A phase II, open label, randomized, noncomparative study of eFT508 (tomivosertib) alone or in combination with avelumab in subjects with relapsed/refractory microsatellite stable colorectal cancer (MSS CRC).

e14145 Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of solid tumors. Tomivosertib (T), a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, selectively regulating translation of a set of mRNAs. Preclinically, T triggers an anti-tumor immune response and enhances responses to checkpoint inhibitors. Avelumab is a fully human checkpoint inhibitor antibody directed against PD-L1. Methods: Part 1: In a 3+3 dose escalation patients (pts) with MSS CRC failing ≥2 prior therapies for metastatic disease received escalating doses of T, administered orally bid, with a fixed dose of 10 mg/kg avelumab q2w. Part 2: Pts were randomized (2:1) to combination therapy at the recommended phase 2 dose (RP2D) from part 1 or T alone. Primary endpoint is objective response rate. All pts have a pretreatment and on treatment biopsy to evaluate target engagement, tumor infiltrating lymphocytes and biomarkers of immune activation. Results: The RP2D for the combination was 200 mg bid T (single agent RP2D) with 10mg/kg avelumab q2w. At this dose level, 1 of 7 pts experienced a dose limiting toxicity being unable to complete the first 28 day cycle due to low grade (1/2) toxicities (nausea, fatigue, myalgia). In part 2, 30 pts were randomized to combination and 15 to monotherapy (25 male, 20 female: mean age 53.9 years, range 32-80 years). The most common adverse events, irrespective of causality were grade 1/2 gastrointestinal (including nausea, vomiting, abdominal pain, constipation and diarrhea) occurring in 77% (n = 23) of the combination and 67% (n = 10) of the monotherapy arm. Toxicities occurring more frequently in the combination arm included diarrhea, constipation, fatigue, myalgia/arthralgia, hypercalcemia and skin rash. Efficacy evaluation is pending from part 2. One pt with confirmed MSS status in part 1 treated at the RP2D achieved a confirmed Partial Response of greater than 8 months. Conclusions: Preliminary data suggest that the combination of T and avelumab has an acceptable safety profile with robust target engagement and demonstrated initial signs of activity. Updated efficacy and biological biopsy data will be presented at the conference. Clinical trial information: NCT03258398.

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353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0353 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A378-A378

Author(s):

Antonio Jimeno ◽

Sophie Papa ◽

Missak Haigentz ◽

Juan Rodríguez-Moreno ◽

Julian Schardt ◽

...

Keyword(s):

Cell Therapy ◽

Checkpoint Inhibitors ◽

Adoptive Cell Therapy ◽

Single Agent ◽

Objective Response ◽

Tumor Resection ◽

Tumor Infiltrating Lymphocytes ◽

Open Label ◽

Safety And Efficacy ◽

Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

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BXCL701, first-in-class oral activator of systemic innate immunity pathway, combined with pembrolizumab (Keytruda) in men with metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.124 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 124-124

Author(s):

Rahul Raj Aggarwal ◽

Dan Costin ◽

Jingsong Zhang ◽

Lawrence Ivan Karsh ◽

Diane I. Healey ◽

...

Keyword(s):

