Recurrent Solid Tumors Research Articles

Abstract CT252: transcendIT-101: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors

Abstract Background: Toll-like receptors (TLRs) play a key role in innate immune cell recognition of foreign pathogens, stimulating innate and adaptive immune responses. TLR agonists amplify tumor antigen-specific immune responses in the context of anti-PD-1 therapy. TransCon TLR7/8 Agonist is designed as a long-acting prodrug to provide localized delivery of resiquimod, a potent TLR7/8 agonist. TransCon TLR7/8 Agonist has the potential to improve on challenges of pattern recognition receptor agonist treatments by providing prolonged high local concentrations of resiquimod and promoting potent anti-tumoral responses while reducing systemic drug exposure and related adverse events. TransCon TLR7/8 Agonist comprises 3 main components: resiquimod, a polymeric hydrogel microparticle carrier, and a linker bound permanently to the hydrogel microparticle carrier on one end and transiently to resiquimod on the other. TLR-mediated T cell activation induces PD-1 expression on T cells, providing a clear rationale to study TransCon TLR7/8 Agonist alone and in combination with pembrolizumab (pembro). Intratumoral TransCon TLR7/8 Agonist is expected to stimulate innate and adaptive immune response in the tumor microenvironment and further enhance the activity of checkpoint inhibitors like pembro. Methods: transcendIT-101 is a multicenter, first-in-human, Phase 1/2 study in 3 parts in adult patients with locally advanced, unresectable, recurrent, or metastatic solid tumors. All patients must have at least 2 measurable lesions by RECIST 1.1 that are predesignated as target-injected and target non-injected lesions, respectively. The primary objectives are to evaluate the safety, tolerability, define the maximum tolerated dose and recommended Phase 2 dose (RP2D) of TransCon TLR7/8 Agonist alone or in combination with pembro. Parts 1 and 2 Dose Escalation (Phase 1) use a standard 3+3 design with increasing doses of TransCon TLR7/8 Agonist alone (Part 1) or with 200 mg intravenous pembro in solid tumors where pembro monotherapy may have clinical activity (Part 2). Each part will enroll ≈20 patients. Part 3 Combination Dose Expansion (Phase 2) will evaluate preliminary clinical efficacy of TransCon TLR7/8 Agonist at the RP2D determined in Part 2 combined with pembro. Currently planned expansion cohorts are 1) head and neck squamous cell carcinoma, 2) other HPV-associated tumors (anal, vulvar, cervical, penile, vaginal). Each cohort will be analyzed using a Simon 2-stage design and will enroll ≈50 patients. Secondary objectives are TransCon TLR7/8 Agonist pharmacokinetics and its antitumor activity using ORR, duration of response, time to response by RECIST 1.1 and itRECIST; progression-free survival; overall survival. Recruitment started March 2021 and is ongoing (NCT04799054). Citation Format: Diwakar Davar, Stina M. Singel, Gil Nyamuswa, Tuan-Anh Tran, Yang Wu, Jaspreet Grewal, Morteza Aghmesheh, Alexander Spira, Vinod Ganju, Jamie Rand, Sophia Frentzas, David Bajor, Nashat Gabrail. transcendIT-101: A phase 1/2, open-label, dose escalation and dose expansion study of TransCon TLR7/8 Agonist alone or in combination with pembrolizumab in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT252.

A phase 1 study of serplulimab, a novel humanized monoclonal anti-PD-1 antibody, in patients with advanced solid tumors.

