Maximum Tolerated Dose Research Articles

Preliminary results from a first-in-human trial of AMT-116, a topoisomerase I inhibitor containing antibody-drug conjugate (ADC), in patients with advanced solid tumors.

e15010 Background: CD44v9 is a tumor-associated antigen highly expressed in various solid tumor types including head and neck, lung, esophageal, pancreatic, colorectal, breast, bladder, hepatic, cervical, and gastric cancers. AMT-116 is a first-in-class antibody-drug conjugate (ADC) targeting CD44v9, by conjugating a novel topoisomerase I inhibitor, belotecan derivative named KL610023 (Sichuan Kelun-Biotech) to a humanized anti-CD44v9 immunoglobulin G1 (IgG1) antibody via a hydrolysable linker with an average drug-to-antibody ratio of 7-8. Methods: This is an ongoing first-in-human, non-randomized, open-label, multicenter, Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AMT-116 in patients (pts) with advanced solid tumors, unselected for target expression. Pts received escalating doses of AMT-116 Q2W starting from 1.5 mg/kg guided by the Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle. Results: As of Feb 1, 2024, eight pts (4 pts at 1.5 mg/kg, 3 pts at 3 mg/kg and 1 pt at 5 mg/kg) have been treated in Australia and pts at 1.5 mg/kg and 3 mg/kg completed the 28-day dose-limiting toxicity (DLT) evaluation period. No DLT events were observed, and the maximum tolerated dose (MTD) has not been reached. Treatment related adverse events (TRAEs) were reported in 5 pts out of 8. The most common TRAEs were fatigue (n=3) and nausea (n=3). Only one Grade 3 TRAE (leukopenia) was reported. There were no Grade 4 or 5 TRAEs or treatment-related SAEs. Seven pts have completed at least one post-treatment tumor assessment. At dose level 3 mg/kg, one pt with anal squamous cell carcinoma achieved unconfirmed PR with a 31% tumor shrinkage and one pt with hepatocellular carcinoma achieved SD with a 23% tumor shrinkage from baseline. Subject enrollment in 5 mg/kg is underway. Conclusions: These preliminary data indicate that AMT-116 is well tolerated at the first two dose levels in patients with heavily pretreated advanced solid tumors. Dose escalation is ongoing. Clinical trial information: NCT05725291 .

Evorpacept plus enfortumab vedotin in patients (Pts) with locally advanced or metastatic urothelial carcinoma (la/mUC): Phase 1a dose escalation results.

4575 Background: Maximizing antibody dependent cellular phagocytosis (ADCP) in the tumor microenvironment requires both the inhibition of the myeloid CD47/SIRPα checkpoint and activation of the macrophage’s FcyR by an anti-cancer specific antibody (Lakhani et al. Lancet Oncol 2021). Evorpacept (EVO) is a CD47 inhibitor with an inactivated Fc effector domain that blocks the CD47-SIRPα interaction. Enfortumab vedotin (EV) is a nectin-4-directed antibody drug conjugate (ADC) which engages the FcyR on the macrophage. We evaluated whether EVO plus EV would be safe, tolerable and active in pts with la/mUC. Methods: 20 pts with la/mUC who had received prior platinum-based chemotherapy and progressed during or after treatment with a PD-1/L1 inhibitor were administered study drug in this phase 1 study (NCT05524545). Dose escalation (DE) cohorts were administered intravenous (IV) EVO 20 mg/kg or 30 mg/kg Q2W plus standard EV 1.25 mg/kg IV on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was first cycle dose limiting toxicity (DLT) using a Bayesian Optimal Interval design. Additional pts were enrolled in both dose levels as backfill cohorts to further characterize safety, PK, PD, and preliminary antitumor activity. Investigator response was based on RECIST v1.1, and data cut off was 18Jan(safety)/24Jan(efficacy) 2024. Results: Fourteen pts were administered EVO 20 mg/kg Q2W (DE n= 3; backfill n=11) and 6 pts EVO 30 mg/kg Q2W (DE n=6) plus standard EV. No DLTs were observed, and the maximum tolerated dose (MTD) of the combination was not reached. The maximum administered dose (MAD) of EVO was 30 mg/kg Q2W combined with EV. There were no treatment-related deaths on study. Treatment emergent adverse events (TEAEs) occurring in > 25% of subjects included fatigue, diarrhea, abnormal loss of weight, dysgeusia, decrease appetite, hyperglycemia, constipation, hypomagnesemia, lacrimation increased, nausea, peripheral sensory neuropathy, rash maculo-papular and urinary tract infection (UTI). There were 3 serious adverse events that were related to EVO plus EV (G3 UTI [1 pt]; G4 neutrophil count decreased and G3 UTI [1 pt]). Sixteen patients were response evaluable. The overall response rate (ORR) was 63% (1CR, 9PR). Accrual is ongoing and updated data will be provided at the time of presentation. Conclusions: This is the first study, to our knowledge, reporting data on the combination of a CD47 blocking agent in combination with an ADC in la/mUC. EVO plus EV is well tolerated at doses evaluated with no MTD reached and a MAD of 30 mg/kg Q2W. The combination shows early promising clinical activity compared to an ORR of 41% with EV alone in pts with la/mUC who had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor (Powles et al. N Engl J Med 2021). Further investigation in this refractory population, including patients with prior EV exposure, is warranted. Clinical trial information: NCT05524545 .

Safety and efficacy of CD7-CAR-T cell in patients with relapsed/refractory T-lymphoblastic leukemia/lymphoma: Phase I dose-escalation/dose-expansion study.