Prostate Cancer ◽

Single Agent ◽

Objective Response ◽

Fixed Dose ◽

Low Grade ◽

Phase 2 ◽

2Nd Generation ◽

Cytokine Activation ◽

Signaling Inhibitors ◽

Phase 1B

124 Background: BXCL701 (talabostat), oral small molecule inhibitor of dipeptidyl peptidases (DPP), primarily DPP8 and DPP9, triggers inflammasome mediated pyroptosis in macrophages, leading to induction of IL-18 and IL-1ß, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients with Stage IV melanoma (unpublished). Methods: Eligible patients included in Phase 1b portion of this multicenter study, had progressing mCRPC (PCWG3), ≥1 prior systemic therapy, ≤2 lines of cytotoxic chemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancer therapy. In Phase 2 portion, patients with adenocarcinoma must have received 1 or 2 2nd generation androgen signaling inhibitors; patients with SCNC/t-NEPC must have received ≥1 prior line of chemotherapy. Patients received fixed-dose pembrolizumab (200 mg IV q21-days) with BXCL701 on days 1-14 at recommended Phase 2 dose (RP2D)/schedule. Primary endpoint is Composite Response (RECIST 1.1, PSA, CTC). Change in relevant immune effector cells was also evaluated. Results: In Phase 1b portion 13 patients were treated with BXCL701 in 3 cohorts: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 patients had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer phenotype. Prior treatment included androgen deprivation therapy (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), radiation therapy (n = 11). On-target adverse events (AEs) consistent with cytokine activation were seen at highest dose levels. In 0.6 mg qd cohort, all patients had events consistent with cytokine release syndrome: 3/3 had hypotension, including 1 grade 3 syncope—dose-limiting toxicity (DLT)—and 2 patients each had dizziness and lower extremity edema. Splitting 0.6 mg dose improved tolerability while maintaining total daily dose (TDD) previously associated with objective response; 3/7 patients had fatigue, and 1 patient each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 patient achieving a PSA response and 4 patients with RECIST1.1 stable disease. Consistent dose and time dependent increases in serum IL-18 levels were observed. Conclusions: BXCL701 0.3 mg BID (0.6mg TDD) administered on days 1-14 was identified as RP2D when administered with pembrolizumab 200 mg every 21 days. Splitting TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other AEs of interest e.g. hypotension and peripheral edema. Preliminary data from Phase 2 portion will be presented. Clinical trial information: NCT03910660.

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Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.440 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 440-440 ◽

Cited By ~ 7

Author(s):

Petros Grivas ◽

Yohann Loriot ◽

Susan Feyerabend ◽

Rafael Morales-Barrera ◽

Min Yuen Teo ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Parp Inhibitor ◽

Single Agent ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Clinical Activity ◽

Open Label ◽

Platinum Based Chemotherapy ◽

Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

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A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway: TRAM-01

BMC Cancer ◽

10.1186/s12885-019-6442-2 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 9

Author(s):

Sébastien Perreault ◽

Valérie Larouche ◽

Uri Tabori ◽

Cynthia Hawkin ◽

Sarah Lippé ◽

...

Keyword(s):

Single Agent ◽

Objective Response ◽

Plexiform Neurofibroma ◽

Progression Free Survival ◽

Primary Objective ◽

Low Grade ◽

Erk Pathway ◽

Phase 2 ◽

Open Label ◽

Phase 2 Study

Abstract Background Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. Up to 50% will be refractory to conventional chemotherapy. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. The same pathway is also activated in plexiform neurofibromas (PNs) which are low-grade tumors involving peripheral nerves in patients with neurofibromatosis type 1 (NF1). These lesions are known to be refractory to chemotherapy. Specific MEK inhibitors such as trametinib are now available and have been approved for other cancers harboring mutations in the MAPK/ERK pathway such as melanoma. We have observed significant responses to trametinib in patients with refractory PLGG in our institutions and results from the phase I study are promising. The treatment appears not only efficacious but is also usually well tolerated. We hypothesize that we will observe responses in the majority of refractory PLGG and PN treated with trametinib in this phase 2 study. Methods The primary objective is to determine the objective response rate of trametinib as a single agent for treatment of progressing/refractory tumors with MAPK/ERK pathway activation. The TRAM-01 study is a phase II multicentric open-label basket trial including four groups. Group 1 includes NF1 patients with progressing/refractory glioma. Group 2 includes NF1 patients with plexiform neurofibroma. Group 3 includes patients with progressing/refractory glioma with KIAA1549-BRAF fusion. Group 4 includes other patients with progressing/refractory glioma with activation of the MAPK/ERK pathway. Eligible patients for a given study group will receive daily oral trametinib at full dose for a total of 18 cycles of 28 days. A total of 150 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, overall survival, safety and tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment. Discussion Trametinib will allow us to target directly and specifically the MAPK/ERK pathway. We expect to observe a significant response in most patients. Following our study, trametinib could be integrated into standard treatment of PLGG and PN. Trial registration ClinicalTrials.gov Identifier: NCT03363217 December 6, 2017.

