Patients with advanced, recurrent or metastatic cancer have poor prognosis despite treatment advancements. Vesicular stomatitis virus (VSV)-GP (BI 1831169) is a chimeric VSV with its neurotropic glycoprotein G replaced by the non-neurotropic glycoprotein (GP) of the lymphocytic choriomeningitis virus. This live, recombinant oncolytic virus has demonstrated preclinical efficacy as a viral-based immunotherapy due to its interferon-dependent tumor specificity, potent oncolysis and stimulation of antitumor immune activity. Co-administration of the immune checkpoint inhibitor, ezabenlimab (BI 754091), alongside VSV-GP may synergistically enhance antitumor immune activity. Here, we describe the rationale and design of the first-in-human, phase I, dose-escalation study of VSV-GP alone and in combination with the immune checkpoint inhibitor ezabenlimab in patients with advanced, metastatic or relapsed and refractory solid tumors ( NCT05155332 ).

5030 Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling activates the PI3K/AKT pathway and may lead to androgen receptor (AR) transactivation and progression to endocrine treatment resistance. Xe, an IGF-ligand-neutralizing antibody, binds to IGF-1 and IGF-2 and inhibits IGF-1R signaling. This multi-center randomized phase II trial (NCT02204072) evaluated anti-tumor activity of Xe plus En in mCRPC. Methods: Men with histologically/cytologically confirmed mCRPC and progression after DCt+Abi were randomized to receive Xe 1000mg IV QW + En 160mg/day oral, or En alone (28-day cycles until progression or intolerable adverse events [AEs]). Primary endpoint: progression-free survival by investigator assessment (PFS-IA); secondary: PFS by central review (PFS-CR), overall survival (OS), AEs. Results: Overall, 43 patients were randomized per arm; 70% Caucasian and 29% Asian (median age 70 y; range 46–88). At baseline (BL) the two arms were generally well balanced, although 33% v 47% were ECOG PS O, and 72% v 56% had a Gleason total score ≥8. By data cut-off (23 October 2017), 39/43 (Xe+En) and 38/43 patients (En) had discontinued, most due to disease progression. The median PFS-IA was 7.4 m for Xe+En (95% CI: 3.5–8.7) and 6.2 m for En (3.5–11.1) [HR = 0.99 (0.56–1.73); p = 0.96]. The results were similar after adjusting for BL ECOG PS and Gleason score. The median PFS-CR was 3.6 m for Xe+En (3.5–8.1) and 6.2 m for En (3.6–8.3) (HR = 1.22 [0.70–2.13]; p = 0.48). OS data are immature. For the two arms, prostate-specific antigen (PSA) response rates were 21% and 19%; maximum decline in PSA: -20 v -9 μg/L; PSA change at week 12: 19% v 18%; maximum decline in circulating tumor cells (CTC): -52% v -35%; and CTC response: 16% v 11%. The most frequently reported AEs were: fatigue 67% v 49%; decreased appetite 56% v 54%; weight reduction 37% v 12%; anemia 33% v 44%; back pain 30% v 37%. Nine patients discontinued Xe due to AEs. Conclusions: Addition of Xe to En did not prolong PFS in mCRPC compared with En alone. There were no notable differences in PSA-related endpoints and CTC between arms. Clinical trial information: NCT02204072.

TPS1103 Background: The mTOR inhibitor Ev, combined with Ex, is a mainstay in the treatment of post-menopausal women with advanced HR+/HER2- BC. However, the activity of Ev is limited by counter-regulatory feedback mechanisms in cancer cells, involving reactivation of insulin-like growth factor (IGF)/mTOR survival signaling. Combining Ev with the humanized IGF-1 and IGF-2 ligand-blocking antibody Xe abrogates this feedback, thus intensifying inhibition of tumor growth; this leads to a pronounced effect in patients with non-visceral (e.g., bone and lymph node) metastases. The phase II XENERA-1 trial evaluates the combination of Xe with Ev and Ex in post-menopausal women with HR+/HER2- BC. Methods: XENERA-1 (NCT03659136) is a double-blind, placebo-controlled, randomized study to assess the efficacy and safety of Xe in combination with Ev and Ex, in post-menopausal women with HR+/HER2- locally advanced/mBC and non-visceral disease. The population comprises post-menopausal mBC patients who have progressed on ≤1 previous line of a non-steroidal aromatase inhibitor, with or without a CDK 4/6 inhibitor, who may have received fulvestrant. Other inclusion criteria are: an Eastern Cooperative Oncology Group Performance Status of 0 or 1; adequate organ function; and non-visceral disease (absence of brain, liver, lung, peritoneal or pleural metastases). Patients are randomized (1:1) to receive Xe (1000 mg/week, iv) or placebo (weekly, iv), in combination with Ev (10 mg/day) and Ex (25 mg/day). Treatment will continue until disease progression, unacceptable toxicity or other reasons. The primary endpoint is progression-free survival according to RECIST 1.1 criteria, by independent review. Secondary endpoints are: overall survival; disease control; duration of disease control; objective response; and time to progression of pain/intensification of palliation. Safety and pharmacokinetic endpoints, and exploratory biomarkers will also be evaluated. The first patient was enrolled in January 2019; target enrollment is 80 patients in 12 countries. Clinical trial information: NCT03659136.

taxel) plus trastuzumab (cohort C2). ET options are either an aromatase inhibitor, fulvestrant or tamoxifen +/-ovarian suppression. Stratification factors include the number of previous regimens for advanced BC (1-2 vs 3-4) and the presence of visceral disease (yes vs no). Primary objective is to compare the PFS between two arms. The study has an 80% power with two-sided alpha¼0.05 to detect a HR of 0.62 in favor of the palbociclib arm. An interim analysis (IA) adjusted for multiplicity from O'Brien-Fleming method and an estimation of the conditional power (CP) will be performed at 70% of the events. Secondary objectives include response rate, overall survival, safety, and Quality of Life. Tumor tissue and blood samples will be collected for biomarker analyses. A total of 516 patients will be screened and 232 patients will be recruited. As of January 16 th , 2020, 7 patients were randomized in the trial. The study is sponsored by SOLTI and financially supported by Pfizer.Clinical trial identification: NCT02448420.