BACKGROUND:New treatment options are needed for patients with metastatic anti-programmed cell death 1 (PD-1)-resistant melanoma. The final analysis of a phase 1b study evaluating the Toll-like receptor 9 agonist vidutolimod is reported here. METHODS:This two-part, open-label, multicenter, phase 1b study in adults with metastatic/unresectable anti-PD-1-resistant melanoma evaluated the safety and clinical activity of intratumoral vidutolimod plus systemic pembrolizumab (part 1) or vidutolimod alone (part 2). Two vidutolimod formulations were evaluated with different concentrations of polysorbate (PS20-A, 0.005%-0.01% polysorbate 20; PS20-B, 0.00167% polysorbate 20). Key end points were safety and investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors, version 1.1). RESULTS:A total of 159 patients were treated in part 1 (PS20-A, n = 98; PS20-B, n = 61), and 40 patients were treated in part 2. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% of patients. Grade ≥3 TEAEs occurred in 55.3% (part 1) and 37.5% (part 2) of patients. No treatment-related deaths occurred. Best ORR was 23.5% (95% CI, 15.5%-33.1%; complete response [CR], 7.1%) for vidutolimod PS20-A plus pembrolizumab, 11.5% (95% CI, 4.7%-22.2%; CR, 1.6%) for vidutolimod PS20-B plus pembrolizumab, and 20.0% (95% CI, 9.1%-35.6%) for vidutolimod monotherapy. Median duration of response was 25.2 months with vidutolimod PS20-A plus pembrolizumab, 11.4 months with vidutolimod PS20-B plus pembrolizumab, and 5.6 months with vidutolimod monotherapy. CONCLUSIONS:Vidutolimod PS20-A alone or in combination with pembrolizumab had an acceptable safety profile and promising clinical activity in patients with PD-1 blockade-resistant melanoma.

Intratumoral TLR9 agonists and anti-PD-1 produce clinical responses and broad immune activation. We conducted a single-arm study of neoadjuvant TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in high-risk resectable melanoma. In 31 evaluable patients, 55% major pathologic response (MPR) was observed, meeting primary endpoint. MPR was associated with necrosis, and melanophagocytosis with increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+CD8+ T cells peripherally. MPRs had an enriched pre-treatment gene signature of myeloid cells, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. MPRs gut microbiota were enriched for Gram-negative bacteria belonging to the Bacteroidaceae and Enterobacteriaceae families and the small subgroup of Gram-negative Firmicutes. Our findings support that combined vidutolimod and nivolumab stimulates a broad anti-tumor immune response and is associated with distinct baseline myeloid gene signature and gut microbiota. ClinicalTrials.gov identifier: NCT03618641.

Importance:The effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown. Objective:To determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial. Design, Setting, and Participants:Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history). Interventions:Participants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days. Main Outcomes and Measures:The primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction-positive, or toxigenic culture-positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic. Results:Baseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants' median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo). Conclusions and Relevance:Among adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings. Trial Registration:ClinicalTrials.gov Identifier: NCT03788434.