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341 Phase 1b/2 study of BXCL701, an oral activator of the systemic innate immunity pathway, combined with pembrolizumab (pembro), in men with metastatic castration-resistant prostate cancer (mCRPC)

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0341 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A366-A366

Author(s):

Rahul Aggarwal ◽

Dan Costin ◽

Jingsong Zhang ◽

Paul Monk ◽

Mark Linch ◽

...

Keyword(s):

Prostate Cancer ◽

Single Agent ◽

Objective Response ◽

Fixed Dose ◽

Tumor Growth Inhibition ◽

Low Grade ◽

Phase 2 ◽

Split Dose ◽

Cytokine Activation ◽

Phase 1B

BackgroundBXCL701 (talabostat) is an oral small molecule inhibitor of dipeptidyl peptidases (DPP) primarily DPP8 and DPP9, which triggers inflammasome mediated pyroptosis in macrophages leading to induction of IL-18 and IL-1beta, bridging between innate and adaptive immunity. PD-L1 expression correlates with amplification of DPP8 and DPP9. In syngeneic animal models, significant tumor growth inhibition was observed with BXCL701 plus checkpoint inhibition. In a prior clinical study, single-agent BXCL701 resulted in objective responses in patients (pts) with Stage IV melanoma (unpublished).MethodsIn Phase 1b portion of this multicenter study, eligible pts had progressing mCRPC (PCWG3), at least 1 prior systemic therapy, ≤ 2 lines of cytotoxicchemotherapy for mCRPC, no prior anti-PD-1/PD-L1 or other T-cell directed anticancertherapy. Using a 3+3 design, pts received fixed-dose pembro (200 mgIV q21-days) with escalating doses of BXCL701 on days 1–14. The primary endpoint was determination of the recommended Phase 2 dose (RP2D). Response (RECIST 1.1, PSA, CTC), plasma drug concentration and change in relevant immune effector cytokines were also evaluated.Results13 pts were treated in 3 cohorts of BXCL701: 0.4 mg qd (n = 3); 0.6 mg qd (n = 3) and 0.6 mg split dose (n=7). 7 pts had adenocarcinoma, 6 had small cell/neuroendocrine prostate cancer features. Prior treatment included ADT (n = 10), 2nd-generation androgen signaling inhibitors (n = 9), chemotherapy (n = 11), RT (n = 11). On-target AEs consistent with cytokine activation were seen at the highest dose levels. In the 0.6 mg qd cohort, all pts had events consistent with cytokine release: 3/3 had hypotension (including 1 grade 3 syncope (DLT)) and 2pts each had dizziness and LE edema. Splitting the 0.6 mg dose improved the tolerability while maintaining the TDD previously associated with objective response; 3/7 pts had fatigue, and 1pt each had low grade hypotension, dyspnea, chills, myalgia. Preliminary anti-tumor activity was seen with 1 pt achieving a PSA response and 3 pts with RECIST1.1 stable disease. BXCL701 was quantifiable in plasma. Consistent dose and time dependent increases in serum IL-18 levels were observed with 0.6 mg split dose.ConclusionsBXCL701 0.3 mg BID (0.6 mg TDD) administered on days 1–14 was identified as the RP2D when administered with pembro 200 mg every 21 days. Splitting the TDD was associated with improved tolerability as evidenced by no reported DLTs and lower rates of other adverse events of interest such as hypotension and peripheral edema. The Phase 2 portion of the study is enrolling.AcknowledgementsAll patients, their families, and caregivers who make this study possible; the participating investigators and their staff; Cedric Burg PhD and J. MacDougall PhD of BioXcel Therapeutics, Valery Chatikhine MD of Iqvia Biotech and the Iqvia Biotech team for assisting in the conduct of the study.Trial RegistrationNCT03910660EUDRACT 2018-003734-32Ethics ApprovalThis study was approved by Institution Review Boards or Ethics Committees affiliated with participating institutions.

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Randomized Phase II Study of Gemcitabine and Docetaxel Compared With Gemcitabine Alone in Patients With Metastatic Soft Tissue Sarcomas: Results of Sarcoma Alliance for Research Through Collaboration Study 002

Journal of Clinical Oncology ◽

10.1200/jco.2006.10.4117 ◽

2007 ◽

Vol 25 (19) ◽

pp. 2755-2763 ◽

Cited By ~ 438

Author(s):

Robert G. Maki ◽

J. Kyle Wathen ◽

Shreyaskumar R. Patel ◽

Dennis A. Priebat ◽

Scott H. Okuno ◽

...

