G3 Nausea Research Articles

Dendrimer-enhanced (DEP) SN38 (DEP irinotecan) in patients (pts) with advanced solid tumors: A phase 1/2 trial.

3014 Background: Dendrimer nanoparticles enable prolonged cytotoxic drug targeting to tumors. DEP SN38 is a water-soluble version of SN38, the active metabolite of irinotecan, attached to a dendrimer, so avoiding usual metabolic pathways of conventional irinotecan (c-IRI). This phase 1/2 (P1/2) trial evaluated safety, tolerability and efficacy of DEP SN38 in pts with advanced solid tumors, including colorectal (CRC), platinum-resistant high-grade serous ovarian (HGSOC) and breast (BC). Methods: Pts who had exhausted standard therapy were enrolled in dose assessment (P1)/dose expansion (P2) cohorts of DEP SN38 given IV 3-weekly (Q3W) or Q2W alone or in combination with 5-fluorouracil & leucovorin (5FU/LV combo). Efficacy was evaluated by RECIST 1.1 and serum tumor markers. (EudraCT 2019-001318-40). Results: 114 pts were enrolled. The Q3W Recommended Dose (RD) was 12.5 mg/m2 SN38 with dose limiting toxicity (DLT) in 1/7 pts (grade (G) 4 neutropenia > 7d). The Q2W RD was 12.5 mg/m2 for SN38 alone or with 5FU/LV. DEP SN38 was well-tolerated for all dose regimens with mostly mild/moderate (G1/2) treatment-related adverse events (TRAEs) & no new events compared with c-IRI. TRAEs in ≥ 10% pts included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, diarrhea, constipation and alopecia. Of734 DEP SN38 cycles only 1 event of G3 diarrhea (0.9% pts) and no cholinergic symptoms have been observed, contrasting with c-IRI (~20% & 47% pts respectively). G3 nausea (1.8% pts) and vomiting (0.9% pts) occurred less frequently than with c-IRI (both ~10% pts). Febrile neutropenia was the DLT at 15 mg/m2 Q2W monotherapy (2/6 pts), with neutropenia otherwise essentially uneventful and managed with G-CSF. 38 CRC pts received DEP SN38 monotherapy (31 evaluable) and 17 received the 5FU/LV combo (14 evaluable). CRC pts had a mean 4 prior lines with 97% receiving ≥ 1 c-IRI containing line. The disease control rate (DCR) in monotherapy was 48% (stable disease (SD) up to 72 wks). The 5FU/LV combo cohort DCR was 85.7%, the objective response rate (ORR) was 14.3%, with disease control observed for at least 35 wks. Several CRC pts continue combo treatment. 23 HGSOC pts with a mean of 6 prior lines received DEP SN38 monotherapy (18 evaluable). The DCR for Q2W was 100% with 33.3% ORR, and 72% DCR for all HGSOC pts. 3 pts have PRs for at least 36 wks; with 1 pt achieving complete tumor & ascites resolution. Reduced CA-125 of up to 98% was observed in 75% pts. Several HGSOC pts continue DEP SN38 treatment. 8 BC pts with a mean of 7 prior lines received DEP SN38 monotherapy Q3W (5 evaluable). The DCR was 100% with SD up to 72 wks. Conclusions: DEP SN38 shows promising clinical utility with encouraging antitumor activity including prolonged disease control & durable PRs in heavily pre-treated CRC, HGSOC & BC pts. DEP SN38 is well-tolerated with significantly fewer severe gastrointestinal TRAEs compared to c-IRI, & warrants further clinical assessment. Clinical trial information: 2019-001318-40 .

Inb-100: A Pilot Study of Donor Derived, Ex-Vivo Expanded/Activated Gamma-Delta T Cell (EAGD) Infusion Following Haploidentical Hematopoietic Stem Cell Transplantation and Post-Transplant Cyclophosphamide (PTCy)