6515 Background: Patients with relapsed/refractory T-lymphoblastic leukemia/lymphoma (r/r T-ALL/LBL) are clinically manifested by rapid disease progression, poor prognosis and lack of therapeutic options. There is an urgent need to develop other effective modalities. Apart from its expression in normal T and NK cells and no expression in other tissue cells, CD7 is highly expressed in T-ALL/LBL cells. Therefore, CD7 is considered a potential target for the development of CAR-T therapy for T-ALL/LBL. The challenge, however, is to avoid fratricide caused by the expression of CD7 in T cells. We developed a CAR-T cell injection based on CD7 nano antibodies, named PA3-17 injection, by blocking the expression of CD7 molecule on the surface of T cells through anti-CD7 protein expression blocker (PEBL) and evaluate the safety, efficacy and Recommended Phase II Dose (RP2D) of PA3-17 Injection in patients with r/r T-ALL/LBL in a phase I clinical study. Methods: The clinical study (NCT05170568) adopted a "3+3" dose escalation schema and proceed cohort expansion. T-ALL/LBL patients who met the inclusion/exclusion criteria were deployed by entering three dose groups (DL: 0.5×106, 2×106, 4×106 CAR-T/kg) to evaluate the initial safety, efficacy and dose-limited toxicities (DLTs). All patients were treated with lymphodepleting chemotherapy pre-treatment before CAR-T cell infusion. The primary endpoints were DLTs and maximum tolerable dose (MTD). Results: As of Nov 28th, 2023, a total of 12 patients were enrolled (3 patients in dose 1, 2, 3 group, 3 patients in RP2D group), all of whom received a single infusion of PA3-17 injection and completed a 28- day DLTs assessment. The median age of enrolled patients was 33.5 years (range 20-64), and 25.0% (3/12) of patients had previously received hematopoietic stem cell transplantation. No DLTs occurred. The RP2D was 2×106 CAR-T/kg. The safety analysis showed that 83.3% (10/12) of patients developed cytokine release syndrome (CRS), of which 25% (3/12) had grade 3, and no grade 4 CRS occurred, 16.7% (2/12) of patients experienced 1-2 grade of immune effector cell-associated neurotoxicity syndrome (ICANS), and no grade 3 or higher ICANS occurred. The efficacy data showed that the best ORR was 83.3% (10/12) and the CR rate was 75% (9/12). The median follow-up time was 213.5 days. Five patients (Pt 1/5/6/7/9) maintained CR for more than 6 months. One patient (Pt6) had a tumor mass with a diameter greater than 7cm at baseline prior CAR-T infusion but achieved CR 28 days after infusion, then she underwent transplantation at sixth month but died at eighth month because of heart problems, which is unrelated with PA3-17 infusion. Conclusions: PA3-17 injection has shown a good safety profile and encouraging efficacy in r/r T-ALL/LBL patients. RP2D has been determined and the key Phase II clinical study is about to begin. Clinical trial information: NCT05170568 .

Preliminary data of a phase Ib/II trial evaluating the efficacy and safety of adebrelimab, camrelizumab plus apatinib as first-line therapy in patients with advanced hepatocellular carcinoma.

e16221 Background: The CARES-310 study has demonstrated that the combination of the anti-PD-1 antibody camrelizumab and the VEGFR2 tyrosine kinase inhibitor apatinib exhibits improved progression-free survival (PFS) and overall survival (OS) in patients with advanced hepatocellular carcinoma (HCC). We conducted this study to investigate whether the addition of the anti-PD-L1 antibody adebrelimab to camrelizumab and apatinib would further improve clinical outcomes. Methods: This is a prospective, phase 1b/2 clinical trial employing the i3 + 3 dose escalation design. Eligibility includes adults with unresectable or metastatic HCC, a ECOG PS of 0 or 1, a Child-Pugh score ≤ 7, and at least one measurable lesion per RECIST v 1.1. In phase 1b, patients (pts) received adebrelimab (10 mg/kg or 20 mg/kg, I.V., D1, Q3W), camrelizumab (200mg, I.V., D1, Q3W), and apatinib (250 mg orally daily). Phase 2 is a single arm, open-label trial in the first-line setting. The primary objective were dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended phase II dose (RP2D). With α = 0.05 and 80% power, the pts needed for stage I and total of the Simon 2-stage design was 17 and 41 pts, respectively. Results: As of 4 February 2024, 6 HCC pts progressed after or were intolerant to first-line treatment (systemic therapy ± surgical resection) were treated in 1 dose cohorts. 1 DLT occurred (Grade 3 elevated blood bilirubin increased). The RP2D was adebrelimab (10 mg/kg), camrelizumab (200mg), and apatinib (250 mg). The most common drug-related AEs were Hypertension (83.3%) and Rash (50%); and Serum amylase increased, Itching, ALT/AST increased, and Hypothyroidism (each 33.3%). Immune-related AEs were similar to those seen with other checkpoint blockade agents. No drug-related AEs led to death. 1 pts (16.7%) discontinued due to drug-related AEs. Conclusions: The combination of Adebelimumab, Camrelizumab, and Apatinib demonstrated manageable safety for unresectable HCC. Enrollment in the phase II trial is ongoing and updated clinical data will be presented. Clinical trial information: NCT05924997 .

A first-in-human phase 1 trial of T cell membrane-anchored tumor targeted IL12 (ATTIL12) -T cell therapy in advanced/metastatic soft tissue and bone sarcoma.

TPS11586 Background: Interleukin-12 (IL12) is a cytokine that induces antitumor immune response and immune memory by activation of NK cells, induction of IFNg, and maturation of DC cells in the tumor microenvironment (TME). However, prior clinical experience with IL12 has been limited by toxicities including cytokine release syndrome (CRS) and hepatotoxicity. We developed a novel tumor-targeted IL12 gene (ttIL12) that encodes the p35 and p40 VNTANST fusion subunits that targets cell surface vimentin (CSV). Vimentin is expressed intracellularly in many normal and neoplastic mesenchymal cells but our group discovered that intracellular vimentin is often flipped to the cell surface (referred to as CSV) across multiple tumor types.2 Preclinical studies demonstrated efficacy and induction of long-term memory of ttIL12 against metastatic osteosarcoma with reduced toxicity in immune competent models.3 However, ttIL12 had limited efficacy in treating large volume tumors and did not completely eliminate toxic peripheral cytokines. To address this, our team generated a membrane anchored ttIL12 to arm T cells known as attIL12-T cell therapy. We hypothesize attIL12 will minimize toxic cytokines in peripheral tissues but promote induction of INFg/TNFa in the TME to decrease the toxicity and boost efficacy. Methods: This is a phase 1 trial of attIL12-T cells in patients (pts) with locally advanced or metastatic soft tissue or bone sarcomas to assess safety, maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D). Pts in part A (dose finding) will be enrolled using a Bayesian optimal interval (BOIN) design in up to 6 dose levels. Part B (dose expansion) will evaluate preliminary efficacy in 10 additional pts with osteosarcoma treated at the RP2D. Treatment:Pts will undergo leukapheresis to collect peripheral blood mononuclear cells (PBMCs) for generation of attIl12-T cells. Bridging therapy is permitted but not required. Pts will receive cyclophosphamide (Cy) IV prior to planned T cell administration. attIL12 T cells will be administered at the specified dose level IV in a single infusion (dose level 1 and 2) or 2 serial doses (dose level 3-6) on day 0 and day 14. Pts will be monitored for toxicity and response evaluation. Pts will also undergo pre-treatment/on-treatment tumor biopsies for translational and correlative analysis. Eligibility:Pts must be ≥ 12 years of age, have a confirmed diagnosis of locally advanced or metastatic sarcoma, evaluable disease, received at least 1 prior line of standard systemic therapy, ECOG PS 0-1, and adequate organ function to tolerate immune-effector cell therapy. Pts with known sensitivity to Cy, active/prior autoimmune disease, uncontrolled CNS disease, or other uncontrolled comorbidities that pose potential safety risk will be excluded. Enrollment to cohort 1 began in Dec 2023. Clinical trial information: NCT05621668 .

