Phase Ib Study Research Articles

1100P Open-label non-randomized phase IB study to characterize the safety, tolerability and recommended dose of tinostamustin in combination with nivolumab in patients with advanced melanoma (ENIGMA)

1100P Open-label non-randomized phase IB study to characterize the safety, tolerability and recommended dose of tinostamustin in combination with nivolumab in patients with advanced melanoma (ENIGMA)

655O Phase Ib study of cofetuzumab pelidotin, an anti-PTK7 antibody-drug conjugate, in patients with PTK7-expressing recurrent non-small cell lung cancer (rNSCLC)

655O Phase Ib study of cofetuzumab pelidotin, an anti-PTK7 antibody-drug conjugate, in patients with PTK7-expressing recurrent non-small cell lung cancer (rNSCLC)

1335P Phase Ib study to evaluate the safety and tolerability of osimertinib with ipilimumab in EGFRm NSCLC

1335P Phase Ib study to evaluate the safety and tolerability of osimertinib with ipilimumab in EGFRm NSCLC

1532P Phase Ib study of futibatinib plus pembrolizumab in patients with esophageal carcinoma: Updated results of antitumor activity and tolerability results in combination with chemotherapy

1532P Phase Ib study of futibatinib plus pembrolizumab in patients with esophageal carcinoma: Updated results of antitumor activity and tolerability results in combination with chemotherapy

Keverprazan, a novel potassium-competitive acid blocker: Single ascending dose safety, tolerability, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

BackgroundKeverprazan is a novel potassium-competitive acid blocker for the treatment of acid-related diseases. AimsTo evaluate the safety, pharmacokinetics, pharmacodynamics, and food effect of single oral doses of keverprazan in healthy Chinese subjects. MethodsIn the dose-escalated phase Ia trial, the first 8 subjects received keverprazan 5 mg, the others successively entered 10 mg, 20 mg, 40 mg, 60 mg groups and were randomized to receive keverprazan (n = 8), lansoprazole (LSZ) 30 mg (n = 2) or placebo (n = 2) in each dose group. The phase Ib study randomly enrolled subjects to the fasting-fed (n = 7) or fed-fasting (n = 7) groups for evaluating the food effect of keverprazan. ResultsTwenty (35.71%) adverse events (AEs) occurred in phase Ia, including 13 (32.50%), 3 (37.50%), and 4 (50.00%) AEs in the keverprazan, placebo, and LSZ groups, respectively. Four (28.57%) AEs occurred in Phase Ib. The Tmax of keverprazan was 1.25–1.75 h. Cmax and AUC increased with the dose, and the t1/2, CL/F were 6.00–7.17 h, 88.8–198 L/h, respectively. The intragastric pH >5 holding-time ratio (HTR) increased with the dose but reached a ceiling at 20 mg. In the 30 mg LSZ and 5–60 mg keverprazan groups, the intragastric pH >5 HTRs during 24 h were 57.1%±26.4%, 7.9%±8.1%, 26.2%±22.8%, 80.2%±8.8%, 88.1%±8.6%, and 93.0%±1.7%, respectively. The geometric mean ratios (90% CI) of Cmax and AUC0-∞ of keverprazan in plasma under the fed vs. fasting state were 126.8% (109.0%-147.5%) and 134.9% (123.8%-146.9%). ConclusionKeverprazan is tolerable, and provides significant stable and lasting inhibition efficacy of intragastric acidity at 20 mg.

Phase Ib Study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis (1243)

Phase Ib Study of intraperitoneal ipilimumab and nivolumab in patients with recurrent gynecologic malignancies with peritoneal carcinomatosis (1243)

Regorafenib Plus Vincristine and Irinotecan in Pediatric Patients With Recurrent/Refractory Solid Tumors: An Innovative Therapies for Children With Cancer Study.

