Phase Ia Study Research Articles

1007P Systemic STING agonist BI 1703880 plus ezabenlimab in patients (pts) with advanced solid tumors: Initial results from a phase Ia study

1007P Systemic STING agonist BI 1703880 plus ezabenlimab in patients (pts) with advanced solid tumors: Initial results from a phase Ia study

1002P A phase Ia study of the myeloid-derived suppressor cell modulator HF1K16 in refractory and metastatic cancer patients: Preliminary efficacy and safety

1002P A phase Ia study of the myeloid-derived suppressor cell modulator HF1K16 in refractory and metastatic cancer patients: Preliminary efficacy and safety

A phase Ia, dose-escalation study of IMB071703 injection in patients (pts) with recurrent or metastatic, advanced solid tumors.

e14502 Background: IMB071703(XFab-α4-1BB/CD40L), a 4-1BB Fab and triCD40L fusion protein that activates dendritic cell and primes tumor-reactive T cells, mediates immune response, and further inhibits tumor development. We confirmed the expansion of antigen-specific T cells in various mouse models and potent tumor regression administrated by IMB071703 alone or in combination with gemcitabine in vivo, concomitant with improved tumor-reactive T-cell infiltration. IMB071703 showed no signs of liver toxicity at the dose levels up to 51 mg/kg in a repeated-dose study in non-human primates. Here, we describe initial data from a phase Ia study (CTR20230326). Methods: Eligible patients with recurrent or metastatic, advanced solid tumors were enrolled in this study. IMB071703 was administrated at escalating doses of 0.05, 0.15, 0.5,1.0 and 1.5 mg/kg intratumorally Q1W in Cycle 1 (C1:21days), and Q2W from Cycle 2 and subsequent cycles (Cn+1:28 days). Enrolled pts would first undergo DLT observative assessment (21 days). After pts were assessed safely during DLT observation, they would continue the scheduled dosage of IMB071703 until disease progression, intolerable toxicity or other reasons specified in the clinical protocol. The study objectives included the safety, tolerability, PK, pharmacodynamics, immunogenicity, and preliminary efficacy. Results: 7 pts with recurrent or metastatic, advanced solid tumors (median age 60 years, range 42-71; 4 male, 3 female; prior lines of therapy with range 1-6) were treated. Three dose levels, 0.05 mg/kg(n=1), 0.15 mg/kg(n=3), and 0.5mg/kg(n=3), had been evaluated. 1.0mg/kg dose escalation is ongoing. On cutoff date of 18 Dec. 2023, 1 pt is on the study and 6 pts had discontinued treatment. The reasons for discontinuation included confirmed disease progression (n=5) and other reason(n=1). 7 pts (100%) experienced treatment-emergent adverse events (TEAEs). 5 pts (71%) experienced treatment-related adverse events (TRAEs≥10%): Injection reaction (pain, fever, chill) (28%), fatigue (11%). All TRAEs were ≤grade 2. No DLT was observed. One death due to disease progression, as only a SAE, was identified to be unrelated. No objective response was observed in 6 evaluable pts. 1 pt was SD and 5 pts were PD. Pharmacodynamic data showed CD40 was occupied ≥50% in the 0.5 mg/kg level. The percentage of CTL (CD3+CD8+) in peripheral blood was increased (0.15mg/kg and 0.5mg/kg) Pharmacokinetic analysis also showed the mean half-life of IMB071703 was 2.45 hours in three dose levels. Biomarker analysis indicated 4-1BB up-regulation and PD-1 down-regulation was associated with the favorable response. Conclusions: IMB071703 Showed a good safety profile at the dose levels of 0.05 mg/kg, 0.15 mg/kg, and 0.5mg/kg. Both favorable tolerability and preliminary antitumor activity warrant further evaluation in patients with advanced malignancies. Clinical trial information: CTR20230326 .

A phase I study of ATR inhibitor BAY1895344 (elimusertib) plus topotecan (ETCTN 10402): Results of dose escalation.

