Dose Escalation Cohorts Research Articles

Neoadjuvant treatment with regorafenib and capecitabine combined with radiotherapy in locally advanced rectal cancer: a multicenter phase Ib trial (RECAP)–SAKK 41/16

BackgroundThe multi tyrosine kinase inhibitor regorafenib is active in metastatic colorectal cancer. Improvement in clinical outcome by adding regorafenib to long-course chemoradiotherapy (LcCRT) was investigated in molecularly undefined LARC. MethodsPatients with T3–4 and/or N+ but M0 rectal cancer were included. Neoadjuvant LcRCT consisted in capecitabine (C) 825mg/m2 d1–d38 and 28 fractions of 1.8Gy (50.4Gy). Regorafenib was added d1–14 and d22–35 in three dose escalation (DE) cohorts (40mg/80mg/120mg). The recommended dose (RD) was used for the expansion (EXP) cohort. Primary endpoints were dose-limiting toxicity (DLT) for DE and pathological response (near-complete regression [npCR] or complete regression [pCR]) for EXP. ResultsOverall, 25 patients were included. Two DLTs occurred at the regorafenib dose level of 120 mg, thereby establishing the RD at 80mg daily. Among the 19 patients who were treated at the RD, eight (42.1%; one-sided 80% confidence interval [CI] (lower bound): 30.7%; 95% CI: 20.3%–66.5%) reached the primary endpoint (five [26.3%] had npCR and three [15.8%] pCR). One additional patient received no surgery due to clinical complete response. All patients had R0 resections and clear circumferential margins. Postoperative complications occurred in six patients (35.3%). The most common grade ≥3 treatment-related adverse event in the EXP cohort was diarrhea (two patients). ConclusionAdding regorafenib 80mg to LcCRT in LARC resulted in both primary endpoints being met and yielded an expectedpathological response rate. Toxicity was manageable, and postoperative complications were as expected. Micro AbstractThe SAKK 41/16 study investigated the addition of regorafenib to the standard neoadjvuant chemoradiation with capecitabine. We could show expected pathological response rate and manageable toxicity at the recommended dose of regorafenib. Regorafenib may be potential partner for future trials investigating treatment intensification for high-risk locally advanced rectal cancer.

Industry Perspective on First-in-Human and Clinical Pharmacology Strategies to Support Clinical Development of T-Cell Engaging Bispecific Antibodies for Cancer Therapy.

T-cell-engaging bispecific antibodies (TCEs) that target tumor antigens and T cells have shown great promise in treating cancer, particularly in hematological indications. The clinical development of TCEs often involves a lengthy first-in-human (FIH) trial with many dose-escalation cohorts leading up to an early proof of concept (POC), enabling either a no-go decision or dose selection for further clinical development. Multiple factors related to the target, product, disease, and patient population influence the efficacy and safety of TCEs. The intricate mechanism of action limits the translatability of preclinical models to the clinic, thereby posing challenges to streamline clinical development. In addition, unlike traditional chemotherapy, the top dose and recommended phase II doses (RP2Ds) for TCEs in the clinic are often not guided by the maximum tolerated dose (MTD), but rather based on the integrated dose-response assessment of the benefit/risk profile. These uncertainties pose complex challenges for translational and clinical pharmacologists (PK/PD scientists), as well as clinicians, to design an efficient clinical study that guides development. To that end, experts in the field, under the umbrella of the American Association of Pharmaceutical Scientists, have reviewed learnings from published literature and currently marketed products to share perspectives on the FIH and clinical pharmacology strategies to support early clinical development of TCEs.

An Innovative Approach to Optimize First-In-Human Minimal Anticipated Biological Effect Level Based Starting Dose in Oncology Trials for Bispecific T-Cell Engagers: Experience from A Solid Tumor Bispecific T-Cell Engager.