This phase Ib study defined the safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. Patients aged 6 months to <18 years with relapsed/refractory solid malignancies (≥50% with rhabdomyosarcoma [RMS]) received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8 and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AEs) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. We enrolled 21 patients (median age 10 years; 12 RMS; five Ewing sarcoma [EWS]). The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2/2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate (complete response/partial response/stable disease/non-CR/non-PD) was 86%. Median progression-free survival was 7.0 months (95% CI, 2.9 to 14.8) and median overall survival was 8.7 months (95% CI, 5.5 to 16.3). When combined with VI, regorafenib PK were comparable to single-agent PK in children and adults (treated with regorafenib 160 mg/day). Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (clinicaltrials.gov NCT02085148).

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer

Introduction: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2−) MBC and recurrent ovarian cancer (ROC). Methods: Cohorts of 3–6 patients with HER2− MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. Primary endpoint: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. Results: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2− MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. Conclusion: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2− MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

A Phase Ib Study of Durvalumab (MEDI4736) in Combination with Carbon-Ion Radiotherapy and Weekly Cisplatin for Patients with Locally Advanced Cervical Cancer (DECISION Study): The Early Safety and Efficacy Results.

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

DIPG-54. UPDATED FINDINGS FROM THE PHASE IB STUDY OF UNESBULIN (PTC596) IN CHILDREN WITH NEWLY-DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)

Abstract BMI-1 represents a potential therapeutic target in pediatric HGG given its role in self-renewal and DNA-damage signaling, high expression levels in these tumors, and resultant proliferation blockade, mitotic abnormalities, and radiosensitization when modulated by unesebulin, a microtubule polymerization inhibitor. This phase Ib study sought to determine the recommended phase 2 dose (RP2D) and pharmacokinetic (PK) profiles of unesbulin administered concurrently with radiotherapy and as maintenance therapy in children with newly-diagnosed DIPG or HGG, as well as assess intratumoral PKs and target inhibition within a surgical cohort. As previously reported, the established RP2D from the dose-finding cohort (parts A [capsule] and C [tablet]), consisting of 27 patients (median age: 9 years; 18 with DIPG, 9 with HGG) is 200mg/m2 twice weekly. Eleven additional patients (5 with DIPG, 6 with HGG) have been enrolled in an expansion cohort (part D [tablet]), with no dose-modifying toxicities to date. Among 38 total patients, most common drug-related grade 3/4 adverse effects observed are neutropenia (49%), leukopenia (31%), and elevated ALT (18%). Pharmacokinetic profiles are comparable between capsule and tablet formulations, and corroborate adult data. Genomics correlatives are underway on 13 biopsy and 5 autopsy specimens (2 paired samples). Five patients (median age: 5 years; 4 with DIPG, 1 with HGG) have enrolled in the surgical cohort (part B [tablet]) at the RP2D. PK analyses performed on the first three samples confirm intratumoral unesbulin exposure. In summary, the RP2D of unesbulin at 200mg/m2 twice weekly concurrent with and post-radiotherapy is feasible and well-tolerated, with evidence of blood-brain barrier and tumor penetrance. Survival outcomes as well as ongoing analyses of intratumoral BMI-1 pathway inhibition in surgical cohort samples, plus comprehensive molecular profiling (focusing on BMI-1 and cell cycle signaling) of biopsy and autopsy specimens from the entire cohort, will be shared at time of presentation.

A phase Ib trial of combined PKC and MEK inhibition with sotrastaurin and binimetinib in patients with metastatic uveal melanoma.