3076 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase is activated by replication stress and recruited to stalled forks or single strand DNA abnormalities in various cancers. The topoisomerase-I (Top1) inhibitor topotecan induces DNA damage. The ATR inhibitor BAY 1895344 (elimusertib) has demonstrated cytotoxic potential in small cell lung cancer and gastrointestinal cancer xenografts when combined with Top1 inhibitors . Methods: This is phase Ia study of elimusertib combined with topotecan in adult patients with refractory advanced solid tumors for whom topotecan can be considered as part of standard care. Patients with previous topotecan exposure were excluded. The study combination was assessed starting at Topotecan 1 mg/m2 IV (D1-D5) plus elimusertib 20 mg BID (D2, D5) (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) of the combination. Secondary objectives included estimating pharmacokinetic (PK) profiles and assessing anti-tumor activity of the combinations. Results: Eight patients were treated in dose escalation. Participants were a median of 63 years old and had received 2 median lines of previous therapy. The initial two patients enrolled into dose level (DL) 1 had dose-limiting toxicities with one of patient experiencing respiratory failure and cardiac arrest in setting of pancytopenia related to study drug. Six patients were subsequently enrolled in and received DL-1 (elimusertib decreased from 20 mg BID to 20 mg Daily) and no DLTs were observed. Notable grade 3+ treatment-related adverse events and summary best response are summarized in Table. Disease control rate was 43% among evaluation patient including one unconfirmed partial response. Median progression-free survival in the RP2D cohort was 3.45 months. PK studies are in process and results will be presented at time of meeting. Conclusions: RP2D and MTD was established for elimusertib in combination with Topotecan: Topotecan 1 mg/m2 IV [D1-D5] plus elimusertib 20 mg Daily [D2, D5] every 3 weeks. Dose escalation was notably limited by myelotoxicity. Due to sponsor decision, the study was halted prior to planned expansions cohorts but the concept of ATR + topo I inhibition remains relevant. Clinical trial information: NCT04514497 . [Table: see text]

First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer

BEBT-109 is an oral pan-mutant-selective inhibitor of epidermal growth factor receptor (EGFR) that demonstrated promising antitumor potency in preclinical models. This first-in-human study was a single-arm, open-label, two-stage study. Phase Ia dose-escalation study evaluated the safety and pharmacokinetics of BEBT-109 in 11 patients with EGFR T790M-mutated advanced non-small cell lung cancer (aNSCLC). Phase Ib dose-expansion study evaluated the safety and efficacy of BEBT-109 in 18 patients with EGFR exon 20 insertion (ex20ins)-mutated treatment-refractory aNSCLC. The primary outcomes were adverse events and antitumor activity. Clinical trial registration number CTR20192575. The phase Ia study demonstrated no dose-limiting toxicity, no observation of the maximum tolerated dose, and no new safety signals with BEBT-109 in the dose range of 20-180mg/d, suggesting that BEBT-109 had an acceptable safety profile among patients with EGFR T790M-mutated aNSCLC. Plasma pharmacokinetics of BEBT-109 showed a dose-proportional increase in the area under the curve and maximal concentration, with no significant drug accumulation. The dose-expansion study demonstrated that BEBT-109 treatment was tolerable across the three dose levels. The three most common treatment-related adverse events were diarrhea (100%; 22.2% ≥Grade 3), rash (66.7%; 5.6% ≥Grade 3), and anemia (61.1%; 0% ≥Grade 3). The objective response rate was 44.4% (8 of 18). Median progression-free survival was 8.0months (95% confidence intervals, 1.33-14.67). Preliminary findings showed that BEBT-109 had an acceptable safety profile and favorable antitumor activity in patients with refractory EGFR ex20ins-mutated aNSCLC. National Natural Science Foundation of China.

Safety and Efficacy of a Locally Produced Novel Anti-BCMA Chimeric Antigen Receptor T-Cell (CART) (HBI0101) for the Treatment of Relapsed and Refractory Multiple Myeloma