Background and aims: Anti–PD-(L)1 monotherapy is the preferred treatment for patients with advanced Merkel cell carcinoma (MCC), but many patients do not respond. Vidutolimod, a CpG-A Toll-like receptor 9 agonist packaged in a noninfectious virus-like particle, bridges innate and adaptive immunity to induce antitumor responses. Intratumoral vidutolimod with systemic anti–PD-1 showed promising clinical activity and a manageable safety profile in several studies in patients with melanoma, both in the treatment-naïve and in anti– PD-1 refractory settings. This combination is therefore being investigated in patients with non-melanoma skin cancers, including MCC. Methods: CMP-001-009 (NCT04916002) is an open-label, multicenter, phase 2 study investigating the clinical activity and safety of intratumoral vidutolimod with systemic anti–PD-1 in adult patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cohort A), MCC (cohort B), or triple-negative breast cancer (cohort C). Inclusion in cohort B requires histopathologically confirmed diagnosis of locally/regionally advanced or metastatic MCC, ECOG PS 0/1, measurable disease per RECIST v1.1, and ≥1 lesion amenable to repeated intratumoral injection. Cohort B2 enrolls ∼23 patients with disease progression on anti–PD-(L)1 therapy or within 3 months of discontinuation; cohort B1 will enroll ∼39 patients who have not received prior systemic therapy for MCC. Patients who have received radiation within 2 weeks or systemic corticosteroids (>10 mg/day prednisone) within 30 days of study drug initiation, or who had immune-mediated adverse events leading to discontinuation of anti–PD-1 therapy are excluded. Enrolled patients will receive intratumoral vidutolimod 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. All patients will also receive intravenous cemiplimab (anti–PD-1) 350 mg Q3W. Treatment will continue for ≤2 years or until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed objective response rate per RECIST v1.1. Secondary endpoints include safety, duration of response, progression-free survival, overall survival, and responses in injected and noninjected lesions (all per RECIST v1.1). Clinical activity will also be assessed using immunotherapy RECIST. See ClinicalTrials.gov/NCT04916002 for enrolling sites. Results: Pending. Conclusions: Pending

Background Neoadjuvant PD-1 blockade produces major pathological responses (MPR) in ~30% of patients (pts) with high-risk resectable MEL with durable relapse-free benefit, and increased circulating activated CD8+ T cells.1,2 Vidutolimod (vidu) comprises a CpG-A oligodeoxynucleotide packaged within a virus-like particle (VLP) and is designed to activate tumor-associated plasmacytoid dendritic cells (pDC) via TLR9, inducing an IFN-rich tumor microenvironment and anti-tumor CD8+ T cell responses. Vidu/anti-PD-1 resulted in durable tumor responses in PD-1 refractory MEL.3 This phase II study evaluated the pathological, clinical and immunological activities of neoadjuvant vidu/nivo in high-risk stage III B/C/D resectable MEL. Methods Vidu/nivo was administered over 7 weeks (vidu 10mg IT Q1W x7, nivo 240mg Q2W x3) pre-surgery. Post-surgery, vidu/nivo (vidu SC 5mg, nivo 480mg Q4W) was continued for 48 weeks. Primary endpoints included MPR rate, and incidence of DLT. Secondary endpoints were radiographic response, relapse-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS). Pathological response assessment was performed to evaluate % residual volume of tumor (RVT) per consensus criteria4-6 by 3 blinded dermatopathologists: 0% (pCR); 0%50% (pNR). Radiographic response assessed using RECIST v1.1. Serial blood, tumor and stool were collected for correlative analyses. Results 31 pts were enrolled, of whom 30 evaluable for per-protocol (PP) analyses as 1 pt progressed pre-surgery. No DLTs were observed. 