e14560 Background: Serplulimab, a novel humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T cells and showed anti-tumor activity in several xenograft models. This phase 1 study was designed to assess the safety and tolerability of serplulimab in patients with metastatic or recurrent solid tumors. Methods: This prospective, open-label, two-cohort (dose-finding cohort [up to 30 patients]; dose expansion cohort [up to 27 patients]) phase 1 study was conducted in patients with metastatic or recurrent solid tumors who had failed standard therapy. In the dose-finding cohort, Bayesian optimal interval (BOIN) design was adopted to explore the MTD of serplulimab. Patients were administered serplulimab (Q2W) at doses of 0.3, 1, 3, or 10 mg/kg via intravenous infusion until disease progression, the maximum of 1 year, withdrawal from the study, or death, whichever occurred first. In the dose expansion cohort, nine eligible patients were enrolled in each dose group to receive fixed doses of serplulimab at 200 (Q2W), 300 (Q3W) or 400 mg (Q4W). The primary objective of this study was to identify the safety profile and the MTD of serplulimab. The PK profile and the preliminary efficacy were also examined as secondary objectives. Results: Here we only report the results from the dose-finding cohort. As of July 27, 2020, 29 patients were enrolled and treated with at least one dose of serplulimab (0.3 mg/kg group, n = 3; 1 mg/kg group, n = 4; 3 mg/kg group, n = 6; 10 mg/kg group, n = 16). At baseline, the mean age of enrolled patients was 60.0 years, with a mean BMI of 24.7 kg/m2, a mean BSA of 1.7 m2, and a mean LVEF of 67.1%. All patients presented with stage IV tumors at baseline, among whom 79.3% were diagnosed with metastatic disease. Only one patient in the 3 mg/kg dose group experienced DLTs, which was reported during the first cycle. The MTD was not determined yet. Overall, 28 (96.6%) patients experienced at least one TEAE during the study, mostly of grade 1 or 2. No notable differences were observed among the dose groups with regard to the incidence of TEAEs. The most frequently reported TEAEs was decreased appetite (41.4%), fatigue (31.0%), nausea (27.6%), pyrexia (27.6%), and pleural effusion (27.6%). Minimal accumulation of serplulimab was observed following multiple dose administrations. The preliminary anti-tumor efficacy of serplulimab was demonstrated by a DCR of 60.0%, an ORR of 8.0%, and a median PFS of 107.0 days. Conclusions: In summary, serplulimab up to 10 mg/kg was well tolerated and showed promising anti-tumor activity in patients with metastatic or recurrent solid tumors. Serplulimab is currently being investigated in phase 3 studies among patients with NSCLC, SCLC, esophageal cancer, mCRC, etc. Clinical trial information: NCT03468751.

A pilot clinical study of VAL-413 (oral irinotecan HCl) in patients with recurrent pediatric solid tumors.

TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. Methods: Eligibility: Up to 20 patients ≥ 1 year and ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 100mg/m2/day will be studied in combination with a fixed-dose of temozolomide using a standard 3 + 3 phase I design. In the event that the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; and comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed in all patients. This trial is ongoing (CT.gov: NCT04337177). Enrolment of the first dose level is ongoing, with no DLT observed to date. Clinical trial information: NCT04337177.

IBI110 (anti-LAG-3 mAb) as a single agent or in combination with sintilimab (anti-PD-1 mAb) in patients with advanced solid tumors: Updated results from the phase Ia/Ib dose-escalation study.

2650 Background: Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor protein that functions to control T cell response, activation and growth. Dual inhibition of PD-1 and LAG-3 may improve anti-tumor effect synergistically. A phase Ia/Ib dose-escalation study evaluated IBI110 ± sintilimab in patient with advanced solid tumors; initial efficacy and safety data were previously presented (C Zhou et al. ASCO 2021; NCT04085185). Here, we reported the updated results. Methods: Eligible patients were ECOG PS 0-1 and had locally advanced, recurrent or metastatic solid tumors for whom standard therapy had failed. Patients received escalating doses of IBI110 (0.01/0.1/0.3/1/3/10/20mg/kg) IV Q3W in phase Ia and escalating doses of IBI110 (0.3/0.7/1.5/3/5/8/10 mg/kg) in combination with sintilimab 200 mg IV Q3W in phase Ib. Crossover from monotherapy to combination therapy was allowed at progression. The primary objectives were safety, tolerability, and anti-tumor activity of IBI110 alone or IBI110+sintilimab (per RECIST v1.1). Results: Phase Ia: 28 patients (median age of 60.5 years [range 35-72], ECOG PS of 0 [n = 14] and 1 [n = 14]) were enrolled. Dose escalation was completed and no dose-limiting toxicity (DLT) was observed in all dose cohorts. The safety profile was generally consistent with the initial. By investigator-assessment, best response was 1 confirmed partial response (PR) and 6 stable diseases (SD) with monotherapy. After crossing to combination therapy at progression, 8 patients who failed prior anti-PD-(L)1 mAb therapy achieved SD. Phase Ib: Overall, 45 patients (median age: 60.0 yr [range 33-74]; ECOG PS: 0 [n = 14], 1 [n = 31]) were enrolled in all dose levels. Dose escalation was completed and no DLT was observed. The most common treatment-related adverse events (TRAEs) were aspartate aminotransferase increased (28.9%), anaemia (24.4%), and alanine aminotransferase increased (22.2%). TRAEs ≥ grade 3 occurred in 10 (22.2%) patients. Immune-related AE (irAE) incidence was 31.1%, and the most common irAE was hypothyroidism (15.6%). In 43 patients who had undergone at least 1 post-baseline tumor assessment, the investigator-assessed best response included 6 PRs (1 endometrial cancer, 4 NSCLC, and 1 SCLC patients) and 23 SDs. Three patients showed a progression-free survival > 1 year and continued treatment. Conclusions: IBI110 alone or plus sintilimab demonstrated acceptable safety profile and promising antitumor activity in patients with advanced solid tumors. Clinical trial information: NCT04085185.

