Merchan, Jaime R.

Abstract Purpose: VV1 is designed to induce selective oncolysis of tumor cells and amplify cellular antitumor immune responses. This open-label, phase I, multicenter clinical trial assessed the safety and tolerability of VV1 monotherapy administered intratumorally or intravenously or administered intravenously in combination with avelumab. Patients and Methods: Patients with advanced solid tumors received intratumoral (n = 27) or intravenous VV1 monotherapy (n = 33) or intravenous VV1 plus avelumab (n = 16). Infusion durations (15–180 minutes) and viral dose (1.7 × 1010 or 1 × 1011 TCID50) were also evaluated. Study objectives included VV1 safety and tolerability, pharmacokinetics, pharmacodynamics, preliminary efficacy, and immune responses. Results: Intratumoral and intravenous VV1 were well tolerated, and injection reactions were infrequent. The most common adverse events of any grade related to VV1 were cytokine release syndrome (58%), fatigue (33%), and decreased lymphocyte count (32%). Virus infection of tumors was confirmed by NIS imaging and increases in serum levels of virally encoded interferon-β (IFNβ). Histologic tumor analysis at 28 days after intratumoral VV1 administration indicated increases in tumor-infiltrating immune cells. Two durable partial responses were recorded: a patient with pheochromocytoma after one intravenous dose of VV1 and a patient with thymic cancer in the combination arm. Stable disease was observed in 17 of 49 patients (34.7%) who received intravenous VV1. Conclusions: This first-in-human study demonstrates that intratumoral or intravenous VV1 administration had an acceptable safety profile as monotherapy and intravenously in combination with avelumab. There is preliminary antitumor activity. Intratumoral VV1 plus cemiplimab is now showing promise in the neoadjuvant setting. Significance: VV1 is a tumor-selective oncolytic vesicular stomatitis virus engineered to express IFNβ and the thyroidal NIS reporter gene. In this phase I study, we have demonstrated that a single administration of VV1, as a monotherapy or with an immune checkpoint inhibitor is safe, infects tumor lesions resulting in intratumoral infiltration of immune cells, and exhibits early signs of antitumor activity in patients with advanced unresectable and metastatic solid tumors.

TPS3164 Background: TUB-030 is a novel antibody-drug conjugate (ADC) targeting 5T4, an oncofetal antigen expressed in various solid tumors with limited expression in healthy tissues. TUB-030 leverages optimized biophysical properties, an effector-silenced antibody, and an exatecan payload to maximize the therapeutic index and minimize off-target toxicities. Preclinical studies demonstrated potent anti-tumor activity, including long-lasting tumor regression at doses as low as 1 mg/kg and durable responses even in tumors with low 5T4 expression. Methods: 5-STAR 1-01 is a multicenter, first-in-human dose escalation and dose optimization Phase I/IIa clinical trial designed to investigate safety, tolerability, pharmacokinetics (PK), and efficacy of the anti-5T4 ADC TUB-030 in patients with advanced and metastatic solid tumors. Eligible patients have one of the following tumor types: head and neck squamous cell carcinomas (HNSCC), non-small-cell lung cancer (NSCLC), small cell lung cancer, pleural mesothelioma, triple-negative breast cancer, HR+/HER2- breast cancer, esophageal cancer, gastric cancer, pancreatic adenocarcinoma, colorectal cancer, bladder cancer, prostate cancer, cervical cancer, osteosarcoma, or soft tissue sarcomas and must have exhausted available standard-of-care therapies. Phase I is an open-label, single-arm dose escalation trial, with administration every 21 days. Dose escalation follows an accelerated titration design (ATD) transitioning to Bayesian optimal interval (BOIN) upon predefined toxicity thresholds. Backfill cohorts are planned in NSCLC and HNSCC to further evaluate the safety and efficacy profile at, or near, the maximum tolerated dose (MTD). Primary endpoints include safety and tolerability of TUB-030 as monotherapy, determination of the MTD and the recommended phase II doses; secondary endpoints assess pharmacokinetics, immunogenicity, and preliminary clinical activity using RECIST v1.1 criteria. Exploratory endpoints include analysis of circulating tumor DNA. In phase IIa, dose-optimization will evaluate two dose levels in select indications in order to identify the optimal dose for further development. Enrollment of approximately 130 patients across the US and Canada is planned, with dose escalation currently underway. This study investigates TUB-030, a novel 5T4 targeted ADC as a therapy for advanced/metastatic solid tumors. Clinical trial information: NCT06657222 .