8 Gr3 TRAE, including hypertension (7/8) and colitis (1/8) were observed; no delays in surgery occurred. ORR by BICR was 45% (all) and 47% (PP). In PP population, MPR was observed in 57% (17/30) including 47% pCR (14/30) and 10% pMR (3/30). With median follow-up of 26.5 months, median RFS was not reached (table 1). Post-treatment, MPR was associated with increased CD8+ tumor infiltrating lymphocytes (p<0.0001), and peripheral immune activation and pDC activation by multiparameter flow cytometry (p < 0.001). Spatial investigation of immune cell infiltrates by mIHC revealed significantly immune cell infiltrates (p<0.05) and higher pDC (p=0.053) within tumor (but not stroma) of MPRs post-treatment (figure 1a,b). Deconvoluted RNAseq confirmed these findings compared to a control cohort of PD-1 treated MEL. Conclusions Neoadjuvant vidu/nivo has minimal tox and demonstrated promising activity with 47% pCR rate and 57% MPR rate. MPR was associated with improved 1-/2- year RFS (94%/88%), and 1-/2- year DMFS (94%/94%) and 2-year OS (100%). MPR is associated with pDC and immune infiltrate (figure 1c). Further evaluation of this combination is ongoing in an ongoing randomized phase II trial (EA6194, NCT04708418). Acknowledgements We thank and Checkmate Pharmaceuticals for funding and vidutolimod. This research was supported in part by the University of Pittsburgh Center for Research Computing through the resources provided. Specifically, this work used the HTC cluster, which is supported by NIH award number S10OD028483. This research was supported by the Melanoma Research Foundation Breakthrough Consortium (MRFBC) Award (Davar, Stein); NIH R01 CA257265 (Zarour, Davar); and NIH P50 CA254865 (Zarour). Trial Registration Clinical trial information: NCT03618641. References Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018 Nov;24(11):1649–1654. Huang AC, Orlowski RJ, Xu X, et al. A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma. Nat Med. 2019 Mar;25(3):454–461. doi: 10.1038/s41591-019-0357-y. Ribas A, Medina T, Kirkwood JM, et al. Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma. Cancer Discov. 2021 Dec 1;11(12):2998–3007. doi: 10.1158/2159-8290.CD-21-0425. Tetzlaff MT, Messina JL, Stein JE, et al. Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma. Ann Oncol. 2018 Aug 1;29(8):1861–1868. Cottrell TR, Thompson ED, Forde PM, et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Ann Oncol. 2018 Aug 1;29(8):1853–1860. doi: 10.1093/annonc/mdy218. Stein JE, Soni A, Danilova L, et al. Major pathologic response on biopsy (MPRbx) in patients with advanced melanoma treated with anti-PD-1: evidence for an early, on-therapy biomarker of response. Ann Oncol. 2019 Apr 1;30(4):589–596. doi: 10.1093/annonc/mdz019. Ethics Approval The study was approved by University of Pittsburgh9s Institutional Review Board, approval number MOD19040237-002. Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Manipulation of the gut microbiota via fecal microbiota transplantation (FMT) has shown clinical promise in diseases such as recurrent Clostridioides difficile infection (rCDI). However, the variable nature of this approach makes it challenging to describe the relationship between fecal strain colonization, corresponding microbiota changes, and clinical efficacy. Live biotherapeutic products (LBPs) consisting of defined consortia of clonal bacterial isolates have been proposed as an alternative therapeutic class because of their promising preclinical results and safety profile. We describe VE303, an LBP comprising 8 commensal Clostridia strains under development for rCDI, and its early clinical development in healthy volunteers (HVs). In a phase 1a/b study in HVs, VE303 is determined to be safe and well-tolerated at all doses tested. VE303 strains optimally colonize HVs if dosed over multiple days after vancomycin pretreatment. VE303 promotes the establishment of a microbiota community known to provide colonization resistance.

