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Purpose:Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs.Patients and Methods:CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease).Results:Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events.Conclusions:Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

Purpose: Combination immunotherapy with anti–CTLA-4 and anti–PD-1 blockade has demonstrated significant clinical activity across several tumor types. Neuroendocrine tumors (NET) are a heterogeneous group of rare tumors with limited treatment options. CA209-538 is a clinical trial of combination immunotherapy with ipilimumab and nivolumab in rare cancers, including advanced NETs. Patients and Methods: CA209-538 is a prospective multicenter clinical trial in patients with advanced rare cancers. Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every three weeks for four doses, followed by nivolumab 3 mg/kg every two weeks and continued for up to 96 weeks, until disease progression or the development of unacceptable toxicity. Response was assessed every 12 weeks by RECIST 1.1. The primary endpoint was clinical benefit rate (CBR; complete remission + partial remission + stable disease). Results: Twenty-nine patients with advanced NETs received treatment. Three (10%) patients had low-, 13 (45%) had intermediate-, and 13 (45%) had high-grade tumors; lung was the most common primary site (39%). The objective response rate was 24% with a CBR of 72%; 43% of patients with pancreatic neuroendocrine neoplasms (NEN), and 33% of patients with atypical bronchial carcinoid achieved an objective response. The median progression-free survival was 4.8 months [95% confidence interval (CI): 2.7–10.5] and overall survival was 14.8 months (95% CI: 4.1–21.3). Immune-related toxicity was reported in 66% of patients with 34% experiencing grade 3/4 events. Conclusions: Combination immunotherapy with ipilimumab and nivolumab demonstrated significant clinical activity in subgroups of patients with advanced NETs including patients with atypical bronchial carcinoid and high-grade pancreatic NENs.

TPS7587 Background: Follicular lymphoma (FL) is the commonest indolent lymphoma, comprising 20% of non-Hodgkin Lymphoma, with approximately 80% of patients (pts) requiring therapy. At present, advanced stage is incurable; most pts require >1 treatment. Overall response rates (ORR) to standard chemoimmunotherapy (bendamustine or CHOP with rituximab or obinutuzumab) approximate 85% with considerable toxicity (grade 3-5 in 69-75%) (Hiddemann 2018). With the FL population predominantly >65 years, 10-year median survival and need for further therapy, efficacious treatments with low toxicity are desirable. PD1/PDL1 axis inhibitors are active in FL. A phase I study of obinutuzumab (O) + atezolizumab (A) induced 57% ORR in pts with rituximab-refractory FL (Palomba 2017). Our phase II ‘1st FLOR’ study, combining nivolumab + rituximab in treatment naïve FL yielded 92% ORR, (54% Complete Response, CR). Toxicity profiles compared favourably with conventional chemotherapy: 41% grade 3-5 events (Hawkes 2021). FL is sensitive to low dose radiotherapy (RT), with abscopal effects reported, and potential to improve treatment efficacy with minimal additional toxicity when combined with PD1/PDL1 inhibitors (Sharabi 2015). This investigator initiated, multicentre single-arm phase II PET-adapted trial aims to assess the response of O + A +/- RT for treatment-naïve FL, reducing treatment-related toxicity using a chemotherapy-free, multi-modality, synergistic regimen. Methods: Eligible pts are >18 years, ECOG 0-2 with untreated, biopsy proven, grade 1-3A stage II-IV FL. Exclusions are significant compressive symptoms, autoimmune disease, pneumonitis and treatment urgency. All pts receive 6 cycles (q21 days) of O 1000mg + A 1200mg (plus O given on days 8 & 15 of cycle 1). Interim PET-CT is performed post cycle 2. Pts with less than CR will undergo RT (4Gy) to residual disease after cycle 3. At end of induction, responding patients will receive maintenance O (up to 12 cycles, 1000mg Q8W). Pts with significant progression will be taken off study. Total follow-up is 2 years post treatment. Primary endpoint is CR rate following 6 x O&A +/- RT. Secondary endpoints include ORR, PFS, OS and adverse events. PET centres are ARTnet accredited with central analysis. An extensive exploratory biomarker substudy is planned. Sample size is 46 according to a Simon’s 2-stage design. If ≥5 positive responses (CR +/- PR) without prohibitive toxicity are seen in the first 15 pts, 31 further pts will be recruited.The trial has currently enrolled 7 pts from 4 Australian sites. Clinical trial information: NCT04962126.