472 Background: Enfortumab Vedotin (EV), an antibody-drug conjugate that targets nectin-4, is approved for metastatic urothelial carcinoma (mUC) progressing post-platinum and PD1/L1 inhibitor therapy. Erdafitinib is approved in patients for post-platinum mUC with activating genomic alterations in FGFR2/3, but the activity of EV in this subset is unclear. We investigated the activity of EV in patients (pts) with mUC based on FGFR2/3 genotype to inform management. Methods: In this multi-center, retrospective analysis, we assessed the objective response rate (ORR) to EV in mUC pts with and without FGFR2/3 genomic alterations detected by targeted panel next-generation sequencing. Activating gene fusions and known hotspots mutations in the two genes were considered. Descriptive analysis of ORR and patient characteristics was performed. Fisher’s exact test and binomial test with two-tailed p-value were used. Results: 40 pts were available from 4 institutions. Most pts were male (31/40, 78%) and the median age at start of EV was 74.1 (range 49 – 90) years. Ten patients (25%) had upper tract urothelial carcinoma (UTUC), and 33 (82%) had baseline ECOG performance status of 0-1. 31 of 39 patients had received both platinum-based chemotherapy and PD1/L1 inhibitors. Seven patients had confirmed activating hotspot FGFR3 mutations (p.S249C or p.Y373C). One pt had FGFR2 high-level amplification (HA), and one had FGFR3 HA. Of 36 patients evaluable for ORR, 18 had partial response (PR), 12 had stable disease (SD) and 6 had progressive disease (PD). Patients with FGFR2/3 activating mutations exhibited an ORR that was not statistically different compared to patients without no mutations: 2/7 (29%; 90% CI: 5 – 66%) vs. 16/29 (55%; 90% CI: 38 – 71%) respectively ( p-value = 0.4). 3/7 patients with FGFR3 hotspot mutations received an FGFR2/3 inhibitor and none responded; one of them had a sequential response to EV. Conclusions: In this multi-center retrospective cohort, FGFR2/3 activating genomic alterations did not appear to compromise response to EV in mUC. Larger studies are required to confirm our findings and optimal sequencing of EV and erdafitinib in mUC pts with FGFR2/3 genomic alterations requires further assessment.

5039 Background: Combined mTOR and VEGF blockade is a potentially promising and rational strategy for the treatment of advanced RCC. We previously reported the phase I safety and efficacy results of CCI 779 (C) +bevacizumab (B) n RTKI naïve stage IV RCC patients (pts) (J Clin Oncol. 2007;25[18S Suppl]:5034). We now report the interim results of the phase 2 study of C+B in RTKI refractory RCC patients. Methods: Design: Open label, phase I/II study of C+B in advanced RCC pts. Patients with measurable stage IV RCC with a component of clear/conventional cell type, performance status 0–2 and good organ function were eligible. Up to two prior treatment regimens were allowed (at least one prior RTKI). Phase II dose was C = 25 mg IV weekly and B = 10 mg/kg every 2 weeks repeated in 4 week cycles. The primary objective of the phase II portion was to assess the proportion of patients who were progression-free 6 months after study entry. Secondary objectives were assessment of response rates and toxicity. Accrual goal = 40 pts. Results: Thirty-five pts have been enrolled into the phase 2 portion to date with 4 pts ineligible. Twenty-five pts are evaluable for response assessment and 29 pts are evaluable for toxicity. Baseline characteristics (N: 35): M/F: 28/7; Number of met. sites: 1/2/3+: 15/9/11; prior nephrectomy: 31; Number of prior therapies: 1 = 29; 2 = 2. Most common (>5%) Gr 3–4 AEs (N = 29) included fatigue (6), hypercholesterolemia (2), hypertriglyceridemia (2), anorexia (2), rash (2), and anemia (2). Responses were: PR/SD/PD = 4 (16%)/18 (72%)/3 (12%). Median number of cycles administered was 4. Six month progression free rates will mature by may 2009. Conclusions: C+B combination at the recommended phase 2 doses is feasible and well tolerated. Clinical benefit rates (PR/SD) in RTKI refractory RCC patients (88%) are encouraging. Data on 6 month progression-free rates are expected to mature in 4/09. Updated data on safety, response rates, and 6-month progression free rates will be presented on all evaluable patients. Correlative studies on available plasma, serum and tumor samples for angiogenic and molecular biomarkers are underway. Supported by N01-CM62205, R21 CA 119545–02, and Commonwealth Foundation. [Table: see text]