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CART) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM), with recent phase 3 studies showing clear advantage of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel)over standard-of-care. However, access to these commercial CART products is a major barrier, and it is estimated that only around a quarter of eligible R/R MM patients will receive CART nowadays. HBI0101 is a novel second generation optimized anti-BCMA CART with 4-1BB co-stimulatory domain, that was developed in an academic setting, at Hadassah Medical Center and Bar-Ilan University. The phase Ia study evaluating HBI0101 (NCT04720313) demonstrated a manageable safety profile and an initial high efficacy (Asherie, Haematologica 2022). Here, we present the updated results of 50 patients receiving 800x10^6 CART cells in the NCT04720313 phases 1a-b / 2. METHODS: The phase 1a study with HBI0101 which first evaluated 20 R/R MM patients with ≥3 prior lines of therapy, including a PI, IMiD and anti-CD38 antibody, revealed a dose of 800x10^6 CART cells to be safe and effective. The phase Ib and phase 2 of the study evaluated this dose infusion in 43 additional patients. Inclusion criteria were relatively permissive with minimum creatinine clearance of 20ml/min, platelet count of 30x10 9/ml, left ventricular ejection fraction of 40%, and ECOG performance status of ≤2. Lymphodepletion included fludarabine 25mg/m 2 and cyclophosphamide 250mg/m 2 on days -5 to -3 before infusion (bendamustine 90mg/m 2 and on days -4 and -3 for patients with creatinine clearance <30ml/min). Planned manufacturing time was 10 days. RESULTS: Of 51 patients who underwent lymphocyte apheresis, 50 (98%) were treated with 800x10^6 CART cells; 7 patients in the phase Ia cohort and 43 in the phases 1b / 2 cohorts. HBI0101 production success rate was 100%, with manufacturing time of 10 days for all patients. The median age was 65y (range 40-84). The median number of prior lines was 4 (range 3-13) and most patients (47/50, 94%) were triple refractory to PI, IMiD and anti-CD38 antibody. Twenty patients (40%) were penta-refractory and 10 (20%) were refractory to the anti-BCMA antibody drug conjugate belantamab mafodotin. Forty-six patients (92%) were refractory to the last line of therapy. Twelve patients (24%) had high risk cytogenetics (t(4:14), t(14:16) or deletion 17p); 31 (62%) when 1q gain included. Sixteen patients (32%) had extramedullary involvement at study entry. Grade 3-4 hematological toxicities were common (anemia- 62%, thrombocytopenia- 54%, neutropenia- 98%, lymphopenia- 100%). Cytokine release syndrome (CRS) occurred in 48/50 (96%)- grade 1/2- 17 patients (82%); grade 3- 7 patients (14%). Tocilizumab was used in 40/48 patients with CRS (median of 1 dose, range 1-4) and corticosteroids in 8/48. Two cases of immune effector cell associated neurotoxicity syndrome (ICANS) were observed (grade 1 and 2). Two patients developed CART-associated hemophagocytic lymphohistiocytosis syndrome (HLH). No irreversible organ toxicities or treatment related deaths occurred. The overall response rate (ORR) was 45/50 (90%), including 29 patients (58%) with complete response (CR)/stringent CR, 10 (20%) with very good partial response and 6 (12%) with partial response. Thirty-five patients (70%) achieved minimal residual disease (MRD) negativity at day +30. At a median follow-up of 11.9 months (range: 0.6-19), the median progression-free survival was 10.6 months, and the median overall survival was not reached (Figure 1). Although the presence of extra-medullary disease and prior anti-BCMA therapy correlated with worse outcome, high response rates were still observed (ORR of 98%/75% for patients without/with extra-medullary disease, respectively, and 95%/75% for patients without/with prior anti-BCMA therapy, respectively). Updated results will be communicated at the presentation time. CONCLUSION: Our findings demonstrate the manageable safety and high efficacy profiles of HBI0101 also in high-risk patients. Fast production time enabled the timely treatment of 98% of apheresed patients. These favorable data are encouraging and support decentralization of CART production at an academic setting, ensuring a sufficient CART supply in the light of the increasing demand.

A Phase Ib Open-Label Study of MRG001 in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL)