Preliminary results of atezolizumab and pirfenidone in non-small cell lung cancer.

e15197 Background: Checkpoint inhibitors (CPI) targeting the PD1/PD-L1 axis improved outcomes for stage IV non-small cell lung cancer (NSCLC). Poor response to PD-L1 antibody has been linked to increased cancer-associated fibroblasts (CAF), which interact with cytotoxic T cells (CTLs) similarly to regulatory T cells (Tregs). CAFs, through cytokine production, impair antitumor immunity by affecting CTL function (TGF beta) and inhibiting CTL recruitment into tumors, suggesting that CAFs could be a therapeutic target in CPI-resistant NSCLC. Pirfenidone (P) exhibits anti-fibrotic effects by blocking fibroblast differentiation into CAFs and suppressing TGF beta production and associated signaling pathways/collagens. Atezolizumab (A) targets PD-L1, inhibiting its interaction with PD-1 and B7-1 (CD80) receptors on T cells. We initiated a phase I/II trial to test the combination of AP in recurrent NSCLC after CPI progression. The phase I study aims to determine the maximum tolerated dose (MTD) of AP and assess its safety and tolerability. The phase II study will evaluate its efficacy. The Exploratory Objectives are to measure circulating levels of TGF beta and investigate the expression of CAF-related proteins. Methods: phase I will enroll 3 patients using P at 801 mg PO TID and A at 1200mg IV every 3 weeks. If there is ≤ 1 Dose Limiting Toxicity (DLT), the study will proceed to phase II. If there are ≥2 DLTs, P will be reduced to 534 mg TID. If there is ≤ 1 DLT at this dose, we will proceed to phase II. If there are ≥2 DLTs, then the study will be terminated. Phase II will enroll 16 patients to assess efficacy. The main inclusion criteria are patients with recurrent NSCLC without actionable mutation, after progression with first-line therapy CPI with or without platinum-based doublet chemotherapy, no more than 2 lines of therapy, measurable disease, ECOG 0-2, and adequate organ function. Results: The study enrolled a total of 5 patients (4 males, 1 female), median age of 63.4; 5 were white; 3 patients did not complete the required 21 days of therapy for evaluation (1 non-compliance, 1 disease progression,1 unrelated Urinary Tract Infection); 2 patients were evaluable for toxicity, without DLT; 1 exhibited a partial response to cutaneous metastatic disease, with overall stable disease, 1 had disease progression. Adverse events (AE) in more than 5% of patients included blood disorders, cardiac, gastrointestinal, administration site, metabolic, musculoskeletal, psychiatric, respiratory, and skin disorders. Serious AEs were noted in 2 patients: one experienced gastrointestinal bowel perforation due to disease progression resulting in death, and the other had a respiratory disorder. Conclusions: The combination of AP did not produce unexpected side effects or reach the dose-limiting toxicity threshold. After the phase I portion is completed, the study will proceed to phase II expansion to enroll patients with recurrent NSCLC. Clinical trial information: NCT04467723 .

A phase I study of irinotecan combined with BAY1895344 (ATR inhibitor) in advanced solid tumors: Results of ETCTN 10402 dose escalation.

3077 Background: ATR protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA defects in various cancers. The topoisomerase-I (Top1) inhibitor irinotecan induces DNA damage. The ATR inhibitor BAY1895344 (elimusertib) has demonstrated cytotoxic potential in SCLC and GI cancer xenografts when combined with Top1 inhibitors . Methods: This phase Ia trial assessed elimusertib in combination with irinotecan in adult patients with refractory advanced solid tumors for whom irinotecan can be considered standard care. Patients with previous irinotecan exposure were excluded. Two dosing schedules were used: 1) Biweekly - irinotecan IV (starting at 150 mg/m2) D1 + elimusertib (starting dose 20 mg PO BID) D1,D2 (cycle=14 days); 2) Weekly - irinotecan (starting at 50 mg/m2) IV on D1,8,15 with elimusertib (starting at 20 mg PO daily) on D2,D3,D9,D10 and D16,D17 (cycle=21 days). Dose escalation utilized a 3+3 design. Primary objectives were to assess safety and tolerability and estimate the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity. Results: A total of 21 patients were enrolled in dose escalation (N=9 [Biweekly] and N=12 [Weekly], median age 58 and 2 lines of prior therapy. For the Biweekly cohort: 3/3 patients enrolled at dose level (DL) 1 experienced hematologic dose-limiting toxicity (DLT); 6 patients received DL-1 without any DLTs. The weekly regimen escalation comprised of 12 patients: 6 enrolled in DL1 with 2/6 having hematologic DLT and 5/6 unable to complete ≥75% of cycle 1 dosing; 6 enrolled in DL-1 with no DLTs observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized (Table 1). The majority of evaluable patients in both schedules had initial disease control (56% [biweekly] and 67% [weekly]). One confirmed partial response was seen in the biweekly RP2D. Median progression-free survival was 2.1 mo [biweekly] and 2.5 mo [weekly]. PK results will be presented at time of meeting. Conclusions: Both RP2D and MTD of elimusertib in combination with irinotecan were reached for both dosing schedules: irinotecan 150 mg/m2 IV D1 + elimusertib 10 mg BID PO D1,D2 (biweekly) and irinotecan 25 mg/m2 IV on D1 + elimusertib (20 mg PO daily) on D2,D3 (weekly). Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansion but the concept of ATR + topo I combination remains scientifically relevant. Clinical trial information: NCT04514497 . [Table: see text]

A phase 1/2, open label study of amivantamab in combination with tyrosine kinase inhibitors among participants with advanced NSCLC harboring ALK, ROS1, and RET gene fusions.