Uveal melanoma is a disease characterized by constitutive activation of the G alpha pathway and downstream signaling of protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) pathway. While limited clinical activity has been observed in patients with metastatic disease with inhibition of PKC or MEK alone, preclinical data has demonstrated synergistic antitumor effects with concurrent inhibition of PKC and MEK. We conducted a phase Ib study of the PKC inhibitor sotrastaurin in combination with the MEK inhibitor binimetinib in patients with metastatic uveal melanoma using a Bayesian logistic regression model guided by the escalation with overdose control principle (NCT01801358). Serial blood samples and paired tumor samples were collected for pharmacokinetic (PK) and pharmacodynamic analysis. Thirty-eight patients were treated across six dose levels. Eleven patients experienced DLTs across the five highest dose levels tested, most commonly including vomiting (n=3), diarrhea (n=3), nausea (n=2), fatigue (n=2) and rash (n=2). Common treatment related adverse events included diarrhea (94.7%), nausea (78.9%), vomiting (71.1%), fatigue (52.6%), rash (39.5%), and elevated blood creating phosphokinase (36.8%). Two dose combinations satisfying criteria for the maximum tolerated dose (MTD) were identified: (1) sotrastaurin 300 mg and binimetinib 30 mg; and, (2) sotrastaurin 200 mg and binimetinib 45 mg. Exposure to both drugs in combination was consistent with single-agent data for either drug, indicating no PK interaction between sotrastaurin and binimetinib. Stable disease was observed in 60.5% of patients treated. No patient achieved a radiographic response per RECIST v1.1. Concurrent administration of sotrastaurin and binimetinib is feasible but associated with substantial gastrointestinal toxicity. Given the limited clinical activity achieved with this regimen, accrual to the phase II portion of the trial was not initiated.

Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study.

In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure. We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined. Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively. Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.

Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1. The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles. Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle. Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified). Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors. ClinicalTrials.gov identifier NCT02482311; registered June 2015.

Efficacy and safety of IBI110 in combination with sintilimab and lenvatinib in first-line of advanced hepatocellular carcinoma: Preliminary results from a phase Ib study.

2577 Background: Sintilimab plus bevacizumab has been approved as first-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC). Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 plus sintilimab has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the efficacy, tolerability, and safety of IBI110 in combination with sintilimab and lenvatinib as first-line treatment in pts with advanced HCC. Methods: This phase Ib study enrolled pts with histologically or cytologically diagnosed or clinically confirmed unresectable or metastatic hepatocellular carcinoma, no previous systemic treatment. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W, in combination with lenvatinib (weight &lt;60kg: 8mg, weight ≥60 kg: 12mg) orally administered once daily, until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As the data cutoff date on January 9th 2023, 28 pts were enrolled (median age: 59 years; ECOG PS=0: 6 pts; stage C per Barcelona Clinic Liver Cancer [BCLC]: 13 pts). All 28 pts were included for safety analysis. Treatment-related adverse events (TRAEs) of any grade occurred in 27 pts (96.4%) and the most frequent TRAEs included hypertension (50%), hypothyroidism (42.9%), neutrophil count decreased (39.3%). Grade ≥ 3 TRAEs occurred in 16 pts (57.1%) and grade ≥3 irAEs occurred in 4 (14.3%) pts. Two (7.1%, 2/28) pts experienced TRAE leading to drug discontinuation. One pt experienced investigator-assessed treatment related death. As of data cutoff, for 27 pts with at least one efficacy evaluation, the objective response rate (ORR) was 29.6% (95% CI, 13.8-50.2). The disease control rate (DCR) was 85.2% (95% CI, 66.3-95.8), and 11 pts were still in treatment. With a median follow up of 12.2 months (95%CI, 11.0-12.6), the median progression-free survival (PFS) was 9.9 months (95%CI, 5.7-NC) and the 9-month PFS rate was 54.5% (95%CI, 33.8-71.2). The median overall survival (OS) was not reached. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and lenvatinib as first line therapy demonstrated robust response and survival benefit with manageable safety profile in patients with advanced hepatocellular carcinoma. This combination therapy need to be further explored in this population. Clinical trial information: NCT04085185 .

Safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with non-small cell lung cancer (NSCLC): An open-label, phase Ib trial.

