Search

Background Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. Methods We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. Findings Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5–60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74–1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. Conclusion DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Purpose: This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E). Patients and Methods: LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D). Results: Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline). Conclusions: LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Background PD-1/L1 inhibitors are treatment options for patients with HCC who have progressed after first-line sorafenib treatment. Tislelizumab, an anti-PD-1 monoclonal antibody, has demonstrated single-agent antitumor activity in patients with advanced, previously treated HCC in two early phase studies (NCT02407990, NCT04068519). Association of biomarkers, including PD-L1 expression and gene expression profiles (GEP), with response and resistance to tislelizumab were explored. Methods PD-L1 expression was evaluated on tumor cells (TC) using the VENTANA PD-L1 (SP263) assay in baseline tumor samples collected before or after sorafenib treatment. GEP were assessed using the 1392-gene HTG GEP EdgeSeq panel. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures (GS). Wilcoxon rank-sum test was used to analyze differential gene signatures (DEG); GS association with PFS and OS was evaluated using Cox proportional hazards models. Results Single-agent tislelizumab demonstrated antitumor activity in advanced, previously treated HCC (ORR=13%; CB [PR+SD >6 months]=31%, median PFS=3.3 months; median OS=13.3 months). PD-L1+ (TC≥1%) prevalence and GEP showed different patterns in samples collected before and after sorafenib exposure (figure 1). While non-exposed samples (n=16) were enriched for immune suppressive signatures, sorafenib-exposed samples (n=41) showed higher PD-L1+ prevalence (53.7% vs 25%; P=0.08) and immune-cell activation signatures along with co-inhibition molecules. In sorafenib-exposed samples, PD-L1 expression was positively correlated with CB (P=0.0027) and a trend of longer PFS (HR=0.56, 95% CI:0.28–1.13). ORR was higher in PD-L1+ than PD-L1− sorafenib-exposed samples (23.8% vs 0%; P=0.049). DEG analysis in sorafenib-exposed samples demonstrated that NK-mediated cytotoxicity GS was positively correlated with CB (P=0.03), as well as a trend of longer PFS (HR=0.43, 95% CI:0.17–1.06). Across the different analyses, no correlation with OS was observed. Patients considered non-responders (NRs) were found clustered into three distinct GEP subgroups (NR1, NR2, NR3). Compared with responders, NR1 had enhanced angiogenesis signatures (P=0.01), including TEK, KDR, HGF, and EGR1. Despite high inflamed tumor signatures, NR2 had increased expression of T-cell inhibition GS scores (P=0.01), including CD274, CTLA4, TIGIT, and CD96. The NR3 subgroup showed higher cell-cycle GS scores compared with responders (P=0.05), including E2F7, FOXA1, and FANCD2. Conclusions Prior sorafenib exposure appears to be associated with increased PD-L1 expression and tumor microenvironment-related GS, as well as response and PFS from tislelizumab in advanced HCC patients. Elevated angiogenesis, immune exhaustion, and cell-cycle GS levels may indicate resistance to single-agent PD-1 inhibitors and is suggestive of potential treatment strategies. Validation is warranted in future clinical trials (NCT03412773). Acknowledgements This study was sponsored by BeiGene, Ltd. Writing and editorial assistance was provided by Regina Switzer, PhD, and Elizabeth Hermans, PhD (OPEN Health Medical Communications, Chicago. IL), and funded by the study sponsor. Trial Registration NCT02407990, NCT04068519