This study compared basketball training and match demands between player roles (starters, in-rotation bench players, out-rotation bench players) and between competition levels (semi-professional, professional). Thirty-seven players from one professional women’s team, one semi-professional women’s team, and one semi-professional men’s team wore accelerometers during training and matches throughout a competitive season. All teams were used for player role comparisons and the women’s teams were used to compare competition levels. Match and training session average intensity and volume, and durations of relative exercise intensities (inactive, light, moderate-vigorous, maximal, supramaximal) were calculated. Compared to out-rotation bench players, starters experienced twice the average match intensity and volume, spent 50% less match time being inactive, and spent 1.7–4.2× more match time in all other activity categories (p &lt, 0.01). Compared to in-rotation bench players, starters experienced 1.2× greater average match intensity and volume, spent 17% less match time being inactive, and spent 1.4–1.5× more match time performing moderate-vigorous and maximal activity (p &lt, 0.01). No differences in match demands were found between women’s competition levels, however the professional team experienced double the cumulative weekly training volume of the semi-professional team and spent 1.6–2.1× more cumulative weekly time in all activity categories (p &lt, 0.01). To improve performance and reduce injury risk, players should prepare for the greatest match demands they could encounter during a season while considering potential changes to their role. Additionally, players might need their training volume managed when transitioning from a semi-professional to a professional season to reduce the injury risk from sharp increases in training demands.

Background: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. Methods: CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). Results: Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. Conclusions: This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.

Importance Biliary tract cancers represent a rare group of malignant conditions with very limited treatment options. Patients with advanced disease have a poor outcome with current therapies. Objective To evaluate the efficacy and safety of combination immunotherapy with nivolumab and ipilimumab in patients with advanced biliary tract cancers. Design, Setting, and Participants The CA209-538 prospective multicenter phase 2 nonrandomized clinical trial included patients with advanced rare cancers including patients with biliary tract cancers. This subgroup analysis evaluated 39 patients from CA209-538 with biliary tract cancers who were enrolled from December 2017 to December 2019. Most of the patients (n = 33) had experienced disease progression after 1 or more lines of therapy and had tumor tissue available for biomarker research. Interventions Patients received treatment with nivolumab at a dose of 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg every 2 weeks and continued for up to 96 weeks until disease progression or the development of unacceptable toxic events. Main Outcomes and Measures The primary end point was disease control rate (complete remission, partial remission, or stable disease) as assessed by RECIST 1.1. Results Among the 39 patients included in this subgroup analysis of a phase 2 clinical trial (20 men, 19 women; mean [range] age, 65 [37-81] years), the objective response rate was 23% (n = 9) with a disease control rate of 44% (n = 17); all responders had received prior chemotherapy, and none had a microsatellite unstable tumor. Responses were exclusively observed in patients with intrahepatic cholangiocarcinoma and gallbladder carcinoma. The median duration of response was not reached (range, 2.5 to ≥23 months). The median progression-free survival was 2.9 months (95% CI, 2.2-4.6 months), and overall survival was 5.7 months (95% CI, 2.7-11.9 months). Immune-related toxic events were reported in 49% of patients (n = 19), with 15% (n = 6) experiencing grade 3 or 4 events. Conclusions and Relevance This subgroup analysis of a phase 2 clinical trial found that combination immunotherapy with nivolumab and ipilimumab was associated with substantial positive outcomes patients with advanced biliary tract cancers. This treatment compares favorably to single-agent anti–programmed cell death protein 1 (anti–PD-1) therapy and warrants further investigation. Ongoing translational research is focused on identifying biomarkers that can predict treatment response. Trial Registration ClinicalTrials.gov Identifier:NCT02923934

BackgroundPatients with rare cancers represent 55% of all gynecological malignancies and have poor survival outcomes due to limited treatment options. Combination immunotherapy with the anti-programmed cell death protein 1 (anti-PD-1) antibody nivolumab and the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab has demonstrated significant clinical efficacy across a range of common malignancies, justifying evaluation of this combination in rare gynecological cancers.MethodsThis multicenter phase II study enrolled 43 patients with advanced rare gynecological cancers. Patients received induction treatment with nivolumab and ipilimumab at a dose of 3 mg/kg and 1 mg/kg, respectively, every 3 weeks for four doses. Treatment was continued with nivolumab monotherapy at 3 mg/kg every 2 weeks until disease progression or a maximum of 2 years. The primary endpoint was the proportion of patients with disease control at week 12 (complete response, partial response or stable disease (SD) by Response Evaluation Criteria In Solid Tumor V.1.1). Exploratory evaluations correlated clinical outcomes with tumor programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB).ResultsThe objective response rate in the radiologically evaluable population was 36% (12/33 patients) and in the intention-to-treat population was 28% (12/43 patients), with additional 7 patients obtaining SD leading to a disease control rate of 58% and 44%, respectively. Durable responses were seen across a range of tumor histologies. Thirty-one (72%) patients experienced an immune-related adverse event (irAE) with a grade 3/4 irAE observed in seven (16%) patients. Response rate was higher among those patients with baseline PD-L1 expression (≥1% on tumor cells) but was independent of TMB.ConclusionsIpilimumab and nivolumab combination treatment has significant clinical activity with a favorable safety profile across a range of advanced rare gynecological malignancies and warrants further investigation in these tumor types.

