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46 Background: Bone is frequently involved in metastatic hormone sensitive prostate cancer (mHSPC). Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) is a promising imaging technique for the assessment of bone response in prostate cancer. It is not known whether the addition of antiresorptive agents can improve disease response in bone in mHSPC patients undergoing next generation hormonal agents. Methods: In this multicenter phase II study patients with de novo or relapsed mHSPC and bone metastases at bone scan were randomly allocated with a 1:1 ratio to receive either androgen deprivation therapy (ADT) plus Enzalutamide (E arm) or the same combination with the addition of Zoledronic Acid (EZ arm). The study was designed to observe a significant increase in bone response rate in the experimental arm after 12 months of treatment, as assessed through WB-DW-MRI. WB-DW-MRI was performed centrally at baseline and after 6 and 12 months and images were evaluated by the same radiologist. Results: From February 2018 to June 2021, 126 mHSPC patients were randomized, 64 in EZ arm and 62 in E arm. A total of 111 patients, 54 from E arm and 57 from EZ arm, were eligible for WB-DW-MRI assessment (15 patients were excluded because of the absence of bone target lesions at MRI or specific contraindications to MRI). Bone response at 6 months was observed in 41 patients (76%) in E arm and 41 patients (72%) in EZ arm; the corresponding bone response at 12 months were 44 (82%) and 44 (77%), respectively (OR 0.77; 95%IC 0.30-1.93; p = 0.6). Complete response was the best overall bone response after 12 months in 9 patients (17%) from E arm and in 11 patients (19%) from EZ arm. In the same period, treatment was interrupted due to disease progression in 7 (13%) and 7 (12%) patients in E and EZ arm, respectively. Conclusions: The addition of Zoledronic Acid to Enzalutamide and ADT did not improve bone disease response in patients with mHSPC. WB-DW-MRI was able to detect bone responses in a great proportion of patients. Clinical trial information: NCT03336983 .

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

2524 Background: The phase I GATTO study explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab (GAT), a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin-1 (TA-MUC1) and an anti-EGFR antibody. Preclinical evidence suggests a complex interaction between TA-MUC1 and EGFR on the cell surface of epithelial tumors driving carcinogenesis processes and synergistic antibody dependent cell cytotoxicity activity with the dual targeting. Methods: Initially the study enrolled in a primary phase (PP) 20 patients with EGFR positive metastatic solid tumors, for whom no standard treatment was available. The first 6 patients were enrolled into a safety run-in phase and the number of dose-limiting toxicities (DLTs) was evaluated, in order to de-escalate the doses if needed. Patients received GAT administered at 1400 mg Q2W in combination with the glyco-optimized anti-EGFR antibody tomuzotuximab (TOM) at 1200 mg Q2W. Due to the risk of infusion related reactions (IRR), the first dose of TOM was reduced to 720 mg split over 2 consecutive days and three cycles of TOM monotherapy were given before start of treatment with GAT. As this regimen was proven safe, no DLT was observed and the initial dose remained unchanged, the study was amended to enroll in an expansion phase (EP) 30 additional patients with refractory colorectal cancer (CRC), non-small cell lung cancer (NSCLC), head and neck and breast cancers. TOM and GAT were given at the same doses and GAT treatment started already one week after the first dose of the anti-EGFR antibody. Additionally investigator had the choice to use a commercial anti-EGFR antibody in place of TOM. Results: By the time of the final analysis in January 2021, 52 refractory patients were enrolled and 50 received at least one dose of both GAT and anti-EGFR antibodies. Panitumumab (PAN) was used in 9 CRC patients. Because of the difference in treatment schedule, results are summarized separately for the 20 and 30 patients in PP and EP. Overall, the combined treatment was well tolerated and no DLT was observed in the whole study, nor related SAE or death. There were no treatment emergent adverse events (TEAEs) leading to dose interruptions or reductions in the PP and 2/30 (6.7%) patients in EP stopped both TOM and GAT. 16 IRRs were reported in 8/20 (40%) PP patients, and 40 IRRs in 10 (33.3%) EP patients. Only one event of chills was severe and only 6 events were related to GAT in the EP, all others to TOM. Other frequent TEAEs were those commonly observed with anti-EGFR treatment such as skin toxicity in 17 (85%) PP and 26 (86.7%) EP patients and hypomagnesemia in 10 (50%) PP and 7 (23.3%) EP patients. Conclusions: Combination of TA-MUC1 and EGFR targeting antibody is safe and feasible. Future studies should test this combination together with chemotherapy Clinical trial information: NCT03360734.

2522 Background: The phase I GATTO study explored the feasibility, tolerability and preliminary activity of combining Gatipotuzumab (GAT), a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin-1 (TA-MUC1), and an anti-EGFR antibody. Preclinical evidence suggests a complex interaction between TA-MUC1 and EGFR on the cell surface of epithelial tumors and synergistic antibody dependent cell cytotoxicity activity with the double targeting. Methods: Initially 20 patients with refractory metastatic disease were treated with GAT administered at 1400 mg Q2W in combination with the glyco-optimized anti-EGFR antibody Tomuzotuximab (TOM) at 1200 mg Q2W. Due to the risk of infusion related reactions, three cycles of TOM were given before start of combined treatment with GAT. After this regimen was proven safe and no DLT was observed, 30 additional patients including colorectal cancer (CRC) already treated with anti-EGFR antibodies, non-small cell lung cancer (NSCLC), head and neck and breast cancers received TOM and GAT administered at the same doses, with GAT treatment starting already one week after the first dose of the anti-EGFR antibody. As allowed in the study expansion, Panitumumab (PAN) was used in place of TOM in 9 CRC patients at investigator’s choice. Results: By the time of the final analysis in January 2021, 52 patients were enrolled, and 50 received at least one dose of both GAT and anti-EGFR antibodies. Safety was overall good and results are reported in a separate abstract. Because of the difference in treatment schedule, activity results of the two parts of the study are summarized separately. There were 2 and 4 RECIST partial responses in the first and second part of the study, all in CRC patients. In the expansion phase, the median Progression Free Survival (PFS) of CRC patients who received TOM (10) and PAN (9) was 1.9 and 5.5 months, respectively. There were 2 responses in each subgroup and the duration of response was 3.8 and 7.2 months in patients receiving TOM and PAN, respectively. The PFS for NSCLC was 5.3 months and 2 heavily pretreated patients achieved a prolonged control of disease of 10.6 and 9.4 months. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 in serum. In the extension phase patients with baseline values above median appeared to have improved PFS and overall survival; this was not the case for patients of the first part of the study who received GAT only after 3 doses of TOM. Conclusions: Combination of TA-MUC1 and EGFR targeting antibody is safe and feasible. Interesting anti-tumor activity was observed in heavily pretreated CRC and NSCLC patients. Levels of soluble TA-MUC1 may have predictive value and potentially be a companion biomarker for further development of the combination Clinical trial information: NCT03360734.