3090 Background: VV1 (Voyager V1) is derived from VSV, an RNA virus with low human seroprevalence, engineered to replicate selectively in and kill human cancer cells. In Part 1 of this study, we demonstrated the safety of intratumoral VV1 and dose-response, using serum IFNβ as a biomarker; we observed viral replication in tumor and concomitant lymphocyte/neutrophil trafficking (SITC 2018). 2 other studies suggested greater efficacy and higher IFNβ levels with IV administration. Longer infusion durations were reported to mitigate infusion reactions (IRRs) for another oncolytic. Methods: We studied 3 different infusion durations of VV1 monotherapy at the recommended phase 2 IV dose (1.7 x 1010 TCID50) in patients with advanced solid tumors. Endpoints included safety, preliminary anti-tumor activity, viral titers, IFNβ PD and shedding. Patients received IV VV1 once on D1 and were monitored for DLT over 21 days with efficacy assessments every 6 weeks. IRRs were classified using Lee 2014 criteria for CRS as either constitutional symptoms only (G1) or involving hypotension (G2). Results: 18 patients were treated at 30, 60 and 180-minute durations (n = 7, 5 and 6, respectively). No DLTs, deaths or G3-4 related IRR AEs were observed. Most pts were female (67%), white (100%), with ECOG PS 0 (61%) and median 4 lines of prior systemic therapy (range 1-14) for colorectal (CRC; 56%), squamous cell carcinoma (11%), pheochromocytoma (11%), sarcoma (11%) or other (11%) cancers. The table shows results (number of patients) by infusion duration. Conclusions: There was no difference in safety between the 3 infusion durations, while efficacy and PD markers suggested better anti-tumor effect with 30-minute infusion. VV1 is safe for caregivers, with no viral shedding. Part 3 of this study will now treat CRC patients with VV1 in combination with a checkpoint inhibitor (avelumab). A 5-arm phase 2 basket study in combination with cemiplimab is proceeding with 30-minute infusions. Clinical trial information: NCT02923466 . [Table: see text]

8010 Background: In patients (pts) with metastatic melanoma (MM), tumor angiogenesis has been associated with tumor progression and survival (Ugurel et al, JCO 19:577). Microtubule and cyclooxygenase (COX)-2 inhibitors, both alone and in combination, have been shown to have inhibitory effects on endothelial cells and tumor angiogenesis both in vitro and in vivo (Merchan et al, Int J Ca 113:490. Jones et al, Nat Med 5:1418). We tested the safety and efficacy of a regimen involving low dose, continuous infusion (CIV) paclitaxel and oral celecoxib in pts with MM. Methods: Pts received paclitaxel 10mg/m2 for 96 hours weekly by CIV and Celecoxib 400 mg po/bid. Systemic tumor response was assessed at 6 wk intervals (1 cycle (C)). Pts without unacceptable toxicity or clinically significant disease progression (PD) received additional cycles. Pts exhibiting PD after C 2 relative to end of C 1 were removed from study. Pts on anticoagulants, with recent MI or untreated brain metastases were ineligible. Results: 20 pts (12 M/ 8 F), median age 55 (range 44–65), ECOG PS 0/1/2 (5/13/2), M1a/M1b/M1c: 1/1/18 (90%), and prior systemic therapy regimens 0/1/2/3+: 1/7/5/7 were enrolled in the protocol. Sites of systemic disease included: lung (13 pts), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11). 3 pts came of study prior to treatment with rapid disease progression. Treatment related grade 3–4 toxicities included line related (LR) bacteremia (3 pts), LR DVT (3 pts), LR PE (3). There were no grade 3–4 toxicities attributed to paclitaxel or celecoxib. No pt exhibited a major tumor response; 6/20 (30%) pts had stable disease for 17, 18, 18, 18+, 30+, 60 wks. Median TTP was 6 wks (range 3- 60); median overall survival was 6 months (range 1–29). Conclusions: Low-dose, CIV paclitaxel and oral celecoxib leads to disease stabilization in a significant portion of previously treated pts with MM. This suggests a role for combination anti-angiogenic therapy in MM. The incidence of LR toxicities indicates that alternative microtubule inhibitors, such as oral taxanes, should be considered in combination with COX-2 inhibitors for future studies. Results of biomarker studies will be presented at the meeting. Supported by Pfizer Inc. and NIH R21 CA097730. [Table: see text]