TPS8661 Background: Patients with ALK, ROS1, or RET rearranged NSCLC demonstrate dramatic and sustained responses to tyrosine kinase inhibitors (TKI). Unfortunately, acquired resistance remains a major clinical challenge. The EGFR and MET pathways have been reported as important escape mechanisms for cancer cells treated with highly potent TKIs. Combining amivantamab with ALK, ROS1, or RET TKIs upon radiographic progression represents a rational combination strategy in addressing TKI mediated resistance. Methods: This is an open-label, multicenter, Phase 1b / 2 study of amivantamab in combination with TKIs among participants with advanced NSCLC harboring ALK, ROS1, and RETgene fusions progressing on FDA-approved TKIs for their respective oncogene. Participants must be on their TKI at the same dose for at least 3 months prior to enrolling in the study. A pre-treatment biopsy is required to rule out neuroendocrine transformation and for translational objectives. Local confirmation of an ALK, ROS1, or RET gene fusion through tissue or circulating tumor DNA (ctDNA) assessment is allowed. Plasma collection for ctDNA assessments will occur prior to treatment, on C3D1, and post-treatment. This study will have both a safety lead-in cohort and a dose expansion cohort. A safety lead-in cohort will be treated with amivantamab at the RP2D in combination with their ALK, ROS1, or RET TKI. The primary endpoint will be dose-limiting toxicity (DLT) within the first cycle of dosing at a given dose level. A Bayesian optimal interval (BOIN) design will be employed as a safety lead-in using a dose de-escalation design to find the maximum tolerated dose (MTD) of amivantamab in combination with a standard fixed dose of common ALK, ROS1, and RET TKIs. The RP2D dose for amivantamab was previously set at 1050mg (for patients < 80kg) and 1400mg (for patients ≥ 80kg). Patients will be treated in cohorts of size 3, and the maximum sample size for the dose escalation portion of the trial is 12 patients. The dose expansion cohort will evaluate the safety and efficacy of amivantamab (at the RP2D dose) in combination with standard FDA-approved doses of ALK, ROS1, and RET TKIs. The primary endpoint will be objective response rate (ORR). All patients enrolled at the RP2D level will be included in the phase II efficacy analysis, including patients enrolled in the safety lead-in cohort. A total of 16 to 35 evaluable patients, depending on the safety of the tested treatments in the dose escalation phase, are expected to be accrued to this study. Relevant exclusion criteria include: (1) prior EGFR directed therapy, (2) prior receipt of a MET monoclonal antibody or MET-ADC, (3) crizotinib use as immediate prior line of therapy, (4) small cell transformation, and (5) active, untreated, CNS metastases. The study has initiated enrollment without DLT and is ongoing. Clinical trial information: NCT05845671 .

Open-label, phase 1, multicenter study to evaluate the safety and preliminary anti-tumor activity of NT-175 in human leukocyte antigen-a*02:01-positive adult subjects with unresectable, advanced and/or metastatic solid tumors that are positive for the TP53 R175H mutation.

e14514 Background: The TP53 tumor suppressor gene is the most commonly mutated gene across all cancer types, and TP53 R175H is the most common recurrent mutation across indications, identified in 6.7% of patients with breast cancer, 6% of patients withs colorectal cancer, and 4.2% of patients with pancreatic cancer. No therapy is approved for treatment directly targeting TP53 R175H. NT-175 is an armored autologous T-cell product expressing an HLA-A*02:01-restricted TCR recognizing TP53 R175H with disruption of the endogenous TCR and the transforming growth factor beta receptor type 2 (TGFBR2) genes. Methods: This first-in-human phase I, open label study will assess the safety and preliminary anti-tumor activity, identify the maximum tolerated dose (MTD), and evaluate the persistence, and functional capacity of NT-175 in subjects with advanced, recurrent unresectable/metastatic solid tumors refractory to treatment options. The study will enroll approximately 24 subjects harboring TP53 R175H and HLA-A*02:01. Enrolled patients will undergo leukapheresis from which CD4 and CD8 T cells will be enriched and activated ex vivo. The endogenous TCR α and β chain gene are knocked out utilizing clustered Regularly Interspaced Short Palindromic repeats (CRISPR-Cas9) and the TCR encoding an HLA-A*02:01-restricted TCR specific to the TP53 R175H mutation is inserted in the TCR α locus. Additionally, the T cells are edited to disrupt the gene encoding the TGFBR2 to reduce the immunosuppressive effect of TGF-β in the tumor microenvironment. Subjects will undergo lymphodepletion chemotherapy with fludarabine and cyclophosphamide followed by a single infusion of NT-175 and subcutaneous recombinant IL-2 administration for up to 8 days. Dose escalation will occur across 3 ascending dose levels following the BOIN design. Subjects will be monitored for dose-limiting toxicities for 28 days after NT-175 infusion. Tumor response will be assessed by RECISTv1.1 criteria. All subjects will be followed for up to 15 years. Primary endpoints include safety, dose limited toxicities, MTD determination, and recommended Phase II dose. Secondary endpoints include preliminary efficacy measures. Translational analysis will evaluate potential biomarkers for insights into mechanism of action, response prediction, or resistance mechanisms. The study was activated in March 2023 and is open to accrual; 5 patients have been enrolled as of 4 Jan 2024.

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 .

First-in-human study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients (pts) with advanced solid tumors and in combination with fulvestrant in pts with advanced breast cancer.