Purpose We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. Methods We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. Results A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. Conclusion This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Purpose The appropriate selection of patients for early clinical trials presents a major challenge. Previous analyses focusing on this problem were limited by small size and by interpractice heterogeneity. This study aims to define prognostic factors to guide risk-benefit assessments by using a large patient database from multiple phase I trials. Patients and Methods Data were collected from 2,182 eligible patients treated in phase I trials between 2005 and 2007 in 14 European institutions. We derived and validated independent prognostic factors for 90-day mortality by using multivariate logistic regression analysis. Results The 90-day mortality was 16.5% with a drug-related death rate of 0.4%. Trial discontinuation within 3 weeks occurred in 14% of patients primarily because of disease progression. Eight different prognostic variables for 90-day mortality were validated: performance status (PS), albumin, lactate dehydrogenase, alkaline phosphatase, number of metastatic sites, clinical tumor growth rate, lymphocytes, and WBC. Two different models of prognostic scores for 90-day mortality were generated by using these factors, including or excluding PS; both achieved specificities of more than 85% and sensitivities of approximately 50% when using a score cutoff of 5 or higher. These models were not superior to the previously published Royal Marsden Hospital score in their ability to predict 90-day mortality. Conclusion Patient selection using any of these prognostic scores will reduce non–drug-related 90-day mortality among patients enrolled in phase I trials by 50%. However, this can be achieved only by an overall reduction in recruitment to phase I studies of 20%, more than half of whom would in fact have survived beyond 90 days.

TPS2596Background: TO (CetuGEX) is a second-generation anti-EGFR antibody that specifically binds to EGFR and acts as a competitive antagonist at the ligand binding site. GAT (PankoMab-GEX) is a no...

e16031Background: To assess the clinical impact of VFL in pts with mTCCU and verify the prognostic factors in a large, unselected population treated according to routine clinical practice (CP). Met...

2535 Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ≤1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2+ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ≥ 6 months, and stable disease in 15/36 pts (42%) lasting ≥ 6 months in 3 pts. PK indicated no interactions of O+B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.

3080 Background: O is a vascular-disrupting agent derived from combretastatin A4-phosphate that induces rapid but transient tumor vascular shutdown. In experimental models, the combination of O with VEGF-blockade induced more regressions than O alone. This phase I study was performed to determine the maximum tolerated dose (MTD), and assess the overall safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O plus B. Trial is funded by sanofi. Methods: Patients (pt) with advanced solid tumors, ECOG PS ≤1, and adequate organ function were eligible. Increasing doses of O (mg/m²) was administered intravenously (IV) on day (d) 1; B (5 or 10mg/kg) was administered IV on d2, in 21d cycles (C). A Bayesian design was applied to determine dose escalation steps and MTD. PK sampling was performed in C1 and C2. PD sampling for circulating endothelial cells (CEC) and progenitors (CEP) were performed throughout. Dynamic contrast-enhanced ultrasound (DCE-US) to assess tumor perfusion was performed before and after C1 and C2 dosing. Results: 25 pts (M:F 6:19; median age 49 years [range 27-75]) have been treated at 8 dose levels of O/B: 8/5 (3), 11.5/5 (4), 11.5/10 (3), 15.5/10 (3), 20/10 (3), 25/10 (3); 35/10 (3) and 42/10 (3). Ovarian cancer was the most frequent tumor type (n=11). Median Cs received was 3 (1 to 14). No DLTs were observed during C1. Drug-related grade (g) 3-4 adverse events (AE) included hypertension in 2 pts (8/5; 11.5/5) and ileal perforation in 1 pt with peritoneal carcinomatosis at laparotomy (11.5/10). A case of duodenal perforation was unlikely related (25/10). Two pts with ovarian cancer (11.5/5; 20/10) had confirmed partial responses (4.4 months (mo) and 7+ mo). 13/23 (57%) pts with ≥ 1 tumor assessment had stable disease (n=8; median 4.3 mo [1.8-9.5]; 5 ongoing). Data from cohorts 1 and 2 demonstrated no evidence of a PK interaction.17/25 patients demonstrated a peak in CEC, and 7/9 patients a peak in CEP. 4/7 DCE-US evaluable pts had >50% drop in tumor perfusion (AUC) at Day 8 of C1. Conclusions: O combined with B is well tolerated with early evidence of clinical activity. The MTD has not been reached (current dose level 50/10); cohorts of O combined with B at 15 mg/kg will be tested.

8235 Background: Because of the progressive rise in the mean age of the first delivery and the progressive lowering in the age of onset of tumors, the continuous increas in the number of patients w...