were mostly grade ≤ 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease (Table 1).Conclusions: Oral vorinostat was generally well tolerated at 250 mg bid for 5 days each week of a 4 week cycle or 200 mg bid for 14 days/3 week cycle in patients with advanced multiple myeloma. Modest activity was demonstrated in relapsed and/or refractory multiple myeloma and combination studies with other anti-myeloma agents are warranted.Table 1Clinical outcomes of patients per EBMT Criteria*Allocation NumberAgeBaseline Myeloma StagePrior Systemic TherapiesPrior Bone Marrow TransplantBaseline β2-microglobulinOn-study Duration (days)Best ResponseCohort 1 (200 mg twice daily x 5 days/week) 100155III121ND41NE 100247II312.0254SD 100364III402.662SDCohort 2 (250 mg twice daily x 5 days/week) 100438I501.755SD 100574III716.7240MR 100665ND723.374NE 100767ND1010.1118SD 100842III504.7109SD 100950III501.4123SDCohort 4 (200 mg twice daily x 14 days/3 weeks) 86169IIIa1614.656SD 86263IIIa2013.125NE 86361IIIa1012.762SD 86471IIIa16111.0155SDEBMT = European Group for Blood and Marrow Transplantation; MR = Minimal Response; ND = Not Determined; NE = Not Evaluable; SD = Stable Disease. *Cohorts 3, 5, and 6 were not initiated.

Report of a Phase1/2 Study of 5-Azacitidine and Cytarabine in Patients with Relapsed, Refractory Acute Myelogenous Leukemia.

Background: Epigenetic silencing, particularly of tumor suppressor genes, is known to play a significant role in development of leukemia, and is thought to play a role in acquired drug resistance. In vitro, 5-azacitidine (azacitidine) can reverse methylation and activate expression of genes involved in response to chemotherapy, including proapoptotic genes, DNA repair genes and genes that regulate cell cycle. Thus, reversal of DNA methylation can potentially restore chemosensitivity in leukemia and combined use of DNA hypomethylating agent with chemotherapy can be an effective treatment strategy for leukemia.Methods: We developed a phase 1/2 study of azacitidine and cytarabine administered concurrently in patients with relapsed/refractory AML. Newly diagnosed patients deemed ineligible for standard therapy were eligible. Two dose levels of azacitidine were explored, dose level 0= 37.5 mg/m2 intravenously (I.V) daily for 7 days and dose level 1=75 mg/m2 IV daily for 7 days. Similarly two dose levels of cytarabine explored were; low dose- 100 mg/m2 IV continuously (CI) for 7 days and high-dose - 1 gm/m2 CI for 4 days. This resulted in 4 potential groups (Table1). After 2 cycles of induction therapy as in table 1, patients were to receive maintenance therapy upon recovery of counts. In the phase 1 portion of the study groups were opened sequentially in a “3+3” design. The phase 2 part was designed in a 2 by 2 factorial maner with adaptive randomization.Results: Twenty-seven patients with AML (male=13) have been enrolled so far, Group 1= 7, group 2= 6, group 3=11 and group 4= 3. One patient (group 1) did not receive treatment as she withdrew consent. Median age was 61 years (range, 31 to 79) and median number of prior therapies was 2 (range, 0 to 4). Twenty-one patients had received prior cytarabine including 19 who received high-dose cytarbine. Karyotype was complex in 7 patients, deletion 7 in 3 and 11q abnormality in 2. The median number of cycles administered on study was 1 (range, 1–5). One patient (group 2) developed dose-limiting toxicity (DLT) of grade 3 mucositis. No other DLTs were encountered. There was limited efficacy seen, with no patient achieving complete remision (CR). The combination achieved transient control of WBC counts in most patients treated, and one patient had reduction in marrow blasts from 24% to 3% after the 3rd cycle without recovery of blood counts and had progression of disease after 5 cycles.Conclusion: The simultaneous combination of azacitidine with cytarabine as administered in this study is safe. Efficacy evaluation of the combination was compromised by the small number of cycles of azacytidine given, but appears to be limited in a patient population composed predominantly of relapsed/refractory AML.Table 1Low-dose cytarabineHigh-dose cytarabineAzacitidine dose level 0Group 1Group 3Azacitidine dose level 1Group 2Group 4

Phase I study of the combination of anti-GD2 antibody 3F8 and barley-derived (1→3,1→4)-β-D-glucan for patients with resistant neuroblastoma

9566 Background: Beta glucans are complex, naturally occurring polysaccharides that prime leucocyte dectin and CR3 receptors. Based on our preclinical observations that oral barley-derived (1→3,1→4)-β-D-Glucan (BG) synergizes with the murine anti-GD2 antibody 3F8 against neuroblastoma (NB) (Clin Cancer Res 8:1217), we conducted a phase I study to determine the safety of the combination of BG and 3F8 in patients with resistant NB. Methods: Heavily pre-treated patients with recurrent or refractory advanced stage NB were treated with 3F8/BG. Each cycle consisted of intravenous (IV) 3F8 at a fixed dose of 10 mg/m2/day ×10 days, plus oral BG dose escalated from 10 to 80 mg/kg/day ×10 days in 4 cohorts of 6 patients each. Patients without human anti-mouse antibody (HAMA) could be re-treated up to a total of 4 cycles. Results: Twenty-three patients with stage 4 and one with stage 3 NB (M:F = 11:13; median age 8 (range 2–19) years completed 47 cycles of therapy with 3F8/BG. 8 patients had progressive disease (PD) while 16 had stable refractory NB (SD) at enrollment. All patients completed at least one cycle of therapy and were evaluated for toxicity and response. Maximum tolerated dose for BG was not reached. Two patients developed dose-limiting toxicities (DLT). Both had grade 4 thrombocytopenia after completing one cycle of treatment: one at BG dose of 20mg/kg/day and the other at 40 mg/kg/day. Both cases responded to therapy with a short course of ITP (idiopathic thrombocytopenic purpura) therapy; one subsequently developed chronic ITP. There were no other &gt;grade 2 toxicities related to 3F8/BG therapy. 14, 4, 2 and 6 patients completed 1, 2, 3 and 4 cycles respectively. Reasons for withdrawal in patients who did not complete 4 cycles were PD in 10, persistently elevated HAMA in 6 and DLT in 2. Overall 11 patients had SD and 13 PD. 14/23 patients with positive MIBG scans prior to therapy demonstrated improvement after one cycle. Responses did not correlate with BG dose received. 7 patients, all with residual disease survive at a median of 40 (range 24–45) months post-treatment. Conclusions: 3F8/BG is well tolerated and shows activity against resistant NB. Further clinical investigation of this novel combination is warranted. No significant financial relationships to disclose.