Dose-escalation Trial In Patients Research Articles

Abstract C033: Preliminary pharmacodynamic evaluation of AU-007 in phase 1 dose escalation trial in patients with advanced solid tumors

Abstract AU-007 is a monoclonal antibody currently being evaluated in a Phase 1/2 clinical trial. In conjunction with evaluation of clinical activity, a pharmacodynamic program has been established to assess the biological activity of AU-007 alone or with low dose subcutaneous aldesleukin in patients with advanced solid cancers. AU-007 binds IL-2 on its CD25-binding epitope, thus inhibiting IL-2’s interaction with CD25 in the trimeric IL-2 receptor (IL-2R) but allowing for IL-2’s binding to the dimeric IL-2R. This effectively inhibits the trimeric IL-2R expressing Tregs without impacting dimer expressing memory T cells, NK cells, NKT cells and naïve T cells. We evaluated the effect of AU-007 +/- aldesleukin on peripheral blood cell populations, IFN-gamma, IL-2 and sCD25. Here we report the interim pharmacodynamic data from the ongoing dose escalation portion of the trial. Peripheral blood samples were collected in Cyto-Chex BCT tubes and phenotyped for T cells, NK cells, B cells, and monocytes. A TruCount system was used to obtain absolute cell numbers. In addition, eosinophils were assessed through standard CBC differentials. Serum collections were done to assess circulating markers using the MSD ECL platform. It was observed that, regardless of AU-007 dose with or without aldesleukin, patients had a reduction in the circulating levels of Treg cells (i.e., based on assay validation, a change greater than +/-10% was considered a real change). This is consistent with the mechanism of action of AU-007, by binding IL-2 such that it prevents the interaction with the trimeric IL-2R, Tregs are affected. There was an increase in the CD8+ to Treg ratio consistent with the overall decrease in Tregs. Trends for increases in NK cells and CD8+ T cells were observed in most patients. Eosinophils express the trimeric IL-2R and are known to increase after IL-2 therapy. To date, no drug related increases in eosinophils with AU-007 +/- aldesleukin were observed, and in most cases the levels of circulating eosinophils decreased. IFN-g is a cytokine released after activation of the inflammatory/cytotoxic arm of the immune system. Twelve of the initial 17 patients for whom data are available demonstrated at least a 2-fold or greater increase in the circulating levels of IFN-g, often occurring within 48 hours after dosing. This was observed regardless of dose given. Higher frequency and amounts of IFN-g expression were observed when subcutaneous low dose aldesleukin was also given (dosed 2 – 24h post AU-007 dosing). A dose dependent trend with single-agent AU-007 was observed, leading to more patients with a >2-fold IFN-g. All patients who received low dose aldesleukin had at least 1 timepoint post dose with a >2-fold increase. Overall, AU-007 has demonstrated pharmacodynamic responses consistent with the mechanism of action, with decreases in the regulatory population of cells and increases in inflammatory cells and markers. The initial pharmacodynamic data support continued dose escalation of AU-007 +/- aldesleukin in patients with advanced cancer. Citation Format: Timothy Wyant, Sophia Frentzas, Elizabeth Ahern, Andrew Weickhardt, Andrew Haydon, John Powderly, Drew Rasco, Meredith McKean, Paul De Souza, Jenny Tang, Lori Richards, Aron Knckerbocker, Yanay Ofran, Inbar Amit, James Vasselli. Preliminary pharmacodynamic evaluation of AU-007 in phase 1 dose escalation trial in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C033.

Guadecitabine plus ipilimumab in unresectable melanoma: five-year follow-up and integrated multi-omic analysis in the phase 1b NIBIT-M4 trial

Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.

Phase I study of intraperitoneal irinotecan combined with palliative systemic chemotherapy in patients with colorectal peritoneal metastases.

Patients with colorectal peritoneal metastases who are not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) owing to extensive peritoneal disease have a poor prognosis. It was hypothesized that these patients may benefit from the addition of intraperitoneal irinotecan to standard palliative systemic chemotherapy. This was a classical 3 + 3 phase I dose-escalation trial in patients with colorectal peritoneal metastases who were not eligible for CRS-HIPEC. Intraperitoneal irinotecan was administered every 2 weeks, concomitantly with systemic FOLFOX (5-fluorouracil, folinic acid, oxaliplatin)-bevacizumab. The primary objective was to determine the maximum tolerated dose and dose-limiting toxicities. Secondary objectives were to elucidate the systemic and intraperitoneal pharmacokinetics, safety profile, and efficacy. Eighteen patients were treated. No dose-limiting toxicities were observed with 50 mg (4 patients) and 75 mg (9 patients) intraperitoneal irinotecan. Two dose-limiting toxicities occurred with 100 mg irinotecan among five patients. The maximum tolerated dose of intraperitoneal irinotecan was established to be 75 mg, and it was well tolerated. Intraperitoneal exposure to SN-38 (active metabolite of irinotecan) was high compared with systemic exposure (median intraperitoneal area under the curve (AUC) to systemic AUC ratio 4.6). Thirteen patients had a partial radiological response and five had stable disease. Four patients showed a complete response during post-treatment diagnostic laparoscopy. Five patients underwent salvage resection or CRS-HIPEC. Median overall survival was 23.9 months. Administration of 75 mg intraperitoneal irinotecan concomitantly with systemic FOLFOX-bevacizumab was safe and well tolerated. Intraperitoneal SN-38 exposure was high and prolonged. As oncological outcomes were promising, intraperitoneal administration of irinotecan may be a good alternative to other, more invasive and costly treatment options. A phase II study is currently accruing.