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Phase Ii ◽

Single Agent ◽

Objective Response ◽

Soft Tissue Sarcomas ◽

Fixed Dose ◽

Open Label ◽

Adaptive Randomization ◽

Number Of Patients

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

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LGG-49. SAFETY AND EFFICACY OF TRAMETINIB (T) MONOTHERAPY AND DABRAFENIB + TRAMETINIB (D+T) COMBINATION THERAPY IN PEDIATRIC PATIENTS WITH BRAF V600-MUTANT LOW-GRADE GLIOMA (LGG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.427 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii375-iii375

Author(s):

Eric Bouffet ◽

James A Whitlock ◽

Christopher Moertel ◽

Birgit Geoerger ◽

Isabelle Aerts ◽

...

Keyword(s):

Combination Therapy ◽

Pediatric Patients ◽

Objective Response ◽

Safety Data ◽

Dose Finding ◽

Combination Group ◽

Clinical Activity ◽

Low Grade ◽

Open Label ◽

Independent Review

Abstract BACKGROUND Children with BRAF V600-mutant LGG have suboptimal response to standard chemotherapy. Previously, D (BRAF V600 inhibitor) monotherapy has demonstrated clinical benefit in this population. We report interim analysis results of pediatric patients with recurrent/refractory BRAF V600-mutant LGG treated with either T (MEK1/2 inhibitor) monotherapy or D+T combination therapy. METHODS This is a 4-part, open-label, multicenter, phase I/II study (NCT02124772) in pediatric patients (<18 y) with refractory/recurrent tumors. The dose-finding phase, including dose confirmation stratified by age, was followed by disease-specific cohorts at recommended dose levels. Efficacy was determined by both investigator and independent review using RANO criteria. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. RESULTS Of 49 pediatric patients with BRAF V600-mutant LGG (T, n=13; D+T, n=36) enrolled, pooled efficacy data was available for both treatments while safety data was available for 30 patients (T, n=10; D+T, n=20). Most patients (n=8/10) receiving T monotherapy withdrew/discontinued the treatment in contrast to 3/20 in the D+T group. Pyrexia occurred in 50% of patients (n=5/10) in the monotherapy group and was a frequent AE in the combination group (75%; n=15/20). Objective response rate per independent review was 15% (95% CI, 2%–45%) with T monotherapy and 25% (95% CI, 12%–42%) with D+T combination therapy. Seven patients (54%) on monotherapy and 33 patients (92%) on combination therapy had stable disease or better. CONCLUSION In pediatric patients with previously treated BRAF V600-mutant LGG, T monotherapy and D+T combination therapy demonstrated clinical activity, with pyrexia being a common AE.

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Atezolizumab in combination with bevacizumab in patients with unresectable locally advanced or metastatic mucosal melanoma: Interim analysis of an open-label phase II trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9511 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9511-9511

Author(s):

Lu Si ◽

Meiyu Fang ◽

Yu Chen ◽

Lili Mao ◽

Peng Zhang ◽

...

Keyword(s):

Interim Analysis ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Mucosal Melanoma ◽