9105 Background: Currently, limited targeted therapies are available for HER2 mutant NSCLC patients. Previous studies have shown the antitumor activity of pyrotinib in advanced NSCLC patients with HER2 mutations. Inetetamab is a recombinant humanized anti-HER2 monoclonal antibody. Whether inetetamab combined with pyrotinib could show manageable safety and more active antitumor activity remains unknown. This study was designed to evaluate the safety and efficacy of inetetamab in combination with pyrotinib in HER2 mutant patients with advanced NSCLC. Methods: This study was an open-label, phase Ib study. The HER2 mutant patients with locally advanced or metastatic NSCLC were assigned to receive inetetamab combined with pyrotinib. The study consisted of dose-escalation part and dose-expansion part. During dose-escalation period, the parallel "3+3" dose-escalation design was used to determine the dose-limiting toxicity (DLT). Inetetamab was administered every 3 weeks (8 mg/kg loading dose for cycle 1, followed by 6 mg/kg in subsequent cycles) with pyrotinib (dose-escalation part, 240mg QD, 320mg QD; dose-expansion part, 320mg QD). Primary endpoint of the study was DLT dosage and safety. The DLT was assessed during the 21-day DLT evaluation period after the first dose. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression free survival and overall survival. Results: Between August 6, 2021, and August 25, 2022, 48 patients were enrolled. No DLT occurred during pyrotinib 240mg and 320mg escalation period. Therefore, pyrotinib 320mg was chosen as expansion dose. The most common treatment-related adverse events (TRAEs) were diarrhea (66.7% [2/3] in pyrotinib 240mg group, 95.6% [43/45] in pyrotinib 320mg group), rash (66.7% [2/3] in pyrotinib 240mg group, 22.2% [10/45] in pyrotinib 320mg group) and vomiting (0 in pyrotinib 240mg group, 24.4% [11/45] in pyrotinib 320mg group). TRAEs were generally Grade (G) 1-2. Only 7 patients reported G3 TRAE (1 in pyrotinib 240mg group, 6 in pyrotinib 320mg group). The preliminary efficacy was shown in the table below. The ORR and DCR of group receiving inetetamab with pyrotinib 240mg were 0% and 66.7%, respectively. The ORR and DCR of inetetamab with pyrotinib 320mg group were 36.6% and 85.4% respectively. The relationship between different mutation subtypes or co-mutations and efficacy will be updated during the conference reports. Conclusions: The preliminary data of inetetamab in combination with pyrotinib showed manageable safety and compelling antitumor activity in advanced NSCLC patients harboring HER2 mutations. Clinical trial information: NCT05016544 . [Table: see text]

Glofitamab + Pola-R-CHP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL): Results from a phase Ib study.

7549 Background: Polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) has shown a significant progression-free survival benefit versus R-CHOP as first line (1L) therapy for DLBCL (Tilly et al. 2022). Glofitamab is a bispecific antibody with a novel 2:1 (CD20:CD3) format; bivalency for CD20 on B cells enables combination with anti-CD20 antibodies, including rituximab. Glofitamab monotherapy induced durable responses in patients (pts) with relapsed/refractory DLBCL and its incorporation in the 1L setting may further improve outcomes (Dickinson et al. 2022). We present results from the expansion stage of an ongoing Phase Ib study (NCT03467373) of glofitamab (Glofit) + Pola-R-CHP in pts with 1L DLBCL. Methods: Pts received Pola-R-CHP on Day (D) 1 of each 21-day cycle (C; max. 6 cycles) and glofitamab in C2‒C6 (C2 step-up dosing [2.5mg C2D8, 10mg C2D15]; target dose [30mg] C3D8 and onwards). Response was assessed by PET-CT using Lugano criteria (Cheson et al. 2014). Efficacy-evaluable pts were those that reached end of treatment (EOT), progressed or died by data cut-off (EOT population). Cytokine release syndrome (CRS) events were graded by ASTCT criteria (Lee et al. 2019) and other adverse events (AEs) by CTCAE (v4.0). Results: As of Nov 14, 2022, 24 pts had enrolled and received study treatment (safety population). Median age was 65 years (range: 32–85), 96% of pts had stage III–IV disease and median IPI score was 3 (IPI 1: 4% [1/24], IPI 2: 33% [8/24], IPI 3: 38% [9/24], IPI 4: 25% [6/24]). Of 24 pts, 17 were efficacy evaluable. After a median follow up of 5.1 (range: 3–8) months, complete metabolic response rate was 76.5% (13/17) and overall response rate was 100% in the EOT population (best overall response). In safety-evaluable pts, Grade (Gr) ≥3 AEs occurred in 15 (63%) pts and Gr ≥3 AEs related to glofitamab in 9 (38%) pts. One Gr 5 AE was reported (acute respiratory distress syndrome, unrelated to study treatment). Serious AEs (SAEs) were reported in 12 (50%) pts and SAEs related to glofitamab in 4 (17%) pts. AEs leading to glofitamab dose interruption occurred in 5 (21%) pts; median dose intensity was 100% for all Glofit + Pola-R-CHP components. Only Gr 1 CRS (n = 3, 13%) was reported, with no treatment or hospitalization required. Neurological AEs (NAEs) occurred in 11 (46%) pts and were mostly Gr 1/2 (10 pts, 42%); one patient had a Gr 3 NAE (hypomania). No NAEs potentially consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 12 (50%) pts (Gr 3, n = 6; Gr 4, n = 6), febrile neutropenia in 2 (8.3%) pts and Gr 3/4 infection in 4 (17%) pts (Gr 3, n = 2; Gr 4, n = 2). Conclusions: Early data suggest that Glofit + Pola-R-CHP has promising efficacy and a similar safety profile to Pola-R-CHP and Glofit + R-CHOP for 1L DLBCL treatment. Glofit + Pola-R-CHP dose intensity was maintained in all pts. Updated data will be presented. Clinical trial information: NCT03467373 .