Bispecific T-cell engagers (Bi-TCEs) have revolutionized the treatment and management of both hematological and solid tumor indications with opportunities to become best-in-class therapeutics for cancer. However, defining the dose and dosing regimen for the first-in-human (FIH) studies of Bi-TCEs can be challenging, as a high starting dose can expose subjects to serious toxicity while a low starting dose based on traditional minimal anticipated biological effect level (MABEL) approach could lead to lengthy dose escalations that exposes seriously ill patients to sub-therapeutic dosing. Leveraging our in-depth and broad clinical development experience across three generations of Bi-TCEs across both liquid and solid tumor indications, we developed an innovative modified MABEL approach for starting dose selection that integrates knowledge based on the target biology, indication, toxicology, in vitro, in vivo pharmacological evaluations, and translational pharmacokinetic/pharmacodynamic (PK/PD) modeling, together with anticipated safety profile. Compared to the traditional MABEL approach in which high effector to target (E:T) cell ratios are typically used, our innovative approach utilized an optimized E:T cell ratio that better reflects the tumor microenvironment. This modified MABEL approach was successfully applied to FIH dose selection for a half-life extended (HLE) Bi-TCE for gastric cancer. This modified MABEL approach enabled a 10-fold higher starting dose that was deemed safe and well tolerated and saved at least two dose-escalation cohorts before reaching the projected efficacious dose. This approach was successfully accepted by global regulatory agencies and can be applied for Bi-TCEs across both hematological and solid tumor indications for accelerating the clinical development for Bi-TCEs.

A Phase II Study Assessing Long-term Response to Ibrutinib Monotherapy in Recurrent or Refractory CNS Lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8-9.2] with 1-year PFS at 23.7% (95% CI, 12.4%-45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3-14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.

Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis

IntroductionIn rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and...

Phase 1b study of the anti-CD38 antibody mezagitamab in patients with relapsed/refractory multiple myeloma

AbstractThis phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines in which 1 included a PI + IMiD, and were refractory or intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and 6 received mezagitamab 300 mg in combination with pomalidomide plus dexamethasone. Patients received mezagitamab weekly for 8 doses, every other week for 8 doses, and monthly thereafter. No dose-limiting toxicities were reported with single-agent mezagitamab, and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohort (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and 4 injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among the 22 patients receiving 600 mg mezagitamab, the overall response rate was 47%, and the median duration of response was 22.1 months. Mezagitamab had a manageable safety profile and activity in patients with RRMM, with comparable outcomes to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but given its encouraging safety, studies are underway in autoimmune conditions with underlying abnormal autoantibodies. This trial was registered at www.ClinicalTrials.gov as #NCT03439280.

CML-399 CARDINAL: A Phase 1, Multicenter, Open-Label, Dose-Escalation and Dose-Optimization Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of TERN-701 in Chronic Myeloid Leukemia

ObjectiveDespite improvements in outcomes achieved with BCR::ABL1 active-site-targeting tyrosine kinase inhibitors (TKIs) for treatment of chronic-phase (CP) chronic myeloid leukemia (CML), many patients need to switch treatments due to disease progression, intolerance, or resistance. Because active-site TKIs utilize similar mechanisms of action, novel treatment options are needed for patients. TERN-701 is a highly selective, oral, investigational, allosteric BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket. Preclinical data suggest that TERN-701 is highly potent against native BCR::ABL1 and most common BCR::ABL1 mutations, including T315I, acquired with use of second-generation active-site TKIs. CARDINAL (NCT06163430) is an open-label, global, 2-part, phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of TERN-701 in patients with previously treated CP-CML. MethodsEligible patients are ≥18 years old with an Eastern Cooperative Oncology Group performance status of 0–2, a confirmed diagnosis of BCR::ABL1-positive CP-CML, with or without the T315I mutation, and treatment failure/intolerance of ≥1 prior second-generation TKI (dasatinib, nilotinib, or bosutinib). Patients intolerant of asciminib without overt resistance are eligible. Patients with CML in accelerated or blast phase are ineligible. Patients will receive TERN-701 orally once daily in continuous 28-day cycles. Part 1 (dose escalation) has been initiated and will include ≈24–36 patients assigned to sequential dose-escalation cohorts, starting at 160 mg, and optional backfill cohorts; dose escalation will be guided by a Bayesian optimal interval algorithm. Primary endpoints of Part 1 include incidence of dose-limiting toxicities during the first treatment cycle and other measures of safety and tolerability; secondary endpoints include PK and efficacy measures, such as hematologic and molecular responses. Based upon the results of Part 1, ≥2 TERN-701 dose levels will be selected for further evaluation in Part 2. In Part 2 (dose expansion), ≈40 patients will be randomized to one of the selected dose levels. Part 2 primary endpoints will measure efficacy (hematologic response, molecular response, and best categorical shift in BCR::ABL1 transcript levels from baseline); secondary endpoints include safety, tolerability, and PK. The study is being conducted in the US, Europe, Australia, and South Korea.

Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC.

Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC. In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200mg every 2 weeks in a dose-escalation (n = 38) or dose-expansion (n = 68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Secondary endpoints included investigator-assessed best overall response, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate was below the prespecified 20% objective response rate threshold set to evaluate the efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients). Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.

Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ-B3525 in Chinese patients with advanced cancers.

Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs). Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety. TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached. TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

A phase 1 study of biweekly nab-paclitaxel/oxaliplatin/S-1/LV for advanced upper gastrointestinal cancers: TCOG T1216 study.

Oxaliplatin- and fluoropyrimidine-based triplet regimens have demonstrated feasibility and efficacy in the treatment of upper gastrointestinal (UGI) cancers. Herein, we evaluate the feasibility and preliminary efficacy of biweekly nab-paclitaxel plus oxaliplatin and S-1/leucovorin (SOLAR) in chemonaïve UGI cancers. A 3 + 3 phase 1 study was conducted to determine the maximal tolerated dose (MTD) of oxaliplatin in SOLAR (nab-paclitaxel [150 mg/m2 in D1], oxaliplatin [60, 75, or 85 mg/m2 in D1], and oral S-1/leucovorin [35 mg/m2 and 30 mg bid from D1 to D7]). The secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Thirteen and 6 accruals were in the dose-escalation and MTD expansion cohorts, respectively. One of 6 patients at level III experienced dose-limiting toxicity (grade 3 diarrhea), which revealed that the MTD of oxaliplatin was 85 mg/m2. After a mean of 15.9 cycles of treatment, the most common treatment-related grade 3/4 toxicities were neutropenia (57.9%) and diarrhea (21.1%). The ORR was 63.2%. The median PFS and OS were 12.5 and 24.7 months, respectively. The current study revealed the MTD of oxaliplatin and demonstrated the preliminary efficacy of SOLAR in UGI cancers, which deserves further investigation. NCT03162510.

Phase I Trial of Brentuximab Vedotin Plus Cyclosporine in Relapsed/Refractory Hodgkin Lymphoma

IntroductionBV is an antibody-drug conjugate directed against CD30 and is safe and effective in relapsed/refractory (R/R) Hodgkin lymphoma (HL). Most patients with r/r cHL respond well to BV monotherapy; however, the large of majority of them eventually progress on this drug, and BV-resistant HL remains an unmet need. Preclinical data suggest that BV resistance is mediated at least in part by increased drug efflux associated with increased expression of multidrug resistance pump 1 (MDR1) while CD30 expression appears to be preserved in BV resistant cell lines and patient samples. We conducted a phase 1 study evaluating BV + cyclosporine (CsA) in BV-refractory HL and previous reported results in the dose finding cohort. Here we report the final results from the phase 1 study. MethodsThis was a phase I trial of BV + CsA in patients with r/r HL with dose-finding and dose escalation cohorts. Eligibility criteria included age ≥ 18 years with r/r HL after at least 1 prior line of therapy. Treatment consisted of 1.8 mg/kg BV intravenously on day 1 and CsA 5 to 7.5 mg/kg PO twice daily on days 1 to 5; cycles were 21 days long. Patients in the expansion cohort had to have cHL refractory to BV. The primary objectives were to evaluate safety and tolerability and to determine MTD of BV + CsA; the secondary objective was to determine efficacy of this combination. Results29 patients were enrolled onto the study, 14 in the dose finding cohort and 15 in the dose expansion BV refractory cohort. Study accrual was terminated before target accrual due to unacceptable toxicity. 62% of patients were male, and the median age was 36 years (range: 20-69). The median number of prior therapies was 5 (range: 3-12); all patients had prior BV, and 93% had PD-1 directed therapy, and 93% were BV-refractory. Of 22 evaluable patients, CR rate was 27% and ORR 64%; median DOR 4.9 months. Treatment-related deaths occurred in 3 patients, and another patient died during cycle 1 due to cardiac arrest deemed unlikely related to be protocol therapy. All grade GI toxicity was seen in 90% of patients (G3+ in 24%); other common adverse events were nausea (90%), hypertension (90%), nausea (90%), hypertension (90%), anemia (86%), fatigue (76%), neutropenia (76%), leukopenia (76%), hypomagnesemia (76%), anorexia (66%), and hyponatremia (66%). DiscussionBV + CsA demonstrated modest activity in BV-refractory r/r HL; however, toxicity is substantial.