Background: Patients with R/R DLBCL who fail multi-agent chemoimmunotherapy have a poor prognosis and a need for more treatment options. MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE). MRG001 has been evaluated in a first-in-human phase Ia study and determined 1.8 mg/kg Q3W as RP2D. Here we present results from phase Ib study of MRG001 in patients with R/R DLBCL who had failed established therapies for the safety and preliminary antitumor activity evaluation. Methods: Patients aged ≥18 years with ECOG PS 0-1, histologically diagnosed R/R DLBCL who had failed ≥ 2 prior therapies (a prior anti-CD20 antibody treatment was necessary) were enrolled in this single-arm, open-label phase Ib study. All patients received MRG001 1.8 mg/kg IV Q3W until disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was overall response rate (ORR) assessed by investigators according to the Lugano response criteria, duration of response (DoR) and safety. Results: At data cutoff (Jul 28, 2023), 35 patients were enrolled and received ≥1 dose of MRG001; 29 (82.9%) had discontinued the treatment and 6 (17.1%) were ongoing. Median age was 62 years (34-76), 24 (68.6%) patients were male, 24 (68.6%) had an ECOG PS of 1. The median antitumor systemic prior lines was 3 (2-7), and most patients (62.9%) had ≥3 prior lines of therapy. 3 patients received prior ASCT, and 7 patients received prior CAR-T. Median follow-up (range) was 6.8 months (0.7-18.0) for all patients. Among the 34 evaluable patients, ORR by investigator review was 38.2% (95% CI, 22.2-56.4), with 6 patients (17.6%) having a CR and 7 (20.6%) having a PR; 10 patients (29.4%) had SD, and disease control rate (DCR) was 67.7% (95% CI, 49.5-82.6). Median DoR for the 13 responders was 10.5 months (95% CI, 6.5-NE). For patients with a CR, mDoR was 13.7 months (95% CI, 10.5-NE). Treatment related adverse events (TRAEs) occurred in 33 (94.3%) pts, most commonly reported were leukopenia (68.6%), neutropenia (65.7%), anemia (45.7%), AST increased (40.0%), and lymphopenia (31.4%). Grade 3/4 TRAEs occurred in 20 (57.1%) pts, most commonly reported were neutropenia (40.0%), leukopenia (17.1%), and lymphopenia (11.4%). Discontinuation due to a TRAE occurred in 2 (5.7%) patients. Patients all successfully recoverd from these TRAEs through the implementation of clinical supportive care. Grade 1/2 treatment-related peripheral neuropathy occurred in 22 (5.7%) patients; no grade 3/4 AEs occurred. No dose reduction occurred due to TRAE. No infusion reaction or tumor lysis syndrome due to treatment occurred and no pts died because of TRAEs. Conclusion: Phase Ib results show that MRG001 had clinically meaningful antitumor activity in patients with R/R DLBCL who progressed after multiple lines of therapy. Additionally, the safety profile was manageable and patients tolerated treatment well. Clinical trial information: NCT05155839.

1054P A phase Ia study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of a modular CLDN18.2-targeting PG CAR-T therapy (IBI345) in patients with CLDN18.2+ solid tumors

1054P A phase Ia study to evaluate the safety, tolerability, pharmacokinetics and preliminary efficacy of a modular CLDN18.2-targeting PG CAR-T therapy (IBI345) in patients with CLDN18.2+ solid tumors

First-in-human, phase I study of CBP-1008, a bi-specific ligand drug conjugate, in patients with advanced solid tumors.

5577 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors including ovarian cancer hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug conjugate targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (PROC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of September 30, 2022, 178 patients received at least one dose of study drug were enrolled (phase Ia: n=35; phase Ib: n=143) and received median 3 prior regimens. Included tumor species were PROC (n=101), TNBC (n=25), ER+/Her2+ breast cancer (BC) (n=17), colorectal cancer (n=6), pancreatic cancer (n=12) and others (n=17). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n=1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT) elevation. MTD was not yet reached. Majority of adverse events were mild to moderate. Grade 3/4 treatment-emerging adverse events (TEAEs) occurred in ≥ 3% subjects were neutropenia (n=85), decreased leukocyte count (n=49), anaemia (n=10), AST elevation (n=7), ALT elevation (n=7). Drug-related death was observed in 1 patient. A total of 82 PROC patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 21 patients achieved partial response (PR) and 30 patients achieved stable disease (SD). The objective response rate (ORR) and the disease control rate (DCR) were 25.6% and 62.2%, respectively. The median progression-free survival (mPFS) was 3.7 months (95% CI: 2.7-5.1). In 34 PROC patients with FRα expression ≥25% and ≤3 prior treatment regimens, ORR was 32.4% and mPFS was still 3.7 months (95% CI: 3.3-7.3). Given the small sample size, efficacy data of breast cancer and other solid tumors will be analyzed after recruiting more patients. Conclusions: The current result showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in PROC patients at dose of 0.15mg/kg or above, especially in PROC patients with FRα expression ≥25% and ≤3 prior treatment regimens. Jifang Gong, Jian zhang and Ning Li contributed equally to this work. Xichun Hu , Lin Shen and Lingying Wu are the corresponding authors. Clinical trial information: NCT04740398 .