Background MUC16 is a tumor-specific antigen overexpressed in ovarian (OC) and pancreatic (PC) cancers. The antibody–drug conjugate (ADC), DMUC5754A, contains the humanized anti-MUC16 monoclonal antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE). Patients and methods This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamics of DMUC5754A given every 3 weeks (Q3W, 0.3–3.2 mg/kg) or weekly (Q1W, 0.8–1.6 mg/kg) to patients with advanced recurrent platinum-resistant OC or unresectable PC. Biomarker studies were also undertaken. Results Patients (66 OC, 11 PC) were treated with DMUC5754A (54 Q3W, 23 Q1W). Common related adverse events (AEs) in >20% of patients (all grades) over all dose levels were fatigue, peripheral neuropathy, nausea, decreased appetite, vomiting, diarrhea, alopecia, and pyrexia in Q3W patents, and nausea, vomiting, anemia, fatigue, neutropenia, alopecia, decreased appetite, diarrhea, and hypomagnesemia in Q1W patients. Grade ≥3-related AE in ≥5% of patients included neutropenia (9%) and fatigue (7%) in Q3W patients, and neutropenia (17%), diarrhea (9%), and hyponatremia (9%) in Q1W patients. Plasma antibody-conjugated MMAE (acMMAE) and serum total antibody exhibited non-linear PK across tested doses. Minimal accumulation of acMMAE, total antibody, or unconjugated MMAE was observed. Confirmed responses (1 CR, 6 PRs) occurred in OC patients whose tumors were MUC16-positive by IHC (2+ or 3+). Two OC patients had unconfirmed PRs; six OC patients had stable disease lasting >6 months. For CA125, a cut-off of ≥70% reduction was more suitable for monitoring treatment response due to the binding and clearance of serum CA125 by MUC16 ADC. We identified circulating HE4 as a potential novel surrogate biomarker for monitoring treatment response of MUC16 ADC and other anti-MUC16 therapies in OC. Conclusions DMUC5754A has an acceptable safety profile and evidence of anti-tumor activity in patients with MUC16-expressing tumors. Objective responses were only observed in MUC16-high patients, although prospective validation is required. Clinical Trial Number NCT01335958.

Pamiparib, an investigational, oral PARP 1/2 inhibitor, demonstrated preclinical brain penetration and synergistic cytotoxicity with TMZ. We report updated safety and antitumor data for pamiparib plus RT and/or TMZ in ND-GBM or R/R-GBM (SNO 2019, ACTR-39). This dose-escalation/expansion study includes three arms: A, pamiparib (2, 4, or 6 weeks) plus RT (6–7 weeks) in ND-GBM with unmethylated MGMT promoter (unmethylated-GBM); B, pamiparib (6 weeks) plus RT and increasing TMZ doses in Weeks 1 and 5 of RT in unmethylated ND-GBM; and C, pamiparib plus increasing TMZ doses in methylated/unmethylated R/R-GBM. Most patients in Arms A (expansion) and B received maintenance pamiparib plus TMZ after post-RT rest period at Arm C expansion. As of April 10, 2020, enrollment was complete (N=116; A, n=60; B, n=9; C, n=47). Median study follow-up was 11.3 mo (A/B) and 7.1 mo (C). Common grade ≥3 AEs were anemia (10%) in Arm A; decreased neutrophil and white blood cell count (each 22%) in B; anemia, fatigue, and decreased lymphocyte count (each 11%) in C. Brain edema (A) and pneumonia (C) (n=1 each) were fatal treatment-unrelated AEs. In ND-GBM, modified disease control rate (DCR following post-RT rest period) was 69.8% (95% CI, 55.7–81.7) overall, 68.8% (50.0–83.9) in A, and 80.0% (28.4–99.5) in B. Median duration of response was 5.1 mo (overall), 3.8 mo (A), and NE (B). In Arms A/B, median progression-free survival (PFS) and median overall survival (OS) were 4.4 mo and 12.7 mo, respectively; 12-mo OS rate, 54% (95% CI, 40–66). In R/R-GBM (Arm C), confirmed ORR was 9.1% (95% CI, 2.5–21.7); median PFS and OS were 1.9 mo and 7.3 mo, respectively; 6-mo PFS rate, 19% (95% CI, 9–32). These results showed a manageable safety profile for pamiparib +/- RT +/-TMZ; response and survival results support further evaluation of these combinations in GBM.

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid derived suppressor cells and tumor associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6–19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting > 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended Ph2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the Phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