Background: Vidu is a first-in-class CpG-A TLR9 agonist in a virus-like particle that activates plasmacytoid dendritic cells (pDC), thus bridging innate and adaptive immunity. Intratumoral (IT) vidu alone or in combination with intravenous (IV) anti-PD-(L)1 has shown evidence of antitumor activity in pts with anti-PD-(L)1-refractory melanoma or NSCLC. As biomarkers associated with anti-PD-(L)1 response were not predictive of vidu activity, we sought to identify novel transcriptional signatures. Methods: RNA-Seq was performed on baseline biopsies from pts with anti-PD-(L)1-refractory melanoma (NCT02680184; RECIST v1.1 responders [R; n=20]; nonresponders [NR; n=78; 30 pts with stable disease + 48 pts with progressive disease [PD]]) or NSCLC (NCT03438318; N=11) treated with vidu ± anti-PD-(L)1. IFNg18 signature was used to characterize melanomas as non-T cell-inflamed (non-Tinfl), T cell-inflamed (Tinfl), or intermediate. Gene Set Enrichment Analysis (GSEA) using MSigDB and other signatures (>19,000) was performed on non-Tinfl melanoma in R vs NR (false discovery rate [FDR] <0.25). Deconvolution of immune cells was performed using TIMER2.0. Prediction models were generated using QLattice. Signatures were characterized using both publicly available bulk and single-cell (sc) RNA-Seq datasets of pDC subsets or PD-1/CTLA-4 blockade response datasets. Results: GSEA on non-Tinfl melanoma biopsies revealed 2 gene signatures (COPII vesicle and Golgi targeting) most strongly associated with R (FDR <0.16). Leading edge analysis of these signatures identified 35 common core genes (CC) that strongly differentiated RECIST 1.1 R vs PD. As independent validation, CC enrichment was also significantly associated with R in intermediate melanoma (p=0.009) and with tumor shrinkage in NSCLC (p=0.027). CC was significantly associated with R to vidu single-agent or combination treatment, but not with clinical baseline prognostic factors or IFNg18. In Tinfl melanoma, CC was not associated with R, but myeloid signatures were significantly associated with NR. A model based on CC and transcription factor ELF2 predicted R in melanoma (AUC 0.93 [95% CI 0.82-1.00]). In public datasets, CC was not associated with R to PD-1/CTLA-4 blockade, but CC was highly expressed in the type I interferon-secreting subset of pDCs and some myeloid cells. CC expression was prevalent in most tumor types and was independent of IFNg18 in TCGA. Conclusion: In pts with anti-PD-1-refractory melanoma or NSCLC, transcriptional signatures of COPII vesicle and Golgi targeting (functionally related to TLR9 activation) were associated with antitumor activity of IT vidu ± IV anti-PD-(L)1. Ongoing bulk and sc RNA-Seq analyses may clarify the underlying biology and the signature’s potential role as a predictive biomarker for clinical response to vidu. Citation Format: Hong Liu, Luping Zhao, Ping Zheng, Riyue Bao, Jason J. Luke, Marcelo V. Negrao, Shakoora A. Sabree, George J. Weiner, Sujatha Kumar, Dmitri Bobilev, James E. Wooldridge, Arthur M. Krieg. Novel transcriptional signatures associated with antitumor activity in vidutolimod (vidu)-treated patients (pts) with anti-PD-1-refractory melanoma and non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB107.

Background There are limited therapeutic options for patients with progressive disease (PD) on or after PD-1–blocking antibody therapy. Vidutolimod (CMP-001) is a first-in-class, immunostimulatory virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist. This phase 1b study evaluated the safety and clinical activity of intratumoral vidutolimod with and without pembrolizumab in patients with refractory melanoma. Methods This two-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled adults with histologically confirmed metastatic or unresectable cutaneous melanoma who had stable disease after ≥12 weeks or PD on anti−PD-1 treatment, measurable disease per RECIST v1.1, ECOG PS 0/1, and ≥1 lesion accessible for intratumoral injection. Part 1 evaluated vidutolimod + pembrolizumab and Part 2 evaluated vidutolimod monotherapy. Key objectives included assessment of safety and clinical activity, and exploratory analyses were performed on available tumor biopsies using immunohistochemistry and RNAseq. Results At data cutoff (August 17, 2021), 159 patients had enrolled in Part 1 and 40 patients in Part 2. The median age was 64 years in Part 1 (range, 30-90) and 68 years in Part 2 (range, 30-89). Most patients had PD as their last response to prior anti–PD-1 therapy (Part 1, 93.1%; Part 2, 80.0%). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 37.1% of patients treated with vidutolimod + pembrolizumab and in 22.5% of patients treated with vidutolimod monotherapy. No treatment-related deaths occurred. Based on the efficacy data presented in Table 1, vidutolimod polysorbate 20 (PS20) A was selected for further development as this formulation in combination with pembrolizumab had a best objective response rate (ORR; RECIST v1.1) of 23.5%, with a median duration of response (DOR) of 25.2 months. Vidutolimod monotherapy had an ORR of 20.0%, with a median DOR of 5.6 months. Exploratory translational analyses identified association of unique biomarkers with response among patients with T cell–inflamed versus non-T cell–inflamed tumors at baseline. Conclusions Promising clinical activity was observed with vidutolimod + pembrolizumab and vidutolimod monotherapy in patients with PD-1 blockade–refractory melanoma. A manageable safety profile was observed. The DOR with vidutolimod + pembrolizumab was substantially longer than with vidutolimod monotherapy. Clinical studies to confirm the efficacy of vidutolimod + PD-1 blockade in patients with previously untreated unresectable/metastatic melanoma (phase 2/3, NCT04695977) or PD-1 blockade–refractory melanoma (phase 2, NCT04698187) are ongoing. Acknowledgements This work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Steffen Biechele, PhD (ApotheCom, San Francisco, CA, USA), and funded by Checkmate Pharmaceuticals. Trial Registration NCT02680184 Ethics Approval This study was approved by the WCG-WIRB; WIRB approval tracking number: 20152597.