Overview Glioblastoma multiforme (GBM) is the most frequent and lethal primary brain neoplasm, with only 10% of patients surviving 5 years.1 EphA3 is a tumor restricted antigen expressed in various solid tumors and the tumor vasculature of 100% of GBM.2,3 Ifabotuzumab is a non-fucosylated IgG1κ humaneered antibody targeting the EphA3 receptor.4 A Phase I study of ifabotuzumab in haematological malignancies showed it was well tolerated and clinically active.5 Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent GBM. Study Design The primary objective is to determine the safety and recommended Phase II dose of ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr- ifabotuzumab, the frequency of EphA3 positive GBM and response rates. On day 1, eligible pts with measurable tumors received a trace (5mg) dose of zirconium labelled ifabotuzumab (89Zr-ifab) followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and quantitative tumor uptake. Safety assessments and PK sampling were also undertaken. On day 8, pts commenced weekly ifabotuzumab infusions over 2 hours in one of two cohorts (3.5mg/kg, 5.25 mg/kg). On day 36, pts received both 89Zr-ifab and ifabotuzumab, allowing assessment of receptor occupancy. Response rate (RANO) and survival data were collected. Pts then continued on ifabotuzumab until progression. Results In total, 12 pts have been enrolled, including 6 in the 3.5mg/kg and 6 in the 5.25 mg/kg dose cohorts. Mean age was 51.6 years (±14.24) and 7/12 pts were male. Treatment emergent adverse events included infusion reactions in 4 pts, seizures in 3 pts, cerebral oedema in 1, rash in 1, headaches in 8, eye disorder in 1. Most were considered related to study drug except seizure in 2 pts, headaches and eye disorder. Seizures and infusion reactions were readily managed with increased premedications after the first occurrence. The best response was stable disease for 23 weeks. 89Zr-ifab-PET scans showed rapid, tumor-specific targeting at all known tumor sites and in all pts, but with no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect of ifabotuzumab on tumor vasculature. The mean ± SD (n=12) PK parameters for first infusion 89Zr-ifab were T½α= 9.03 ± 4.45 hr, T½β = 92.50 ± 65.65 hr, V1 = 3.75 ± 0.67 L, CL= 132.11 ± 70.16 mL/hr. Conclusions: Ifabotuzumab demonstrates highly sensitive, specific and reproducible targeting of the tumor and tumor microenvironment in all patients in this study. The imaging changes suggest direct modulation of the tumor vasculature. Additional studies are planned to evaluate ifabotuzumab as part of an antibody-drug conjugate in various solid tumor types. References: 1. Stupp R, et al, Lancet Oncology 10:459-66, 2009 2. Day BW, et al. Cancer Cell 23:238-48, 2013 3. Vail ME, et al. Cancer Research 74:4470-81, 2014 4. Tomasevic N, et al. Growth Factors 32:223-35, 2014 5. Swords RT, et al. Leukemia Research 50:123-131, 2016 Citation Format: Hui K. Gan, Lawrence Cher, Po Inglis, Zarnie Lwin, Eddie Lau, Christian Wichmann, Alex McDonald, Ashray Gunjur, Uwe Ackermann, Kirsten Remen, Kate Fluck, Gel Bolarnos, Nancy Guo, Sze Ting Lee, Sylvia Gong, Jodie B. Palmer, Kunthi Pathmaraj, Graeme J. O'Keefe, Fiona E. Scott, Bryan W. Day, Andrew W. Boyd, Paul Thomas, Omar Ahmed, Dale Chappell, Cameron Durrant, Andrew M. Scott. Phase I safety and bioimaging trial of ifabotuzumab in patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT101.

Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. Immune checkpoint inhibition (ICI) with PD/PD1 inhibitors (PD1i) yield high response rates in some lymphomas; though single agent PD1i yields a disappointing ORR of 10% in heavily pre-treated DLBCL, some responses are durable. RT stimulates anti-tumour immunity through several mechanisms and may enhance response to ICI. Concurrent ICI & RT is synergistic in preclinical studies & solid tumours, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumour antigen release and overcome clonal variation between disease sites to further augment the immune response. A dose-response relationship between RT and antigen release has yet to be established. This phase I dose escalation study aims to determine the safety profile of RT in combination with durvalumab, an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL and FL. Study Design and Methods: RaDD (NCT03610061) is a phase I dose escalation study to determine the safety profile of escalating dose and number of sites of RT in combination with durvalumab in relapsed/refractory (RR) DLBCL & FL. Eligible patients (pts) have received ≥ 1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplant (auto-SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic-SCT or chronic steroid use are excluded. RT dose and site escalation proceeds according to a 3+3 design with 6 dose levels (cohorts 1-6). Treatment comprises external beam RT to target site(s) daily for 5 days (Cohorts 1-5); Cohort 6 receives a further 5 daily fractions (max 30Gy). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The dose limiting toxicity period is 28 days from start of RT. The primary endpoint is the toxicity, drug pharmacokinetics, maximum tolerated dose (MTD) and recommended phase two dose (RP2D) of simultaneous RT and durvalumab. Secondary endpoints include response rates, progression-free survival and overall survival. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrolment for determination of the MTD and RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 22 pts are enrolled to date in the main study, with 2 patients enrolled in the PET-substudy. Acknowledgements: Victorian Cancer Agency (grant funding - TRP16006), Astra Zeneca (durvalumab and funding), Celgene (funding), Imaginab (89Zr -Df-IAB22M2C). Citation Format: Kate Manos, Richard Khor, Geoffrey Chong, Jodie Palmer, Michael MacManus, Colm Keane, Andrew M. Scott, Jake Shortt, David Ritchie, Leonid Churilov, Laura Johnston, Tom Witkowski, Allison Barraclough, Sze Ting Lee, Wendi Lin, Rachel Koldej, Eliza Hawkes. Phase I Dose Escalation Study of Radiotherapy and Durvalumab (MEDI4736) in Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL): The RaDD Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT208.

Background Metastatic uveal melanoma is a highly aggressive disease with no standard of care treatment option. A large proportion of patients have liver-only metastatic disease which raises the question if liver-directed therapy can be efficacious in this subpopulation. Aims The study aims to evaluate the safety and efficacy of radiosensitizing chemotherapy in combination with yttrium-90 microspheres in patients with uveal melanoma with liver-only metastases. Methods and results This single arm, open labeled, non-randomized study enrolled 10 patients with liver-only metastatic uveal melanoma between November 2012 and January 2018. Eligible patients received intrahepatic yttrium-90 microspheres followed by intravenous cisplatin (20 mg/m2) for 5 days. Ten patients were enrolled, but nine patients received treatment who were included in the final analysis with a median follow-up of 30 months (range 7 to 44). Five (50%) were female, five (50%) had an elevated lactate dehydrogenase (LDH), and one (10%) had prior anti-PD-1 therapy. The combination was well tolerated with no greater than or equal to grade 3 toxicity observed. The liver objective response rate (ORR) was 33% (3/9), the median progression-free survival (PFS) in the liver was 3 months (95% CI, 3-NA), and the extrahepatic PFS was 3 months (95% CI, 3-NA). Seventy-eight percent (7/9) received an immune checkpoint inhibitor on disease progression, with no responses seen. The median overall survival (OS) was 10 months (95% CI, 7-NA). Conclusion The combination of cisplatin with yttrium-90 microspheres was well tolerated; however, it was associated with intrahepatic disease control of relatively short duration. No responses were seen in patients treated with immune checkpoint inhibitors post radioembolization.

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]

4588 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with first and second line chemotherapy resulting in modest survival benefits. Immunotherapy using single agent anti-PD-1 therapy has also shown low activity with an objective response rate (ORR) of less than 10%. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell carcinoma. To date, no trials in BTC pts with ipi/nivo therapy have been reported. Methods: 39 pts with metastatic BTCs were enrolled into the CA 209-538 clinical trial for rare cancers. Patients received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for 4 doses, followed by nivo 3mg/kg q 2 weekly. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers including PD-L1 expression and tumour mutation burden. Results: 39 pts with BTC were enrolled and 33 pts (85%) had received at least one prior line of systemic treatment (0-2 lines). The ORR was 24% and the CBR 45% with the median duration of response not been reached (range 2-26+months). Responses were observed in 3/14 intrahepatic, 1/10 extrahepatic, 0/2 unspecified cholangiocarcinoma and 5/13 gallbladder ca pts. None of the responding pts had a microsatellite instable tumour. 2 pts with durable partial responses were subsequently rendered surgically free of disease. Median OS and PFS were 6.1 and 3.1 months respectively. 22 (56%) pts experienced an immune –related adverse event (irAE) with grade3/4 irAEs being observed in 8 (20%) pts. Conclusions: Combination immunotherapy with ipi/nivo demonstrates significant clinical activity in a subset of patients with advanced microsatellite stable BTC. The response rate compares favourably to clinical trials investigating single agent anti-PD-1 therapy. Clinical trial information: NCT02923934 .