A phase Ia trial to evaluate the safety and efficacy of HB0030, an anti-TIGIT antibody, in patients with advanced solid tumors: Preliminary results.

e14673 Background: HB0030 is an IgG1 type humanized monoclonalanti-TIGIT antibody. Its heavy chain Fc fragment is wild-type that preserves function for inducting CDC and ADCC effects. Nonclinical data showed that HB0030 has a good affinity for TIGIT and anti-tumor activity. Methods: This is an ongoing single-center, open-label, dose escalation Phase Ia study to mainly evaluate HB0030 safety, antitumor activity and immunogenicity in patients (pts) with advanced solid tumor. HB0030 is administered by IV infusion every 21 days. An accelerated titration method combined the standard 3+3 design was utilized for dose escalation, which of contained 8 dose groups (0.1, 0.3, 1.0, 3.0, 10, 20, 30, 40mg/kg). The tumor assessment evaluated by investigator according to RECIST v1.1. Results: As of Jan 9, 2023, 20 pts (4Male/16Female) with advanced malignant solid tumor have been enrolled and dosed at 0.1mg/kg (n = 1), 0.3mg/kg (n = 3), 1mg/kg (n = 3), 3mg/kg (n = 4), 10mg/kg (n = 3) and 20mg/kg (n = 6). The median age was 56.9 years. All pts had stage IV disease and failed from the anti-tumor standard therapy with a median of 3 lines. The main tumor types included lung(n = 6), breast(n = 3), colorectal(n = 3) and cervical (n = 2) cancer. Total 16 pts have completed at least once tumor assessment. The ORR and DCR were 6.3% (1/16) and 62.5% (10/16), respectively. The best response was a PR with 47% tumor regression pt who was diagnosed non-small cell lung cancer (NSCLC) accompanied with TP53 gene mutation. The pt relapsed with multiple metastasis after radical operation and adjuvant chemotherapy, and failed to systemic chemotherapy combined targeting anti-vascular therapy. He achieved PR with 3 cycles of 20mg/kg HB0030 treatment, and PR status continued at present. A NSCLC pt maintained 24 weeks SD after 3mg/kg HB0030 administration. The most common treatment related adverse events (TRAEs) were lymphopenia (9/20, 45%) and shortened activated partial thromboplastin time (APTT) (6/20,30%). Grade 3 TRAEs occurred in 15% of pts (3/20) which included thrombocytopenia, anemia, syncope and hypertension. There were no Grade 4-5 AEs, serious adverse events (SAEs), dose-limiting toxicity (DLT) and death. The anti-drug antibodies (ADAs) were detected in 2 pts in 20 mg/kg dose group, and not caused by HB0030 therapy because it had existed in baseline. Conclusions: HB0030 showed very well safety in the stage of dose escalation from 0.1 to 20 mg/kg, and potential promising anti-tumor activity above 3mg/kg dose in advanced solid tumors pts, especially in NSCLC. Currently, 30mg/kg and 40mg/kg dose escalation are ongoing. Clinical trial information: NCT05706207 .

Modulating MDSCs by HF1K16: A mono-therapy phase Ia study examining safety and preliminary efficacy in patients with refractory and metastatic cancer.

e14040 Background: Immature myeloid cells or the so called Myeloid-derived suppressor cells (MDSCs) are found to be present in higher numbers in cancer patients' PBMCs and in tumor infiltrating cells. All-trans retinoic acid (ATRA) is a natural vitamin A metabolite that's capable of inducing MDSC maturation and differentiation at uM concentrations. HF1K16 is an ATRA liposome formulation developed by Hangzhou Highfield Biopharm that aims to deliver ATRA to the tumor microenvironment by i.v. infusion for MDSC mediated immuno-therapeutic effects. Methods: The HF1K16 phase Ia clinical trial (NCT05388487) is being conducted to study the tolerability and safety of HF1K16 in patients with refractory solid tumors based on a "3+3" dose escalation scheme. HF1K16 infusions were given every other day for 2 weeks followed by a break week, and the 3wk cycle were repeated until EOT. Safety and tolerability records, repeated dose PK parameters, as well as exploratory PD analysis of PBMC samples are evaluated during the first cycle of treatment. Efficacy evaluations are followed every 6 weeks or less until EOT. Results: As of January 30, 2023, there have been 11 patients enrolled into the study in the dose groups of 45 mg/m2, 90mg/m2 and 120 mg/m2. The patient diagnosis and up to date treatment information is shown. Clinical trial information: NCT05388487 . Conclusions: HF1K16 is well tolerated at the 45 mg/m2 and 90 mg/m2 dose levels when given as monotherapy. Using the RECIST 1.1 criteria, one patient achieved an objective response with a progressive reduction of the target lesion from 70mm to 23.7mm. Four patients had PFS longer than 3 months. There is a subgroup of five enrolled patients who have recurrent and refractory Glioblastoma with multiple prior treatments. Three of them had control of disease and are still under treatment. The study is also still on going. We will collect more data based on additional enrolled cases and plan for the next phase study of HF1K16. [Table: see text]