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1–confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10–26%), and DCR was 61% (62/101; 95% CI, 51–71%). Median DOR was not reached (NR; 95% CI, 5.7 months–NR), and median PFS was 3.5 months (95% CI, 2.7–4.1 months), at a median follow-up of 10.3 months (range, 0.5–42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272.

An open-label, multicenter, phase Ib/II study of the ATR inhibitor SC0245 in combination with irinotecan in patients with relapsed and refractory extensive stage small cell lung cancer (ES-SCLC).

8102 Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress induced by topoisomerase 1 inhibitors (TOP1i) and other DNA damaging agents. SC0245 is a novel potent ATR inhibitor, showing synergistic inhibitory effects when combined with TOP1i in DMS-114 and H446 small cell lung cancer. This is the first report on an ongoing phase Ib/II study of SC0245 in combination with irinotecan (IRI) in patients (pts) with ES-SCLC (ClinicalTrials.gov: NCT05731518). Methods: Multiple escalating doses of SC0245 are being administered orally with a fixed dose of IRI. Pts are being enrolled into five escalating dose cohorts (80 mg once daily (QD), 120 mg QD, 80 mg twice daily (BID), 120 mg BID, 160 mg BID) using a BOIN design. SC0245 is administered daily for 3 days weekly x 3 (e.g, Days 1-3, 8-10 and 15-17) with IRI 80 mg/m2 on Days 1, 8 and 15. Cycles are repeated every 4 weeks. The primary endpoint is the rate of dose-limiting toxicity (DLT). Tumor assessments are being performed every 8 weeks using RECIST v1.1. Dose expansion in ES-SCLC patients will follow after definition of the recommended phase 2 dose (RP2D). Results: As of the data cut-off-date (December 21, 2023), 15 pts (median age, 65; male, 73.3%) with previously treated solid tumors have been enrolled, with 3, 4, 3 and 5 pts in 80mg QD, 120mg QD, 80mg BID and 120 mg BID dose cohorts, respectively. 12 of 15 pts were DLT evaluable, and one DLT event (Grade 3 febrile neutropenia) occurred in the 80 mg QD dose cohort. Cytopenia, diarrhea, and liver function test elevations, were the main adverse events (AEs) experienced in 73.3%, 46.7% and 40% pts, respectively. Most AEs were grade 1 or 2 in severity and manageable. The only ≥ Grade 3 TRAEs experienced by more than 2 subjects has been leukopenia (3/15, 20.0%). No drug-related deaths occurred. Among the 9 pts who were evaluable for tumor response, one confirmed partial response (PR) was reported in a pt with ES-SCLC (progressed on prior 1st line of etoposide + carboplatin + serplulimab treatment) treated in the 120mg QD dose cohort, and the response sustained for 32+ weeks; five pts (5/9, 55.6%) had stable disease (SD) as their best response. PK characteristics indicated that SC0245 was rapidly absorbed (median Tmax, 1.0 to 2.0 h), and drug exposure was proportional to dose for the QD and BID regimens. No drug-drug interactions (DDI) between SC0245 and either IRI or its active metabolite SN38 were observed. Conclusions: SC0245 exhibited favorable safety and PK characteristics when administered in combination with IRI at doses ranging from 80mg QD to 120mg BID and the regimen has demonstrated preliminary antitumor activity in ES-SCLC, supporting further evaluation of the regimen in ES-SCLC and other relevant malignancies. Clinical trial information: NCT05731518 .

Phase II Study of Ulixertinib in Children and Young Adults With Tumors Harboring Activating Mitogen-Activated Protein Kinase Pathway Alterations: APEC1621J of the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.