TPS8075 Background: Most DLBCL & FL responds well to first line treatment, yet relapsed disease outcomes are poor. PD1/PDL1 inhibitors yield high response rates in some lymphomas, but single agent therapy in heavily pre-treated pts are disappointing. RT stimulates anti-tumor immunity through several mechanisms and may enhance response to immune checkpoint inhibition (ICI). Concurrent ICI & RT is synergistic in preclinical studies & solid tumors, improving local & distant (abscopal) response. RT to multiple disease sites may broaden the spectrum of tumor antigen release and overcome clonal variation between disease sites to further augment the immune response. Methods: RaDD (NCT03610061) is a phase I, 3+3 dose escalation study to determine the safety profile of escalating dose & number of sites of RT in combination with Durvalumab (anti-PD-L1 antibody) in RR DLBCL & FL. Eligible pts (i.e. ≥1 prior therapy, ineligible for auto-SCT, no contraindication to PDL1i) receive 5 fractions of external beam RT to target site(s). 5 RT dose & site levels are included (dose range 2.5Gy-20Gy to 1-3 sites). Durvalumab 1500mg IV commences day 2 of RT and continues 4-weekly until confirmed disease progression. The DLT period is 28 days from start of RT. Primary endpoint is the recommended phase two dose (RP2D) of RT in combination with durvalumab. Secondary endpoints include response rates, PFS & OS. Correlative studies will examine the tumour-immune system interaction; an exploratory PET substudy with novel tracers for durvalumab (89Zr-Durvalumab) & CD8+ T cells (89Zr -Df-IAB22M2C) will also be performed. Projected enrollment for determination of maximum tolerated dose (MTD) & RP2D is 6-30 pts pending toxicity. Recruitment will continue to 36 pts for secondary endpoint analysis. 9 pts are enrolled across cohorts 1-3 to date. Clinical trial information: NCT03610061 .

Background: Although ~60% of patients with DLBCL are cured with frontline therapy, outcomes for those with relapsed/refractory disease remain poor. Tumour cells exploit immune checkpoint pathways, including the PD1/PDL1 axis, to evade and inhibit host anti-tumour immune responses. PD1/PDL1 expression and cytogenetic 9p24 alterations in some DLBCL subtypes provide additional rationale for PDL1 inhibition (PD-L1i) in DLBCL. Though single agent PD1i yields a disappointing ORR of 10-30% in heavily pre-treated DLBCL, some responses are durable.1 Radiotherapy (RT) is an established mechanism of stimulating anti-tumour immunity via increased circulating tumour antigen, immunogenic cell death and T-cell recruitment and activation in the tumour microenvironment. Synergy between concomitant immune checkpoint inhibition (ICI) and RT has been demonstrated in preclinical studies2 and solid tumours; a recent study in non-small cell lung cancer demonstrated an ORR of 36% with pembrolizumab + RT compared with 18% with pembrolizumab alone.3 RT hypofractionation appears critical to the abscopal effect when used with ICI,4 and concurrent RT and PD-L1i is more successful than sequential treatment.5 RT to multiple sites may broaden the spectrum of tumour antigen released and overcome clonal variation between disease sites; a dose-response relationship between RT and antigen release has yet to be established. This phase I study aims to determine the safety profile of escalating dose and number of sites of RT in combination with Durvalumab (MEDI4736), an anti-PD-L1 monoclonal antibody, in relapsed/refractory DLBCL, including primary refractory DLBCL and transformed follicular lymphoma. Study Design and Methods: RaDD (NCT03610061) includes eligible pts who have received ≥1 prior line of therapy and are ineligible for or relapsed after autologous stem cell transplantation (SCT). Pts with active autoimmune disease, CNS involvement, prior allogeneic SCT or chronic steroid use are excluded. Treatment comprises external beam RT to target site(s) daily for 5 days (Fig 1). Durvalumab 1500mg IV commences on day 2 of RT and continues 4-weekly until disease progression. Pts can continue until a second radiological progression if clinical benefit is ongoing. The primary endpoint is the toxicity, drug pharmacokinetics, maximum tolerated dose (MTD) and recommended phase two dose (RP2D) of simultaneous RT plus durvalumab. Secondary endpoints are response rates; progression free survival; and overall survival. An exploratory PET substudy will employ novel tracers to characterise the local and systemic immune response via assessment of the biodistribution of durvalumab (with 89Zr-Durvalumab) and CD8+ T cells (with 89Zr -Df-IAB22M2C). Biomarker sample collection is synchronised with PET response assessment. A comprehensive translational substudy will apply high throughput technologies to tissue and sequential blood samples to characterise the tumour-immune system interaction and correlate novel host, tumour and tumour microenvironment factors with treatment responses and toxicity. Findings may inform the RP2D. RT dose and site escalation will proceed according to a 3+3 design with 5 dose levels (cohorts 1-5, Fig 2). The dose limiting toxicity assessment window is the first 28 days. Projected enrolment for determination of MTD and RP2D is 6-30 pts pending toxicity. Recruitment will continue to a total of 36 pts to allow for secondary endpoint analysis. 5 pts have been enrolled to date. Acknowledgements: Victorian Cancer Agency (funding), Astra Zeneca (durvalumab and funding), Celgene (funding), Imaginab (89Zr -Df-IAB22M2C) References: 1. Ansell SM et al. Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation. J Clin Oncol. 2. Deng L et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 3. Theelen W et al. Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer. JAMA oncology. 4. Golden EB et al. An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer. Cancer Immunol Res. 5. Sharabi AB et al. Radiation and checkpoint blockade immunotherapy: radiosensitisation and potential mechanisms of synergy. Lancet Oncology. Disclosures Hawkes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Roche: Research Funding; Takeda: Speakers Bureau; Astra Zeneca: Research Funding; Merck KgA: Research Funding; Mundi pharma: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. Manos:Janssen: Honoraria; Novo Nordisk Pharmaceuticals: Other: Travel. Chong:Merck Serono: Research Funding; Hutchison Medipharma: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bayer: Research Funding; BMS: Research Funding. MacManus:National Health and Medical Research Council Australia: Research Funding. Keane:MSD: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BMS: Research Funding; Roche: Consultancy, Other: Travel Grant. Scott:Cancer Council Victoria: Research Funding; Cancer Australia: Research Funding; Avipep: Consultancy; IBA: Consultancy; Paracrine Therapeutics: Equity Ownership, Patents & Royalties; Life Science Pharmaceuticals: Equity Ownership; NHMRC: Research Funding; Abbvie: Consultancy, Patents & Royalties; Cure Brain Cancer: Research Funding; Medimmune: Consultancy; Humanigen: Patents & Royalties. Shortt:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Astex: Research Funding; Amgen: Research Funding; Gilead: Speakers Bureau; Takeda: Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Lee:Australian Nuclear Science and Technology Organisation: Membership on an entity's Board of Directors or advisory committees. Koldej:NanoString Technologies: Other: Travel grant. OffLabel Disclosure: Durvalumab is an anti-PD-L1 monoclonal antibody.