Background: Gamma-delta (gd) T cells are MHC unrestricted lymphocytes that recognize and lyse malignant cells in allogeneic settings. Although haploidentical transplant with PTCy has reduced the risk of graft-versus-host disease (GvHD); the incidence of relapse remains up to 50% at year 1. Early post-transplant infusion of haploidentical EAGD cells may decrease relapse risk through a graft-versus-leukemia (GvL) effect without severe GvHD. We present updated clinical and correlative data from our Phase I trial using our recommended phase 2 dose (RP2D). Methods: Adults with newly diagnosed or relapsed ALL, CML, AML undergoing first haploidentical transplant with reduced-intensity flu/cy/TBI conditioning received EAGD intravenously within 7 days of neutrophil engraftment. Peripheral blood was collected at EAGD infusion and monthly through day 90, with additional collections every 6 months through 1 year. Primary endpoints include dose-limiting toxicities (DLT), grade (G) 3-4 adverse events including GvHD with secondary endpoints of relapse and overall survival. Biologic parameters included multiparameter flow cytometric immunophenotyping and additional serum cytokine analysis using the Olink ® 48 target panel. Results: 14 subjects were enrolled with 4 treated at Dose Level (DL) 1 of 1 x 10 6 EAGD/kg and 6 subjects treated at the RP2D of DL2 (3 x 10 6 EAGD/kg). Untreated subjects included: One screen failure, a manufacturing failure, one subject who died prior to dosing, and one subject who received an out of study specification product. Treated subjects were 60% male, median age of 68, and primarily AML subjects in CR1. RP2D was defined by an acceptable toxicity profile, no DLT's, prolonged RFS and elevated gd levels. Peripheral lymphodepletion persisted through the first 100 days post-BMT followed by T cell recovery from a CD45+CD27-effector phenotype to central and effector memory phenotype. Notably, DL2 showed significant increases in gd T cell count recovery at days 60, 100 and 180 post-BMT vs. DL1 and historically untreated Haplo/PTCy patients, p = <0.05. NK cells remained within the low normal range and <3% of circulating T cells were Tregs. Preliminary serum cytokine analysis revealed elevated IL-6 and IL-15 in serum post- transplant prior to EAGD infusion, but dropped to normal median levels at day 60, 20-30 days after EAGD infusion. One subject received intermittent hypomethylating therapy for emergence of recipient chimerism. Treatment emergent AE's included transient WBC and ANC decreases (100% each), platelet count decrease and anemia (88.9% each) and maculopapular rash, hypomagnesemia and blood creatine increased (55.6% each). EAGD related toxicities were primarily G1-2, included G1-2 skin acute GvHD and gastrointestinal GvHD, and one case of G3 platelet count decrease. Treatment related serious AE's of G3 nausea and G2 rash were reported. No DLTs, neurotoxicity, cytokine release syndrome or treatment related deaths were reported. Conclusions: Post-BMT infusion of donor-derived, EAGD cells has demonstrated manageable safety with no infusional toxicity or ≥G3 acute GvHD or extensive chronic GvHD. Durable relapse free survival at a maximum of >3 years in subjects with poor risk cytogenetics and adverse clinical risk factors combined with ongoing homeostatic reconstitution of increasing gd T cell effectors post-BMT suggests this therapy may be an effective measure in mitigating relapse after HaploBMT. NCT03533816

First-in-human phase 1/2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4/6 inhibitor resistant HR+/HER2- breast cancer.

3010 Background: PF-07104091 is a novel CDK2-selective inhibitor under investigation in pts with selected advanced or metastatic solid tumors. We present the first disclosure of data from the first-in-human, multicenter, phase 1 study of PF-07104091 monotherapy (NCT04553133). Methods: Pts with HR+/HER2- advanced/metastatic breast cancer (mBC) who received ≥ 2 lines of treatment for mBC including prior endocrine therapy (ET) + CDK4/6 inhibitors (CDK4/6i), and pts with other solid tumors, were included. Prior therapy with fulvestrant and chemotherapy was allowed for pts with mBC. PF-07104091 (75-500 mg) was given twice daily (BID) orally in 28-day cycles, following Bayesian design with overdose control, to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE). Primary objective was to assess safety and tolerability. Secondary objectives included pharmacokinetics and preliminary anti-tumor activity. Results: At data cut off (Aug 23, 2022), 35 pts with advanced solid tumors (n = 29 mBC) with median age 62y (range 32-80y), median 4 lines of prior systemic therapy (range 1–12) and ECOG PS 0 (20% pts) or 1 were enrolled. Of 29 pts with mBC, all had prior CDK4/6i, 25 (86.2%) prior fulvestrant, and 21 (72.4%) prior chemotherapy. Treatment-emergent adverse events (TEAEs) were observed in 34 pts (97.1%; 20 [57.1%] grade [G] ≥ 3). The most frequent TEAEs (all G≤3) were nausea (77.1%; 14.3% G3), diarrhea (48.6%; 8.6% G3), vomiting (48.6%; 2.9% G3), fatigue (45.7%; 20.0% G3) and anemia (45.7%; 8.6% G3). Dose-limiting toxicity occurred in 5 pts: 1 pt (G3 fatigue) at 300 mg BID; 2 pts (1 G3 nausea and G3 anorexia, 1 G3 nausea) at 375 mg BID, and 2 pts (1 G3 fatigue and 1 G3 diarrhea) at 500 mg BID. Steady-state PF-07104091 plasma exposures increased proportionally with dose. A trend of early decrease in ctDNA was observed. Further pharmacodynamic studies are ongoing. PF-07104091 300 mg BID was identified as the MTD and selected as the monotherapy RDE. Among 16 response evaluable mBC pts (all prior CDK4/6i+ET) with measurable disease at baseline, confirmed RECIST v1.1 partial responses were observed in 3 (18.8 %) pts (2 pts with duration of response > 6 months and 1 ongoing at data cut off), and stable disease in 6 (37.5%) pts. Disease control rate was 61.5% in mBC pts (response evaluable set, 95% CI: 40.6, 79.8). Conclusions: Treatment with PF-07104091 monotherapy was generally well tolerated and showed antitumor activity in heavily pretreated HR+ HER2- mBC pts who progressed on prior CDK4/6i. Dose expansions of PF-07104091 are ongoing as monotherapy in pts with ovarian cancer and in combination with fulvestrant in pts with breast cancer. Clinical trial information: NCT04553133 .