TPS1128 Background: Oncogenic mutations in PIK3CA occur in ~35% of HR+, HER2– breast cancer (BC) and are frequent in multiple solid tumors. The approval of alpelisib, a non-mutant selective PI3Kα inhibitor, validates PI3Kα as a therapeutic target. However, inhibition of wild-type PI3Kα leads to significant toxicity, including hyperglycemia and rash. RLY-2608, a novel, oral allosteric PI3Kα inhibitor, is designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability, and anti-tumor activity. ReDiscover (NCT05216432) is the ongoing, first-in-human study to investigate the maximum tolerated dose (MTD), recommended phase 2 doses (RP2Ds), safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of RLY-2608 monotherapy in pts with PIK3CA-mutant advanced solid tumors; and of RLY-2608 plus fulvestrant with or without ribociclib in pts with PIK3CA-mutant, HR+, HER2– BC. To date RLY-2608 plus fulvestrant has completed dose escalation; 400 and 600 mg BID is being investigated in the combination regimens, based on safety, PK, PD, and anti-tumor activity. Methods: This global, multi-center, dose escalation/expansion study of RLY-2608 monotherapy includes adult pts with advanced solid tumors who are refractory or intolerant to, or have declined, standard therapy. RLY-2608 is also being investigated in combination with fulvestrant and in combination with fulvestrant and ribociclib, each in previously treated pts with HR+, HER2– advanced/metastatic BC. Eligibility criteria include presence of a PIK3CA mutation (blood or tumor) per local assessment, ECOG performance status 0–1, evaluable disease per RECIST 1.1, and no prior treatment with a PI3K pathway inhibitor. RLY-2608 is administered daily in 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (pAKT, mutant ctDNA and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify the MTD. Following dose escalation, expansion cohorts are enrolling patients with select PIK3CA-mutated solid tumors for treatment with RLY-2608 monotherapy and patients with HR+, HER2– metastatic BC for treatment with RLY-2608 plus fulvestrant with or without ribociclib. Primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are PIK3CA genotype in blood and tumor, PK, biomarkers, and overall response rate. All dose expansion cohorts in ReDiscover are now enrolling in the United States and Europe. Clinical trial information: NCT05216432 .

DAREON-8: A phase I, open-label, dose escalation/expansion trial of the DLL3-targeting T-cell engager, BI 764532, combined with first-line (1L) standard of care (platinum, etoposide, and anti-PD-L1 antibody) in patients (pts) with extensive-stage small cell lung carcinoma (ES-SCLC).

TPS8127 Background: Platinum/etoposide chemotherapy in combination with anti-PD-L1 antibodies is the 1L standard of care (SoC) for pts with ES-SCLC. However, most pts relapse and subsequent treatment (Tx) options are limited. Hence, outcomes are poor with a 5-year survival rate of < 7%. Delta-like ligand 3 (DLL3) is a Notch receptor ligand expressed on tumor cells but not on normal cells. BI 764532 is an IgG-like T-cell engager (TcE) that binds simultaneously to CD3 on T-cells and DLL3 on tumor cells, resulting in selective, T-cell mediated tumor cell lysis. An ongoing Phase I trial of BI 764532 (NCT04429087) in pts with pretreated DLL3-positive tumors demonstrated an overall response rate of 28%, a disease control rate of 54%, and a manageable safety profile. Here, we describe DAREON-8 (NCT06077500), a Phase I open-label dose escalation/expansion trial of BI 764532 plus SoC as a 1L Tx for pts with ES-SCLC. Methods: Pts will be recruited from ~20 sites into this two-part trial. In Part A (dose escalation), ~30 pts will receive escalating doses of intravenous BI 764532 (target dose after step-in dosing) plus carboplatin/etoposide + atezolizumab. Dose escalation will be guided by a Bayesian logistic regression model with overdose control. Tx with BI 764532 will continue for 36 months, withdrawal or progressive disease (PD). The primary objective is to determine the maximum tolerated dose (MTD) of BI 764532 and/or the recommended dose for expansion (RDE)/recommended Phase II dose (RP2D) for BI 764532 plus SoC. Safety, efficacy and/or PK assessments will guide the RDE/RP2D. The primary endpoint focuses on the occurrence of dose-limiting toxicities (DLTs) in the MTD evaluation period. In Part B (dose expansion), ~30 pts will receive BI 764532 at the RDE/RP2D determined in Part A for 36 months, withdrawal or PD and platinum/etoposide + either atezolizumab or durvalumab. The primary objective of Part B is to confirm the safety and tolerability of BI 764532 at the RDE/RP2D plus SoC Tx as measured by the occurrence of DLTs during the on-Tx period. Key inclusion criteria include confirmed ES-SCLC; no prior systemic treatment for ES-SCLC; and eligibility to receive platinum/etoposide chemotherapy + anti-PD-L1 antibodies. Key exclusion criteria include previous Tx with DLL3-targeting TcEs; persistent, unresolved toxicity from previous Txs; immunodeficiency, or systemic steroid or other immunosuppressive therapy ≤7 days prior to first dose of BI 764532; and significant cardio/cerebrovascular disease. Clinical trial information: NCT06077500 .

4CAST: A phase 1b dose exploration, open-label, single-center study evaluating the safety of INO-464 in combination with chemotherapy in patients with metastatic breast cancer.

e13112 Background: Metastatic triple negative breast cancer (TNBC) has a poor prognosis and the development of new targeted therapies is an area of unmet need. The androgen receptor (AR) antagonist, INO-464, but not abiraterone or enzalutamide, blocks chemotherapy induced cell plasticity to inhibit and primary and metastatic breast cancer (MBC) growth. Single agent INO-464 at a dose of 450mg/d is well tolerated but has low efficacy. Laboratory data demonstrates suppression of metastatic TNBC and an increase in survival with the combination of INO-464 and taxane chemotherapy. Methods: We designed a Phase 1b open-label, single center dose exploration (Part 1) and dose expansion (Part 2) clinical trial of INO-464 450mg/d with docetaxel (IV 75mg/m2 q3wkly) or nab-paclitaxel (IV 100mg/m2 D1/8/15 q4wkly) in any subtype of MBC. The primary objective was to assess the safety and tolerability of INO-464 (450mg/d) and docetaxel or nab-paclitaxel utilizing a rolling 6 design, as well as to determine the maximum tolerated dose (MTD) and the recommended dose of INO-464 to be given with a taxane in the dose expansion study. Secondary objectives included anti-tumor activity and testosterone levels. Results: Recruitment began in August 2022. The cut-off date for this analysis was 19 January 2024. Eight patients have been treated to date and 6 patients were DLT evaluable. All were women with MBC with mean age of 56 (range 48-64) years. Patients had received a median of 5 (range 2 to 7) lines of chemotherapy for MBC. Patient 001 had G3 anaphylaxis due to docetaxel that resolved with adrenaline but came off study and was not DLT evaluable. The protocol was amended to give INO-464 with 1mg of dexamethasone. No DLTs were subsequently observed. Adverse events (AEs) were mostly low grade and chemotherapy related although G2 pneumonitis occurred beyond the DLT period in two patients, one of whom had prior sacituzimab govotecan-related pneumonitis. INO-464-related AEs were G1 fatigue/headache in 4/6 patients. Seven of seven patients had a best response (RECIST1.1) SD, and CA15.3 stability was seen in 4/7 patients. Baseline serum testosterone was detectable in 4/6 patients (range 0.5-1.3 nmol/L, lower limit of detection of <0.5), and remained undetectable or at the lower limit of detection throughout treatment. Conclusions: The MTD of INO-464 is 450mg daily with 0.5mg dexamethasone in combination with docetaxel or nab-paclitaxel chemotherapy. The combination is well tolerated with early efficacy signals. Dose expansion will test the combination in metastatic TNBC with nuclear AR positive breast cancer. Clinical trial information: NCT04947189 .