Phase 2 study of the IDO/PD-L1-targeted immune-modulatory vaccine, IO102-IO103, plus pembrolizumab as first-line treatment for metastatic non–small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), or urothelial bladder cancer (UBC).

TPS2699 Background: Immunotherapy has transformed the treatment of NSCLC and other solid tumors, such as SCCHN and UBC. However, even with standard-of-care anti-PD-1/PD-L1 therapies, few patients achieve durable benefit even when PD-L1 is overexpressed. IO102-IO103 is a potentially first-in-class, dual-antigen, immune-modulatory therapy that stimulates T cells to target tumoral immune escape via key checkpoint molecules IDO and PD-L1. It is thought that activating IDO/PD-L1-specific T cells in cancer patients through vaccination may support anticancer immunity by restricting immunosuppressive signaling and restoring the tumor immune microenvironment to render the tumor more susceptible to anti-PD-1 blockade. Thus there is a rationale for combining IO102-IO103 with anti-PD-1 therapy in the first-line treatment of metastatic tumors, such as NSCLC, SCCHN, or UBC. Combined IO102-IO103 and anti-PD-1 therapy (nivolumab) has already shown a robust signal of clinical activity (overall response rate [ORR], 80%; complete response rate [CRR], 43%; median progression-free survival [PFS], 26 months) and was well tolerated with minimal added toxicity to nivolumab in a Phase 1/2 study of anti-PD1-naïve patients with metastatic melanoma (Kjeldsen, et al. Nat Med 2021). Methods: This is a Phase 2, international, multicenter (US and Europe), non-comparative, open-label, multi-arm (basket) trial (EudraCT No. 2021-003026-69; ClinicalTrials.gov No. NCT05077709). Patients with recurrent, unresectable or metastatic solid tumors in 3 indications and no prior treatments for metastatic disease are being enrolled: NSCLC with a PD-L1 Tumor Proportion Score (TPS) ≥50% (Arm A); SCCHN with PD-L1 Combined Positive Scores (CPS) ≥20 (Arm B); or UBC with PD-L1 CPS ≥10 and not eligible for platinum-containing chemotherapy (Arm C). All patients, ̃30 in each arm, will receive 3-week cycles of IO102-IO103 (85-85 µg on Day [D] 1 and 8 of Cycle 1 and 2, and D1 thereafter) subcutaneously plus pembrolizumab (200 mg on D1) intravenously, for up to 2 years. Primary endpoints are ORR by RECIST v1.1 or 6-month PFS rate by investigator assessment (to be analyzed either 6 months after last patient started treatment or after target ORR is achieved, whichever is earliest). Secondary endpoints include PFS, duration of response, complete response rate, disease control rate, time to response, overall survival, and safety. Exploratory endpoints include biomarker and immune marker correlative studies, and PFS by iRECIST. The trial will assess the opportunity for a positive risk–benefit based on 2 efficacy boundaries for the ORR and 6-month PFS rate in each arm, with cohort expansion permitted if a clinically relevant efficacy signal is observed. Clinical trial information: EudraCT No. 2021-003026-69; ClinicalTrials.gov No. NCT05077709.

Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors.

3096 Background: NT219 is a small molecule, effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. A Phase 1/2 study (NCT04474470) includes a dose escalation of NT219 administered weekly for the treatment of relapsed and/or refractory cancer patients. Methods: In the dose escalation part of the study involving a conventional 3+3 design, patients with recurrent and/or metastatic solid tumors were administered intravenously with NT219 at 3, 6, 12 and 24mg/kg. Safety was assessed according to CTCAE v5 and anti-tumor activity was assessed by the investigators according to RECISTv1.1 using CT/MRI. The primary objectives of this part of the study are to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D). The study includes evaluation of potential biomarkers including measurements of STAT3, IRS1/2 phosphorylation, and TILs in biopsy specimens. Results: As of data cutoff date of February 8, 2022, a total of 13 patients were enrolled to 4 NT219 dose levels (3 - 24mg/kg) in the dose escalation phase, of which 11 were evaluable for dose limiting toxicity (DLT) determination, including 4 with colorectal cancer (CRC), 2 with pancreatic cancer, 2 with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal, appendiceal, papillary thyroid, and mesothelioma. Median number of prior treatment regimens for metastatic disease was 4 (2-11). Six Grade 3 adverse events (AEs) were observed, including alkaline phosphatase increase, aspartate aminotransferase increase, toxic encephalopathy, worsening back pain, abdominopelvic ascites, closed displaced fracture of right femoral neck, with the first 2 considered as possibly related to NT219. No Grade 4 AEs or treatment related deaths were reported. For the 11 evaluable patients, best overall response included one confirmed PR (GEJ patient, 5.5 months duration of response), and 3 SD (3 of 4 CRC patients; duration of 5.2, 4, and 2 months with ongoing follow up) with two patients awaiting follow up MRI/CT scans. As of the cutoff date, 9/11 patients that completed the DLT period are either on treatment or in follow up (range 1.1 to 14.7 months). Conclusions: Interim analysis of safety results obtained in 4 NT219 dose levels found NT219 to be well tolerated without DLTs in advanced cancer patients. The observed durable PR in a GEJ patient and SDs in 3 CRC patients are an encouraging initial signal of efficacy. Combination treatment of cetuximab with escalating NT219 doses in patients with recurrent/metastatic CRC and squamous cell carcinoma of the head and neck (SCCHN) has begun. An expansion cohort in patients with recurrent/metastatic SCCHN will be initiated at the conclusion of this part. Clinical trial information: NCT04474470.

Phase I dose-escalation study of IBI351 (GFH925) monotherapy in patients with advanced solid tumors.

3110 Background: IBI351(GFH925) is an irreversibly covalent inhibitor of KRASG12C. In this first-in-human dose-escalation study, we report the preliminary safety and anti-tumor activity of IBI351 (GFH925) in patients (pts) with advanced solid tumors harboring the KRAS p.G12C mutation. Methods: Pts with locally advanced, recurrent or metastatic solid tumors with KRASG12C mutation for whom standard therapy had failed were enrolled. Phase I dose escalation had an accelerated titration design for dose level 250mg QD and a BOIN design with 450/700/900mg QD. The primary end points were safety and tolerabilityThe secondary end points were pharmacokinetics (PK) and anti-tumor activity of IBI351(GFH925) monotherapy per RECIST v1.1. Results: As of Feb 07 2022, 15 pts (13 men, 2 women; median age: 62 yrs, range: 48–74 yrs) were enrolled, among whom 12 had non-small cell lung cancer (NSCLC), and 3 had colorectal cancer (CRC). 4 pts had ≥3 prior lines of treatment (tx). Median tx duration was 66.5 ds (range: 21–98 ds). No dose-limiting toxicity (DLT) or any ≥grade 3 treatment-related adverse events were observed in any dose cohorts. A total of 12 patients (80.0%) had treatment-related adverse events (grade 1, n = 6; grade 2, n = 6). By investigator-assessment, tumor response was evaluated in 9 pts (4 with ≥2 assessments); 6 pts had not reached their first assessment. 2 pts had PR (1 NSCLC at wks 12, 450mg, tx ongoing; 1 CRC at wks 6, 700mg, tx ongoing), 4 pts (NSCLC) had SD, and 3 pts had PD (1 NSCLC at wks 12, 2 CRC at wks 6). As data cut-off date, 11 pts were continuing to receive IBI351 (GFH925). Conclusions: IBI351(GFH925) was well-tolerated without unanticipated adverse events across all doses explored in pts with advanced solid tumors harboring the KRAS p.G12C mutation. The data also demonstrated the preliminary efficacy signal of IBI351 (GFH925) in previously treated advanced NSCLC and CRC. Clinical trial information: NCT05005234.