A CRUK first-in-human phase I trial of LY3143921, a novel CDC7 inhibitor, in patients with advanced solid tumors.

3103 Background: CDC7, a protein with key roles in regulating cell-cycle progression is often over-expressed in malignant cells, particularly those with TP53 mutations. LY3143921, an orally administered ATP-competitive CDC7 inhibitor, demonstrated favorable pre-clinical anti-cancer activity in colorectal cancer (CRC) and squamous non-small cell lung cancer (sqNSCLC), particularly in TP53 mutant models. Methods: Phase Ia (dose escalation) recruited patients (pts) with advanced solid tumors enriched for malignancies associated with TP53 mutation. Pts received LY3143921 OD or BD continuously on a 21-day schedule, using an accelerated 3+3 escalation design, starting at 30 mg OD. Phase Ib recruited pts with CRC or sqNSCLC treated continuously at RP2D, or pts with other advanced tumors treated at RP2D on days 1-3 every 7 days. Radiological assessment was performed every 2 cycles initially. Pts in phase Ib could consent to pre- and on-treatment skin +/- tumor biopsies. Primary objectives: assess safety/tolerability and determine MTD and RP2D of LY3143921. Secondary objectives: evaluate preliminary efficacy and pharmacokinetic (PK) profile of LY3143921. Exploratory objective: correlate efficacy to baseline molecular/genetic alterations, including TP53 mutation and measure markers including pMCM2 in pre- and on- treatment tumor and skin samples. Results: 68 pts were recruited and 67 treated (38 phase Ia, 29 phase Ib). Most frequent drug-related CTCAEs (all grades): nausea (75%), orthostatic hypotension (50%), vomiting (47%), fatigue (45%) & diarrhea (44%). Grade 3-4 LY3143921 related AEs occurred in 17 pts. In phase Ia 8 DLTs occurred in 5 pts (G3 nausea, vomiting, fatigue & hyponatraemia and G2 diarrhea, anorexia & lethargy). RP2D was 360 mg BD (continuous non-fasted dosing schedule). 37 pts were evaluable for radiological response with no complete or partial responses seen, and stable disease (SD) was observed in 24 pts (65%). In phase Ia 3 pts achieved long term SD of 1, 2.5 and 3+ years duration. For evaluable pts treated in phase Ib, SD was seen in 8/12 CRC pts, 1/2 sqNSCLC pts and 2/2 pts treated with the intermittent schedule (median duration 15 weeks, range 6-18+). 2 pts remain on-study. Recruitment ceased due to lack of radiological response according to RECIST. Dose-dependent increases in LY3143921 exposure (Cmax & AUC0-24) were seen. IHC analyses of skin biopsies demonstrated reductions in pMCM2, indicating on-target activity of LY3143921. Pre-clinical testing of combination with standard of care agents is ongoing. Additional PD and PK data will be presented. Conclusions: LY3143921 is well tolerated, exhibits dose-dependent increases in plasma exposure and demonstrates evidence of target inhibition. Significant monotherapy clinical activity was not observed; further analyses should investigate potential predictive response biomarkers and rational combination approaches. Clinical trial information: NCT03096054.

Efficacy of cisplatin plus vinorelbine adjuvant chemotherapy with split-dose administration of cisplatin after complete resection of stage II-IIIA non-small cell lung cancer.

Although co-administration of cisplatin (CDDP) and vinorelbine (VNR) has been established as a standard of care adjuvant chemotherapy for non-small cell lung cancer (NSCLC), there is a lack of clinical data on its safety and efficacy in Japanese patients receiving split-dose administration of CDDP. The present study analyzed patients who received CDDP + VNR with split-dose administration of CDDP after undergoing complete resection of NSCLC. Patients received four courses of CDDP (40 mg/m2) and VNR (25 mg/m2) on days 1 and 8, every 3 weeks. There were 27 male and 13 female patients; the mean age was 65 years (range 38-78 years), the postoperative disease staging distribution was IIA/IIB/IIIA: 14/8/18 patients, and histological distribution was adenocarcinoma/squamous cell carcinoma/others: 24/12/4 patients, respectively. Of the 40 patients, 28 (70%) completed the four courses of treatment. The mean total dose administered was 279 mg/m2 CDDP (87.2%) and 172 mg/m2 VNR (86%). The major adverse events included Grade (G) 3 or higher neutropenia (80%), G3 phlebitis (5%) and vomiting (2.5%). There was no G2 or higher serum creatinine level elevation, G3 or higher anorexia and nausea, or any treatment-related deaths. The overall completion rate of four courses was 70 and 62.5% for patients aged 70 years and older, whereas the overall percentage of patients that could complete three or more courses was 85 and 87.5% for patients aged 70 years and older. The relapse-free survival rate was 60% at 3 years and 57.5% at 5 years. Overall survival rate was 80% at 3 years and 60% at 5 years. The present study demonstrated the sufficient tolerability, safety and efficacy of combined CDDP + VNR adjuvant chemotherapy with split-dose administration of CDDP, with a low risk of gastrointestinal toxicities or nephrotoxicity.