Phase I trial of chidamide, an oral HDAC inhibitor, in combination with oral etoposide in patients with refractory/recurrent neuroblastoma.

10034 Background: Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor, has been shown to be effective in adult patients with hematological tumors. However, there is no data on its safety and efficacy in pediatric cancer patients. Combination of HDAC inhibitors and etoposide have shown synergistic anti-tumor effects in preclinical studies of neuroblastoma. We conducted a phase I trial in pediatric patients with recurrent or refractory neuroblastoma to determine the maximum tolerable dose (MTD) of chidamide combined with oral etoposide treatment. Methods: Daily oral etoposide 35 mg/m2/dose was administered on days 1–21 in combination with escalating doses of chidamide (14 and 17 mg/m2/d) twice weekly in each 28-day cycle using the standard 3 + 3 design. Patients with response or stable disease after two cycles would maintain treatment until disease progression or unacceptable toxicity occurred. Chidamide pharmacokinetic testing was performed. Results: 31 patients were enrolled in this study. The median age was 7 years (range 3 – 18). 14 patients were included in the dose escalation phase (Ia), 17 patients in the expansion cohort (Ib). The MTD of chidamide was 14 mg/m2/d, with dose limiting neutropenia and thrombocytopenia observed at 17 mg/m2/d. Median number of cycles completed was 2.5 (range 1–11). A total of 19 patients (61.3%) experienced treatment-related grade 3/4 hematologic toxicity, and no grade 3/4 non-hematological toxicity was observed. No objective responses were seen. Conclusions: In children with refractory/recurrent neuroblastoma, chidamide is well-tolerated at 14 mg/m2/d twice weekly when combining with oral etoposide 35 mg/m2/d daily. Prolonged disease stability achieved in patients with minimal residual diseases deserves further investigation. Clinical trial information: NCT05338541 .

Phase I, open-label, dose-escalation trial investigating the safety and efficacy of oncolytic virus BI 1821736 in patients with advanced solid tumors.

TPS2688 Background: Despite some advances, the need for novel anti-cancer therapies remains high in patients with advanced solid tumors. Although immunotherapy with checkpoint inhibitors is the preferred treatment for several cancer types, a proportion of patients will have non-responsive tumors or develop resistance. Oncolytic viruses have potential as novel immunotherapies, due to their tumor-selectivity and ability to stimulate a systemic anti-tumor immune response. BI 1821736 is a genetically engineered pseudotype variant of VSV-GP encoding an immune-stimulatory cargo. The VSV-GP backbone is a recombinant chimeric vesicular stomatitis virus modified to replace the innate neurotropic G glycoprotein with the non-neurotropic GP glycoprotein from the lymphocytic choriomeningitis virus. BI 1821736 selectively replicates and lyses cells with defective interferon signaling, which is seen particularly in cancer cells. The immune-stimulating cargo leads to T-cell priming and reactivation within the immunosuppressed tumor microenvironment. Preclinical efficacy, toxicology, and environmental safety results support BI 1821736 administration in humans. Methods: 1467-0001 (NCT05839600) is a Phase I, open-label, dose-escalation study evaluating the safety and early efficacy of BI 1821736 in patients with advanced solid tumors. The study is enrolling adult patients who have exhausted available treatment options, with an Eastern Cooperative Oncology Group Performance Status of 0 or 1, ≥1 lesion amenable to biopsy, and adequate organ function. Patients with brain metastases are excluded unless they have completed brain radiotherapy and are asymptomatic. Patients will receive escalating doses of intravenous BI 1821736 for up to 3 months. Dose escalation will be guided by a Bayesian 2-parameter logistic regression model with overdose control (BLRM-EWOC). The primary objective is to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose based on occurrence of dose-limiting toxicities (DLTs) during the MTD evaluation period of the first treatment cycle (Cycle 1; 21 days). Other safety endpoints include the occurrence of DLTs and adverse events during the treatment period. Further objectives include the assessment of BI 1821736 preliminary efficacy, pharmacokinetics, immunogenicity, shedding, and biomarkers. Patients are being recruited from approximately 10 sites across North America and Europe. Enrollment began in May 2023. A total of six patients have received BI 1821736 as of January 29, 2024. Patients are currently being enrolled to dose level 2. Clinical trial information: NCT05839600 .

TAZNI: A phase I/II combination trial of tazemetostat with nivolumab and ipilimumab for children with INI1-negative or SMARCA4-deficient tumors.