DNA damage caused by TMZ or RT sensitizes tumors to PARP inhibitors, especially in highly replicating tumors (eg, GBM). Pamiparib is a selective PARP1/2 inhibitor with potent PARP trapping that can cross the blood-brain barrier and has shown synergistic cytotoxicity with TMZ in nonclinical experiments. At 60mg BID, the human-equivalent dose-to-trough brain concentrations above the nonclinical efficacy threshold, pamiparib was generally well tolerated and showed antitumor activity in early clinical studies ({"type":"clinical-trial","attrs":{"text":"NCT02361723","term_id":"NCT02361723"}}NCT02361723; {"type":"clinical-trial","attrs":{"text":"NCT03333915","term_id":"NCT03333915"}}NCT03333915). This ongoing dose-escalation/expansion study ({"type":"clinical-trial","attrs":{"text":"NCT03150862","term_id":"NCT03150862"}}NCT03150862) will determine the safety/tolerability and antitumor effects of pamiparib (60mg BID)+RT and/or TMZ. The dose-escalation component consists of three arms. Arm A will establish tolerable duration of pamiparib (2, 4, 6 weeks)+RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethyl-GBM). In Arm B, newly diagnosed patients with unmethyl-GBM will receive pamiparib+RT with increasing TMZ doses. Enrollment in Arm B will commence once RP2D for pamiparib+RT is established. In Arm C, patients with recurrent/refractory methylated- or unmethyl-GBM receive pamiparib with increasing TMZ doses. As of 28 March 2018, 15 patients were enrolled (A: 2-wk, n=3; 4-wk, n=6; C: TMZ [40mg], n=6). One DLT (grade 3 nausea) was reported in Arm C. Across arms, pamiparib-related AEs occurring in >3 patients were nausea (n=6) and fatigue (n=5). Two patients experienced three pamiparib-related AEs grade 3 (diarrhea [A: 4-wk, n=1]; fatigue and nausea [C: n=1]). All three resolved with concomitant medication and treatment interruption (A) or discontinuation (C). Of the seven patients with 1 tumor assessment, one (A: 4-wk) achieved an unconfirmed PR; four (A: 2-wk, n=2; 4-wk, n=2) had SD, and two (A: 2-wk, n=1; C: n=1) had PD. Preliminary data suggests pamiparib at 60mg BID is generally well tolerated by patients when administered 4 weeks concurrently with RT for newly diagnosed unmethyl-GBM and when combined with 40 mg TMZ for recurrent/refractory GBM.

Fluorine-18-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET)-guided focal dose escalation in oropharyngeal cancer may potentially improve local control. We evaluated the feasibility of this approach using volumetric-modulated arc therapy (RapidArc) and compared these plans with fixed-field intensity-modulated radiotherapy (IMRT) focal dose escalation plans. Materials and methods: An initial study of 20 patients compared RapidArc with fixed-field IMRT using standard dose prescriptions. From this cohort, 10 were included in a dose escalation planning study. Dose escalation was applied to (18)F-FDG-PET-positive regions in the primary tumor at dose levels of 5% (DL1), 10% (DL2), and 15% (DL3) above standard radical dose (65 Gy in 30 fractions). Fixed-field IMRT and double-arc RapidArc plans were generated for each dataset. Dose-volume histograms were used for plan evaluation and comparison. The Paddick conformity index (CI(Paddick)) and monitor units (MU) for each plan were recorded and compared. Both IMRT and RapidArc produced clinically acceptable plans and achieved planning objectives for target volumes. Dose conformity was significantly better in the RapidArc plans, with lower CI(Paddick) scores in both primary (PTV1) and elective (PTV2) planning target volumes (largest difference in PTV1 at DL3; 0.81 ± 0.03 [RapidArc] vs. 0.77 ± 0.07 [IMRT], p = 0.04). Maximum dose constraints for spinal cord and brainstem were not exceeded in both RapidArc and IMRT plans, but mean doses were higher with RapidArc (by 2.7 ± 1 Gy for spinal cord and 1.9 ± 1 Gy for brainstem). Contralateral parotid mean dose was lower with RapidArc, which was statistically significant at DL1 (29.0 vs. 29.9 Gy, p = 0.01) and DL2 (29.3 vs. 30.3 Gy, p = 0.03). MU were reduced by 39.8-49.2% with RapidArc (largest difference at DL3, 641 ± 94 vs. 1261 ± 118, p < 0.01). (18)F-FDG-PET-guided focal dose escalation in oropharyngeal cancer is feasible with RapidArc. Compared with conventional fixed-field IMRT, RapidArc can achieve better dose conformity, improve contralateral parotid sparing, and uses fewer MU.