ADVL1514, a phase 1 study of ABI-009 (nab-sirolimus) in pediatric patients with recurrent or refractory solid tumors, including CNS tumors as a single agent and in combination with temozolomide and irinotecan: A Children’s Oncology Group pediatric early-phase clinical trial network study.

10022 Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m2/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m2/dose, DL-1: 20mg/m2/dose, and DL-2: 15mg/m2/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m2/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.

Bevacizumab, With Sorafenib and Cyclophosphamide Provides Clinical Benefit for Recurrent or Refractory Osseous Sarcomas in Children and Young Adults.

ObjectiveChildren and adolescents with recurrent and metastatic solid tumors have a poor outcome. A previous phase 1 study (ANGIO1) targeting angiogenesis with bevacizumab, sorafenib, and cyclophosphamide, demonstrated a signal of activity in a subset of patients. Here we report the results of a cohort of pediatric and young adult patients treated at the recommended phase 2 doses.MethodsElectronic medical records of patients with refractory or recurrent solid tumors who received ANGIO1 therapy were reviewed. Treatment cycles lasted 21 days and included bevacizumab, sorafenib, and cyclophosphamide. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v5.0. Responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST1.1).ResultsThirty-nine patients (22 male, 17 female; median age 15 years; range 1-22 years) received the treatment regimen. The most common diagnoses included bone sarcomas (n=21; 14 Ewing sarcoma, 7 osteosarcoma) and soft tissue sarcomas (n=9; 2 rhabdomyosarcoma, 3 synovial sarcoma, 2 desmoplastic small round cell tumors, and 2 high-grade sarcoma). The most common Grade 3 non-hematologic toxicities included hypertension (2, 5.4%) and hematuria (2, 5.4%). Five patients (13.5%) had a pneumothorax (3 at progressive disease, 1 post lung biopsy, and 1 spontaneous). Common Grade 3/4 hematologic toxicities were lymphopenia (19, 51%) and leukopenia (13, 35%). Sixteen patients (43.2%) developed palmar-plantar erythrodysesthesia Grade 2 or less. A total of 297 cycles were administered. Twenty-three patients required a dose reduction of cyclophosphamide, sorafenib or bevacizumab during therapy, all of whom continued to have clinical benefit following dose modification. One patient (Ewing sarcoma) achieved a complete response after 11 cycles; 2 patients (Ewing sarcoma, high grade sarcoma) achieved a partial response following cycles 2 and 4, respectively and 20 patients had stable disease as a best response.ConclusionsIntravenous bevacizumab combined with oral sorafenib and metronomic cyclophosphamide was tolerated and required minimal supportive care or additional clinic visits. Disease stabilization for prolonged time periods was observed in greater than half of the treated patients. Patients with bone sarcoma demonstrated a signal of activity suggesting possible benefit from incorporation of the therapy as a maintenance regimen in upfront setting, or as a palliative regimen.