TPS10077 Background: The prognosis for children with INI1-negative cancers is dismal, with historic 5-year overall survival <30%. These cancers (including malignant rhabdoid tumors [MRT], atypical teratoid rhabdoid tumors [ATRT], epithelioid sarcomas [ES], and poorly differentiated chordomas) have few novel treatment options. These tumors exhibit a heightened dependence on the Polycomb Repressive Complex, whereby EZH2 is the catalytic subunit. Two recent pediatric phase 1/2 trials with EZH2 inhibitor tazemetostat (EZH-102, NCT02601937 and APEC1621C, NCT03213665) demonstrated 17% overall objective response rate, with 19% response in ATRT patients and higher response rates in patients with chordoma and ES. One patient had PR on the phase 2 Pediatric MATCH study and 5 patients had prolonged SD. Studies of INI1-deficient tumors have shown significant immune infiltration, including T-cells with high levels of inhibitory checkpoint receptors. As EZH2 has a role in tumor immunity and tazemetostat increases MHC presentation and immune signaling, we hypothesized that combining EZH2 inhibitor with checkpoint inhibitors may provide benefit for pediatric patients with INI1- or SMARCA4-deficient tumors. Methods: TAZNI is a phase 1/2, multi-center trial of Tazemetostat, Nivolumab and Ipilimumab for children with INI1- or SMARCA4-deficient tumors after upfront therapy. All patients receive standard pediatric nivolumab and ipilimumab doses/dosing schedule with continuous tazemetostat dosing determined by disease strata: Stratum A- subjects with ATRT; Stratum B for all other (non-ATRT) INI1/SMARCA4-deficient tumors. Each stratum is subdivided by disease status: A1/B1- subjects with refractory disease after upfront therapy; A2/B2- subjects with relapsed disease; and A3/B3: subjects with no evidence of disease (NED) after upfront therapy. The study is conducted in 2 parts: Part 1 will be two concurrent “rolling six” phase 1 studies to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) by disease stratum. Starting dose level 1 for Stratum A is 900mg/m2 orally BID and for Stratum B: 520mg/m2 orally BID, with one dose escalation and one dose de-escalation planned. Part 2 will be two phase 2 studies to estimate the overall response rate (ORR) in Substrata A1 and A2 (with refractory disease or with relapse, respectively), based on a primary endpoint of ORR (CR+PR) in a Simon’s 2-stage design at the RP2D. All other substrata will be descriptive analyses. Patients may receive up to 26 cycles of therapy. Key inclusion/exclusion criteria include INI1 loss by immunohistochemistry (IHC) or molecular confirmation; age between 6 mo and 21 yo; no prior immunotherapy; limited corticosteroid; and no history or concern for hematologic malignancy. To date, 4 patients have enrolled, and the study is ongoing in the United States. Clinical trial information: NCT05407441 .

Phase 1b study of EZH1/2 inhibitor valemetostat in combination with trastuzumab deruxtecan in patients with HER2 low/ultra-low/null metastatic breast cancer.

TPS1120 Background: In the DAISY study (NCT04132960), meaningful clinical response was observed with Trastuzumab deruxtecan (T-DXd) in HER2 IHC 0 MBC. Valemetostat is an oral, selective dual inhibitor of enhancer of zeste homolog 1 and 2 (EZH1/2) methyltransferases that specifically methylate histone H3 lysine 27. EZH2-mediated PP2A inactivation confers resistance to HER2-targeted therapy. Additionally, valemetostat upregulates Schlafen11 (SLFN11), a putative DNA/RNA helicase, that regulates the sensitivity to DNA damaging agents such as topoisomerase I inhibitors. Based on these preclinical studies, this study examines the safety and anti-tumor activity of valemetostat in combination with T-DXd in subjects with HER2 low/ultra-low/null MBC. Methods: This is a single-arm, phase-1b study to evaluate the safety and clinical activity of T-DXd in combination with valemetostat in patients with HER2 low/ultra-low/null MBC (NCT05633979). The dosing for T-DXd is 5.4 mg/kg Q3W administered intravenously as indicated for current clinical use by FDA approval. Valemetostat will be evaluated at three dose levels (100 mg, 150 mg, and 200 mg orally), with a starting dose (level 1) at 100 mg QD. The dose-limiting toxicity (DLT) evaluation period will be the first 2 treatment cycles (42 days). Major eligibility criteria: Pathologically confirmed HER2 low/ultra-low/null breast cancer; ECOG performance status ≤1; Measurable disease; Received at least one line of chemo in the metastatic setting; Progressed and would no longer benefit from endocrine therapy; Normal organ and marrow function. Exclusion criteria: symptomatic brain metastases, interstitial lung disease, cord compression, prior treatment with any anti-HER2 therapy. Objectives: To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE); To evaluate the objective response rate (ORR); To determine the duration of response (DoR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS); To evaluate the pharmacokinetics and pharmacodynamic markers. Statistical methods: Approximately 12 evaluable patients will be enrolled for the dose-escalation portion based on the Bayesian optimal interval design with a target DLT rate of 25%. Patients will be enrolled in cohorts of 3. The expansion will be performed at the RDE using the 2-stage Bayesian optimal dose-expansion design. In the first stage, 13 evaluable patients will be enrolled. If <5 patients respond in the first stage, the study will be stopped for futility. If ≥5 responses are observed, 13 additional evaluable patients will be enrolled. If 11 or more responses are observed among 26 patients, the treatment will be regarded as promising. This two-stage design yields 78% power under the alternative hypothesis of ORR = 50% (null ORR = 30%) while controlling the one-sided type I error at 10%. Clinical trial information: NCT05633979 .

Cadonilimab plus lenvatinib in patients with advanced endometrial cancer: A multicenter, single-arm, phase II trial.

5600 Background: Lenvatinib plus pembrolizumab is the standard treatment for patients with advanced endometrial cancer with mismatch repair-proficient (pMMR) disease who had disease progression after the receipt of prior systemic platinum-based therapy. Cadonilimab is a PD-1/CTLA-4 bi-specific antibody. We aimed to assess the combination of cadonilimab and lenvatinib in patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy. Methods: In this phase II study with a safety-run in, eligible patients were aged 18 years or older with advanced endometrial cancer of any histologic subtype, except sarcoma, progressed after at least one prior platinum-based chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1. In the safety run-in period, a 3+3 dose de-escalation design was used to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of lenvatinib (16 mg or 12 mg once daily) combined with cadonilimab 10 mg/kg every 3 weeks. After the completion of safety run-in period, the phase II cohort at the RP2D will open. Approximately 29 patients are planned to receive treatment at the RP2D. The primary endpoint was objective response rate (ORR) at the RP2D. Key secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: Between 8 May 2023 and 18 December 2023, 24 patients were enrolled. As of 31 December 2023, enrollment was ongoing. No DLTs were observed during the safety run-in period. The RP2D of lenvatinib is 16 mg once daily. Among 21 efficacy-evaluable patients, the ORR was 52.4% (95% CI: 29.1–75.7), and the DCR was 90.5% (95% CI: 69.6–98.8). The Medians for DOR, PFS, and OS were not reached. Grade 3–4 treatment-related adverse events included increased ALT (2 [8.3%]), increased AST (1 [4.2%]), increased creatine phosphokinase (1 [4.2%]), hypertension (1 [4.2%]), and intestinal perforation (1 [4.2%]). Conclusions: Cadonilimab plus lenvatinib showed promising antitumor activity in patients with advanced endometrial cancer who have experienced disease progression after prior systemic platinum-based therapy. The combination therapy had a favorable and manageable safety profile. Clinical trial information: NCT05824481 . [Table: see text]

