An Exploration of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Pretreated Advanced Gastric Cancer

Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer but with limited efficacies. We investigated the combination of FTD/TPI and irinotecan for such patients.Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used an escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on days 1 and 15] with 2 schedules of FTD/TPI 35 mg/m2/dose: twice daily, on days 1-5 and 8-12 (Level A) or on days 1-5 and days 15-19 (Level B) of a 28-day cycle. The primary and secondary objectives were determination of maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) , and evaluation of disease control rate (DCR), respectively. Results: Eleven patients were enrolled; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A, and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively.Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation for its efficacy in the RP2D is necessary. Mini-abstract: A phases Ib study of trifluridine/tipiracil in combination with irinotecan for advanced gastric cancer determined the recommended dose with manageable hematologic toxicities and feasible non-hematologic toxicities.

473 Immune profiling of patients with advanced solid tumors treated with intratumorally administered CV8102 as a single-agent or in combination with anti-PD-1 antibodies in phase I clinical trial

BackgroundCV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system.1 2 An ongoing phase I trial is investigating the intratumoral (i.t.) administration of CV8102 in patients with advanced cutaneous melanoma (cMEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC), either as a single agent or in combination with systemic anti-PD-1 antibodies. Preliminary immune profiling results will be reported.MethodsAn open-label, cohort-based, dose escalation and expansion study in patients with advanced cMEL, cSCC, hnSCC or ACC is ongoing investigating CV8102 i.t. as single agent and in combination with anti-PD-1 antibodies. Eight i.t. injections of CV8102 were administered over a 12 week period with optional continuing treatment in case of clinical benefit. In the initial dose escalation part, the recommended phase II dose for subsequent cohort expansion was defined. Blood samples for immune cell phenotyping, RNA sequencing (RNAseq) and serum cytokine/chemokine analysis were collected at baseline and multiple time points during the treatment period. For characterization of the tumor microenvironment (TME), optional core needle biopsies of injected and/or non-injected lesions were taken before, during and after treatment. Changes on various tumor-infiltrating immune cells were assessed by multiplex immunofluorescence (MultiOmyx < sup >TM</sup > ) and immune-related gene expression profiling using nCounter® Pan Cancer IO360 < sup >TM</sup > panel (NanoString).ResultsDuring the dose escalation part, 33 patients received CV8102 (dose range of 25–900 µg) as single agent and 25 patients received CV8102 in combination with an anti-PD-1 antibody. A dose of 600 µg was selected as recommended phase II dose. Serum cytokine/chemokine and blood RNAseq analysis showed transient increases in several markers like interferons alpha and gamma after the first dose. First analyses of paired biopsies showed changes in the TME of injected and non-injected lesions. Complete results of cytokine and chemokine analysis in serum and blood RNAseq for the dose escalation cohorts will be presented. Multiplex immunofluorescence and gene expression profiling from paired biopsies from individual patients will be also included.ConclusionsIntratumoral injection of CV8102 activated several cytokine/chemokine pathways in the peripheral blood and showed immunological changes in the tumor microenvironment of injected and non-injected lesions.Trial RegistrationNCT03291002ReferencesZiegler A, Soldner C, Lienenklaus S, Spanier J, Trittel S, Riese P, Kramps T, Weiss S, Heidenreich R, Jasny E, Guzmán CA, Kallen KJ, Fotin-Mleczek M, Kalinke U. A New RNA-Based Adjuvant Enhances Virus-Specific Vaccine Responses by Locally Triggering TLR- and RLH-Dependent Effects. J Immunol 2017;198(4):1595–1605. doi: 10.4049/jimmunol.1601129.Heidenreich R, Jasny E, Kowalczyk A, Lutz J, Probst J, Baumhof P, Scheel B, Voss S, Kallen KJ, Fotin-Mleczek M. A novel RNA-based adjuvant combines strong immunostimulatory capacities with a favorable safety profile. Int J Cancer 2015 Jul 15;137(2):372–84. doi: 10.1002/ijc.29402.Ethics ApprovalThe study was approved by the Central Ethics Committees in Tuebingen, Germany under 785/2016AMG1, in France by the COMITE DE PROTECTION DES PERSONNES SUD-EST I under 2019–49, approval dated 17-May-2019, in Barcelona, Spain by the CEC COMITÉ DE ÉTICA DE INVESTIGACIÓN CLÍNICA CON MEDICAMENTOS del Hospital Universitari Vall d’Hebron, approval date 28-Nov-2019 under the EUdraCT number, in Austria by the Central Ethics Committee in Graz under 31–426 ex 18/19 approved on 19-Sep-2019.ConsentWritten informed consent from the patient was obtained 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.