Abstract 837: Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases

Abstract Antibody-drug conjugates (ADCs) exhibit limited efficacy against brain malignancies due to their inability to cross the blood-brain barrier (BBB) and penetrate into solid tumors. In clinical imaging studies C’Dots readily crossed tumor-disrupted BBB and penetrated across/localized in tumors in the brain avoiding healthy brain. CDCs are ultra-small (6-7 nm) nanoparticles with a silica core coated by short polyethylene glycol chains conjugated to up to 80 small payload and targeting moieties, creating highly potent and avid agents. CDCs’ small size mediates rapid renal clearance leading to limited exposure to healthy tissues. ELU001 is a potent anti-FRα CDC with an average of 21 exatecan topoisomerase-1 inhibitor payload molecules and 13 folic acid targeting molecules on its surface. ELU001 is currently in a dose escalation trial in patients with systemic solid tumor indications that have the potential to overexpress FRα. Early signs of activity with a manageable safety profile have been seen across antigen expression levels. ELU001 exhibits in vitro potency in the sub/low nanomolar range against cancer cell lines that express 3+, 2+ or 1+ levels of FRα. In studies performed in immunodeficient mice bearing intracranial NCI-H2228-luc bioluminescent non-small cell lung cancer tumors, ELU001 was observed to penetrate across disrupted BBB and localize in tumors. Microscopic analysis revealed that ELU001 distributed throughout the tumors but not into the healthy brain. Treatment with a single cycle of ELU001 Q3Dx3 in mice bearing either early (Day 7) or late (Day 14) brain tumors was well tolerated and resulted in significant reduction in tumor burden measured by bioluminescence as well as a prolonged survival benefit. Retreatment of these animals resulted in an additional decrease in tumor burden. These results suggest that ELU001 may have promise for the treatment of metastatic brain tumors that are difficult to treat with currently available agents. Citation Format: Gregory P. Adams, Tin Khor, Feng Chen, Kai Ma, Marion Scocca, Aranapakam Venkatesan, Cathy Reddick, Mary Hilgart, Thomas Gardinier, Fei Wu, Melik Turker, Peiming Chen, Vaibhav Patel, Eliel Bayever. Preclinical development of ELU001: A folate receptor alpha (FRα)-targeted C’Dot drug conjugate (CDC) for the treatment of brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 837.

Abstract P5-08-05: Preclinical activity of KB-0742, an oral, highly selective, CDK9 inhibitor, in cell lines and in MYC-high expressing, patient-derived models of multiple breast cancer subtypes

Abstract KB-0742 is an orally available, potent, and selective inhibitor of cyclin-dependent kinase 9 (CDK9). Sensitivity profiling across a panel of 800 adherent and suspension immortalized pan-cancer cell lines using the Broad Institute PRISM platform had previously demonstrated MYC amplification as being a driver of KB-0742 sensitivity. We sought to further determine the activity of KB-0742 in breast cancer cell lines, patient-derived cell and organoid cultures, and patient-derived xenograft (PDX) models. KB-0742 decreased the viability of cell lines derived from primary and metastatic breast cancers, including triple-negative breast cancers (TNBCs). In a panel of 17 breast cancer cell lines, including 2 human epidermal growth factor receptor 2-positive (HER2+), 7 estrogen-receptor positive (ER+), 1 HER2+/ER+ and 7 TNBCs, the effect of KB-0742 on viability was either cytostatic or cytotoxic over the duration of the culture period. KB-0742 was also tested in patient-derived cell lines derived from primary and metastatic tumors including TNBC, and in 2 TNBC MYC-high expressing patient-derived organoid cultures. KB-0742 demonstrated cytostatic and cytotoxic effects on cell growth and superior inhibitory effects on cell growth in the TNBC organoid cultures as compared with paclitaxel and gemcitabine. Since sensitivity to KB-0742 was observed in breast cancer cell lines and patient-derived models, including TNBCs, we evaluated efficacy and target engagement in several MYC-high expressing TNBC PDX animal models. Treatment with KB-0742 using an intermittent dosing schedule (3-days on/4-days off) was well tolerated and resulted in anti-tumor activity comparable to that observed with standard of care chemotherapeutic agents. Tumors collected at 2 and 8 hours post-final dose displayed a decrease in phosphorylated serine residue 2 (pSER2) in the C-terminal domain of RNA polymerase II (RNA pol-II) and decreased MYC protein levels consistent with CDK9 inhibition. These data demonstrate the efficacy of KB-0742 in preclinical models of breast cancer and supports clinical testing in TNBC patients. KB-0742 is currently being evaluated in a phase I dose-escalation trial in patients with relapsed or refractory solid tumors or non-Hodgkin lymphoma (NCT04718675). Citation Format: Douglas C. Saffran, Melinda A.L. Day, Nathalie Rioux, Tom Chen, Christina Lee, Suha Naffar-Abu Amara, David B. Freeman, Tressa Hood, Charles Y. Lin, Pavan Kumar, Jorge DiMartino. Preclinical activity of KB-0742, an oral, highly selective, CDK9 inhibitor, in cell lines and in MYC-high expressing, patient-derived models of multiple breast cancer subtypes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-05.

Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

BackgroundGlioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM.MethodsThis was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment.ResultsFifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone.ConclusionsThis study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection.Trial registrationNCT00977431 (first posted September 15, 2009).