Glioblastoma (GBM) is the most frequent and lethal primary brain neoplasm. EphA3 is a tumor restricted antigen expressed in 38–40% of GBM and 100% of the tumor vasculature. Ifabotuzumab is a non-fucosylated IgG1κ antibody targeting EphA3 receptor. A Phase 1 study of ifabotuzumab in haematological malignancies was well tolerated and clinically active. Here we report on a Phase I dose escalation and biodistribution study of ifabotuzumab in recurrent glioblastoma. DESIGN The primary objective is to determine the toxicity and recommended phase II dose of Ifabotuzumab in GBM patients (pts). Secondary objectives are to determine the biodistribution and pharmacokinetics (PK) of 89Zr-Ifabotuzumab, the frequency of EphA3 positive GBM and response rates. Eligible pts received a trace (5mg) dose of zirconium-89 labelled ifabotuzumab (89Zr-ifab) on day 1 followed by sequential PET imaging over 1 week to determine its biodistribution, frequency of in situ EphA3 expression and tumor uptake. Safety and PK assessments were undertaken. On Day 8, pts commenced weekly ifabotuzumab infusions until PD. Three cohorts are planned (3.5mg/kg, 5.25 mg/kg, 7.9 mg/kg). On day 36, pts received both 89Zr-ifab and Ifabotuzumab, to assess receptor occupancy. Response rate (RANO) and survival data were collected. RESULTS: To date, 7 of 12 pts have enrolled (6 at 3.5 mg/kg,1 at 5.25 mg/kg; Mean age: 55 years (±12.6), 4 are male). Treatment emergent AEs included infusion reactions, seizures, cerebral oedema, rash, pruritis, headaches, eye disorder. Most were considered related to study drug, seizures and infusion reactions were readily managed with increased premedications after the first occurrence. Best response in cohort 1 is SD for 23 weeks. 89Zr-ifab PET/CT scans showed rapid, specific targeting at all known tumor sites and in all pts, but no normal tissue uptake. MRI scans showed predominant T2/FLAIR changes, occasionally marked, which were consistent with treatment effect on tumor vasculature.