A Phase I Trial of Dasatinib and Osimertinib in TKI Naïve Patients With Advanced EGFR-Mutant Non-Small-Cell Lung Cancer

BackgroundOsimertinib is an effective first-line therapy option for EGFR-mutant NSCLC, but virtually all patients develop resistance. CRIPTO, through Src activation, has been implicated in resistance to EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy. Dasatinib, a Src inhibitor, has shown preclinical synergy with EGFR-TKI therapy.MethodThis is a single-arm phase I/II trial of osimertinib and dasatinib in TKI-naïve advanced EGFR-mutant NSCLC (NCT02954523). A 3 + 3 design was used in the phase I to establish the recommended phase II dose (RP2D). Osimertinib 80 mg QD was combined with dasatinib 70 mg BID (DL2), 50 mg BID (DL1), 70 mg QD (DL-1), and 50 mg QD (DL-2).ResultsTen patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches/body pain, neutropenia, rash, one each). Common treatment-related adverse events included pleural effusion (n=10), diarrhea (n=8), rash (n=7), transaminitis (n=7), thrombocytopenia (n=7), and neutropenia (n=7). While the MTD was not determined by protocol-defined DLT criteria, DL-2 was chosen as the RP2D, considering overall tolerability. Nine (90%) patients had a PR, including 1 unconfirmed PR. Median PFS was 19.4 months and median OS 36.1 months. The trial was closed to accrual prematurely due to slow accrual after the approval of osimertinib as first-line therapy.ConclusionsThe combination of dasatinib and osimertinib demonstrated anticancer activity. The treatment was limited by chronic toxicities mainly attributed to dasatinib. To improve the safety and tolerability of Src and EGFR co-inhibition, Src inhibitors with a more favorable safety profile should be utilized in future studies.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02954523

A phase I/II study of rovalpituzumab tesirine in delta-like 3—expressing advanced solid tumors

Delta-like protein 3 (DLL3) is highly expressed in solid tumors, including neuroendocrine carcinomas/neuroendocrine tumors (NEC/NET). Rovalpituzumab tesirine (Rova-T) is a DLL3-targeting antibody-drug conjugate. Patients with NECs and other advanced DLL3-expressing tumors were enrolled in this phase I/II study (NCT02709889). The primary endpoint was safety. Two hundred patients were enrolled: 101 with NEC/NET (large-cell NEC, gastroenteropancreatic NEC, neuroendocrine prostate cancer, and other NEC/NET) and 99 with other solid tumors (melanoma, medullary thyroid cancer [MTC], glioblastoma, and other). The recommended phase II dose (RP2D) was 0.3 mg/kg every 6 weeks (q6w) for two cycles. At the RP2D, grade 3/4 adverse events included anemia (17%), thrombocytopenia (15%), and elevated aspartate aminotransferase (8%). Responses were confirmed in 15/145 patients (10%) treated at 0.3 mg/kg, including 9/69 patients (13%) with NEC/NET. Rova-T at 0.3 mg/kg q6w had manageable toxicity, with antitumor activity observed in patients with NEC/NET, melanoma, MTC, and glioblastoma.

Phase I or II Study of Ribociclib in Combination With Topotecan-Temozolomide or Everolimus in Children With Advanced Malignancies: Arms A and B of the AcSé-ESMART Trial

PURPOSE AcSé-ESMART is a proof-of-concept, phase I or II, platform trial, designed to explore targeted agents in a molecularly enriched cancer population. Arms A and B aimed to define the recommended phase II dose and activity of the CDK4/6 inhibitor ribociclib with topotecan and temozolomide (TOTEM) or everolimus, respectively, in children with recurrent or refractory malignancies. PATIENTS AND METHODS Ribociclib was administered orally once daily for 16 days after TOTEM for 5 days (arm A) or for 21 days with everolimus orally once daily continuously in a 28-day cycle (arm B). Dose escalation followed the continuous reassessment method, and activity assessment the Ensign design. Arms were enriched on the basis of molecular alterations in the cell cycle or PI3K/AKT/mTOR pathways. RESULTS Thirty-two patients were included, 14 in arm A and 18 in arm B, and 31 were treated. Fourteen patients had sarcomas (43.8%), and 13 brain tumors (40.6%). Main toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II dose was ribociclib 260 mg/m2 once a day, temozolomide 100 mg/m2 once a day, and topotecan 0.5 mg/m2 once a day (arm A) and ribociclib 175 mg/m2 once a day and everolimus 2.5 mg/m2 once a day (arm B). Pharmacokinetic analyses confirmed the drug-drug interaction of ribociclib on everolimus exposure. Two patients (14.3%) had stable disease as best response in arm A, and seven (41.2%) in arm B, including one patient with T-acute lymphoblastic leukemia with significant blast count reduction. Alterations considered for enrichment were present in 25 patients (81%) and in eight of nine patients with stable disease; the leukemia exhibited CDKN2A/B and PTEN deficiency. CONCLUSION Ribociclib in combination with TOTEM or everolimus was well-tolerated. The observed activity signals initiated a follow-up study of the ribociclib-everolimus combination in a population enriched with molecular alterations within both pathways.