Stage I ◽

Efficacy Evaluation ◽

Open Label ◽

Full Analysis ◽

Ecog Ps

9511 Background: Mucosal melanoma is a rare malignant melanoma in Caucasians but ranks the second most common subtype in the Asian population. It is more often diagnosed at an advanced stage and responds poorly to current PD-1/PD-L1 inhibitors. Here we report the interim analysis results of ML41186, an open-label, multicenter, single-arm phase II study, aiming to evaluate the efficacy and safety of atezolizumab in combination with bevacizumab in patients (pts) with advanced mucosal melanoma. Methods: Eligible pts aged 18 to 75 years with histologically confirmed unresectable locally advanced or metastatic mucosal melanoma had at least one measurable lesion per RECIST version 1.1 at baseline, with an ECOG PS 0 or 1 and adequate hematologic and organ function. ML41186 is a Simon two-stage design study, if 22 pts completed ORR evaluation and more than 3 pts respond in stage I, the study then continue to Stage II. Atezolizumab and bevacizumab were administered at a fixed dose of 1200 mg and 7.5 mg/kg Q3W respectively (on day 1 of each 21-day cycle) until unacceptable toxicity or loss of clinical benefit. The primary endpoint is the objective response rate (ORR). The secondary endpoints include progression-free survival (PFS), duration of objective response (DoR), disease control rate (DCR), and safety. Results: By the cut-off date of 9th September 2020, 35 pts has been enrolled, among whom 22 pts in the stage I analysis set has completed two efficacy evaluation, while 28 pts (full analysis set) has completed at least one efficacy evaluation. In ITT populations (n=35), mean age was 58.9 years with 10 (28%) pts had ECOG PS of 1. LDH level elevated in 9 (25.7%) pts. More than half pts (19, 54.3%) had metastatic mucosal melanoma, of whom 3 (15.8%) pts had more than 3 metastasis sites and 4 (21.1%) pts had liver metastasis. In stage I analysis set (n=22), the best confirmed ORR was 36.4% (95% CI, 17.0%-59.3%). Median progression-free survival was 5.32 months (95% CI, 1.58-not reached), and the best confirmed DCR was 59.1% (95%CI, 36.4%-79.3%). The median confirmed DoR was not reached (95% CI, 2.76-NR). In the full analysis set (n=28), the unconfirmed ORR was 42.9% (95%CI, 24.5%-62.8%). In ITT populations (n=35), 28 pts (80%) experienced at least one adverse event (AE) and 5 pts (14.3%) experienced at least one grade 3-4 AEs. Only one patient experienced AE leading to treatment discontinuation. One patient died of autoimmune lung disease. Conclusions: The combination of atezolizumab plus bevacizumab showed promising benefit and was tolerable in pts with advanced mucosal melanoma. At the time of this interim analysis, the primary endpoint did not cross the futility boundary, thus the study will run into Stage II. Clinical trial information: NCT04091217.

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413 Toripalimab in combination with concurrent chemoradiation in patients with advanced/metastatic esophageal carcinoma: protocol for a single-arm, prospective, open-label, phase II clinical trial

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.413 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A444-A444

Author(s):

Lei Wu ◽

Yi Wang ◽

Gang Wan ◽

Jiahua Lv ◽

Qifeng Wang ◽

...

Keyword(s):

Esophageal Carcinoma ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Stage Iv ◽

Predictive Biomarkers ◽

Primary Objective ◽

High Morbidity ◽

Efficacy And Safety ◽

Open Label ◽

Carboplatin Auc

BackgroundEsophageal carcinoma is a disease with high morbidity and mortality in China and, recently, Immune checkpoint inhibitors(ICIs) combined with chemotherapy have shown good efficacy and safety for treatment; however, some patients still suffer from tumor progression or metastasis after treatment. Clinical studies have confirmed that immunotherapy combined with chemoradiotherapy can significantly improve the prognosis of patients with advanced esophageal cancer, but the efficacy and safety of adding radiotherapy to immunotherapy and chemotherapy have been less reported.MethodsThis is an open-label, single-arm, and single-center phase ll trial.Patients with unresectable stage IV esophageal squamous cell carcinoma(ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3W) combined with induction chemotherapy (paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30–50 Gy in 15–25 fractions, paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy;and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1- and 2-year overall survival(OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. Furthermore, we aimed to identify predictive biomarkers (such as the expression of PD-L1 ctDNA and cytokines) and to explore the relationship between these biomarkers and tumor response to the study treatment.AcknowledgementsWe thank all the participants and their advisors involving in this study. We owe thanks to the patients in our study and their family members.Trial RegistrationChiCTR(ChiCTR2100046715). Registered on the 27th of May 2021.Ethics ApprovalThe study protocol is approved by Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2021-021).Changes to the protocol will be communicated via protocol amendment by the study principal investigators. Written informed consent will be obtained from all participants.

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550 ARTACUS: An open-label, multicenter, phase 1b/2 study of RP1 in solid organ transplant recipients with advanced cutaneous malignancies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.550 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A580-A580

Author(s):

Jason Luke ◽

Michael Migden ◽

Wanxing Chai-Ho ◽

Diana Bolotin ◽

Trisha Wise-Draper ◽

...