Abstract Background In the treatment-naive setting, PD-1 blockade is associated with greater response in T cell-inflamed vs non-T cell-inflamed tumors. CMP-001 is a CpG-A oligonucleotide TLR9 agonist in a virus-like particle that is hypothesized to activate tumor-associated plasmacytoid dendritic cells (pDCs) to secrete type I interferons. Through this activity, CMP-001 may convert the tumor microenvironment to a Th1-like chemokine milieu (eg, increased CXCL10) and induce an antitumor CD8+ T-cell response. We have recently reported that intratumoral injection of CMP-001 + IV pembrolizumab (pembro) had an acceptable safety profile and can reverse PD-1 blockade resistance in patients (pts) with melanoma (Milhem et al, SITC 2019). Regression was observed in injected and uninjected lesions. Herein we report pharmacodynamic and translational data. Methods This 2-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled pts with metastatic/unresectable melanoma and stable disease (SD) or progressive disease (PD) on/after anti−PD-1 therapy. In part 1 (3+3 dose-escalation and dose-expansion), pts received CMP-001 + pembro. In part 2, pts received CMP-001 monotherapy. Determination of safety and clinical activity were the study's main objectives. Prespecified pharmacodynamic and translational studies evaluated serum chemokines and evaluated tumor biopsies using RNA and/or whole exome sequencing and immunohistochemistry for PD-L1 (reported as H-score), CD8, and CD303 (pDC marker). Results As of September 30, 2020, 159 pts (part 1) and 40 pts (part 2) have been treated. A greater median fold increase of serum CXCL10 (a marker of innate immunity, n=40) was observed in responders (R) to CMP-001 + pembro (18.8x) vs nonresponders (NR) after treatment (9.9x in SD; 6.15x in PD; differences were not statistically significant). Preliminary analyses showed that interferon gene expression distinguished R vs NR. Tumor biopsy analyses (part 1, n=139; part 2, n=34) showed that pts with high PD-L1, high CD8+ T cells, or inflamed transcriptional signatures at baseline were less likely to respond to CMP-001 + pembro vs pts without inflammation markers at baseline. Baseline mean PD-L1 expression (H-score) was 8.1 in R (n=10) vs 21.8 in NR (n=49). Posttreatment biopsies generally showed increased PD-L1, CD8+ T cells, and inflamed transcriptional signatures in R vs NR. Neither tumor mutational burden nor baseline pDC density distinguished R vs NR. Conclusions In pts with anti-PD-1 refractory melanoma, intratumoral CMP-001 ± pembro appears to disproportionately induce antitumor responses in noninflamed tumors. Clinical response to CMP-001 ± pembro was associated with induction of markers of both innate and adaptive antitumor immunity. Citation Format: Jason John Luke, Riyue Bao, John M. Kirkwood, Yousef Zakharia, Diwakar Davar, Elizabeth Buchbinder, Theresa Medina, Adil Daud, Antoni Ribas, Jiaxin Niu, Geoffrey Gibney, Kim Margolin, Anthony J. Olszanski, Inderjit Mehmi, Takami Sato, Montaser Shaheen, Aaron Morris, Dmitri Bobilev, Katie Campbell, George Weiner, James E. Wooldridge, Arthur M. Krieg, Mohammed Milhem. CMP-001 demonstrates improved response in noninflamed anti-PD-1 refractory melanoma and response is associated with serum CXCL10 [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 CT032.