PolyPEPI1018 vaccine in combination with TAS-102 in participants with late-stage microsatellite-stable metastatic colorectal cancer (MSS mCRC): A phase Ib study to evaluate safety, tolerability, immunogenicity and efficacy (OBERTO-201).

3595 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 tumor-specific antigens frequently expressed in patients with mCRC. Following early evidence of clinical activity of PolyPEPI1018 in first-line MSS mCRC, here we report the results of a phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-15 of a 28-day cycle. Treatment continued for up to 7 cycles, until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be presented. Results: 15 patients started treatment. Median age was 55 years (range 31–71), 73% had liver metastases (mets), 73% had KRAS mutant tumors. The most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events (n = 15) at least possibly related to treatment were fatigue, decreased white blood cell, lymphocyte and neutrophil counts, nausea, diarrhea, myalgia, and maculo-papular rash. There were no Gr 4 or 5 events. The ORR was 0%. The DCR was 53.3% in the overall population and 36% and 100% for the patients with liver mets and without liver mets, respectively. The mPFS was 4 months (95%CI 2.2-6.1) in the overall population and 2.3 months (95%CI 2.1-NE) and 7.6 months (95%CI 4.4-NE) for the patients with liver mets and without liver mets, respectively (HR = 5.73 (95%CI 1.21, 27.06); p = 0.015). At the data cut-off date (Feb 10, 2023), the mOS was 8.7 months (95%CI 6.9-NE; not mature) in the overall population and it was not reached in patients without liver mets. Patients with increased PFS (≥ 24 weeks) had more robust vaccine-specific humoral and T cell responses induced by higher number of vaccine peptides than patients with PFS &lt; 24 weeks. Conclusions: To our knowledge, this is the first study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. Despite no objective tumor responses could be detected, correlative data suggest contribution of PolyPEPI1018-induced immunological responses to the improved clinical benefit and the combination warrants further testing. Clinical trial information: NCT05130060 .

Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Updated results from a phase Ib study.