Abstract Introduction. Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular antitumor immune responses and tumor selectivity. VV1 also contains the human sodium iodide symporter (NIS) as an imaging gene. We report here the novel use of virus-encoded IFNβ as a PD marker using correlative data from three Phase I trials of VSV-IFNβ-NIS in patients with refractory cancers (n=46). Methods. 46 patients with solid tumors (n=34) and hematological malignancies (n=12) received 1 dose of VV1 either intratumorally (ITu) or intravenously (IV) at doses ranging from 3 x 106 to 5 x 1010 TCID50. Plasma IFNβ levels were collected pre-treatment, 4 hours post-infusion, Day 2 (24-hour), Day 3, 8, 15 and 29 (IT only). Samples were processed using a standard IFNβ specific ELISA kit. Results. ITu dose escalation is complete with 27 patients treated and no DLTs. IV escalation is ongoing at 5 x 1010 TCID50 with 19 patients treated to date. In the ITu study, plasma IFNβ levels at 24h were undetected at the lowest dose levels (up to 1 x 107 TCID50), and became detectable from 3 x 107 TCID50. In the IV patients, IFNβ was detectable at all dose levels (5 x 109 through 5 x 1010 TCID50) with the highest peak and longest duration in a patient with metastatic endometrial cancer coincident with shrinkage of multiple tumors. The IFNβ produced by virus-infected cells can be differentiated from the acute innate antiviral responses by magnitude of response and AUC as the majority of the inflammatory cytokines returned to baseline by 48h. Peak IFNβ levels were variable between patients, likely reflecting heterogeneity in tumor susceptibility to VV1, ranging from 1.4pg/mL to 656pg/mL across 6 patients (mean 153pg/ml) at the highest ITu dose. Plasma IFNβ 24 hours post-therapy of >20pg/mL appears to predict for RECIST 1.1-evaluated SD vs PD, p=0.048 in the ITu patients. Peak IFNβ ranged from 18 to 1700 pg/mL across 9 patients (mean=442pg/ml) at 1.7 x 1010 in the IV study. Peak IFNβ was highest in two cases of endometrial cancer (1500 and 1700 pg/ml). The patient with the highest IFNβ levels on the IV trial showed 16.7% tumor shrinkage at the first tumor evaluation. SPECT imaging, which shows location of viral replication, was positive in 50% of ITu injected tumors, also validating of VV1 infection of target cells. To date, SPECT images were negative in the IV trial despite IFNβ positivity, reflecting IFNβ as a more sensitive PD marker of viral infection. IHC staining of tumor biopsies collected pre-treatment and 1 month after VSV showed increased numbers of CD3, CD8, CD68, PDL1 or PD1 in some injected or noninjected tumors. Other immune markers and tumor gene signatures are also being evaluated. Conclusions. Plasma IFNβ has emerged as a simple and convenient biomarker of viral replication in tumors. IFNβ will be used in future studies as a PD marker to assess the impact of immune-modulating combination drugs with VV1. Citation Format: Timothy P. Cripe, Jamie Bakkum-Gamez, Jaime R. Merchan, Martha Q. Lacy, Manish R. Patel, Steven Powell, James Strauss, Lianwen Zhang, Toshie Sakuma, Memy Diaz, Nandakumar Packiriswamy, Deepak Upreti, Bethany Brunton, Dragan Jevremovic, Stephen J. Russell, Alice Bexon, Kah-Whye Peng. Rational design of an oncolytic virus permits use of interferon beta as a pharmacodynamic marker for clinical application [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 CT090.