TPS6089 Background: PD-1 blockade ± chemotherapy has recently become a primary systemic therapy recommended by NCCN guidelines for patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, most pts still do not respond to treatment, indicating a large unmet need for pts with unresectable disease. CMP-001 is a toll-like receptor 9 (TLR9) agonist comprising a CpG-A oligodeoxynucleotide packaged in a virus-like particle that can induce type I interferon secretion from tumor-associated plasmacytoid dendritic cells, promoting a Th1-like chemokine milieu in the tumor microenvironment and inducing an antitumor CD8+ T-cell response. In a phase (ph) 1b study in pts with metastatic melanoma, intratumoral (IT) injection of CMP-001 + intravenous (IV) pembrolizumab (pembro) reversed PD-1 blockade resistance, induced responses in injected and noninjected lesions, and had an acceptable safety profile (Milhem et al, SITC 2020). This combination is therefore being tested in pts with HNSCC. Methods: CMP-001-007 (NCT04633278) is an open-label, multicenter, ph 2 study designed to investigate the efficacy and safety of CMP-001 + IV pembro in adult pts with histologically or cytologically confirmed R/M HNSCC considered incurable by local therapies. Eligible pts have undergone a pretreatment tumor biopsy, received no prior systemic therapy in the R/M setting, and have primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. In addition, pts must have PD-L1-positive tumors (combined positive score ≥1), known tumor human papillomavirus (HPV) status (for oropharyngeal cancer), and measurable disease per RECIST v1.1 with ≥1 lesion amenable to IT injection. Pts with primary tumors in the nasopharynx are excluded. Enrolled pts will receive CMP-001 10 mg once weekly for 7 doses and every 3 weeks (Q3W) thereafter. The first dose may be administered subcutaneously or via IT injection, with all subsequent doses administered IT. All pts will also receive pembro 200 mg IV Q3W after the CMP-001 injection. Treatment continues until unacceptable toxicity or disease progression. The primary endpoint is investigator-assessed objective response rate (ORR) per RECIST v1.1. Secondary endpoints include safety, duration of response (DOR), progression-free survival (PFS), overall survival, and effects of HPV infection and PD-L1 expression on ORR, DOR, and PFS. Exploratory endpoints include analyses of baseline and changes from baseline in tumor or serum biomarkers related to TLR9, immune checkpoints, and potential predictors of response, as well as serum concentrations of CXCL10 and CMP-001. Refer to clinicaltrials.gov/ct2/show/NCT04633278 for the most current information on enrolling sites. Clinical trial information: NCT04633278.