Inhibition of Cyclin Dependent Kinase 8(CDK8): A Novel Approach to Target the Leukemia Initiating Cells (LICs) in T-Cell Acute Lymphoblastic Leukaemia (T-ALL)

Background: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic malignancy characterized by an aberrant proliferation of immature thymocytes affecting preferentially children and adolescents. Approximately 70% of T-ALL cases have activating mutations of the NOTCH1 followed by oncogenic pathways PI3K/Akt, the anti-apoptotic BCL-2 family, and CDKN2A/2B cell cycle regulators 1, 2. Unlike other leukemias such as chronic myeloid leukemia (CML) and Philadelphia-positive ALL, which are kinase-driven malignancies 3, 4, the initiating events in T-ALL cause the ectopic expression of transcription factors that drive leukemogenesis, hence targeted therapies needed to focused on this field. Cyclin Dependent Kinase 8 (CDK8) and its paralog CDK19, restrain activation of super-enhancer-associated tumor suppressors and lineage commitment genes in leukemia. Moreover CDK8 phosphorylates intracellular domain (ICD) and regulates activation and turnover of NOTCH1 5, 6, indicating that targeting CDK8 with specific inhibitors may be considered as a novel therapeutic strategy for T-ALL. RVU120 is a first-in-class, specific and selective inhibitor of CDK8/CDK19, currently in phase Ib dose-escalation trial in patients with relapsed or refractory (R/R) AML and HR-MDS (NCT04021368).Objectives: The goals of these studies were to investigated the effectiveness of RVU120 and other non-related CDK8/19 inhibitors against T-ALL cell lines/PDXs, including GSI-resistant lines. Comprehensive analysis of target inhibition and apoptotic signatures were evaluated. The clinical relevance of RVU120 in LICs was confirmed in Patient derived xenografts (PDXs).Results:T-ALL cell lines and PDXs were treated with RVU120 and other chemically non-related CDK8/19 inhibitors in different concentration for 12-18 days, and the changes in cell number and apoptosis using flow cytometry analysis were determined. High differential efficacy in double-digit nM range has been observed for NOTCH1 PEST domain mutant cell lines including GSI-sensitive HPB-ALL cells and GSI-resistant cells PF-382, KOPT-K1, and MOLT4, where both inhibition of cell proliferation and induction of apoptosis were observed. GI-resistant cell lines SUP-T1, SUP-T11, MOLT16 and JURKAT were considered as moderately sensitive and LOUCY (early T-cell phenotype ALL), and CCRF-CEM devoid those phenotype, were considered as resistant to RVU120. Results form etsblished cell lines were further corroborated in patient-derived xenograft cells (PDX) treated with RVU120. In T-ALL PDX 6522288 (Notch1 HD /PEST mut, TET2 mut, U2AF1 mut, WT1 mut and CUL76- CDKN2A/B mut, PTEN-/-) treatment with RVU120 was followed by a reduction in cell number and induction of apoptosis in phenotypically defined leukemia initiating cells (LICs) CD34+CD7+CD19-, with calculated IC50s value for bulk and LICs as 92.8 nM and 141.8 nM, respectively. The clinical relevance of these findings and impact on LICs are under the evaluation in PDX mice model. Mechanistically, treatment with RVU120 reduced the phosphorylation of STAT5 and STAT1 as well as the level of MYC and anti-apoptotic proteins MCL1, but induced expression of BAX in sensitive cells. Hence, inhibition of CDK8 is a novel approach to target the LICs in T-ALL.Conclusion:Inhibition of CDK8 by RVU120 triggers inhibition of cell proliferation and apoptosis in cell lines and LICs in T-ALL. Further clinical study is warranted to study the efficacy of RVU120 and CDK8 inhibition in T-ALL.Keywords: CDK8, RVU120, apoptosis, T-ALL, LICs in PDX modelReference1 Girardi, T., Vicente, C., Cools, J. & De Keersmaecker, K. Blood129, 1113-1123, doi:10.1182/blood-2016-10-706465 (2017).2 Sanchez-Martin, M. & Ferrando, A. Blood 129, 1124-1133, doi:10.1182/blood-2016-09-692582 (2017).3 Braun, T. P., Eide, C. A. & Druker, B. J. Cancer cell 37, 530-542, doi:10.1016/j.ccell.2020.03.006 (2020).4 Gazeau, N. et al. Leukemia 34, 2230-2233, doi:10.1038/s41375-020-0715-2 (2020).5 Pelish, H. E. et al. Nature526, 273-276, doi:10.1038/nature14904 (2015).6 Fryer, C. J., White, J. B. & Jones, K. A. Molecular cell 16, 509-520, doi:10.1016/j.molcel.2004.10.014 (2004). DisclosuresGolas: Ryvu Therapeutics: Current Employment. Windak: Ryvu Therapeutics: Current Employment. Rzymski: Ryvu Therapeutics: Current Employment, Current equity holder in publicly-traded company. Andreeff: ONO Pharmaceuticals: Research Funding; AstraZeneca: Research Funding; Glycomimetics: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Breast Cancer Research Foundation: Research Funding; Karyopharm: Research Funding; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Amgen: Research Funding; Aptose: Consultancy; Medicxi: Consultancy; Oxford Biomedica UK: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy; Senti-Bio: Consultancy. Borthakur: GSK: Consultancy; Astex: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees.

Donor-Derived CAR T Cells Engineered with Sleeping Beauty in Pediatric and Adult Patients with Acute Lymphoblastic Leukemia Relapsed Post-HSCT