Abstract Introduction Voyager-V1TM is derived from VSV, a bullet-shaped negative sense RNA virus with very low human seroprevalence; it is engineered to selectively replicate in and kill human cancer cells. Voyager-V1 encodes the human IFNβ gene to boost antitumoral immune responses and the thyroidal sodium iodide symporter NIS gene to permit noninvasive imaging of virus spread. FIH studies are underway via both IV and IT routes. Here we report safety and preliminary correlative data from the FIH IT study. Methods and objectives This is a classical 3+3 phase 1 design, using escalating single IT viral doses from 3 x 106 to 3 x 109 TCID50 into one target lesion. The primary objective is safety and tolerability, monitored by committee. Other objectives include PK by RT-PCR for viral genomes, serum IFNβ levels, Tc-99m SPECT/CT imaging to monitor virus infection in injected lesions, peripheral blood immunophenotyping with 11-color flow cytometry for activation markers on T cells, T-regs, NK cells, and MDSCs, and serial biopsies to assess the tumor microenvironment (TME). IHC was performed on tumor biopsies for CD3, CD8, CD4, FoxP3, CD68, PD-1 and PDL-1 pre and post treatment in non-injected and injected lesions. CD45 staining is ongoing. Results Dose level 3 is ongoing (n=8+). No DLTs have been observed to date. Most patients were male (75%), white (100%), with ECOG PS1 (75%) and a median of >6 lines of prior systemic therapy. AEs (in 63% patients) reported as related to study drug were mild-moderate, short-lived, and consisted of G1 fever, chills, hot flashes, nausea, vomiting, hyperhidrosis and G2 fatigue. Most patients had some mild AEs (pain, bruising, subclinical pneumothorax) related to biopsy and IT injection procedures and one had an SAE related to biopsy (G2 pneumothorax). There was no difference in incidence, intensity or duration of related AEs between dose levels so far. In patients analyzed to date, at the first three dose levels of 3 x 106, 1 x 107 and 3 x 107 TCID50 (n=7), viremia and serum IFNβ were below levels of detection after IT injection. There is evidence in all patients of an increase in PD-1 expression on CD4 and CD8 T cells, suggesting T cell activation post- single virus injection. One patient at dose level 2 had increased CD4 and CD8 T cells in the peripheral blood. TME analysis revealed increased infiltration of CD3 and CD8 cells in tumors of some patients. In addition, there are changes in numbers of FoxP3 and CD68 positive cells in the injected lesions compared to the pre-treatment and non-injected lesion. Two patients at dose level 3, one with an injected adrenal metastasis of colorectal cancer and another with a chest wall lesion from a head of pancreas primary, have positive SPECT/CTs on days 3-15 showing viral replication in tumor plus concomitant lymphocyte/neutrophil trafficking in the periphery. Conclusions IT injection of a single dose of the novel oncolytic virotherapy Voyager-V1 has proven safe at doses up to 3 x 107 TCID50. There was evidence of T cell activation with increased PD-1 expression in peripheral blood lymphocytes after a single IT injection. Tumor biopsies indicate increased lymphocyte infiltration. Two patients at the highest dose tested show signs of viral replication in the injected lesion plus evidence of systemic impact on leukocyte populations. Citation Format: Steven Powell, Manish R. Patel, Jaime R. Merchan, Timothy P. Cripe, James Strauss, Rosa M. Diaz, Nandakumar Packiriswamy, Bethany A. Brunton, Deepak Upreti, Rehan Khan, Lukkana Suksanpaisan, Rianna Vandergaast, Stephen J. Russell, Alice S. Bexon, Kah Whye Peng. Preliminary correlative and clinical data from a first-in-human (FIH) study of the intratumoral (IT) oncolytic virotherapy, Voyager-V1, in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT051.

AbstractBackgroundRecombinant vesicular stomatitis virus expressing interferon‐β (VSV‐IFN‐β) has demonstrated antitumor activity in vitro and in vivo. In preparation for clinical testing in human squamous cell carcinoma (SCC) of the head and neck, we conducted preclinical studies of VSV‐IFN‐β in syngeneic SCC models.MethodsIn vitro, VSV‐IFN‐β (expressing rat or mouse interferon [IFN]‐β)‐induced cytotoxicity and propagated in rat (FAT‐7) or mouse (SCC‐VII) SCC cells during normoxia and hypoxia. In vivo, intratumoral administration of VSV‐rat‐IFN‐β or VSV‐human‐IFN‐β in FAT‐7 bearing or non‐tumor bearing immunocompetent rats did not result in acute organ toxicity or death.ResultsVSV‐r‐IFN‐β replicated predominantly in tumors and a dose dependent anti‐VSV antibody response was observed. Intratumoral or intravenous administration of VSV‐IFN‐β resulted in growth delay and improved survival compared with controls.ConclusionThe above data confirm safety and feasibility of VSV‐IFN‐β administration in immunocompetent animals and support its clinical evaluation in advanced human head and neck cancer. © 2014 Wiley Periodicals, Inc. Head Neck 36: 1619–1627, 2014