Phase I/II clinical trial of temsirolimus and lenalidomide in patients with relapsed and refractory lymphomas

The PI3K/Akt/mTOR (PAM) axis is constitutively activated in multiple lymphoma subtypes and is a promising therapeutic target. The mTOR inhibitor temsirolimus (TEM) and the immunomodulatory agent lenalidomide (LEN) have overlapping effects within the PAM axis with synergistic potential. This multicenter phase I/II study evaluated combination therapy with TEM/LEN in patients with relapsed and refractory lymphomas. Primary endpoints of the phase II study were rates of complete (CR) and overall response (ORR). There were 18 patients in the phase I dose-finding study, and TEM 25 mg weekly and LEN 20 mg on day 1 through day 21 every 28 days was established as the recommended phase II dose. An additional 93 patients were enrolled in the phase II component with three cohorts: diffuse large B-cell lymphoma (DLBCL, n=39), follicular lymphoma (FL, n=15), and an exploratory cohort of other lymphoma histologies with classical Hodgkin lymphoma (cHL) comprising the majority (n=39 total, n=20 with cHL). Patients were heavily pretreated with a median of 4 (range, 1-14) prior therapies and one-third with relapse following autologous stem cell transplantation (ASCT); patients with cHL had a median of 6 prior therapies. The FL cohort was closed prematurely due to slow accrual. ORR were 26% (13% CR) and 64% (18% CR) for the DLBCL and exploratory cohorts, respectively. ORR for cHL patients in the exploratory cohort, most of whom had relapsed after both brentuximab vedotin and ASCT, was 80% (35% CR). Eight cHL patients (40%) proceeded to allogeneic transplantation after TEM/LEN therapy. Grade ≥3 hematologic AEs were common. Three grade 5 AEs occurred. Combination therapy with TEM/LEN was feasible and demonstrated encouraging activity in heavily-pretreated lymphomas, particularly in relapsed/refractory cHL. ClinicalTrials.gov identifier: NCT01076543.

Phase I study protocol: NKTR-255 as monotherapy or combined with daratumumab or rituximab in hematologic malignancies

NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255.

A phase I/IB study of ipatasertib in combination with carboplatin or carboplatin/paclitaxel or capecitabine and atezolizumab in patients with metastatic triple-negative breast cancer.

1078 Background: Ipatasertib (ipat) is an AKT inhibitor which has shown efficacy in combination with paclitaxel and atezolizumab in patients with triple negative breast cancer (TNBC). In previous trials, ipat was given 21 days on 7 days off due to gastrointestinal toxicities. The current trial was designed to test the safety and efficacy of ipat continuous dosing in combination with carboplatin (carbo) or carboplatin/paclitaxel (carbo/taxol). The trial was later amended to include an additional arm using ipat 21 days on 7 days off with capecitabine/atezolizumab (cape/atezo) to explore the safety of the combination. Methods: Patients with metastatic TNBC and up to 2 lines of prior chemotherapy were enrolled to receive the following: Arm A, ipat 400 mg daily, carbo AUC 2 and taxol 80 mg/m2 IV days 1, 8, 15, every 28 days; Arm B, ipat 400 mg daily, carbo AUC 2 IV days 1, 8, 15, every 28 days; Arm C, ipat 300 mg daily 21 days on 7 days off, cape 750 mg/m2 7 days on 7 days off, atezo 840 mg IV every 28 days. Ipat continuous dosing was used for Arms A and B. Ipat 21 days on 7 days off dosing was used for Arm C. The primary endpoint is safety and recommended phase II dose (RP2D). Secondary endpoints are response rate (RR) and overall survival (OS). Results: Twenty-three patients with median age 49 (29-75) were enrolled from 04/2019 to 12/2020, with 9 in Arm A, 10 in Arm B, and 4 in Arm C. A total of 15/23 (65%) had dose delay and 10/23 (43%) had dose modification. 3/4 (75%) of patients in Arm A had dose limiting toxicities (DLT) including diarrhea and gastric pain, which led to de-escalation to dose -1 with ipat (300 mg daily). 5 more patients were treated at dose -1 of Arm A with only 1 DLT (maculo-papular rash). No DLTs were observed in Arm B. Of the 4 patients treated in Arm C, 1 had DLT (maculo-papular rash). The RP2D for Arms A and B are: ipat 300 mg/carbo AUC2/taxol 80 mg/m2; ipat 400 mg/carbo AUC2. RP2D for Arm C has not been determined and accrual is ongoing. There were no clinically significant G4 toxicities in Arm A; G3 toxicities included 4/9 (44%) diarrhea, 1/9 (11%) hypertension, 1/9 (11%) stomach pain, and 1/9 (11%) neutropenia. For Arm B, G3 toxicities included 2/10 (20%) diarrhea, 1/10 (10%) anemia, 1/10 (10%) maculo-papular rash, and 1/10 (10%) hyperglycemia. For Arm C, there was 1/4 (25%) G3 maculo-papular rash. Best overall responses for Arm A were: 2/9 (22%) PR, 4/9 (44%) SD, and 3/9 (33%) PD. Best responses for Arm B were 2/10 (20%) PR, 6/10 (60%) SD, and 2/10 (20%) PD. For Arm C, best responses were 3/4 (75%) SD, and 1 not evaluable (repeat biopsy showed HER2+ disease). With a median follow up of 8.1 months, the median PFS was 4.0 months (95% CI [2.6, 5.3]). Conclusions: Continuous dosing of ipatasertib in combination with carbo or carbo/taxol is well-tolerated with modest efficacy. Clinical trial information: NCT03853707 .