Abstract CT178: GQ1001: A next generation HER2-targeting ADC that exhibits promising early clinical efficacy with excellent tolerance in a multi-center, Phase Ia study

Abstract Background: GQ1001 is a novel HER2-targeted antibody-drug conjugate (ADC) that was developed using innovative conjugation technologies coined intelligent Ligase-Dependent Conjugation (iLDC), that can significantly improves homogeneity and biostability of ADC. In preclinical studies, GQ1001 showed a robust anti-tumor response in multiple HER2+ models alone or in combination with HER2 TKIs and chemotherapeutics, and excellent pharmacokinetics and safety profiles in rats and monkeys due to low level of payload release. Herein we report the initial results of the ongoing phase Ia study, which aims to investigate the safety, tolerability, pharmacokinetics and antitumor activity of GQ1001 in subjects with HER2+ advanced solid tumors. Methods: In phase Ia dose escalation, a modified 3+3 model was adopted to assess the safety, dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) or dose recommended for dose expansion (DRDE) of GQ1001. GQ1001 was administered intravenously as a monotherapy on Day 1 of 21-day cycles. The starting dose was 1.2 mg/kg, followed by 2.4, 3.6, 4.8, 6.0, 7.2 and 8.4 mg/kg. Results: As of Dec. 28th, 2022, 32 subjects with HER2-positive advanced solid tumors, predominantly in breast (9), gastric or gastro-esophageal junction (9) and salivary gland (4), were enrolled and received GQ1001 treatment. Patients had a median 3 (range, 0-11) prior lines of therapies, and 37.5% of those previously received ≥2 lines of anti-HER2 therapies. Median exposure time of GQ1001 was 18.5 weeks. The longest treatment duration exceeded 370 days. No DLT was observed in all doses, MTD was not reached up to 8.4 mg/kg, the highest dose tested. Treatment-related adverse events (TRAEs) occurred in 24 subjects (75%). The most common TRAEs (>10.0%) were aspartate aminotransferase (AST) increased (37.5%), thrombocytopenia (28.1%), alanine aminotransferase (ALT) increased (25.0%), pyrexia (21.9%), anemia (18.8%), alkaline phosphatase increased (12.5%), vomiting (12.5%) and nausea (12.5%). Grade ≥3 TRAEs occurred in 9 subjects (28.1%), including 5 myelosuppression, 2 abnormal liver function, 1 hypertension and 1 vomiting. There were no drug-related deaths. The pharmacokinetics analysis showed the concentration of GQ1001 and TAb generally peaked rapidly and declined in a roughly biphasic manner. Among 15 evaluable subjects who received ≥ 7.2 mg/kg, 6 cases achieved confirmed partial response, and 3 had stable disease, the median progression-free survival was 4.8 months Conclusions: GQ1001 demonstrates an excellent tolerability and promising antitumor activity in heavily pretreated HER2-positive advanced solid tumors, supporting further evaluation of the safety and efficacy of GQ1001 at DRDE of 8.4 mg/kg in the following phase Ib trial. (NCT04450732; sponsored by GeneQuantum Healthcare (Suzhou) Co., Ltd.) Citation Format: Charlotte Lemech, Chenfei Zhou, Xianbao Zhan, Yan Shi, Jieqiong Liu, Sarina A Piha-Paul, Gary Richardson, Gang Qin, Paul H. Song, Lili Shi, Yajun Sun, Yi Xia. GQ1001: A next generation HER2-targeting ADC that exhibits promising early clinical efficacy with excellent tolerance in a multi-center, Phase Ia study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT178.