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and lethal brain cancer in adults and accounts for 65% of all primary brain tumours. In our unit we routinely utilise fluorescence image guided resection with prior administration of 5-aminolevulinic acid (5-ALA) to the patient for potentially macroscopically resectable GBMs. In the GBM cells 5-ALA is metabolised to protoporphyrin IX, which emits fluorescence when it is excited with violet light, allowing the visualisation of the cancer cells for maximal resection of the tumour. This project looks at the specificity and toxicity of 5-ALA in vitro when characterising the cancer cells isolated from the invasive margin of the tumour. METHODS: Tumour cells are isolated from both the core and the invasive margin of GBM tumours and compared to established cell lines previously derived from the core and to differentiated neural stem cells from mouse cerebellum that were used as a “normal brain” control. Cells were cultured as monolayers, labelled with 5-ALA and analysed by fluorescence microscopy and flow cytometry to determine 5-ALA specific fluorescence. Presto blue assays were carried out to investigate potential toxicity of 5-ALA in vitro. RESULTS: All GBM cells exhibited 5-ALA specific fluorescence whilst the ratio of median fluorescence intensity observed was around 2-fold for the 5-ALA positively labelled compared to the unlabelled cells (SD: 0.51) and no significant fluorescence for the non-neoplastic brain cells. Interestingly, the GBM cells isolated from a recurrent tumour showed some autofluorescence under the microscope. 5-ALA had no toxic effect on the cells. DISCUSSION: The results gained from the fluorescence microscopy and flow cytometry analysis were extremely encouraging and showed that 5-ALA labelling of a mixed population of cells, such as samples obtained from the invasive margin of the tumour, could be used to identify the GBM cells with several downstream applications including cell separation or co-staining. In addition, the technique was found to be non-toxic, with little effect on cell proliferation.

Author Summary Background. Combination blockade of human epidermal growth factor receptor (HER) family signaling may confer enhanced antitumor activity than single-agent blockade. We performed a single-arm study of pertuzumab, a monoclonal antibody that inhibits HER2 dimerization, and erlotinib in relapsed non-small cell lung cancer (NSCLC). Methods. Patients received pertuzumab (840-mg loading dose and 420-mg maintenance intravenously every 3 weeks) and erlotinib (150-mg or 100-mg dose orally, daily). The primary endpoint was response rate (RR) by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) at day 56 in all patients and those with EGFR wild-type tumors. Results. Of 41 patients, 28 (68.3%) experienced treatment-related grade ≥3 adverse events, including pneumatosis intestinalis (3 patients), resulting in early cessation of enrollment. Tissue samples from 32 patients showed mutated EGFR status in 9 of 41 (22%) and wild-type EGFR in 23 of 41 (56%). The FDG-PET RR for patients with assessments at day 56 was 19.5% in all patients (n = 41) and 8.7% in patients with wild-type EGFR NSCLC (n = 23). Investigator-assessed computed tomography RR at day 56 was 12.2%. Conclusion. FDG-PET suggests that pertuzumab plus erlotinib is an active combination, but combination therapy was poorly tolerated, which limits its clinical applicability. More research is warranted to identify drug combinations that disrupt HER receptor signaling but that exhibit improved tolerability profiles.

2529 Background: MSLN is a tumor antigen over-expressed in PC and OC. The ADC DMOT4039A is a humanized IgG1 anti-MSLN monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative...

2504 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in ~70% non-squamous NSCLC and ~90% OC. DNIB0600A is an ADC consisting of a humanized Ig...

5020 Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3+3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twenty-eight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (

2507 Background: NaPi2b (SLC34A2) is a multi-transmembrane, sodium-dependent phosphate transporter expressed in non-squamous NSCLC and non-mucinous OC. DNIB0600A is an ADC consisting of a humanized IgG1 anti-NaPi2b monoclonal antibody and anti-mitotic agent, MMAE, that shows anti-proliferative activity in xenograft models. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamics of DNIB0600A (0.2-2.8 mg/kg) given every 3 weeks (q3w) to pts with NSCLC or OC. A traditional 3+3 design was used for dose escalation followed by expansion by disease at the recommended Phase 2 dose (RP2D). Tumor NaPi2b expression was evaluated in archival tissue. Anti-tumor activity was evaluated per RECIST 1.1. Results: As of 10 Dec 2012, 30 dose escalation pts have enrolled (16 NSCLC; 14 OC), median age 61 (range 45-78), PS 0-1, median number of prior regimens 5 (1-12), received a median of 3 (1-17) doses of DNIB0600A. No DLTs occurred at the maximum assessed dose of 2.8 mg/kg; enrollment in the expansion cohort at 2.4 mg/kg is ongoing. The most common related AEs regardless of Grade were fatigue (43%), decreased appetite (37%), nausea (30%), constipation, dysgeusia, vomiting, and peripheral neuropathy (each 17%), and diarrhea (13%). One pt at 1.8 mg/kg experienced a DLT (Grade 3 dyspnea), however, no additional DLTs occurred through the maximally administered dose of 2.8 mg/kg. Expansion at 2.4 mg/kg was selected based on totality of safety data. No accumulation of total antibody, free MMAE, or conjugated MMAE was observed. Exposure of each analyte was dose proportional. Approximately 70% of NSCLCs and 85% of OC expressed high levels (IHC 2+/3+) of NaPi2b. Of the 18 pts treated at dose levels 1.8-2.8 mg/kg (10 NSCLC; 8 OC) 3 pts had a confirmed partial response (PR) with response durations of 8.8+ (OC), 4.4+ (NSCLC), and 1.4+ (OC) months, censored at data cutoff, and 1 additional pt had an unconfirmed PR (OC). Dose expansion data will be presented. Conclusions: DNIB0600A administered q3w has an encouraging safety profile and evidence of anti-tumor activity in both NSCLC and OC. Further studies are planned. Clinical trial information: NCT01375842.