IntroductionAllogeneic Chimeric Antigen Receptor (CAR) T cells engineered with non-viral methods offer a modality to reduce costs and logistical complexity of the viral process and allow lymphodepleted patients to access CAR T cell treatment. We recently proposed the use of Sleeping Beauty (SB) transposon to engineer donor-derived T cells differentiated according to the cytokine-induced killer (CIK) cell protocol (Magnani CF et al. J Clin Invest. 2021). We report here outcomes on B-cell acute lymphoblastic leukemia (B-ALL) patients, relapsing after transplantation, treated with donor-derived anti-CD19 CAR T cells (CARCIK-CD19).MethodsWe conducted an academic, multi-center, phase I/II dose-escalation trial in patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT). The infusion product was manufactured in-house starting from 50 mL of peripheral blood from the HSCT donor by electroporation with GMP-grade plasmids. All patients underwent lymphodepletion with Fludarabine (30 mg/m 2/day x 4 days) and Cyclophosphamide (500 mg/m 2/day x 2 days), before proceeding to CARCIK-CD19 infusion. We used the Bayesian Optimal Interval (BOIN) design to define a four-dose escalation scheme. Primary objectives were to define the Maximum Tolerated Dose (MTD), safety, and feasibility. Secondary objectives included the assessment of complete hematologic response (CR), duration of response (DOR), progression-free (PFS), event-free (EFS), and overall survival (OS). This study was registered at ClinicalTrials.gov, NCT03389035.ResultsFrom January 2018 to June 2021, a total of 32 patients were screened, 26 enrolled (6 children and 20 adults) and 21 infused (4 children and 17 adults). Reasons for not receiving infusion included consent withdrawal (N=1), disease progression not controlled by bridging therapy (N=3), acquisition of myeloid phenotype (N=1). The median number of prior therapies was 4 (range, 1-7) with a median time interval from HSCT to relapse of 9 months. The median BM blasts was 60% (range, 5-100%) at enrollment and 7% (range, 0-96%) post lymphodepletion. Of the 21 patients infused, CARCIK-CD19 were obtained by HLA-identical sibling (n=6, 29%), matched unrelated (n= 7, 33%), and haploidentical donors (n=8, 38%). Three patients (14%) received the first dose level of 1x10 6 CARCIK-CD19 cells/Kg, three (14%) the second of 3x10 6, and three (14%) the third of 7.5x10 6 whereas 12 patients (57%) received the fourth and last planned dose level of 15x10 6 cells/Kg, as no dose limiting toxicity (DLT) was observed. CRS was observed in six patients (three grade I and three grade II) and immune effector cell-associated neurotoxicity in two patients at the highest dose. Although 9 out of 21 had experienced acute or chronic graft-versus-host disease (GvHD) after the previous HSCT, secondary GvHD was never induced by CARCIK-CD19. Complete response was achieved by 13 out of 21 patients (61.9%, 95%CI=38-82%) and by 11 out of 15 patients treated with the 2 highest doses (73.3%, 95%CI=45-92%). Eleven of these responders were MRD-negative. Notably, the type of donor did not influence the achievement of CR 28 days post-infusion. At a median follow up of 21.6 months (range, 1.0-38.4 months), 10 patients (47.6%) are alive in CR (9 in the 2 highest dose levels). Overall, the median OS and EFS were 9.7 and 3.2 months, respectively, with a median DOR of 4.0 months (range, 1.0-23.5 months). Patients in CR at 28-days had a 6-months relapse-free survival of 48.4% (SE=14.9). EFS at 6 months was 26.5% (SE=9.9) and OS was 67.6% (SE=11.1). Among the 13 patients who achieved CR, two children underwent consolidation with a second allo-HSCT in complete remission. Adult patients did not receive any additional anti-leukemic therapies unless a relapse occurred, and four of them remained in remission and alive (+24, +9, +6, and +4 months). Robust CARCIK-CD19 cell expansion was achieved in most patients and CARCIK-CD19 cells were measurable for up to 22 months.ConclusionsSB-engineered CAR T cells induce sustained responses in B-ALL patients relapsed after HSCT irrespective of the donor type and without severe toxicities. DisclosuresLussana: Incyte: Honoraria; Pfizer: Honoraria; Astellas Pharma: Honoraria; Amgen: Honoraria. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Biondi: Incyte: Consultancy, Other: Advisory Board; Bluebird: Other: Advisory Board; Novartis: Honoraria; Amgen: Honoraria; Colmmune: Honoraria.

Abstract CT016: Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors

Abstract Introduction: ZN-c3 is a selective and orally bioavailable small molecule WEE1 inhibitor. WEE1 is a crucial component of the G2/M cell cycle checkpoint preventing cells from entering mitosis to allow repair of DNA damage before cell cycle progression. ZN-c3 has demonstrated significant growth inhibition in vitro in multiple cell lines from various cancer types and antitumor activity in vivo in human xenograft tumor models. Methods: ZN-c3-001 (NCT04158336) is a dose escalation, open-label, multicenter, Phase 1 clinical trial evaluating the safety, tolerability, and efficacy of ZN-c3 in subjects with advanced or metastatic solid tumors, refractory to standard therapy or for whom no standard therapy is available. ZN-c3 dosing was escalated from 25mg to 450mg administered orally QD. The primary objective of this study is to determine the schedule, Maximum Tolerated Dose (MTD), and Recommended Phase 2 Dose (RP2D) of ZN-c3. Subjects underwent imaging every 9 weeks to assess disease response. Here we report early signal of clinical activity of ZN-c3. Results: As of 30Nov2020 there were 39 subjects treated and of those, 30 experienced treatment related adverse events (TRAEs), the most frequently reported TRAEs were nausea, diarrhea, vomiting, and fatigue. Of the 16 subjects with post-baseline tumor assessments, 5 patients had stable disease (SD) and 2 subjects had partial responses (PR), as per RECIST 1.1. One was a 63-yo Caucasian male with Stage IV colorectal cancer with metastases to the liver, lymph nodes, and pleura who achieved a PR with 42% reduction in overall tumor burden. Carcinoembryonic Antigen tumor marker decreased from 327 ng/mL at baseline to less than 50 ng/mL after 3 weeks on treatment. The second subject was a 72-yo Caucasian female with Stage IV ovarian cancer with metastases to the pleura, peritoneum, and retroperitoneum who achieved a PR with a 56% reduction in overall tumor burden. CA-125 dropped from 610 kU/L at baseline to 125 kU/L within 4 weeks after first dose and normalized 3 weeks later. Based on MTD, as determined by the Bayesian Continual Reassessment model, the overall tolerability and toxicity, and the dose dependent pharmacokinetic profile, the recommended RP2D for ZN-c3 is determined to be 300mg, given orally as continuous once daily dosing. Conclusions: ZN-c3 shows early signal of clinical activity in heavily pretreated advanced solid tumor subjects. It appears safe and tolerable as a single agent at the identified RP2D. An expansion cohort will be included in this Phase 1 study to treat additional subjects. In addition, a Phase 2 clinical study is being planned to enroll additional subjects to further evaluate the efficacy of ZN-c3. Ongoing correlative studies will continue to determine specific mechanisms and biomarkers of response to ZN-c3. Citation Format: Anthony Tolcher, Hirva Mamdani, Pavani Chalasani, Funda Meric-Bernstam, Mihaela Gazdoiu, Lukas Makris, Philippe Pultar, Dimitris Voliotis. Clinical activity of single-agent ZN-c3, an oral WEE1 inhibitor, in a phase 1 dose-escalation trial in patients with advanced solid tumors [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 CT016.