Abstract P4-01-07: FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study

Abstract Background: FS-1502 is a HER2-targeting antibody drug-conjugate with a cleavable β-glucuronide linker and an antimitotic agent (monomethyl auristatin F) which showed promising antitumor activity in preclinical studies. We are evaluating the safety and tolerability of FS-1502 in patients with HER2-expressing advanced solid tumors (NCT03944499). Methods: Patients with HER2-expresssing advanced solid tumors who had failed prior standard of care therapies were enrolled in a single-arm, open-label, dose-escalation phase Ia study in China. FS-1502 was given IV once in 21-day or 28-day cycles. The primary endpoint was incidence of dose-limiting toxicity (DLT). Adverse events (AEs), objective response rate (ORR) and duration of response (DoR) were also assessed. Data cutoff was December 30, 2021. Results: A total of 67 patients, 64 with breast cancer and 3 with other solid tumors, with median 3 prior therapies (range 1-10), were enrolled in 5 sites and treated with FS-1502 at doses of 0.1-3.5 mg/kg. Two DLTs, as defined by the protocol, were observed, with one G2 decrease in creatinine clearance at 3.0 mg/kg and one G3 thrombocytopenia with hemorrhage at 3.5 mg/kg. No Grade 4/5 events were observed. Grade 3 TRAEs were observed in 24 (35.8%) patients with the most common AEs of hypokalemia (14.9%) and decreased platelet count (9.0%). ORRs were observed at doses at or above 1.0 mg/kg with an ORR of 66.7% (4/6) at the recommended phase 2 dose (RP2D) of 2.3 mg/kg. Median duration of response (DoR) across all dose levels was 9.2 months (95%CI 5.6-NR). ORR for HER2-low patients was 42.9% (3/7). Plasma concentration and exposure (AUC) based on total ADC and total antibody increased dose proportionally at ≥1.0 mg/kg, with a T1/2 of 2.4-4.9 days. The incidence and magnitude of immunogenicity were low. While no MTD was determined, the 2.3mg/kg dose once in a 21-day cycle was selected as the RP2D based on safety, antitumor activity and PK data. Conclusions: FS-1502 was well-tolerated and demonstrated encouraging antitumor activity in both HER2-high and -low patients. Phase Ib and phase II clinical trials with FS-1502 are currently ongoing in various solid tumor indications including breast, gastric, and colorectal cancer. Citation Format: Qiao Li, Xian Wang, Ying Cheng, Yunjiang Liu, Jianhua Chang, Zhuo Wang, Chunjiao Wu, Mingxia Wang, Ai-Min Hui, Zhuli Wu, Yongli Jin, Xin Huang, Liping Zhong, Lei Diao, Han Zhao, Binghe Xu. FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-07.

First-in-human phase Ia study of the PI3Kα inhibitor CYH33 in patients with solid tumors

PIK3CA mutations are highly prevalent in solid tumors. Targeting phosphatidylinositol 3-kinase α is therefore an attractive strategy for treating cancers harboring PIK3CA mutations. Here, we report the results from a phase Ia, open label, dose-escalation and -expansion study (NCT03544905) of CYH33, a highly selective PI3Kα inhibitor, in advanced solid tumors. The primary outcomes were the safety, tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of CYH33. The secondary outcomes included evaluation of pharmacokinetics, preliminary efficacy and changes in pharmacodynamic biomarkers in response to CYH33 treatment. The exploratory outcome was the relationship between the efficacy of CYH33 treatment and tumor biomarker status, including PIK3CA mutations. A total of 51 patients (19 in the dose escalation stage and 32 in the dose expansion stage) including 36 (70.6%) patients (4 in the dose escalation stage and 32 in the dose expansion stage) with PIK3CA mutations received CYH33 1–60 mg. The MTD of CYH33 was 40 mg once daily, which was also selected as the RP2D. The most common grade 3/4 treatment-related adverse events were hyperglycemia, rash, platelet count decreased, peripheral edema, and fatigue. Forty-two out of 51 patients were evaluable for response, the confirmed objective response rate was 11.9% (5/42). Among 36 patients harboring PIK3CA mutations, 28 patients were evaluable for response, the confirmed objective response rate was 14.3% (4/28). In conclusion, CYH33 exhibits a manageable safety profile and preliminary anti-tumor efficacy in solid tumors harboring PIK3CA mutations.

Translational PK/PD Modeling of Tumor Growth Inhibition and Target Inhibition to Support Dose Range Selection of the LMP7 Inhibitor M3258 in Relapsed/Refractory Multiple Myeloma.