A phase I study of pharmacokinetic (PK)-driven sequential dosing of rucaparib (RUB) with irinotecan liposome (nal-IRI) and fluorouracil (5FU) in metastatic gastrointestinal (mGI) and pancreas (PANC) cancers.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received > 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

A phase Ib trial of belvarafenib in combination with cobimetinib in patients with advanced solid tumors: Interim results of dose-escalation and patients with NRAS-mutant melanoma of dose-expansion.

3007 Background: Belvarafenib, a potent, selective RAF dimer (type II) inhibitor, exhibits clinical activity in BRAFV600E- and NRAS-mutant (NRASm) melanoma patients. The combination of belvarafenib and cobimetinib more potently and durably suppressed MAPK pathway output and tumor growth than currently approved BRAF/MEK inhibitors in RAS- or RAF-mutant tumor xenograft models. This interim results of phase 1b trial evaluated the safety, tolerability, pharmacokinetics, and anti-tumor activity of belvarafenib in combination with cobimetinib in dose-escalation and NRASm melanoma patients among the 9 indication-specific expansion cohorts. Methods: Patients with locally advanced or metastatic solid tumors harboring RAS or RAF mutation were enrolled in the dose-escalation stage, and the recommended doses were explored in the indication-specific expansion stage. Patients in the dose-escalation stage were given belvarafenib (100–300mg BID) in combination with cobimetinib (20–40mg QD) and the dose of subsequent cohorts was decided by a traditional 3+3 design and safety profile. Primary objectives were to evaluate the safety and tolerability, to estimate the maximum tolerable dose, and to identify the RP2D of the combination. Results: A total of 32 patients enrolled were evaluated for safety analysis; 19 were enrolled in 4 cohorts in the dose-escalation stage and 13 NRASm melanoma patients were enrolled in the indication-specific expansion stage (cut-off date: 2020-7-24). There were 3 DLTs (G3 colitis, G3 diarrhoea, G3 nausea) in 2 patients at the starting dose of belvarafenib 200mg BID continuously and cobimetinib 40mg QD 21/7 schedule. Belvarafenib dose was escalated to 300mg BID with cobimetinib 20mg QD, which did not result in DLTs. The most common treatment-emergent adverse events that occurred in ≥30% of 32 patients were dermatitis acneiform, diarrhoea, constipation, and increase in blood creatine phosphokinase. Two combination doses were explored in the indication-specific expansion stage. Out of the 9 indication-specific expansion cohorts, NRASm melanoma patients exhibited promising efficacy signal; 5 patients reached partial responses (PRs) out of 13, giving a response rate of 38.5%. Among them, 11 had been previously treated with checkpoint inhibitors (CPIs), including 5 (45.5%) who achieved PR. The median PFS was 7.3 months and 5 patients remained on the treatment at the cut-off date. Conclusions: Belvarafenib in combination with cobimetinib showed acceptable tolerability and encouraging efficacy in NRASm melanoma, and in those with prior CPI treatment. Further research is ongoing in other cohorts (Clinicaltrial.gov, NCT03284502) and in NRASm melanoma (reference GO42273 by clinicaltrials.gov ID number). *S.J.S and J.L contributed equally to this work. Clinical trial information: NCT03284502.

Every three weekly irinotecan for refractory/relapsed small cell lung cancer.

e20584 Background: Current NCCN guidelines support weekly irinotecan regimen for refractory/relapsed SCLC (small cell lung cancer). Despite prior studies that used irinotecan for other solid malignancies included both weekly and three weekly regimens, NCCN do not acknowledge three weekly regimen for SCLC due to insufficient data, especially from United States patient population. We aimed to study clinical efficacy, side effect profile and cost analysis of three weekly irinotecan regimens for refractory/relapsed SCLC. Methods: Retrospective analysis of relapsed/refractory SCLC or high-grade neuroendocrine carcinoma (HGNEC) patients treated with every 3 weekly irinotecan (300 mg/m2) regimen between 2010 and 2020 at NCI-designated Markey Cancer Center/University of Kentucky healthcare was performed. Median PFS and adverse events per CTCAE 5.0 were determined. Results: A total of thirty-eight patients were included in our analysis, 32 with SCLC and 6 with HGNEC. Of 6 patients with HGNEC, primary site included bladder (n=1), prostate(n=1), gastroesophageal junction(n=1) and unknown primary (n=3). Mean age at diagnosis was 58 years. Mean prior line of therapies were 1.8 (range=1 to 4) and mean number of irinotecan cycles were 3.5 (range=1 to 12). Median progression free survival was 2.1 months (95% CI-1.6 to 8.1). Grade (G) 2, 3 and 4 adverse events were noted among 20.5%, 33.3% and 7.8% respectively. G3 and G4 neutropenia was seen in 2.6% and 5.3%; neutropenic fever was noted among 5.3%; G2 and G3 diarrhea among 7.9% and 15.8%; ileus among 5.3%; enterocolitis among 2.6%; G2 and G3 nausea and vomiting among 7.9% and 10.5%; G3 transaminitis among 2.6%; G3 and G4 acute kidney injury was seen among 5.1% and 2.6% respectively. Estimated overall costs (including infusion related expenses, cost of pre-medications and irinotecan) to deliver three 100mg/m2 doses with every weekly regimen was $661 compared to only $268 for a single 300mg/m2 dose with every three-weekly regimen. Conclusions: In previously treated patients with refractory/relapsed SCLC, every three weekly irinotecan regimen was found to have comparable efficacy and adverse event profile. Diarrhea, nausea, vomiting and neutropenia are the most common adverse events reported. Moreover, cost effectiveness of every 3 weekly regimen and reduced number of infusions should potentially benefit patients who live far from health care facility as is the case in rural Appalachia and also help reduce financial toxicity.