Abstract Background: Gut microbiome composition affects response to PD-1 blockade; and recent proof of concept studies suggest that gut microbiome manipulation is effective in reversing resistance to PD-1 blockade. VE800 is an oral live biotherapeutic consisting of 11 distinct non-pathogenic, non-toxigenic, commensal bacterial strains manufactured in lyophilized form. VE800 induces CD8+ T cell infiltrate into tumors; and significantly enhances anti-tumor activity of PD-1 blockade preclinically in multiple tumor models in a CD103+ dendritic cell and major histocompatibility (MHC) class I dependent fashion (Tanoue et al., 2019). Retrospective analysis of cancer patient's (pt) samples also suggests that greater VE800 strain abundance is associated with improved response to PD-1 blockade. The objective of this phase I study is to evaluate the safety, tolerability, and clinical activity of VE800 administered orally in combination with nivolumab in pts with select cancers. Methods: CONSORTIUM-IO (NCT04208958) is an open-label, first-in-human study evaluating VE800 and nivolumab combination in pts with anti-PD-1/PD-L1 relapsed/refractory melanoma, anti-PD-1/PD-L1 naïve gastric/gastroesophageal junction (GEJ) adenocarcinoma and anti-PD-1/PD-L1 naïve microsatellite-stable (MSS) colorectal cancer. Following a 5-day course of oral vancomycin 125mg QID, VE800 will be administered daily along with nivolumab (480mg Q4W). A single dose level of VE800 will be evaluated. In the interests of maximizing safety, a Simon 2-stage design will be used for each disease cohort. Although no dose-limiting toxicities (DLT) are expected, the first 3 pts will be enrolled serially 1 week apart; and safety data of the first 6 pts will be reviewed prior to further accrual. Pts will continue to receive VE800/nivolumab combination until disease progression or unacceptable toxicity. Primary endpoints include safety, tolerability; and clinical activity by objective response rate (ORR) per RECIST v1.1. Secondary endpoints include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS); and metagenomic strain-level analysis of degree/duration of VE800 strain colonization. Exploratory endpoints include tumor and blood immunophenotyping, serum/stool metabolomics and global changes in fecal microbiome composition. CONSORTIUM-IO is currently actively enrolling pts. Citation Format: Diwakar Davar, Judy S. Wang, Michael Cecchini, Zev Wainberg, Martin Gutierrez, Anita Turk, Rose Szabady, Jason Norman, Bernat Olle, Bruce Roberts, Dmitri Bobilev. Consortium-IO: A safety and efficacy study of VE800 in combination with nivolumab in previously treated patients with select advanced metastatic cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT246.

Background Gut microbiota alterations and resulting functional changes in metabolites involved in colonization resistance and host responses, including bile acids (BA) and short chain fatty acids (SCFA), are hallmarks of C. difficile infection.VE303, a first-in-class drug being developed for the prevention of rCDI, is a rationally defined bacterial consortium manufactured under GMP conditions.VE303 comprises 8 distinct Clostridium species, the commensal bacteria associated with clinical response in FMT, that suppresses C. difficile growth in vitro and improves survival in CDI models.Methods A first-in-human Phase 1 dose-escalation study assessed the safety and tolerability of VE303 in healthy volunteers (HV) after vancomycin (vanco)-induced dysbiosis.VE303 strain abundance, colonization dynamics, and restoration of the resident gut microbiota and metabolites post-vanco were analyzed.Results HV received oral vanco for 5 days followed by VE303 capsules at escalating doses (total dose range 1.6 × 10 9 to 1.1 × 10 11 CFU).VE303-related AEs were observed in 33% of HV, all Grade 1 and transient.Most of these AEs were gastrointestinal.A pharmacokinetics analysis indicated that VE303 expanded 10-100-fold within 2 days after dosing and had a C max (peak relative abundance of all VE303 strains) of 24% and T max of 15 days at the highest dose.Durable colonization was observed with a total VE303 strain abundance averaging at 2-4% at 12 months in multidose cohorts with a 10-fold increase in AUC compared to the single dose cohorts.When compared with the vanco-only cohort, VE303 led to earlier and more complete recovery of beneficial taxa (eg, Bacteroidetes, Firmicutes), reduction in pathobiont taxa (eg, Proteobacteria), and recovery of the secondary BA and SCFA pools.Conclusion The VE303 bacterial consortium was safe and well tolerated.Rapid, robust, abundant and durable colonization is achieved with the multidose schedule of VE303.VE303 was associated with early restoration of colonization resistance including recovery of microbiota composition, bile acid and SCFA pools after vanco-induced dysbiosis.