First phase 1 clinical study of olaparib in pediatric patients with refractory solid tumors

The survival of patients with high-risk, refractory, relapsed, or metastatic solid tumors remains dismal. A poly(ADP-ribose) polymerase (PARP) inhibitor could be effective for the treatment of pediatric solid tumors with defective homologous recombination. This open-label, multicenter phase 1 clinical trial evaluated the safety, tolerability, and efficacy of olaparib, a PARP inhibitor, in pediatric patients with refractory solid tumors to recommend a dose for Phase 2 trials. Olaparib (62.5, 125, and 187.5 mg/m2 twice daily) was administered orally every day (1 cycle=28 days) using a standard 3 + 3 dose-escalation design. Patients aged 3-18 years with recurrent pediatric solid tumors were eligible. Pharmacokinetic and pharmacodynamic analyses were performed. Fifteen patients were enrolled and received olaparib monotherapy, which was well tolerated. The recommended phase 2 dose for daily administration was 187.5 mg/m2 twice daily. Pharmacokinetics were dose proportional. The area under the concentration-time curve from 0 to 12 h and the peak plasma concentration for 187.5 mg/m2 twice daily in children were comparable to previous data obtained in a 200-mg, twice-daily cohort and lower than those in the 300-mg twice-daily cohort in adults. Pharmacodynamic studies demonstrated substantial inhibition of PARP activity. Two partial responses were observed in patients with Wilms tumor and neuroblastoma. This report is the first clinical trial to describe the use of a PARP inhibitor as monotherapy in children. Olaparib was well tolerated, with preliminary antitumor responses observed in DNA damage response-defective pediatric tumors. This Phase 1 trial evaluated the efficacy and safety of olaparib in patients with refractory childhood solid tumors. Olaparib was well tolerated, achieving objective response in 2/15 patients. The DNA damage response was attenuated in nearly one-half of advanced neuroblastoma patients, demonstrating the utility of the PARP inhibitor. The results support further investigation of olaparib as a new treatment for DNA damage-response or repair-defective pediatric cancers.

Application of Non-Blood-Derived Fluid Biopsy in Monitoring Minimal Residual Diseases of Lung Cancer.

Lung cancer is one of the most fatal malignant tumors in the world. Overcoming this disease is difficult due to its late diagnosis and relapse after treatment. Minimal residual disease (MRD) is described as the presence of free circulating tumor cells or other tumor cell derivatives in the biological fluid of patients without any clinical symptoms of cancer and negative imaging examination after the treatment of primary tumors. It has been widely discussed in the medical community as a bridge to solid tumor recurrence. Radiology, serology (carcinoembryonic antigen), and other clinical diagnosis and treatment methods widely used to monitor the progression of disease recurrence have obvious time-limited and -specific defects. Furthermore, as most samples of traditional liquid biopsies come from patients’ blood (including plasma and serum), the low concentration of tumor markers in blood samples limits the ability of these liquid biopsies in the early detection of cancer recurrence. The use of non-blood-derived fluid biopsy in monitoring the status of MRD and further improving the postoperative individualized treatment of patients with lung cancer is gradually ushering in the dawn of hope. This paper reviews the progress of several non-blood-derived fluid samples (urine, saliva, sputum, and pleural effusion) in detecting MRD in lung cancer as well as selecting the accurate treatment for it.

Entrectinib: A New Selective Tyrosine Kinase Inhibitor Approved for the Treatment of Pediatric and Adult Patients with NTRK Fusionpositive, Recurrent or Advanced Solid Tumors.

Entrectinib is a highly potent ATP-competitive and selective inhibitor of tyrosine kinases - Trk A B C, ALK, and ROS1. It was developed by Roche and initially approved in Japan in 2019 to treat pediatric and adult patients with NTRK fusionpositive, recurrent, or advanced solid tumors. In August 2019, entrectinib received accelerated approval by the U.S FDA for this indication. It is also the first FDA-approved drug designed to target both NTRK and ROS1. We aim to summarize recent studies related to the synthesis, mechanism of action, and clinical trials of the newly approved selective tyrosine kinase inhibitor entrectinib. We conduct a literature review of the research studies on the new highly-potent small-molecule entrectinib. Entrectinib, based on three clinical studies (ALKA, STARTRK-1, and STARTRK-2), was well tolerated, with a manageable safety profile. It induced clinically meaningful responses in recurrent or advanced solid tumors associated with NTRK fusion- positive or ROS1+ NSCLC. It demonstrated substantial efficacy in patients with CNS metastases.