Keyword(s):

Immune Checkpoint ◽

Allograft Rejection ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Locally Advanced ◽

Organ Transplant ◽

Solid Organ ◽

Transplant Recipients ◽

Open Label ◽

Multicenter Phase

BackgroundSolid organ transplantation (SOT) has emerged as an important lifesaving procedure for patients with a wide range of end-organ diseases characterized by dysfunction or specific organ function failure. SOT rejection is a major complication requiring patients (pts) to undergo lifelong immunosuppression to prevent allograft rejection.1Skin cancers (SCs) including cutaneous squamous cell carcinoma (CSCC) are common post transplant malignancies.2 SC in SOT pts is generally managed with surgical resection, radiation therapy and chemotherapy or targeted therapy. Use of immune checkpoint inhibitors in SOT recipients has improved outcomes but are associated with the high risk of allograft rejection.3–5 Thus, there is a high unmet need for a safe and effective treatment that also protects pts from allograft rejection. RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity6 and clinical data in combination with nivolumab has demonstrated a high rate of deep and durable response in patients with advanced SCs.7 The objective of this study is to assess the safety and efficacy of single agent RP1 in kidney and liver transplant recipients with SCs, with focus on CSCC. After determining the safety and tolerability in the initial cohort with kidney and liver transplants the study may also enroll heart and lung transplant recipients.MethodsThis study will enroll up to 65 evaluable allograft transplantation pts with locally advanced or metastatic SCs. Key inclusion criteria are pts with confirmed recurrent, locally advanced or metastatic CSCC and up to 10 pts with non-CSCC SC, stable allograft function and ECOG performance status of ≤1. Pts with prior systemic anti-cancer treatment are allowed. Key exclusion criteria are prior treatment with an oncolytic therapy, active herpetic infections or prior complications of HSV-1 infection and a history of organ graft rejection within 12 months. Pts will receive an initial dose of 1 x 10^6 plaque-forming units (PFU) of RP1. Two weeks later they will receive 1 x 10^7 PFU of RP1 and continue every two weeks until pre-specified study endpoints are met. RP1 will be administered by intra-tumoral injection including through imaging guidance as clinically appropriate. The primary objective of the trial is to assess efficacy determined by ORR and safety of single agent RP1. Additional secondary endpoints include DOR, CR, DCR, PFS and OS.Trial RegistrationNCT04349436ReferencesFrohn C, Fricke L, Puchta JC, Kirchner H. The effect of HLA-C matching on acute renal transplant rejection. Nephrol Dial Transplant 2001;16(2):355–60.Madeleine MM, Patel NS, Plasmeijer EI, Engels EA, Bouwes Bavinck JN, Toland AE, Green AC; the Keratinocyte Carcinoma Consortium (KeraCon) Immunosuppression Working Group. Epidemiology of keratinocyte carcinomas after organ transplantation. Br J Dermatol 2017;177(5):1208–1216.Spain L, Higgins R, Gopalakrishnan K, Turajlic S, Gore M, Larkin J. Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Ann Oncol 2016;27(6):1135–1137.Herz S, Höfer T, Papapanagiotou M, Leyh JC, Meyenburg S, Schadendorf D, Ugurel S, Roesch A, Livingstone E, Schilling B, Franklin C. Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 2016;67:66-72.Kittai AS, Oldham H, Cetnar J, Taylor M. Immune checkpoint inhibitors in organ transplant ptss. J Immunother 2017;40(7):277–281.Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019 10;7(1):214.Middleton M, Aroldi F, Sacco J, Milhem M, Curti B, Vanderwalde A, Baum S, Samson A, Pavlick A, Chesney J, Niu J, Rhodes T, Bowles T, Conry R, Olsson-Brown A, Earl-Laux D, Kaufman H, Bommareddy P, Deterding A, Samakoglu S, Coffin R, Harrington K. 422 An open-label, multicenter, phase 1/2 clinical trial of RP1, an enhanced potency oncolytic HSV, combined with nivolumab: updated results from the skin cancer cohorts. J Immunother Cancer 2020;8(3): doi: 10.1136/jitc-2020-SITC2020.0422Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each participating site. Informed consent was obtained from patients before participating in the trial.

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