ImportancePatients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited.ObjectiveTo evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.Design, Setting, and ParticipantsThe TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019.InterventionsThe recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.Main Outcomes and MeasuresThe primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis.ResultsFourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment.Conclusions and RelevanceNiraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.Trial RegistrationClinicalTrials.gov identifier: NCT02657889.

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers in non-small-cell lung cancer (NSCLC). TSR-011 is a dual ALK and tropomyosin-related kinase (TRK) inhibitor, active against ALK inhibitor resistant tumours in preclinical studies. Here, we report the safety, tolerability and recommended phase 2 dose (RP2D) of TSR-011 in patients with relapsed or refractory ALK- and TRK-positive advanced cancers. In this sequential, open-label, phase 1 trial (NCT02048488), patients received doses of 30 mg, escalated to 480 mg every 24 hours (Q24h), followed by an expansion cohort of patients with ALK-positive cancers. The primary objective was to evaluate safety and tolerability. Secondary objectives included pharmacokinetics. TSR-011 320- and 480-mg Q24h doses exceeded the maximum tolerated dose. At the RP2D of 40 mg every 8 hours (Q8h), the most common grade 3–4 treatment-emergent adverse events occurred in 3.2–6.5% of patients. Of 14 ALK inhibitor-naive patients with ALK-positive NSCLC, 6 experienced partial responses and 8 had stable disease. At the RP2D (40 mg Q8h), TSR-011 demonstrated a favourable safety profile with acceptable QTc changes. Limited clinical activity was observed. Based on the competitive ALK inhibitor landscape and benefit/risk considerations, further TSR-011 development was discontinued. NCT02048488.

Abstract Background Gut microbiota alterations and resulting changes in metabolites involved in colonization resistance and host responses, including bile acids (BA) and short-chain fatty acids (SCFA), are hallmarks of C. difficile infection. Reduction in rCDI was shown with fecal microbiota transplants (FMT), but FMT has limitations for routine use and carries unforeseen risks. VE303 is a first-in-class drug being developed for prevention of rCDI consisting of a rationally defined bacterial consortium manufactured under GMP conditions. VE303 comprises 8 distinct species belonging to Clostridium clusters IV, XIVa, and XVII, the commensal bacteria associated with clinical response in FMT, suppress C. difficile growth in vitro and improve survival in vivo. Methods A first-in-human Phase 1 dose-escalation study assessed safety and tolerability of VE303 in HV after vanco-induced dysbiosis. PK (strain colonization and durability) and PD (restoration of the resident microbiota, SCFA pool, and BA pool) were evaluated by metagenomic sequencing and metabolomics analysis of fecal material. Results HV (N = 23) received oral vanco 125 mg QID for 5 days followed by VE303 capsules at escalating single then multiple doses (total dose range 1.6 × 109 to 1.1 × 1011 CFU). VE303-related AEs, mostly gastrointestinal, all Grade 1 and transient, were observed in 35% of HV. Colonization with VE303 strains was abundant, durable (detected at 24 weeks), and dose-dependent. VE303 rapidly expanded 10- to 100-fold and each strain was detectable within 2 days after dosing. VE303 enhanced subjects’ microbiota and metabolic recovery after vanco treatment. When compared with the vanco-only cohort (N = 5), VE303 led to earlier and more complete recovery of beneficial taxa (eg, Bacteroidetes, Firmicutes), reduction in inflammatory taxa (e.g., Proteobacteria) (Figure 1.), and recovery of the secondary BA and SCFA pools. Conclusion VE303, a rationally designed microbial consortium, was safe, well tolerated, and efficiently restored microbiome composition after antibiotic-induced dysbiosis in a dose-dependent manner. VE303 was associated with early recovery of key PD markers of response, including microbiota composition, bile acid, and SCFA pools. A Phase 2 study of VE303 for prevention of rCDI is underway (NCT03788434). Disclosures All Authors: No reported Disclosures.