The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor. As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m2/dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m2/dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS). Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF-altered CNS tumors achieved stable disease >6 months. Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m2/dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

DUET-01: A first-in-human, phase 1/2 study of BOXR1030 in patients with advanced glypican-3-positive solid tumors.

TPS2681 Background: Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan involved in cell proliferation that is overexpressed in several tumor types. BOXR1030 is an autologous T-cell therapy that co-expresses a chimeric antigen receptor (CAR) targeting GPC3 on tumor cells and glutamic-oxaloacetic transaminase 2 (GOT2), a mitochondrial enzyme that plays an important role in maintaining mitochondrial function and improving T-cell functionality in the solid tumor microenvironment. In non-clinical studies, BOXR1030 showed GPC3-specific cytotoxicity, proliferation and cytokine release only in the presence of GPC3+ cells. Methods: DUET-01 (NCT05120271) is an open-label, dose escalation and expansion clinical trial to determine a safe dose of BOXR1030 in patients with advanced GPC3-positive solid tumors. Dose escalation will be guided by the occurrence of dose-limiting toxicities (DLTs) within 28 days of dosing. The Bayesian logistic regression model will be used on the accumulated DLT data to estimate the maximum tolerated dose (MTD). The Dose Escalation Committee will select the recommended phase 2 dose (RP2D) to be used in the expansion phase cohort(s) (10-20 subjects each) based on data accumulated in the dose escalation cohorts. Eligible subjects will undergo leukapheresis to obtain T cells for BOXR1030 manufacturing and will receive 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 5 days prior to BOXR1030 administration. The starting dose is 0.3 × 106 BOXR1030 T cells/kg body weight. Antitumor activity will be assessed every 6 weeks after cell infusion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and RECIST for immune-based therapeutics (iRECIST). Six months after BOXR1030 administration, subjects will enter long-term follow-up for up to 15 years. Long-term follow-up assessments will focus on long-term safety and disease status. Main inclusion criteria are histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma, squamous cell carcinoma of the lung, myxoid/round cell liposarcoma, or Merkel cell carcinoma; GPC3 overexpression by immunohistochemistry assay confirmed centrally on tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject’s most recent systemic anticancer therapy; body weight of ≥ 50 kg (≥ 65 kg for dose level 1); and life expectancy > 16 weeks. The primary endpoints are the incidence of DLTs; determination of the MTD and RP2D; the type, frequency and severity of treatment-emergent adverse events; clinically significant abnormal safety laboratory findings and vital signs. Key secondary endpoints include efficacy parameters such as objective response rate, BOXR1030 T-cell expansion and persistence, and levels of inflammatory markers and cytokines. The first patient was treated with BOXR1030 in December 2022. Clinical trial information: NCT05120271 .

A phase 1/2 study of the TBL1 inhibitor, tegavivint (BC2059), in patients (pts) with advanced hepatocellular carcinoma (aHCC) with β-catenin activating mutations.

TPS4192 Background: β-catenin mutations are present in up to 40% of aHCC pts. Elevated nuclear β-catenin expression levels correlate with poor responses to standard of care and β-catenin regulates both tumor metabolism and the immune microenvironment. Tegavivint is a first-in-class small molecule inhibitor of TBL1, a novel downstream Wnt-signaling pathway target. Tegavivint binds to TBL1 in the β-catenin pocket, disrupting the formation of the activation complex necessary for oncogenic activity, and enabling degradation of free nuclear β-catenin. The safety, clinical activity, and PK/PD of tegavivint was demonstrated through a proof-of-concept study in pts with desmoid tumors and is being studied through multiple Investigator Initiated Trials in AML (NCT04874480), pediatric solid tumors (NCT04851119), NSCLC (NCT04780568), and lymphoma (NCT05755087). Tegavivint was also studied in preclinical mouse models of β-cateninexon3 mutant HCC and the H22 syngeneic HCC model. In these models tegavivint decreased Wnt target gene expression and enhanced CD3+ T-cell infiltration in liver tumors. Tegavivint treatment of established β-cateninexon3 activated tumors resulted in reduced tumor growth and burden. Based on these promising preclinical results, the following phase 1/2 exploratory study was designed. Methods: This is a phase 1/2 study of tegavivint in pts with aHCC to characterize safety, PK/PD, and preliminary antitumor activity (NCT05797805). Eligibility includes aHCC pts ≥18 years old, with AXIN1or CTNNB1 mutation for all pts, except those in the single agent dose escalation; have BCLC Stage C or Stage B disease not amendable to local therapy or curative approaches, have Child-Pugh class A or B7 liver score, and must have received at least one prior line of systemic therapy. This study will be conducted in 2 parts. First, tegavivint will be administered as a single agent in a dose escalation/optimization and subsequent dose expansion cohort. Upon completion of the dose escalation via a 3+3 design, two dose levels will be selected for the dose selection optimization to determine the recommended phase 2 dose (RP2D) for use in the dose expansion. If sufficient clinical benefit is observed, the combination of tegavivint plus pembrolizumab will be explored in the second part of the study in aHCC pts previously treated with a PD-1/PD-L1 inhibitor. Tegavivint will be administered intravenously weekly. Primary objective is safety and secondary objectives are preliminary efficacy and PK/PD. The first patient began treatment in October of 2023 and the first dose escalation cohort was completed in January. Three institutions are open for enrollment; 5 other sites are pending site activation; all sites are in the United States and Canada. Clinical trial information: NCT05797805 .