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

A phase Ib/II study of selinexor in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial.

11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.

Derazantinib (DZB) in combination with atezolizumab (AZB) in patients with solid tumors: Results from the dose-finding phase Ib substudy of FIDES-02.

437 Background: DZB is an oral small-molecule FGFR1/2/3 kinase inhibitor, which demonstrated antitumor activity in preclinical and clinical studies (in cholangiocarcinoma patients [pts] with FGFR2-driven tumors and in FGFR1-3-driven urothelial cancer [UC] PDX models). In CSF1-stimulated mouse bone-marrow derived macrophages, DZB reduced CSF1R phosphorylation with a maximal effect similar to the selective CSF1R inhibitor BLZ945, suggesting DZB could have an effect on tumor-associated macrophage regulation. Thus, DZB+AZB is a rationale combination to be investigated in immunogenic and FGFR-driven tumors like UC. Methods: FIDES-02 is a multi-cohort open-label Phase 1b/2 study evaluating the effect of DZB as monotherapy and DZB+AZB in combination. To determine the RP2D of DZB+AZB, a total of 26 pts with UC (N = 4) and other solid tumors (N = 22), of whom 7 pts carried various FGFR genetic aberrations (GA), were enrolled at 2 dose levels (DL) (1200 mg AZB Q3W + 200 mg [DL1] / 300 mg [DL2] DZB QD) and treated until disease progression or unacceptable toxicity. Both DLs were divided into MTD (endpoint: dose-limiting toxicity [DLT] at D21) and expansion cohorts to investigate both acute and delayed adverse events (AEs) per CTCAE v5. Results: In the MTD cohorts of both DL1 (N = 7) and DL2 (N = 6) no DLTs were observed, and the DL1 and DL2 expansion cohorts subsequently enrolled 7 and 6 pts, respectively. The most frequent treatment-emergent AEs across both DLs were fatigue (31%), nausea (27%), diarrhea (23%), the most frequent laboratory abnormalities were increased ALT (58%), and AST (50%). Non-DLT grade (G) ≥ 3 treatment-related AEs (TRAE) across both DLs were G3 diarrhea (4%), G3 nausea (4%), G3 asthenia (4%), oral fungal infection (4%) and one case of immune-related G4 nephritis (4%). Dose interruptions / reductions and discontinuations due to TRAEs occurred in 19% and 8%, respectively. Pharmacokinetic analyses demonstrated that DZB exposure parameters and AZB serum concentrations in pts treated with DZB+AZB were similar to those assessed in pts under DZB / AZB monotherapy. At data cut-off, 2 of 14 (DL1) and 7 of 12 pts (DL2) were still on treatment. Median duration of treatment in DL1 was 9.7 weeks (range, 9-25), and best overall response per investigator assessment was SD in 4 of 10 efficacy-evaluable DL1 pts. DL2 efficacy analysis was uninformative at cutoff. The combination of 1200 mg AZB Q3W with both 200 mg and 300 mg QD DZB was found to be safe and tolerable. Conclusions: The combination of DZB+AZB is safe at both investigated DLs, the RP2D has been determined as 300 mg DZB QD+1200 mg AZB Q3W. DZB can be safely dosed at its monotherapy RP2D in this novel combination with AZB. The anti-tumor efficacy of DZB+AZB is currently being investigated in adequately designed cohorts of FIDES-02 with enrichment for UC pts with FGFR GA. Clinical trial information: NCT04045613.

A Phase 1 Study Evaluating Safety and Tolerability of Navitoclax Monotherapy in Japanese Patients with Myeloproliferative Neoplasms

A Phase 1 Study Evaluating Safety and Tolerability of Navitoclax Monotherapy in Japanese Patients with Myeloproliferative Neoplasms

Adjuvant chemotherapy in average-risk adult medulloblastoma patients improves survival: a long term study