A phase Ib study of xentuzumab plus abemaciclib and fulvestrant in patients (pts) with advanced hormone receptor-positive (HR+), HER2-negative breast cancer (BC) with visceral or non-visceral disease.

1057 Background: Cyclin-dependent kinase (CDK) 4 & 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 & 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 & 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received >1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 & 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]

Phase Ib study of BI 836880 (VEGF/Ang2 nanobody) plus ezabenlimab (BI 754091; anti-PD-1 antibody) in patients (pts) with solid tumors.

2579 Background: In preclinical studies, the combination of anti-VEGF/Ang2 and anti-PD-1 therapy has been shown to promote an immunopermissive state, which is supportive of T-cell-mediated tumor cell destruction. BI 836880 is a humanized bispecific nanobody that targets VEGF and Ang2, and ezabenlimab (BI 754091) is an anti-PD-1 antibody. Phase I studies investigating each as monotherapies have reported safety and preliminary antitumor activity. This ongoing Phase Ib study is evaluating the combination of BI 836880 and ezabenlimab in pts with advanced solid tumors. In Part 1 (dose escalation), the combination was feasible in pts with advanced NSCLC, with a recommended Phase II dose (RP2D) of BI 836880 720 mg + ezabenlimab 240 mg IV q3w. Here, we report updated results from Part 2 (expansion phase), which is assessing the antitumor activity and safety of the RP2D. Methods: Seven cohorts are currently recruiting pts in Part 2: metastatic (m) NSCLC after checkpoint inhibitor (CPI) monotherapy (Cohort A); mNSCLC after chemotherapy (CT) + CPI (Cohort B); mSCLC after CT ± CPI (Cohort C); 1st and 2nd recurrences of glioblastoma (GBM; Cohort D); immunotherapy-resistant m-melanoma (Cohort E); hepatocellular carcinoma (HCC) after prior sorafenib or lenvatinib ± CPI (Cohort F); and previously untreated/unresectable HCC (Cohort G). Primary endpoint is objective response rate (complete response + partial response [PR]). Results: As of January 2021, 196 pts have received BI 836880 plus ezabenlimab (14 in Part 1, 182 in Part 2 [Cohort A, 26; B, 30; C, 19; D, 31; E, 32; F, 28; G, 16]). 134 (68%) pts were male, median age was 63 years and 102 (52%) had prior CPI use. Any grade and ≥G3 adverse events (AEs; any cause) were reported by 160 (82%) and 62 (32%) pts, most commonly (all%/≥G3%) hypertension (20/8), asthenia (20/3), diarrhea, decreased appetite, and nausea (all 11/1). 95 (48%) pts had a drug-related AE, most commonly hypertension and asthenia (both 11%). 6 pts had a G4 AE (non-related: hyperkalemia + cardiac arrest, laryngospasm, gastrointestinal perforation; drug-related: anaphylactic reaction, acute pancreatitis, transaminases increased); 8 pts had a G5 AE (non-related: general physical health deterioration, epilepsy, hemoptysis, cardio-respiratory arrest, hepatic failure, intracranial hemorrhage, COVID-19 pneumonia; drug-related tracheal hemorrhage). 30 (15%) pts had immune-related AEs (3% ≥G3), including hypothyroidism (3%). 11 (6%) pts had an AE leading to discontinuation. Overall, 145 pts were evaluable for response: 9 pts achieved confirmed PR (2 pts in Part 1 and 7 in Part 2 [NSCLC, n = 3; SCLC, n = 1; GBM, n = 1; melanoma, n = 1; and 2nd-line HCC, n = 1]), 87 pts had stable disease and 49 pts had progressive disease. 111 pts remain on treatment. Conclusions: BI 836880 plus ezabenlimab had a manageable safety profile. The combination showed preliminary antitumor activity in a range of tumor types. Clinical trial information: NCT03468426.