Abstract 414: Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX

Abstract Despite availability of new therapies, outcomes for patients with relapsed metastatic breast cancer is poor with moderate median overall survival. High CXCR4 levels correlate with aggressive metastatic phenotypes and poor prognosis in breast cancer (BC). Anti-cancer mechanisms of CXCR4 antagonists include inhibition of angiogenesis and metastasis, activation of immunosurveillance and chemo sensitization. Balixafortide (POL6326) is a potent, selective inhibitor of the chemokine receptor CXCR4 in PhIII for metastatic HER2-negative breast cancer (BC) in combination with tubulin-binding eribulin (NCT03786094). Clinical proof-of-concept in combination with eribulin was demonstrated in a PhI single arm dose-escalation trial in patients with metastatic HER2-negative BC (NCT01837095). The objective response rate for a dose of 5.5mg/kg balixafortide and 1.4mg/m2 eribulin) was 38% (median duration 4.4 months), and the clinical benefit rate was 63% (median duration 8.1 months). Tolerability and safety of eribulin in combination with balixafortide was comparable to that of eribulin monotherapy. Balixafortide was combined with paclitaxel in a humanized BC patient-derived xenograft (PDX) model to explore the efficacy in combination with another tubulin-binding drugs. Human immunophenotyping confirmed successful human CD34+ cell engraftment and expansion of human immune cells prior implantation of an invasive ductal carcinoma (ypT1a ypN1a R0 G3 L1 V1), ER/PR/Her-2 negative tumor. 10mg/kg paclitaxel was given 2x weekly iv. Dosing of balixafortide was 20mg/kg bid sc for 5 days with 2 days break. Total treatment duration was 28 days. Partial remission was achieved in the combination arm balixafortide+paclitaxel (T/C 13%, 87% inhibition of tumor volume vs vehicle control) which was stat. significantly better than paclitaxel monotherapy (T/C 42%). There was no decrease in tolerability in balixafortide combination vs paclitaxel alone. This data suggests combination with balixafortide is more efficacious and equally tolerated to paclitaxel single agent treatment. Citation Format: Daniel Obrecht, Johann Zimmermann. Efficacy of Balixafortide (POL6326) and Paclitaxel alone and in combination in humanized breast cancer PDX [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 414.

Demcizumab combined with paclitaxel for platinum-resistant ovarian, primary peritoneal, and fallopian tube cancer: The SIERRA open-label phase Ib trial

ObjectivesTo evaluate the safety and preliminary efficacy of demcizumab (DLL4 targeted IgG2 humanized monoclonal antibody; potent inhibitor of the Notch pathway) in combination with weekly paclitaxel in platinum-resistant epithelial ovarian cancer (EOC); and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). MethodsWe conducted a 3 + 3 dose-escalation trial in patients with recurrent, platinum-resistant EOC with RECIST v. 1.1 measurable disease and ≤4 prior chemotherapy regimens. Two dosing cohorts (2.5 mg/kg and 5 mg/kg) were targeted; however, an intermediate dose level (3.5 mg/kg) was to be evaluated if the 5 mg/kg dose was not tolerable. Demcizumab was administered on days 1 and 15 and paclitaxel, weekly on days 1, 8, and 15 for each of three 28-day cycles: the 3-cycle doublet could be repeated once if safe. Thereafter, paclitaxel was administered until unacceptable toxicity or disease progression. ResultsNineteen patients were enrolled. No dose-limiting toxicities (DLT) were observed; however, the intermediate dose level (3.5 mg/kg) was enrolled and expanded based on emerging safety data from other trials in the demcizumab program. The MTD was not reached. The most common treatment emergent adverse events (TEAE) were diarrhea (68%), fatigue (58%), peripheral edema (53%), and nausea (53%). Pulmonary hypertension, grade 2 (n = 2) and grade 1 (n = 1), was observed. Overall response rate (ORR) was 21% (95% CI: 6–45%); clinical benefit rate (CBR) was 42% (95% CI: 20–66%). ConclusionsDemcizumab in combination with paclitaxel has a manageable toxicity profile and showed activity in patients with heavily pretreated platinum-resistant ovarian cancer.