The Efficacy and Safety of Anlotinib in Pediatric Patients With Refractory or Recurrent Solid Tumors

Objective: Refractory or recurrent pediatric solid tumors lack effective treatments, and are associated with dismal outcomes. Hence, there is an urgent need for a novel therapeutic strategy. This study aimed to evaluate the efficacy and safety of anlotinib, a novel oral multi-kinase angiogenesis inhibitor, in pediatric patients with refractory or recurrent solid tumors. Methods: This single-institutional, observational retrospective study was conducted in Sun Yat-sen University Cancer Center, China. Refractory or recurrent pediatric solid tumor patients treated with anlotinib between 2018 and 2020 were evaluated. Results: Forty-one and 30 patients were enrolled to evaluate the efficacy and safety of anlotinib, respectively. There was partial response in five patients, stable disease in 22 patients, no patient with complete response, with an objective response ratio of 12.2% (5/41; 95% CI 1.7-22.7). The disease control rate was 65.9% (27/41; 95% CI 50.7-81) and the median progression-free survival was 2.87 months (95% CI 0.86-4.88). The incidence rates of any grade and grade 3–4 adverse events were 80% (24/30) and 23.3% (7/30), respectively. Bleeding (20%, 6/30), hand-foot syndrome (16.7%, 5/30), and diarrhea (13.3%, 4/30) were the most common adverse events. Grade 3–4 adverse events included hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There were no adverse events-related deaths. Conclusion: For heavily pretreated pediatric solid tumors, anlotinib monotherapy and its combination with chemotherapy may be an effective treatment option with tolerable adverse events. It is necessary to monitor blood pressure when using anlotinib in children.

Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient non-endometrial solid tumors: A post-hoc subgroup analysis of patients with colorectal cancer.

201 Background: Dostarlimab is a programmed death receptor-1 (PD-1) blocking antibody that is approved in the US as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen or dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. Here, we report on the antitumor activity and safety of dostarlimab monotherapy in pts with dMMR colorectal cancer (CRC), a post-hoc subgroup analysis of cohort F of the GARNET trial. Methods: GARNET is a phase 1, multicenter, open-label, single-arm study of dostarlimab monotherapy in pts with advanced or recurrent solid tumors. Cohort F of the GARNET expansion cohorts enrolled pts with dMMR/MSI-H or POLε mutated non-endometrial solid tumors, including pts with CRC. Pts must have progressed per blinded independent central review (BICR) following prior systemic therapy for advanced disease. Pts with CRC were required to have progressive disease after or been intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. Pts received 500 mg intravenous dostarlimab every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks until discontinuation. Primary endpoints were objective response rate (ORR) and duration of response by BICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and had ≥24 weeks of follow-up. All pts who received ≥1 dose of dostarlimab were included in the safety analysis. Results: As of the March 01, 2020 interim analysis data cut, 141 pts with dMMR non-endometrial solid tumors were included in the safety analysis, with 106 in the efficacy analysis. Of the pts in the efficacy analysis, 69 (65.1%) had CRC. Confirmed ORR by BICR per RECIST v1.1 in pts with dMMR CRC was 36.2% (95% CI, 25.0%–48.7%). There were 3 complete responses and 22 partial responses. At the data cut, 23 pts (92%) were still on treatment. Median duration of response had not been reached for pts with CRC. In the overall dMMR non-endometrial solid tumor population, treatment-related adverse events (TRAEs) were reported in 68.1% of pts, with 8.5% of pts experiencing at least 1 grade ≥3 TRAE. The most common grade ≥3 TRAE was lipase increased in 2 (1.4%) of pts. Only 5 pts (3.5%) discontinued dostarlimab due to at TRAE. Treatment-related serious AEs were reported in 9 (6.4%) pts. Conclusions: Dostarlimab demonstrated durable clinically meaningful antitumor activity in pts with dMMR CRC, which was consistent with that seen in patients with dMMR non-CRC solid tumors. No new safety signals were detected in patients with dMMR non-endometrial solid tumors. Clinical trial information: NCT02715284.

CAR-macrophage: An extensive immune enhancer to fight cancer.

CAR-macrophage: An extensive immune enhancer to fight cancer.

Iodine-125 Plaque Radiotherapy for Retinoblastoma Recurrence Following Intra-arterial Chemotherapy.