First-in-human phase 1 trial of the safety, tolerability, pharmacokinetics of BY101298: Initial report from dose escalation cohort.

e15132 Background: Radiotherapy (RT) is a cornerstone of cancer treatment, leveraging the effect of ionizing radiation to induce DNA damage, primarily through DNA double-strand breaks (DSBs). Non-homologous end joining (NHEJ) stands as the predominant pathway for repairing DSBs, with DNA-dependent protein kinases (DNA-PK) playing a pivotal role in NHEJ pathway. DNA damage repair can compromise tumor cells sensitivity to RT, potentially leading to the development of radiation resistance. BY101298, an innovative and highly selective DNA-PK inhibitor, works to diminish DSBs repair. In synergy with RT or chemotherapy, BY101298 enhances tumor cells eradication, preventing local recurrence and metastasis, thereby improving clinical benefits for cancer patients. Methods: This phase Ⅰa multicenter, open-label, dose-escalation study assessed the safety, tolerability, and clinical efficacy of BY101298. Oral doses ranged from (50 mg to 400 mg once/day [QD]) in continuous 28-day cycles. Primary outcome was safety and tolerability; secondary outcome was PK; exploratory outcome was DNA-PK phosphorylation (PD). Adverse events (AEs) were monitored per the Common Terminology Criteria for Adverse Events (CTCAE version5.0). Responses were assessed every other cycle using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Results: Data from 9 pts with advanced solid tumors (cutoff: 26 December 2023; 2 men, 7 women; median age 58.0) revealed a linear increase in BY101298 AUC exposure and Cmax with dose escalation. Daily dosing for 15 consecutive days showed no AUC increase. Serum drug concentration correlated significantly with DNA-PK phosphorylation. All pts, previously systemic treated, received doses of 50 mg QD (n = 2), 100 mg QD (n = 3), and 200 mg QD (n = 4). Median treatment duration was 30 days (range: 1-57), with one patient (11.1%) continuing. Median relative dose intensity was 100%. Common treatment-related AEs (≥25%), primarily grade 1, included hypoalbuminemia (n = 5, 55.56%); anemia (n = 4, 44.44%); nausea (n = 3, 33.33%); weight decreased (n = 3, 33.33%). No pts experienced ≥Gr3 AEs. Two pts experienced serious AEs (none of which were considered treatment-related). No treatment discontinuations, dose reductions, or deaths attributed to treatment-related. The final dose group, representing the fourth cohort, is scheduled to commence shortly and is expected to conclude in April as per our estimation. Conclusions: In pts with advanced solid tumors, BY101298 exhibits a favorable safety profile and manageable toxicity. Vomiting was noted as a potential risk associated with BY101298. Further studies are imperative to elucidate the efficacy of BY101298 in combination with radiotherapy among pts with advanced solid tumors. Research Sponsor: This study received support from Chengdu Baiyu Pharmaceutical Co., Ltd. Clinical trial information: CTR20230997.