IBS23.01 Radiotherapy of OMD in Daily Clinical Practice

IBS23.01 Radiotherapy of OMD in Daily Clinical Practice

Abstract 3965: Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy

Abstract Background: Balixafortide (B) is a highly selective antagonist of the chemokine receptor CXCR4. Clinical proof-of-concept in combination with eribulin (E) was achieved in a recent Phase 1 single arm dose-escalation trial in patients with metastatic HER2-negative breast cancer (NCT01837095). Safety and tolerability of B in combination with E was similar to that of B or E monotherapy. Anti-cancer effects of CXCR4 antagonists include sensitization of tumor cells to chemotherapy, suppression of metastatic spread, inhibition of angiogenesis, and activation of immune cells. Methods: Plasma samples from patients who received initial E monotherapy (1.4 mg/m2, run-in cycle) or combination of B and E (escalating doses of B intravenous up to 5.5 mg/kg plus E 1.4 mg/m2 in 21 days cycles) were immediately processed and stored at -80°C. Circulating levels of IFN-γ, an important marker of anti-tumor immune response, were determined by a high-sensitive S-Plex assay (Meso Scale Diagnostics). Absolute neutrophil counts (ANC) were measured by automated hematology instruments. Results: E monotherapy did not increase IFN-γ levels in the first 8 hours post dosing, but led to an increase after 24 hours. Combination with B modulated IFN-γ levels and led to a sustained ANC increase 5 days post dosing. The increase pre vs post treatment can be up to 100-fold and receded prior to the next treatment cycle. Conclusions: E treatment led to a strong, transient increase of plasma IFN-γ levels in breast cancer patients modulated by B. The ANC increase by B may balance possible neutropenic actions of E. Citation Format: Johann Zimmermann, Garry Douglas, Barbara Romagnoli, Debra Barker, Daniel Obrecht. Circulating levels of IFN gammaand neutrophil counts in breast cancer patients who received balixafortide and eribulin combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3965.

Abstract 1454: Long-term immunogenicity results from a first-in-human study evaluating the anti-ASPH cancer vaccine, SNS-301

Abstract SNS-301 is a first-in-class immunotherapeutic cancer vaccine candidate targeting human aspartate β-hydroxylase (ASPH). ASPH is an oncofetal antigen expressed in multiple human cancers but not in healthy adult tissue. As a biologic modifier of the NOTCH pathway, ASPH is associated with tumor cell growth, motility and invasiveness. SNS-301 is a vaccine which delivers over 400 copies of an extracellular domain of the ASPH protein displayed on a bacteriophage vector. This phase 1 first-in-human study of SNS-301 was primarily designed to evaluate the safety and tolerability of the vaccine and to establish the recommended phase 2 dose. Vaccine was administered intradermally every 21 days in a 3+3 dose-escalation trial in patients with biochemically (rising PSA) relapsed prostate cancer with evidence of ASPH expression. The safety, tolerability and immunogenicity of SNS-301 have been presented previously (Nordquist, et al. Annals of Oncol., 29, suppl_8, 1 October 2018, mdy279.404, Lebowitz, et al., JITC 2018, 6(Suppl 1):P167). Per protocol, all subjects were required to receive at least three doses of SNS-301, but were given the option to continue on-study receiving further vaccinations every 3 weeks. Furthermore, once the safety of higher dose levels of SNS-301 was established, subjects that had initially received lower doses were escalated to the higher dose levels. All patients tolerated the vaccine well with minimal numbers of adverse events and opted to remain on-study, some receiving >20 doses over a period of more than 420 days. Immune responses in these patients were continuously followed at three-week intervals. Specifically, both anti-ASPH and anti-phage antibody levels in serum as well as percentages of ASPH-specific B-cells were monitored. Levels of anti-ASPH antibody and of ASPH-specific B-cells were well correlated. An initial increase in the levels was seen within the first six treatment cycles in a dose dependent fashion with higher doses achieving more rapid and more robust levels of response. As subjects continued on-study, ASPH-specific immune responses reached a peak level, then subsequently declined. Over the longer-term, these responses re-emerged and declined over multiple cycles. This pattern of response may be indicative of immune fatigue and is suggestive that a more refined dosing regimen in which later vaccinations are further spaced in time may be beneficial. Anti-phage antibody responses were also observed and also occurred in a dose-dependent fashion. Interestingly, subjects who received lower doses of vaccine and were subsequently switched to higher doses did not see a concomitant increase in anti-phage antibodies, suggesting that they had achieved a level of tolerance to the phage vector. Phase II trials in heme and solid tumors are planned and will incorporate a vaccine dosing regimen informed by this phase I study. Citation Format: Michael S. Lebowitz, Hong Dai, Kanam Malhotra, Ildiko Csiki, Steven Fuller, Hossein A. Ghanbari. Long-term immunogenicity results from a first-in-human study evaluating the anti-ASPH cancer vaccine, SNS-301 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1454.

Preoperative radiotherapy for high-risk prostate cancer (PORT-PC) trial.

TPS137 Background: Prostatectomy has become the most common treatment for high-risk prostate cancer. After prostatectomy, risk features for local recurrence include extra-capsular extension and/or seminal vesicle invasion (pT3 disease) and positive surgical margins. Post-operative radiotherapy is recommended for patients with pT3 disease, positive margins and/or Group Grade 4-5 and has been shown to reduce the risk of recurrence. In planning adjuvant radiotherapy, the clinical target volume is the prostate bed which is difficult to delineate once the prostate has been surgically removed and can be overestimated by following the location of surgical clips. As such, controversy exists as to the optimal target volume. Guidelines suggest including a significant portion of the posterior and inferior aspects of the bladder, and anterior aspect of the rectum exposing a significant amount of normal tissue to high dose radiation. Pre-operative radiotherapy potentially offers the following advantages: 1) reduced radiation dose to normal tissues; 2) ability to utilize stereotactic body radiotherapy (SBRT) with real-time MRI guidance 3) patient convenience with less fractions and 4) radiobiologic advantage of high dose per fraction treatment delivery. Methods: This is a modified dose escalation trial for patients with high-risk prostate cancer defined as cT3 on MRI or Group Grade 4-5 disease. Patients will sequentially undergo 1) placement of a rectal SpaceOAR, 2) SBRT on the ViewRay MRIdian linear accelerator and 3) prostatectomy. As a modified dose escalation study, patients will be accrued starting at 5 Gy x 5 (up to 8 Gy x 5) with 3 patients per cohort with Grade 4 or 5 gastrointestinal (GI) and/or genitourinary (GU) adverse event related to preoperative radiotherapy as an unacceptable dose limiting toxicity.The primary endpoint is that a patient can undergo a radical prostatectomy after SBRT without a post-operative GI or GU grade 4 or 5 toxicity within 30 days related to preoperative radiotherapy. Secondary objectives include assessment of acute toxicity and quality of life scores. Exploratory analyses include analysis of tumor and normal biopsied and resected tissue and serum markers and interpretation of pre- and post-SBRT MRIs. Clinical trial information: NCT03663218.