2570 Background: Patients (pts) with rare cancers represent an unmet medical need and have an inferior overall survival compared to patients with more common malignancies. Due to their low frequency, no therapies, including immunotherapies, have systematically been investigated in this population. Ipilimumab (ipi)/Nivolumab (nivo) combination treatment has demonstrated significant clinical activity in pts with advanced melanoma and renal cell carcinoma and response rates with this regimen are higher compared to single agent anti-PD-1 therapy. This phase II study assessed the efficacy and safety of ipi/nivo in rare cancer pts. Methods: 60 pts with advanced rare upper gastrointestinal (GI), neuroendocrine (NE) and gynaecological (GY) malignancies were enrolled in 3 cohorts. Patients received nivo 3mg/kg and ipi 1mg/kg every 3 weeks for four doses, followed by nivo 3mg/kg every 2 weeks. Treatment continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR), CR, PR and SD. Exploratory endpoints include correlation of efficacy with relevant biomarkers including PDL1 status and tumour mutation burden. Results: 42 pts have so far undergone restaging, 11 pts clinically progressed prior to their first restaging scan. 50 pts have received prior therapy (1-5 lines). Objective responses have been observed in a range of different malignancies. Clinical trial information: NCT02923934. Grade 3/4 immune related adverse events were detected in 31% of pts. The results of correlative biomarker studies will be presented at the meeting. Conclusions: Ipi/Nivo combination treatment has efficacy in a wide range of advanced rare malignancies. Immune related toxicity is in keeping with previously reported clinical trials using the same dosing regimen.[Table: see text]

Relaxin was recently implicated as a regulator of breast and prostate cancer progression. We characterized upregulated H2 relaxin gene expression during neuroendocrine differentiation of the human prostate cancer model, LNCaP. To examine the impact of relaxin on host cells associated with prostatic adenocarcinomas, we generated recombinant 6 His-tagged relaxin (RLXH) in a mammalian expression system. This immunoreactive and biologically active relaxin preparation was used to screen a variety of cell types for cAMP responsiveness. Of the cell types screened, none was more responsive to RLXH than the well-characterized monocyte/macrophage cell line THP-1.

High levels of circulating interleukin-6 (IL6), and possibly neuroendocrine (NE) differentiation, correlate with advanced prostate cancer (PCa). IL6 has many overlapping biological effects with the related gp130 cytokines LIF and OSM that can be explained by the shared usage of the signalling receptor, gp130. We set out to determine whether LIF and OSM can substitute for IL6 in PCa, particularly in relation to neuroendocrine differentiation. Expression analysis of the gp130 cytokines and receptors by RT-PCR, Southern blotting and immunohistochemistry showed that they are widely expressed in LNCaP, DU145 and PC3 cells, but not in normal prostate epithelial PZ-HPV-7 cells. IL6, but not LIF or OSM inhibited proliferation, induced NE differentiation and tyrosine phosphorylation of STAT3 in LNCaP cells. The data suggests that IL6 has a unique role in the progression of PCa.

Background Neuroendocrine (NE) differentiation in prostate tumors has been correlated with androgen independent disease and increased risk of death. In vitro, IL-6 initiates NE differentiation utilizing the signal transduction initiated by the interaction with IL-6R alpha and gp130. In this study we analysed the NE differentiation process in vitro and in vivo using the LNCaP androgen dependent cell line via ligand independent induction of NE differentiation. Methods LNCaP cells were transfected with a constitutively active gp130 subunit, gp130act. Cell proliferation rate was determined and clones were examined for neuroendocrine differentiation by morphological change, upregulation of CgA and serotonin and formation of dense core vesicles with LNCaP parental cells as the control. Xenograft formation was examined and compared in immunocompromised mice. Results Gp130act expression promoted significant neuroendocrine differentiation in vitro as determined by a NE like morphology change (increased neurite like extension formation), elevated CgA expression and the formation of dense core vesicles (DCV). These measures concurred with those examined in LNCaP cells following 100 ng/ml IL-6 treatment. Further investigation of the LNCaP gp130act cells in vivo, in immunocompromised androgen intact mice, confirmed that the NE like morphology, as determined by histological and high resolution transmission electron microscopy, was maintained. Conclusions NE differentiation was initiated by the expression of gp130act in a ligand independent manner, highlighting the importance of gp130 in the neuroendocrine differentiation process. Further investigation of upregulated/downregulated gene expression in these cells may provide valuable insight into the NE differentiation process. © 2004 Wiley-Liss, Inc.