2576 Background: Sintilimab plus oxaliplatin and capecitabine (XELOX) has become the standard of care in patients (pts) with untreated advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in China. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may further improve anti-tumor effect. The preliminary safety and efficacy data of IBI110 plus sintilimab and XELOX in pts with first-line G/GEJ AC were previously presented (Chenyu Mao et al. ASCO 2022). Here, we presented updated safety and efficacy results of this study. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJ AC. Pts received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus XELOX (oxaliplatin 130 mg/m2 Q3W and capecitabine 1000mg mg/m2/time twice daily [BID]) until disease progression, unacceptable toxicity or death. The primary objectives were to evaluate the safety, tolerability, and efficacy of the combination therapy per RECIST v1.1. Results: As of data cutoff January 9th 2023, 17 pts were assessed as evaluable (median age: 61 years; ECOG PS=1: 14 pts; all gastric cancer). All pts (17/17, 100%) experienced treatment-related adverse events (TRAEs) of any grade, and the most commonly TRAEs were neutrophil count decreased (64.7%), white blood cell count decreased (52.9%), platelet count decreased (52.9%). Grade ≥ 3 TRAEs occurred in 11 pts (64.7%), the most frequent grade ≥ 3 TRAEs were consistent with TRAEs of any grade. Investigator-assessed immune-mediated adverse events (irAEs) occurred in 10 pts (58.8%). Grade ≥ 3 irAEs occurred in 3 pts (17.6%), all led to discontinuation. No treatment-related death occurred. As data cutoff, among 17 efficacy-evaluable pts, the unconfirmed and confirmed objective response rate (ORR) were 88.2% (95% CI, 63.6-98.5) and 64.7% (95% CI, 38.3-85.8), respectively. The disease control rate (DCR) was 94.1% (95% CI, 71.3-99.9). With a median follow up of 13.1 months (95% CI, 7.1-NC), the median duration of response (DoR) and progression-free survival (PFS) were 11.6 months (95% CI, 2.5-14.4) and 12.9 months (95% CI, 3.8-15.8), respectively. The median overall survival (OS) was not reached, and the 12-months OS rate was 70.6% (95% CI, 43.1-86.6). Conclusions: IBI110 in combination with sintilimab and XELOX demonstrated manageable safety and encouraging efficacy results in patients with first-line gastric adenocarcinoma. This is the first positive trial to show clinical benefits of a LAG3 plus PD-1 inhibitor combined with chemotherapy for this population. Clinical trial information: NCT04085185 .

Phase Ib study of neoadjuvant concurrent chemoradiation plus durvalumab followed by surgery and adjuvant durvalumab for resectable stage III NSCLC.

8556 Background: The use of neoadjuvant and adjuvant immunotherapy in resectable non-small cell lung cancer (NSCLC) has become a standard of care. However, the integration of immunotherapy into a trimodality treatment regimen has not been widely explored. We hypothesized that adding durvalumab to neoadjuvant concurrent chemoradiation and surgery would not increase treatment-related adverse events (TRAE) during neoadjuvant period. Methods: This was a prospective, single center, single-arm, open-label phase Ib study. Patients with resectable, stage III N2 NSCLC received concurrent chemoradiation [weekly paclitaxel (45mg/m2)/carboplatin (AUC 2.0) for 5 weeks with radiotherapy 45Gy] and durvalumab 1,500mg Q4W for 2 cycles followed by surgical resection and adjuvant durvalumab for 1 year. The primary endpoint was the frequency of patients who experience grade 3 or more TRAE during neoadjuvant therapy based on CTCAE 4.03. Results: Of 30 patients (median age 65.5 years; 67% male), 56.7% had squamous histology and 60.0% had stage IIIA. Any grade AEs and TRAEs (neoadjuvant/adjuvant) were reported in 83.3%/76.7% and 70.0%/63.3% of patients, respectively. Grade 3 or more AEs and TRAEs (neoadjuvant/adjuvant) were reported in 10.0/3.3% and 10.0%/0.0%, respectively. Grade 3 or more TRAE reported during neoadjuvant treatment were neutropenia, anemia, and nausea, one each; no Grade 5 AEs occurred. Surgical resection was not performed in three patients: two due to treatment-related adverse events (AEs) and one due to patient refusal. Among 27 patients who received complete resection, the pathologic complete response (pCR) rate and major pathologic response (MPR) rate were 40.7% (95% CI, 22.4 – 61.2) and 74.1% (95% CI, 53.7 – 88.9), respectively. Excluding four patients with EGFR, ALK, KRAS G12C, or MET ex14skipping mutations, the pCR rate was 47.8% (95% CI, 26.8 – 69.4) and MPR rate was 87.0% (95% CI, 66.4 – 97.2). Overall, pathologic downstaging was achieved in 70.4% (95% CI, 49.8 – 86.2). Objective response rate according to RECIST v1.1 was 50.0% (95% CI, 31.3 – 68.7). One patient delayed the schedule for surgical resection due to radiation pneumonitis (G2), unrelated to the drug administered. Otherwise, there were no peri-operative mortality or morbidity. All patients who underwent surgery, except one whose disease progressed immediately after resection, received at least one dose of adjuvant durvalumab; 61.5% completed 1-year treatment, 11.5% were continuing treatment, 11.5% discontinued due to AE, and 11.5% discontinued due to disease progression at the time of data cutoff. Grade 3 or more TRAE reported during adjuvant treatment were radiation pneumonitis and proteinuria, one each. Conclusions: This study confirms the manageable safety profile of adding durvalumab to neoadjuvant concurrent chemoradiation for treatment of resectable stage III NSCLC. Clinical trial information: NCT03694236 .