Background: MUC16 is a large transmembrane protein overexpressed by the majority of ovarian cancers (OC), compared with normal tissues. The role of MUC16 in the pathogenesis of ovarian cancer is unknown; however, MUC16 may facilitate the binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity, and may inhibit natural killer cell-mediated anti-tumor cytotoxic responses. Conjugation of a highly potent cytotoxic drug to a MUC16-specific monoclonal antibody represents a novel approach to treatment of MUC16-expressing tumors. DMUC5754A is an ADC containing the humanized IgG1 anti-MUC16 monoclonal antibody linked to the potent anti-mitotic agent MMAE and demonstrates anti-tumor activity in MUC16-expressing tumor xenograft models. Methods: This phase I study evaluated safety, pharmacokinetics (PK), and pharmacodynamic (PD) activity of DMUC5754A (0.3-3.2 mg/kg) given every 3 weeks (q3w) to patients with advanced recurrent platinum-resistant OC. A standard 3+3 design was used to determine the maximum-tolerated dose, followed by cohort expansion. Tumor tissue was assessed for expression of MUC16 and other relevant markers. Clinical activity was evaluated per RECIST. Results: Forty-four patients (22 escalation, 22 expansion at 2.4 mg/kg), median age 62 (44-79), ECOG PS 0-1, received a median of 4 doses (range 1-20) of DMUC5754A. Two DLTs, 1 Grade 4 neutropenia and 1 Grade 4 uric acid increase, occurred at the maximally administered dose of 3.2 mg/kg. Grade ≥ 3 related adverse events (AE) occurring in ≥ 5% of patients included fatigue (4 at 2.4 mg/kg; 9% total) and neutropenia (1 at 3.2 mg/kg, 3 at 2.4 mg/kg; 9% total). The most common related AEs over all dose levels were fatigue (57%), nausea (34%), vomiting (27%), decreased appetite (25%), peripheral neuropathy (25%), and diarrhea (23%). Serious drug-related AEs (SAE) were small intestine obstruction (2 patients), hypocalcemia (1 patient), and neutropenia (1 patient). Total antibody and conjugated MMAE were not impacted by circulating CA125 and displayed dose-dependent PK with clearance decreasing as dose increased. Accumulation of total antibody, conjugated MMAE and free MMAE was not observed due to their short half-lives (≤5 days). Tumor MUC16 expression was evaluable in 42 patients, showing 20% IHC 0, 16% IHC 2+, and 64% IHC 3+. All confirmed responses (1 CR and 4 PRs) occurred in patients treated at 2.4 mg/kg and whose tumors were MUC16 IHC 2+ or 3+. Six additional patients had minor responses (3 at 2.4 mg/kg). Sixteen of the twenty-nine patients at 2.4 mg/kg were on study ≥ 105 days. Human epididymis protein 4 was a potential surrogate marker for serologic response measures in the presence of anti-MUC16/CA125-binding therapy. Conclusions: DMUC5754A at 2.4 mg/kg q3w has an encouraging safety profile and evidence of anti-tumor activity in MUC16-expressing OC. Further studies are planned. Citation Format: Joyce Liu, Kathleen Moore, Michael Birrer, Suzanne Berlin, Ursula Matulonis, Jeffrey Infante, Jian Xi, Robert Kahn, Yulei Wang, Katie Wood, Daniel Coleman, Daniel Maslyar, Eric Humke, Howard Burris. Targeting MUC16 with the antibody-drug conjugate (ADC) DMUC5754A in patients with platinum-resistant ovarian cancer: A phase I study of safety and pharmacokinetics. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-290. doi:10.1158/1538-7445.AM2013-LB-290