A phase 1 trial evaluating the safety, tolerability, PK, and preliminary efficacy of QTX3034, an oral G12D-preferring multi-KRAS inhibitor, in patients with solid tumors with KRASG12D mutation.

TPS3172 Background: KRAS is one of the most mutated driver oncogenes across solid tumors, and KRAS G12D missense mutations have high prevalence in pancreatic, colorectal (CRC), and endometrial cancers. QTX3034 is a highly-selective, non-covalent, orally bioavailable, multi-KRAS inhibitor with potent activity across several KRAS variants, particularly G12D. QTX3034 binds to GDP-bound forms of mutant and wild-type KRAS with (sub)nanomolar affinities, allosterically inhibiting its conversion to the active state. QTX3034 inhibits KRAS signaling in in vitro studies and displays synergy with EGFR inhibitors. In vivo evaluation of QTX3034 resulted in significant tumor growth inhibition across various tumor models, with tumor regressions observed in 100% of animals in both HPAC pancreatic and GP2D colorectal KRAS G12D xenograft models. QTX3034 exhibits brain penetration in preclinical studies, including an orthotopic model of intracranial efficacy. This clinical trial is now enrolling patients with advanced solid tumors harboring a KRASG12D mutation. Methods: This is a first-in-human, multicenter, open-label phase 1 study in adult patients with advanced solid tumors with KRASG12D mutations, without prior direct KRAS inhibitor treatment (NCT06227377). The primary objectives are to evaluate the safety and tolerability and to determine maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of QTX3034 alone, and in combination with cetuximab. Secondary objectives are characterization of the PK profile and preliminary antitumor activity. Part 1 consists of two dose-escalation arms: QTX3034 monotherapy (advanced solid tumors) and QTX3034 plus cetuximab (CRC) and will enroll 3-4 subjects per cohort in a Bayesian Logistic Regression Model (BLRM) design. QTX3034 will be administered orally in 21-day cycles until disease progression, intolerable toxicity, or withdrawal from treatment. Exploratory paired biopsies will be collected in Cycle 2 in a group of patients in the dose-escalation phase. Serial ctDNA will be collected in all patients. Following identification of a RP2D, QTX3034 will be evaluated in dose-expansion cohorts of up to 30 patients with various KRASG12D mutated tumor types to determine preliminary activity: pancreatic cancer, CRC, non-small cell lung cancer and endometrial cancer. To further optimize the recommended dose, patients will be randomized between two dose levels in the pancreatic cancer cohort. QTX3034 plus cetuximab will be explored following identification of a recommended combination dose in patients with CRC. Clinical trial information: NCT06227377 .

First-in-human study of HMPL-295, an ERK1/2 inhibitor, in patients with advanced solid tumors: Dose-escalation results of monotherapy.

e15112 Background: HMPL-295 (’295) is an extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor with potent activity in non-clinical studies. This is a first-in-human, dose escalation study of ’295 in patients (pts) with advanced solid tumors. Here, we report the results of the mono dose escalation stage. Methods: Pts with advanced solid tumors who have failed standard therapy were enrolled to receive ’295 once daily (QD) in 28-day cycles or ’295 QD 2 weeks on/1 week off (2w on/1w off) in 21-day cycles. The mTPI-2 design was used for dose escalation, having explored from 5 to 75 mg QD in 6 cohorts, as well as 75 mg and 100 mg QD 2w on/1w off. The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and preliminary efficacy (best of response, BOR). Results: As of Dec 11, 2023, 47 pts with advanced solid tumors were enrolled (n=1, 1, 3, 6, 12, 5, 13, 6 in 5, 10, 20, 40, 50, 75 mg QD cohorts, 75, 100 mg QD 2w on/1w off cohorts, respectively), with a median age of 58 years, 23 (48.9%) male pts. During the dose escalation from 5 to 75 mg QD cohort, 1 pt given 40 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 dermatitis acneiform and 2 pts given 75 mg QD experienced DLTs of grade 3 rash and acute kidney injury (AKI). As for intermittent-administration cohorts, 2 pts given 100 mg QD 2w on/1w off experienced DLTs of grade 3 AKI and rash maculo-papular. After multiple-dose oral administration, ’295 plasma concentrations reach peak at 1.0-2.0 hours post dose and the exposure (Cmax and AUC) displayed dose dependent increase. The accumulation ratio (AUC) was 2.1–3.4 after repeat dosing, reaching steady-state around day 15. ’295 inhibited ribosomal S6 kinase (RSK) phosphorylation which is a downstream signaling molecule regulated by ERK1/2 and stimulated by phorbol 12-myristate 13-acetate (PMA). The BOR was partial response each in 1 pt with duodenal adenocarcinoma in 40 mg QD cohort,1 pt with endometrial cancer in 50 mg QD cohort and 1 pt with non-small cell lung cancer (NSCLC) in 75 mg QD 2w on/1w off cohort. Stable disease with tumor shrinkage was also observed in 2 pts with NSCLC on 50 mg QD and 75 mg QD 2w on/1w off cohort respectively, and 1 pt with pancreatic ductal adenocarcinoma in 100 mg QD 2w on/1w off cohort. 25 (53.2%) pts reported grade ≥3 TEAEs. The most common (≥10.0%) ≥ grade 3 TEAEs were rash (10.6%) and anemia (10.6%). Conclusions: Considering safety, tolerability, PK/PD and preliminary efficacy results, RP2D was determined to be 50 mg QD. Clinical trial information: NCT04908046 .