A phase Ib/II study to evaluate surufatinib combined with camrelizumab and chemotherapy in the second-line treatment of advanced colorectal cancer: Phase Ib results.

3555 Background: Surufatinib is a novel small-molecule kinase inhibitor targeting VEGFR1-3, FGFR and CSF-1R with confirmed efficacy in epNET and pNET. Preclinical studies have demonstrated that surufatinib combined with immune checkpoint inhibitors (ICIs) have synergistic antitumor effects by modulating tumor immune microenvironment. Additionally, surufatinib plus toripalimab (anti-PD-1) has showed preliminary anti-tumor activity in multiple solid tumors, including colorectal cancer (CRC). This study aimed to evaluate the efficacy and safety of surufatinib plus camrelizumab (anti-PD-1), irinotecan and GM-CSF as second-line treatment in advanced CRC. Here we reported the results of the phase Ib study. Methods: This ongoing phase Ib/II, open-label trial (NCT04929652) enrolled patients (pts) aged 18-75 years old with pathologically confirmed locally advanced or metastatic CRC who have progressed on/been intolerant to the standard first-line therapy. In the Ib dose escalation/de-escalation phase, pts received surufatinib at 250mg once daily (QD) as starting dose, in combination with fixed dose of camrelizumab (200 mg, d1), irinotecan (200 mg/m2, d1) and GM-CSF (5ug/kg, d2-d7), every 3 weeks (Q3W). Based on DLTs, the dose of surufatinib should escalate to 300 mg or de-escalate to 200 mg. The primary objective of the phase Ib study was to determine the safety and DLT in first treatment cycle defining the recommended phase 2 dose (PR2D). Additional 36 pts were enrolled in the phase II dose expansion stage using RP2D. Primary endpoint of phase II was ORR as per RECIST 1.1. Secondary endpoints included PFS, DCR, OS and safety. Results: Enrollment opened in Nov 2021 and data cutoff in Dec 2022. 12 pts (median age 54) were treated in Phase Ib study (surufatinib 250 mg: N = 6; surufatinib 300 mg: N = 6). 75% were male and 17% had ECOG PS 1. 11/12 (92%) pts were positive for KRAS, NRAS or BRAF mutations. No DLT was observed in the starting dose cohort (surufatinib 250 mg), and one patient in the surufatinib 300 mg cohort experienced DLT (Grade [G] 3 vomiting). Surufatinib 300 mg QD was defined as the RP2D. Other G3 treatment related adverse events (TRAEs) were hypertension (1/12; 8.3%) and diarrhea (1/12; 8.3%). All other TRAEs were grade 1-2, and the most common (≥40%) were diarrhea (75%), fatigue (58%), vomiting (58%), nausea (50%), hypertension (42%), proteinuria (42%) and alopecia (42%). Of the 12 pts evaluable for tumor response, 3 pts achieved PR, 9 pts achieved SD. The ORR was 25% (3/12), the DCR was 100% (12/12) and median PFS was 7.2 months (95%CI 3.7-10.7). Conclusions: Surufatinib plus camrelizumab, irinotecan and GM-CSF was well tolerated, with a manageable safety profile, and showed preliminary anti-tumor activity in patients with advanced CRC. The dose-expansion phase is ongoing. Clinical trial information: NCT04929652 .