A phase I study of romidepsin, gemcitabine, dexamethasone and cisplatin combination therapy in the treatment of peripheral T-cell and diffuse large B-cell lymphoma; the Canadian cancer trials group LY.15 study†

We investigated GDP (gemcitabine, 1000 mg/m2 IV d1, d8; dexamethasone, 40 mg po d1-4; cisplatin, 75 mg/m2 IV d1) combined with romidepsin on days 1 and 8 every 21 days to a maximum of six cycles in a standard 3 + 3, phase I dose escalation trial for patients with relapsed/refractory peripheral T-cell (PTCL) or diffuse large B-cell (DLBCL) lymphoma (NCT01846390). After treating four patients, gemcitabine and romidepsin were given on days 1 and 15 every 28 days. On the 21-day schedule at 6 mg/m2 romidepsin, there were three dose-limiting toxicities (DLTs) among four patients. On the 28-day schedule, there were no DLTs at the 6, 8, or 10 mg/m2 dose. At 12 mg/m2, there were four observed grade 3 DLTs among six evaluable patients. Full doses of GDP can be combined with a recommended phase II romidepsin dose of 10 mg/m2 if given on a day 1, 15 every 28 days schedule.

Abstract B175: Rational combination of mTOR and Aurora kinase A inhibition in preclinical models of triple-negative breast cancer

Abstract Background: Alisertib is a highly selective inhibitor of Aurora kinase A and has antiproliferative and proapoptotic activity in a subset of triple-negative breast cancer (TNBC) cell lines and patient-derived tumor xenograft (PDX) models. Cellular senescence and increased expression of genes in the PI3K/AKT/mTOR pathway has been observed in TNBC models following treatment with alisertib that demonstrate de novo or acquired resistance. The purpose of this study was to investigate the combination of alisertib and the TORC1/2 inhibitor TAK-228 in preclinical TNBC models. Methods: MDA-MB-468, HCC1187, HCC1937, CAL51, and BT20 cells were plated in 96 well plates and exposed to increasing concentrations of alisertib (25nM-125nM), TAK-228 (25nM-125nM), or the combination and proliferation was assessed using the Cell Titer-Glo (CTG) assay. Apoptosis was assessed using long-term live cell microscopy and caspase 3/7 staining. Western blotting was used to assess changes in pS6, p4EBP1, and survivin expression. TNBC p53 wildtype CAL51 cells were transfected with the fluorescent ubiquitin cell cycle indicator (FUCCI) reporters and exposed to increasing concentrations of alisertib, TAK-228, or the combination to evaluate the effect on cell cycle progression, growth, and apoptosis. TNBC PDX models CU_TNBC_004 and CU_TNBC_007 were treated with vehicle, alisertib (30mg/kg), TAK-228 (0.5mg/kg), or the combination and assessed for tumor growth inhibition and translational markers by immunofluorescence (IF) and senescence-associated- ß-galactosidase (SA-ß-gal) staining. Results: A combination effect was observed for alisertib and TAK-228 in vitro with a decrease in cellular proliferation with the combination as measured by CTG. We observed an increase in cell death with the combination, as opposed to cell cycle arrest with single-agent treatment. Alisertib treatment was associated with an increase in survivin not observed with combination treatment. TAK-228 treatment was associated with a decrease in pS6 and p4EBP1 as a single agent or in combination. The combination of TAK-228 and alisertib resulted in greater tumor growth inhibition in vivo as compared to either single agent alone, accompanied by an increase in apoptosis as measured by BAX and DR5 expression and a decrease in senescence as evaluated by SA-ß-gal and phenotypic changes. Single agents in the CAL51 FUCCI system resulted in a dose-dependent effect on cell cycle progression and apoptosis by live cell microscopy. The combination, however, led to a complete block of cell growth and simultaneous apoptosis, leading to no expansion of cells after treatment and a gradual loss of the cell population. Conclusions: The combination of alisertib and TAK-228 in vitro and in vivo in TNBC models resulted in greater antiproliferative and proapoptotic activity. This combination is currently being investigated in a phase I dose escalation trial in patients with advanced solid tumors with a planned expansion cohort in metastatic TNBC to further evaluate the mechanism of the combination (NCT02719691). Citation Format: Jennifer R. Diamond, James D. Orth, Anastasia Ionkina, Kyrie Dailey, Todd M. Pitts, Anna Capasso, Joshua M. Marcus, Russell T. Burke, Sarah L. Davis, Jiyhe Kim, Aik-Choon Tan, Sue G. Eckhardt, John J. Tentler. Rational combination of mTOR and Aurora kinase A inhibition in preclinical models of triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B175.