Two distinct biochemical signals are delivered by the CD95/Fas death receptor. The molecular basis for the differential mitochondrially independent (type I) and mitochondrially dependent (type II) Fas apoptosis pathways is unknown. By analyzing 24 Fas-sensitive tumor lines, we now demonstrate that expression/activity of the PTEN tumor suppressor strongly correlates with the distinct Fas signals. PTEN loss-of-function and gain-of-function studies demonstrate the ability to interconvert between type I and type II Fas pathways. Importantly, from analyses of Bcl-2 transgenic Pten(+/-) mice, Pten haploinsufficiency converts Fas-induced apoptosis from a Bcl-2-independent to a Bcl-2-sensitive response in primary thymocytes and activated T lymphocytes. We further show that PTEN influences Fas signaling, at least in part, by regulating PEA-15 phosphorylation and activity that, in turn, regulate the ability of Bcl-2 to suppress Fas-induced apoptosis. Thus, PTEN is a key molecular rheostat that determines whether a cell dies by a mitochondrially independent type I versus a mitochondrially dependent type II apoptotic pathway upon Fas stimulation.

BACKGROUND Neuroendocrine (NE) differentiation (NED) in prostate cancer (PCa) is associated with morbidity and death; however, the underlying cause(s) promoting NED in PCa have yet to be determined. In this study, we examined the effect of both diet and micronutrient supplementation on the expression of NE markers using the Lady (12T-10) transgenic model of PCa. Lady (12T-10) transgenic animals develop advanced adenocarcinoma with NE characteristics that exhibits metastases in approximately 80% of cases. In this model a high fat diet has been shown to increase the severity of disease, while the use of micronutrients can inhibit this progression. METHODS In this study we used immunohistochemical analysis to determine expression of the NE markers: chromogranin A (CgA), neuron-specific enolase (NSE), bombesin, parathyroid hormone-related peptide (PTHrP), neurotensin and serotonin in prostates of PCa-bearing Lady (12T-10) mice. RESULTS High fat diet was correlated with significantly elevated expression of CgA and serotonin in prostate tissue of Lady (12T-10) mice. Addition of micronutrients to the control and high fat diet reproducibly elevated PTHrP and bombesin expression and suppressed NSE expression, while prostate tissue from the control diet supplemented with micronutrients exhibited significantly lower numbers of calcitonin- and neurotensin-positive cells. CONCLUSIONS These results highlight the importance of dietary control in management of disease and identify differential changes in NE marker expression, which may be diagnostically viable in monitoring the impact of therapies on disease status. Prostate 68: 345–353, 2008. © 2008 Wiley-Liss, Inc.

The neuroendocrine status of prostatic adenocarcinomas is considered a prognostic indicator for development of aggressive, androgen-independent disease. Neuroendocrine-like cells are thought to function by providing growth and survival signals to surrounding tumor cells, particularly following androgen ablation therapy. To test this hypothesis directly, LNCaP cells were engineered to inducibly express a constitutively activated form of the cyclic AMP–dependent protein kinase A catalytic subunit (caPKA), which was previously found upon transient transfection to be sufficient for acquisition of neuroendocrine-like characteristics and loss of mitotic activity. Clonal cells that inducibly expressed caPKA enhanced the growth of prostate tumor cells in anchorage-dependent and anchorage-independent in vitro assays as well as the growth of prostate tumor xenografts in vivo, with the greatest effects seen under conditions of androgen deprivation. These results suggest that neuroendocrine-like cells of prostatic tumors have the potential to enhance androgen-independent tumor growth in a paracrine manner, thereby contributing to progression of the disease. [Cancer Res 2007;67(8):3663–72]

Elf5 belongs to the ets family of transcription factors and was cloned by homology in the DNA binding domain to the related, epithelial-specific ets factor, Elf3. Elf5 mRNA is expressed highly in normal tissue rich in secretory epithelial cells, including mammary gland, lung, kidney, prostate, salivary gland and stomach. The function of Elf5 and the cell types in which it is expressed remain uncharacterised. The presence of Elf5 mRNA in normal tissues, but absence in cancer tissues, may suggest a role for Elf5 in differentiation and development. We have generated a rabbit antiserum directed against a peptide in the Elf5 DNA-binding domain that is conserved between murine and human sequences. The antiserum specifically detects human and murine Elf5 proteins on western blots and shows specific staining on paraffin-embedded sections obtained from tissues including mammary gland, kidney, salivary gland and stomach. Epithelia from the bladder lining, lung and prostate did not stain for the presence of Elf5, though these organs express Elf5 mRNA. We show for the first time that Elf5 is primarily expressed in epithelial cells and is likely to be an epithelial-specific protein. The antiserum should prove useful in further analysis of the expression and function of Elf5.

Radiation-induced bladder and rectal complications are recognized complications of intracavitary therapy. In clinical studies the correlation between dose calculated and complications seen are inconsistent. The inconsistency is also present when utilizing the reference points recommended by the ICRU. We attempted to illustrate this inconsistency when looking at the bladder or rectum in intracavitary treatments. If reference points are inconsistent with maximum doses (which directly affect morbidity), their application is dubious.