BackgroundMedulloblastoma is extremely rare in adults. The role of chemotherapy for average-risk adult patients remains controversial. Surgery and radiotherapy provide a significant disease control and a good prognosis, but about 25% of average-risk patients have a relapse and die because of disease progression. No data in average-risk adult patients are available to compareradiotherapy alone and radiotherapyfollowed byadjuvant chemotherapy.MethodsWe analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016.ResultsMedian age was 29 years (range 16–61). Based on histological subtypes, 15 patients (31.3%) had classic, 15 patients (31.3%) had desmoplastic, 5 patients (10.4%) had extensive nodularity and 2 patients (4.2%) had large cells/anaplastic medulloblastoma. Twenty-four patients (50%) received adjuvant radiotherapy alone and 24 (50%) received radiotherapy and chemotherapy. After a median follow-up of 12.5 years, we found that chemotherapyincreases progression-free survival (PFS-15 82.3 ± 8.0% in patients treated with radiotherapy and chemotherapyvs. 38.5% ± 13.0% in patients treated with radiotherapy alone p = 0.05) and overall survival (OS-15 89.3% ± 7.2% vs. 52.0% ± 13.1%, p = 0.02). Among patients receiving chemotherapy, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia (6 cases of G3 neutropenia [25%] and 3 cases of G4 neutropenia [13%]), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%).ConclusionsOur study with a long follow up period suggests that adding adjuvant chemotherapy to radiotherapy might improve PFS and OS in average-risk adult medulloblastoma patients.

The Result of a Phase 1 Study of Selinexor in Combination with High-Dose Melphalan and Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: High-dose melphalan and autologous hematopoietic cell transplantation (HCT) remains a crucial treatment modality for patients with multiple myeloma (MM). Strategies to improve the conditioning regimen have been explored with addition of novel targeted therapies previously with limited success. Selinexor, an orally available selective inhibitor of nuclear export (SINE), targeting Exportin-1 (XPO-1), was recently approved by the Food and Drug Administration (FDA) for relapsed/refractory MM. Our pre-clinical data show synergy between selinexor and bifunctional alkylating agents in several MM models. Therefore, we hypothesized that the addition of selinexor to high-dose melaphalan would be safe and improve outcomes of autologous HCT in MM. Methods: We designed a single institution, standard 3+3 dose escalation phase 1 study to evaluate the combination of selinexor (given at 40 mg po (dose level 1); 60 mg (dose level 2); and 80 mg (dose level 3) on days -3 and -2 before melphalan) and high-dose melphalan (100 mg/m2 IV on days -3 and -2) as a conditioning regimen for autologous HCT in patients with MM achieving either partial response (PR) or very good partial response (VGPR) after less than 4 lines of systemic anti-myeloma chemotherapy (NCT02780609). The primary objective was to establish a maximum tolerated dose (MTD) and identify a recommended phase 2 dose (RP2D). Results: From 08/2017 to 03/2019, a total of 12 MM patients (pts) received autologous HCT under the phase 1 protocol at Moffitt Cancer Center. Baseline characteristics included: a median age of 57 (range, 43-69); M:F = 7:5; IgG subtype=9, light chain type=2, IgD subtype=1; 92% with Durie-Salmon stage 3; 22% with high-risk disease based on del17p/t(4;14) (2/9, n=3 with unknown risk); a median number of induction=1 (range, 1-2); all received bortezomib-based induction, 83% received immunomodulatory agent, 17% received daratumumab. Pre-HCT responses were PR=4; VGPR=8. Pts received a median of 4.16 (range, 2.16-5.73) million CD34+ cells/kg. Neutrophil engraftment occurred with a median of 11 (range 11-12) days, and a platelet engraftment with a median of 15 (range, 10-36) days. Three pts each entered in dose level 1 and 2; and 6 pts at dose level 3. One pt in dose level 2 did not receive dexamethasone on day -1 due to grade (G) 3 hyperglycemia. One pt in dose level 3 (80 mg selinexor) did not receive day -2 dose of selinexor due to liver function test (LFT) abnormality (ALT > 2x ULN) which was considered as dose-limiting toxicity (DLT) as second dose of selinexor was not given. LFTs normalized after HCT. Dose level 3 was expanded to 3 additional pts and no additional DLTs were observed. Treatment-related serious adverse events (SAEs) included: G3 febrile neutropenia=3, G3 diarrhea=1, G3 nausea=1, G3 small bowel obstruction=1, G3 acute kidney injury=1, G3 lung infection=1. Post-HCT responses at day +90 were complete response (CR)=2, VGPR=6, PR=3, and progression=1. CR conversion rate was 16.7% though phase 1 portion of the study was not powered to evaluate the CR rate. Therefore, RP2D was established as selinexor 80 mg on days -3 and -2. The study is proceeding to the phase 2 portion to assess the efficacy of this combination. Conclusions: The combination with selinexor 80 mg po with high-dose melphalan at 100 mg/m2 on days -3 and -2 (dose level 3) was well tolerated and engraftment kinetics were not altered. A phase 2 study of selinexor 80 mg with high-dose melphalan and autologous HCT is ongoing (NCT02780609). Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Alsina:Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding; Janssen: Speakers Bureau. Baz:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding. Shain:Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Brayer:Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Sullivan:Karyopharm: Research Funding. OffLabel Disclosure: Selinexor in combination with high-dose melphalan

Impact of age and sex on chemotherapy (CTx) efficacy, toxicity and survival in early oesophagogastric (OG) cancer: A pooled analysis of 3265 patients from four large randomised trials (OE02, OE05, MAGIC & ST03).