Abstract 4089: Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach

Abstract Duvortuxizumab (also known as JNJ-64052781 and MGD011) is a bispecific CD19 x CD3 DART® molecule designed to simultaneously target CD19-positive cells for recognition and elimination by CD3-expressing T-lymphocytes as effector cells. Duvortuxizumab is currently in clinical development for the potential treatment of B-cell malignancies. Here we report the results from a translational PK model that utilized duvortuxizumab pharmacokinetic (PK) data from cynomolgus monkeys to predict duvortuxizumab PK in humans. The PK of duvortuxizumab administered by intravenous infusion was evaluated in cynomolgus monkeys in two separate studies. Study 1 evaluated intra-animal escalating doses from 0.5 to 100 µg/kg or repeated doses from 0.005 to 0.5 µg/kg administered over a period of up to 4 weeks. Serum concentrations of duvortuxizumab above the lower limit of quantification were obtained at dose levels >0.5 µg/kg. Study 2 evaluated duvortuxizumab doses of 0.2, 2, 5, or 10 µg/kg administered once weekly for 4 weeks. Dose-proportional increases in maximum concentration (Cmax) were observed across the dose ranges evaluated, and no significant differences between male and female animals were observed. PK modeling analysis, which integrated data from both study 1 and study 2 at 0.2 to 100 µg/kg dose levels, was performed to further understand the PK behavior of duvortuxizumab in cynomolgus monkeys. Duvortuxizumab PK was reasonably characterized using a two compartment model with linear clearance (CL) from the central compartment. Model estimated parameters were CL = 0.797 mL/h/kg; volume of distribution for the central compartment (V1) = 51.7 mL/kg; intercompartmental clearance (Q) = 2.29 mL/h/kg; and volume of distribution for the peripheral compartment (V2) = 88.8 mL/kg. Assuming a body weight of 3 kg and 70 kg for a cynomolgus monkey and a human, respectively, human PK parameters were estimated using an allometric scaling factor of 0.75 for CL and 1.0 for volume in the translational PK model. Observed duvortuxizumab PK values obtained from an ongoing, first-in-human (FIH), phase 1 dose-escalation trial in patients with relapsed or refractory B-cell malignancies (NCT02454270) were used to validate the translational PK model. Comparison of the predicted and observed duvortuxizumab PK profiles suggested that the translational PK model using the allometric scaling method reasonably predicted duvortuxizumab PK profiles in humans at multiple dose levels (15 to 100 ng/kg). In conclusion, the developed translational PK model successfully predicted duvortuxizumab PK in humans and has been used to aid dose escalation of duvortuxizumab in the ongoing FIH study. This work showcases the potential of translational PK modeling in supporting the selection of a FIH dose escalation strategy utilizing preclinical PK information. Citation Format: Xiling Jiang, Hua Li, Jeff Nordstrom, Jennifer Brown, Liqin Liu, Syd Johnson, Ralph Alderson, Pamela L. Clemens, Jacintha Shenton, Imran Khan, Olivia Gardner, Yu-Nien Sun, Weirong Wang. Quantitative prediction of human pharmacokinetics for duvortuxizumab from cynomolgus monkey data: a translational pharmacokinetic modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4089. doi:10.1158/1538-7445.AM2017-4089

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.

BackgroundOlaparib is an oral inhibitor of polyadenosine 5’-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC).Patients and MethodsIn this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM).Results18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS.ConclusionsOlaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted.Trial registrationThis clinical trial was registered on ClinicalTrials.gov as NCT01296763.

Abstract OT2-02-01: Photodynamic therapy for the treatment of primary breast cancer: Preliminary results of a phase I/IIa clinical trial

Abstract Background: Photodynamic therapy (PDT) has been used to treat skin metastases from breast cancer. We investigated the use of PDT for the treatment of primary breast cancer. Trial design: Phase I/IIA, open label, non-randomised, single site, light dose escalation trial in patients with primary breast cancer using verteporfin as the photosensitiser. Verteporfin 0.4mg/kg bodyweight is injected intravenously 60-90 minutes before laser activation through a thin optical fibre inserted percutaneously through a needle positioned under ultrasound guidance under local anaesthesia. The light dose is escalated from 20J to a maximum of 50J in intervals of 10J. Eligibility criteria: Patients aged 30 or over and have opted for mastectomy or wide local excision as primary treatment are included. The tumour should be uni-focal invasive ductal breast carcinoma, or discrete uni-focal site, within a multifocal invasive ductal carcinoma, in a single breast. Participants should not have confirmed distant metastases. The exclusion criteria include: patients who are not undergoing surgery as their primary treatment; patients undergoing surgery for DCIS without invasive breast cancer; lobular cancers and necrotic tumours; patients who have porphyria or are sensitive to verteporfin; patients who have severe cardiovascular disease or severe uncontrolled systemic disease (e.g. hepatic impairment); male breast cancer patients; pregnant or lactating patients; patients taking primary endocrine therapy or taking an experimental medicine as a part of a trial. Aims: We aim to establish the minimum light dose required to induce an area of necrosis with a diameter of at least 12mm perpendicular to the optical fibre; or to achieve a plateau with no increase in diameter of necrosis with increasing light dose. Secondary objectives are to examine the effect of Photodynamic Therapy on the abnormal breast tissue and study if necrosis extends to normal breast tissue. We will be assessing the role of MRI in predicting the response to treatment by measuring the diameter of tumour and the zone of necrosis before and after PDT and confirming it with histological findings. We will be monitoring the number of adverse events arising from the PDT. Statistical Methods: The sample size of the study is based on a standard 3+3 dose-escalation algorithm.Statistical analysis will be descriptive in nature with no formal statistical inference. Summary statistics and analysis will be provided for all patients who receive the study treatment, by dose level for each dosing regimen. Accrual Results: 11 patients have been enroled and completed the trial up to June 2016 with primary end point achieved and no adverse side- effects to treatment seen. Target Accrual: 21 patients. Acknowledgement: Royal Free Charity. Citation Format: Banerjee SM, Malhotra A, El-Sheikh S, Tsukagoshi D, Tran-Dang M-a, Mosse A, Parker S, Davidson TI, Williams NR, Bown S, Keshtgar MR. Photodynamic therapy for the treatment of primary breast cancer: Preliminary results of a phase I/IIa clinical trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-02-01.