To assess the efficacy and toxicity of Iodine-125 (I-125) plaque radiotherapy for retinoblastoma following intra-arterial chemotherapy (IAC). Clinical records of patients with retinoblastoma who received I-125 plaque radiotherapy after IAC at the Ocular Oncology Service at Wills Eye Hospital between December 1, 2009 and April 30, 2020, were retrospectively reviewed. Forty-one retinoblastomas in 41 eyes of 41 patients were treated with I-125 plaque radiotherapy after IAC at a median age of 32 months. The indication for plaque radiotherapy was solid tumor recurrence with or without overlying subretinal/vitreous seeds (n = 33, 80%), subretinal seeds alone (n = 6, 15%), and vitreous seeds alone (n = 2, 5%). The median irradiated basal diameter and thickness was 9 and 4 mm, respectively. Mean radiation dose to tumor apex was 3,483 centigray (cGy) delivered at mean rate of 35 cGy/hr. The irradiated site was controlled in 39 eyes (95%) at a median of 20 months after plaque radiotherapy for solid tumor (31 of 33, 94%), subretinal (6 of 6,100%), and vitreous seeds (2 of 2, 100%). A subgroup of tumors occurring within an ischemic retinal/choroidal field was identified on fluorescein angiography (n = 24) and demonstrated control in 22 of 24 (92%). Using Kaplan-Meier analysis, radiation complications at 2 years included vitreous hemorrhage (37%), retinopathy (28%), papillopathy (18%), and cataract (18%). Five eyes (12%) were enucleated for recurrence outside the irradiated area, chronic vitreous hemorrhage, and/or total retinal detachment. Iodine-125 plaque radiotherapy provided 95% control for retinoblastoma tumors that failed IAC, including those in ischemic fields untreatable with further chemotherapy. Radiation complications should be anticipated in eyes exposed to substantial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2022;59(3):164-171.].

ACT-1 Multicenter investigator-initiated registration-directed Phase 2 study of E7090 in subjects with advanced or recurrent solid tumors with fibroblast growth factor receptor (FGFR) gene alteration: FORTUNE trial

Background: Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, 2021), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods: The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043, ClinicalTrials.gov: NCT04962867)

Abstract P162: Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in >10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies.

The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

SYST-01. MULTICENTER INVESTIGATOR-INITIATED PHASE 2 STUDY OF E7090 IN SUBJECTS WITH ADVANCED OR RECURRENT SOLID TUMORS WITH FIBROBLAST GROWTH FACTOR RECEPTOR (FGFR) GENE ALTERATION: FORTUNE STUDY

Abstract Background Genetic alterations of FGFRs are known to play an important role in the proliferation, survival, and migration of cancer cells as well as tumor angiogenesis and drug resistance. E7090 is an orally available selective tyrosine kinase inhibitor for FGFR1-3. A global Phase 2 study of E7090 in subjects with unresectable advanced or metastatic cholangiocarcinoma harboring FGFR2 gene fusion is ongoing (NCT04238715). We recently reported FGFR alterations that are highly sensitive to E7090 using a high-throughput functional evaluation method called MANO method (Nakamura et al. npj Precision Oncology, in press), narrowing down the most promising FGFR alteration targets. Here, we designed a single-arm, open-label, investigator-initiated multicenter Phase 2 basket study to evaluate the efficacy and safety of E7090 in subjects with advanced or recurrent solid tumors harboring FGFR gene alterations, focusing on alterations identified by MANO method, as a sub-study under the nationwide large registry for rare cancers in Japan (MASTER KEY Project). Methods The key eligibility criteria are: 1) Histologically confirmed metastatic or locally advanced solid tumor; 2) Ineffective to or intolerant to first line treatment, or for which standard treatment is no longer available; and 3) Confirmed FGFR gene alterations via next-generation sequencing assays that are reimbursed by insurance. Subjects will receive E7090 140 mg orally once daily until disease progression or development of unacceptable toxicity. The primary endpoint is objective response rate (ORR) by independent central review (RECIST v1.1), and the secondary endpoints include ORR by investigator assessment, progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. For primary brain tumors, RANO criteria is also applied in assessment of response. The study enrolls approximately 45 subjects. (Clinical Trial Registry: jRCT2031210043)