4022 Background: No large scale randomised data exists evaluating the impact of age and sex in patients (pts) undergoing potentially curative surgery and CTx for OG cancer. However, differences in age and sex may be contributing factors to variability in CTx dose-response and toxicity which could also impact survival. Methods: Data from four prospective randomised controlled trials were pooled using a two-stage meta-analysis. For survival data, hazard ratios were calculated for pts <70 and ≥70 years and between males and females. Pts were allocated to receive neoadjuvant platinum and fluoropyrimidine +/- anthracycline and bevacizumab. Mandard tumour regression grade (TRG) and prevalence of ≥G3 toxicities were compared according to the same subgroups using Chi-squared test. Results: 3265 pts were included for survival analysis (2668 (82%) M, 597 (18%) F; 2626 (80%) <70, 639 (20%) ≥70). A significant improvement in disease specific survival (DSS) (HR 0.78; p<0.001) and OS (HR 0.78; p<0.001) was observed in females vs males. Although OS was worse in older vs younger pts (HR 1.15; p=0.01) no significant difference in DSS was observed (HR 1.04; p=0.52). For those pts who underwent resection following neoadjuvant CTx, older patients (19 vs 13%; p=0.01) and female patients (19% vs 13%, p=0.02) were more likely to achieve more favourable Mandard TRG 1&2 scores. Older pts experienced significantly more ≥G3 neutropaenia (30 vs 22%; p=0.004). Females experienced significantly more ≥G3 nausea (12 vs 7%; p=0.006), vomiting (10 vs 5%; p≤0.001) and diarrhoea (9 vs 4%; p=0.001). Conclusions: This study represents the largest pooled analysis of age and sex differences on safety of neoadjuvant CTx and survival in early OG cancer. Females had significantly improved survival while experiencing more GI toxicities. Older pts achieved comparable DSS and thus, dependent on fitness, should be offered the same treatment paradigm as younger pts.

S1206: A dose-finding study followed by a phase II randomized placebo-controlled trial of chemoradiotherapy (CRT) with or without veliparib in stage III non-small cell lung cancer (NSCLC).

8523 Background: Veliparib (V), a PARP inhibitor, may potentiate the antitumor effect of CRT in NSCLC. Methods: Eligibility included newly diagnosed unresectable stage III NSCLC. Patients were randomized to receive concurrent CRT with weekly carboplatin (AUC 2) and paclitaxel (45 mg/m2) with V at 120 mg or placebo (P) twice daily during CRT followed by 2 cycles (every 21 days) of consolidation carboplatin (AUC 6), paclitaxel (200 mg/m2) with V at 80 mg or P (per randomized arm) orally on days 1-7 of each cycle. Progression-free survival (PFS) was the primary endpoint. The accrual goal was 132 patients. Results: The dose-finding study results were previously presented (ASCO 2016;A8537). V 120 mg twice daily was the recommended phase II dose. A total of 31 eligible and evaluable patients were enrolled in the phase II randomized trial: 17 on V and 13 on P (1 patient in the V arm withdrew prior to starting any treatment, thus was not evaluable). The study was closed to accrual early due to the positive results from the PACIFIC trial that changed standard practice. Median follow-up among alive patients was 16 months. During CRT, the following grade (G) 3-4 adverse events (AE) were seen with V vs P: any G3 AE (6 vs 6), any G4 AE (2 vs 3), G3 pneumonitis (0 vs 1), G3 esophagitis (1 vs 1), G3 oral mucositis (1 vs 0), G3 anorexia (1 vs 1), G3 hyponatremia (0 vs 3), G3 anemia (1 vs 0), G3 neutropenia (3 vs 1), G3 thrombocytopenia (1 vs 0), G4 hypoglycemia (0 vs 1). Also, 2 patients per arm had G4 lymphopenia. During consolidation (11 evaluable patients with V; 10 with P), G3 anemia (1 vs 0), G3 anorexia (1 vs 0), G3 weight loss (0 vs 1), G3 dehydration (1 vs 0), G3 dysphagia (2 vs 0), G3 fatigue (1 vs 0), G3 hypomagnesemia (0 vs 1), G3 nausea (1 vs 0), G4 hyperglycemia (0 vs 1), G3-4 neutropenia (3 vs 0), G3 thrombocytopenia (1 vs 0), G3-4 lymphopenia (2 vs 1); a G5 pneumonitis occurred in the P arm. Response rates were 56% (95% CI, 31-78%) and 69% (95% CI, 38-91%) on the V and P arms, respectively. PFS at 1 year was 47% (95% CI, 23% - 68%) with V and 46% (95% CI, 19% - 70%) with P. Overall survival (OS) at 1 year was 89% (95% CI, 61%-97%) with V and 54% (95% CI, 25%-76%) with P. Adding the 6 patients treated at 120 mg in the phase I part, 1-year with V was 91% (95% CI, 69%-98%). Conclusions: V in combination with CRT was tolerable with expected toxicities that relate to the backbone regimen. In the small number of randomized patients there was a suggestion of promising survival with V that may provide rationale for future trials of PARP inhibitors with CRT. Clinical trial information: NCT01386385.

Adjuvant chemotherapy to improve survival in average-risk adult medulloblastoma patients: Long-term results.