A phase I/II study of talazoparib and axitinib in patients with advanced clear cell renal cell carcinoma.

4541 Background: Targeting the VEGF pathway is a backbone therapeutic for patients with advanced clear cell renal cell carcinoma (ccRCC). Tumor and tissue hypoxia may also lead to DNA repair suppression and PARPs are key regulators of DNA damage and genomic maintenance which interact with HIF proteins. Pairing a potent VEGFR TKI with a selective PARP inhibitor (PARPi) may lead to improved outcomes in ccRCC patients. Methods: This was a phase I/II, investigator-initiated, single-center, open-label study (NCT04337970) of talazoparib plus axitinib in previously treated ccRCC patients. In the phase Ib dose escalation, patients must have been previously treated with a PD-1/PD-L1 inhibitor with no maximum lines of prior therapy, and those in dose expansion were required to have prior treatment with a PD-1/PD-L1 inhibitor and prior VEGFR TKI, with a maximum of 2 prior lines of therapy. Patients received escalating doses of talazoparib (0.5 mg, 0.75 mg and 1 mg daily) with axitinib (5 mg twice daily) in a 3+3 design, with primary endpoint of safety and tolerability. After establishing the recommended phase II dose (RP2D), a dose expansion cohort enrolled patients in a Simon two-stage design with a primary endpoint of objective response (ORR), and secondary endpoints including progression-free survival (PFS). Results: From 2020-2023, 23 ccRCC patients were enrolled and treated on study. In the dose escalation, 15 patients enrolled across all 3 dose levels and there were 2 observed DLTS (1 in dose levels 2 and 3). Both DLTs was due to a lack of minimum exposure to study drugs during cycle 1 due to treatment-related toxicities. The maximum tolerated dose and RP2D established was 1 mg talazoparib daily with axitinib 5 mg twice daily. In the phase II dose expansion portion, an additional 9 patients were enrolled to evaluate preliminary efficacy. In total, 13/14 patients treated at the RP2D discontinued therapy due to progressive disease. The objective response rate (ORR) was 7% (90% CI 0, 30), with 1 patient achieving a partial response and 12 patients achieving stable disease (86%). With a median follow-up of 13.2 months (R: 6.6 -29), the median PFS was 6.1 months (95% CI 3.5, 8.4) and median overall survival (OS) was 27 months (95% CI 12- NE). Across the study, 13 (56%) patients had at least one treatment-emergent AE of grade 3+, and 9 (39%) patients had at least one treatment-related AE of grade 3+. Most common grade 3+ AEs included diarrhea, nausea, and anemia. Conclusions: This is the first clinical study evaluating combination PARPi and VEGFR TKI in metastatic ccRCC patients. This study established the RP2D and MTD of combination talazoparib and axitinib and demonstrated a tolerable safety profile across all dose escalation cohorts. The study did not meet the pre-defined efficacy threshold for further enrollment per Simon stage two design. Exploratory efforts to evaluate this treatment approach with tissue biomarker data remain ongoing. Clinical trial information: NCT04337970 .

Repurposing ibrutinib for chemo-immunotherapy in a phase 1b study of ibrutinib with indoximod plus metronomic cyclophosphamide and etoposide for patients with childhood brain cancer.