2037 Background: Medulloblastoma is extremely rare in adults and, therefore, it is difficult to accrual patients in clinical trials. Radical surgery and radiotherapy (RT) provide a significant control of disease. Nevertheless, about 25% of average-risk patients have a relapse and die because of disease progression. The role of chemotherapy (CT) after standard RT for average-risk adult patients remains controversial. Methods: We analyzed 48 average-risk patients according to Chang classification diagnosed from 1988 to 2016. Median age was 29 years (range 16-61), M/F ratio was 26 (54.2%)/22 (45.8%). Fifteen patients had classic medulloblastoma (31.3%), 15 patients had desmoplastic medulloblastoma (31.3%), 5 patients had extensive nodularity (10.4%) and 2 patients had large cells/anaplastic histology (4.2%). The patients were homogeneously distributed in the two groups: 24 (50%) received adjuvant RT alone and 24 (50%) received RT + CT that consisted in a platinum-etoposide based combination. Results: After a median follow-up of 12.5 years, CT increases progression-free survival rate at 15 years (PFS-15 82.3 ± 8.0% in RT-CT group vs. 38.5% ± 13.0% in RT group p = 0.05) and overall survival rate at 15 years (OS-15 89.3% 7.2% vs. 52.0% 13.1%, p = 0.02). Among patients receiving CT, the reported grade ≥ 3 adverse events were: 9 cases of neutropenia; 6 cases of G3 neutropenia (25%) and 3 cases of G4 neutropenia (13%), 1 case of G3 thrombocytopenia (4%) and 2 cases of G3 nausea (8%). Conclusions: Our study with a long follow up period suggests that adding adjuvant chemotherapy to RT might improve PFS and OS in average-risk adult medulloblastoma patients.

Abstract P6-18-30: Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC)

Abstract Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with > G 3 diarrhea in > 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented. Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-30.

Volumetric modulated arc therapy (VMAT) in the treatment of esophageal cancer patients.

The aim of the study is to evaluate feasibility, safety, toxicity profile, and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients. A total of 68 patients were treated with VMAT between March 2014 and March 2018 (44% vs 56% for definitive and neoadjuvant settings, respectively). Dose prescription differed depending on the clinical scenario (54-60Gy in 30 fractions for definitive treatments; 41.4/45Gy in 23-25 fractions in the pre-operative setting). Most of the patients were given concurrent chemotherapy. Two coplanar and one non-coplanar arcs were employed for VMAT delivery. Treatment was generally well tolerated. Acute toxicity was generally mild. In patients treated with definitive intent, ≥ G3 toxicities were observed for esophagitis (30%), anorexia (26.7%), fatigue (26.7%), nausea (6.7%), and vomiting (3.3%). In patients treated within a neoadjuvant approach, ≥ G3 anorexia (21%), esophagitis (15.8%), fatigue (13.3%), nausea (5.3%), and vomiting (2.6%) were observed. Dosimetric results were consistent in term of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe, and effective strategy to deliver definitive or pre-operative radiation in locally advanced esophageal cancer patients.

Hyperfractionated abdominal reirradiation for gastrointestinal malignancies

BackgroundWe sought to determine the role of abdominal reirradiation for patients presenting with recurrent or new primary gastrointestinal (GI) malignancies. At our institution, we have established a hyperfractionated, accelerated reirradiation regimen consisting of 39 Gray (Gy) in 26 twice-daily fractions. Although this regimen is used frequently in the pelvis, we sought to determine its toxicity and efficacy for abdominal tumors.MethodsTwenty-four patients who received abdominal reirradiation with a hyperfractionated, accelerated approach from 2000 to 2017 were identified. Overall survival (OS) and local progression-free survival (LPFS) were calculated using the Kaplan-Meier method. Several patient, tumor and treatment characteristics were evaluated on univariate analyses for association with OS and LPFS using a Cox proportional hazards model.ResultsOf the twenty-four patients identified, the majority (n = 11, 46%) had pancreatic adenocarcinoma as their primary disease but also included upper GI adenocarcinoma (n = 4), colon adenocarcinoma (n = 3), hepatobiliary cancers (n = 4) and other malignancies (n = 2). The majority of patients received 45–50.4Gy in 1.8Gy fractions as their initial abdominal radiation course. The median reirradiation dose was 39Gy in 26 twice-daily fractions with a minimum six hour interval. The median [interquartile range (IQR)] interval between the courses of radiotherapy was 28 [18.6–38.9] months. Only palliative reirradiation intent was associated with decreased OS. While colon adenocarcinoma primary was significantly associated with increased LPFS, the sample size was small (n = 3). The 1-yr rate of LPFS was 38%. The median [IQR] duration of freedom from local progression was 8 [3.8–19.2] months. The 1-year OS was 50% and the median (IQR) OS was 14 [6.3–19.6] months. Thirteen patients (54%) had acute side effects with one patient experiencing G3 nausea and one experiencing a G4 bleed; the remaining patients experienced G1-G2 symptoms.ConclusionHyperfractionated, accelerated reirradiation to the abdomen was relatively well-tolerated but provided limited local control to recurrent or second primary abdominal malignancies. Reirradiation could play a role in treating these patients with palliative or curative intent, but alternative strategies for delivering increased biologically effective dose should be further explored.