TPS2703 Background: In children, brain cancer is the leading cause of cancer related death. The indoleamine 2,3-dioxygenase (IDO) pathway is a metabolic checkpoint, expressed by host myeloid and dendritic cells, that suppresses anti-tumor immune responses following chemotherapy. We recently published results of a first-in-children phase 1 trial (NCT02502708) that showed the oral IDO-pathway inhibitor indoximod was well tolerated and provided meaningful clinical benefit for many patients with progressive childhood brain tumors, when given in combination with oral chemotherapy regimens (1). Using preclinical models, we have also reported the importance of the Bruton’s Tyrosine Kinase (BTK) pathway as a key upstream driver of IDO during chemotherapy (2). Thus, we hypothesize that adding the BTK-inhibitor ibrutinib to the previously studied regimen of investigational indoximod IDO-inhibitor plus oral metronomic cyclophosphamide and etoposide will synergistically enhance anti-tumor immune responses, leading to improvement in Objective Response Rate (ORR) with manageable overlapping toxicity. Methods: The current study (NCT05106296) is an Investigator-Sponsored, open label, single-arm phase 1b trial comprised of a Dose-escalation Cohort (n=18) using a 3+3 dose escalation design to establish safety and dosing of ibrutinib in the combined regimen; followed by an Expansion Cohort (n=19) at the MTD to evaluate efficacy. Patients are treated with the all-oral 4-drug chemo-immunotherapy regimen in 28-day cycles using: (i) ibrutinib [Study Dose once daily on days 1-21]; (ii) indoximod [38.4 mg/kg/day divided twice daily throughout the cycle]; (iii) cyclophosphamide [2.5 mg/kg/dose, maximum dose 100 mg, once daily on days 1-21]; and (iv) etoposide [50 mg/m2/dose once daily on days 1-21]. Eligible patients are age 12 to 25 years with relapsed or refractory brain cancer, MRI evidence of current active disease not recently treated with radiation/proton therapy, ECOG performance score 0-2, and meet standard organ function requirements. Patients with systemic infection, autoimmune disease, recent live-virus vaccination, comorbid conditions that may overlap with expected regimen toxicities, or chronic treatment with anticoagulants or strong CYP3A inhibitors are excluded. Primary Objectives are to: (i) determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib for the combined regimen (Dose-escalation Cohort), and (ii) evaluate preliminary evidence of efficacy for the combined regimen in terms of ORR (Expansion Cohort). Exploratory analyses use single-cell RNA and TCR sequencing (scRNAseq/TCRseq) of cryopreserved serial peripheral blood samples to monitor for treatment-expanded TCR clonotypes and study their phenotype. 1. Neuro-Oncology 26:348-361, 2024. 2. Immunity54:2354-2371, 2021. Clinical trial information: NCT05106296 .

SB221: A proof-of-concept study to assess the combination of SON-1010 (IL12-FHAB) and atezolizumab in patients with platinum-resistant ovarian cancer.

TPS5629 Background: Recombinant interleukins (rIL) have had limited clinical success due to inefficient tumor targeting and short PK, requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 potently activates T and NK cells to produce IFNγ and kill tumor cells, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. We developed a novel platform that delivers immunomodulator(s) linked to a fully-human albumin binding (FHAB) domain (Cini, Front Immunol 2023). Single-chain native IL-12 genetically linked to the FHAB provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC in the tumor microenvironment (TME), with an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Tumor growth inhibition in an immunologically ‘cold’ B16-F10 mouse melanoma model showed the efficacy of IL12-FHAB compared with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. SON-1010 is being studied clinically as monotherapy (study SB101) in advanced solid tumors and in healthy volunteers (study SB102) (Chawla, AACR 2023). Atezolizumab (Tecentriq), an anti-PD-L1 immune checkpoint inhibitor (ICI), has shown preliminary clinical activity in Phase 1 studies of patients with platinum-resistant ovarian cancer (PROC) (Liu, Gyn Onc 2019; Moroney, Clin Canc Res 2020). SON-1010 may ‘warm up’ the TME to improve ICI effectiveness in these immunologically-active tumors that have high levels of SPARC. Methods: Study SB221 is a Phase 1b/2a multicenter, dose-escalation and proof-of-concept study to assess the safety, tolerability, PK, PD, and efficacy of SON-1010 administered SC, either alone or in combination with a fixed dose of atezolizumab given IV (NCT05756907). The study is designed in Part 1 to rapidly establish the maximum tolerated dose (MTD) of the combination in patients with advanced solid tumors with up to 5 dose-escalation groups and to expand the dataset using patients with PROC to establish the Recommended Phase 2 Dose (RP2D). Once the likelihood of efficacy is shown in a Simon 2-stage design, this will be followed in Part 2 by an assessment of the potential for improved efficacy of the combination in patients with PROC over SON-1010 alone or the standard of care (SOC). The first dose-escalation cohorts have been enrolled and additional sites are being added to help with recruitment of patients with PROC. Combination of SON-1010 with an ICI offers a unique opportunity to use this extended PK version of IL-12 to augment the potential for tumor control in PROC, which represents a significant unmet medical need. Clinical trial information: NCT05756907 .