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome, a component of the cellular protein degradation machinery, highly expressed in malignant hematopoietic cells including multiple myeloma. Here we describe the fit-for-purpose pharmacokinetic (PK)/pharmacodynamic (PD)/efficacy modeling of M3258 based on preclinical data from several species. The inhibition of LMP7 activity (PD) and tumor growth (efficacy) were tested in human multiple myeloma xenografts in mice. PK and efficacy data were correlated yielding a free M3258 concentration of 45 nM for half-maximal tumor growth inhibition (KC50). As M3258 only weakly inhibits LMP7 in mouse cells, both in vitro and in vivo bridging studies were performed in rats, monkeys, and dogs for translational modeling. These data indicated that the PD response in human xenograft models was closely reflected in dog PBMCs. A PK/PD model was established, predicting a free IC50 value of 9 nM for M3258 in dogs in vivo, in close agreement with in vitro measurements. In parallel, the human PK parameters of M3258 were predicted by various approaches including in vitro extrapolation and allometric scaling. Using PK/PD/efficacy simulations, the efficacious dose range and corresponding PD response in human were predicted. Taken together, these efforts supported the design of a phase Ia study of M3258 in multiple myeloma patients (NCT04075721). At the lowest tested dose level, the predicted exposure matched well with the observed exposure while the duration of LMP7 inhibition was underpredicted by the model. SIGNIFICANCE STATEMENT: M3258 is a novel inhibitor of the immunoproteasome subunit LMP7. The human PK and human efficacious dose range of M3258 were predicted using in vitro-in vivo extrapolation and allometric scaling methods together with a fit-for-purpose PK/PD and efficacy model based on data from several species. A comparison with data from the Phase Ia clinical study showed that the human PK was accurately predicted, while the extent and duration of PD response were more pronounced than estimated.

459MO Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation

Advanced-stage tumors harboring a KRAS G12C mutation have limited treatment options. GDC-6036, a highly potent and selective KRAS G12C inhibitor, has shown robust tumor growth inhibition in multiple preclinical models of a variety of tumor types. As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), patients (pts) with KRAS G12C mutant other solid tumors (oST), exclusive of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) (NSCLC and CRC reported elsewhere), were administered GDC-6036 orally once a day in 21-day cycles until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). As of 28 Jan 2022, 14 pts with pretreated oST (4 cholangiocarcinoma, 3 pancreatic adenocarcinoma, and 1 each: anus, appendix, breast, duodenum, endometrial, lung neuroendocrine, and stomach cancers) had received GDC-6036 monotherapy at 400 mg. Median (range) number of prior cancer therapies was 2 (1-8). No dose-limiting toxicities were reported across NSCLC, CRC and oST. Median (range) time on study treatment was 63.5 (8-151) days among oST pts, and median GDC-6036 dose intensity was 99%. Five (36%) pts had discontinued study treatment (4 radiographic progression and 1 death due to disease progression). The most frequent GDC-6036-related AEs reported in ≥ 2 pts were nausea, vomiting, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased. Two (14%) pts required a dose modification (interruption, 1 pt; reduction, 1 pt; no withdrawal) for GDC-6036-related AEs. Across NSCLC, CRC and oST pts, the mean half-life for GDC-6036 ranged from 13-17 hours at doses of 50-400 mg. The unconfirmed overall response rate (ORR) in the oST pts was 21% (3/14 pts; anus, lung neuroendocrine and stomach cancers), while the confirmed ORR was 14% (2/14 pts). GDC-6036 demonstrated an acceptable safety profile, a PK profile compatible with once-daily dosing, and encouraging efficacy in pts with pretreated oST with a KRAS G12C mutation. Data from additional pts will be presented.

1402P Initial results of a cohort of advanced prostate cancer patients in a phase Ia study of NGM120, a first-in-class anti-GDNF family receptor alpha like (GFRAL) antibody

Elevated serum Growth Differentiation Factor 15 (GDF15) has been observed in pts with prostate cancer (PC) and correlated with poor survival. Effects of GDF15 on tumor progression, metastasis and immune escape may play a role. NGM120, a novel antibody that blocks the effects of GDF15 through its receptor, GFRAL, has resulted both in antitumor and anti-cachexia effects in experimental models. Here we report initial results of NGM120 monotherapy from a phase 1a study in pts with advanced PC.

362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation

The oncogenic KRAS G12C mutation is found in ∼4% CRC patients (pts). GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor, with robust tumor growth inhibition in multiple preclinical models.

A phase Ia/Ib study of CBP-1008, a bispecific ligand drug conjugate, in patients with advanced solid tumors.

3000 Background: Folate receptor α (FRα) and vanilloid subfamily member 6 of transient receptor potential channels (TRPV6) are overexpressed in many solid tumors hence could be promising therapeutic targets. CBP-1008 is a first-in-class bi-specific ligand drug targeting FRα and TRPV6 carrying monomethyl auristatin E (MMAE) as payload. Here we report the first-in-human, multicenter, phase Ia/Ib study designed to explore the safety, pharmacokinetics and efficacy of CBP-1008 in advanced solid tumors. Methods: CBP-1008 was administered by intravenous infusion. Phase Ia study included a dose-escalation period initiated by accelerated titration (0.015, 0.03mg/kg d1,15; q28d) and then switched to 3+3 scheme (0.12, 0.15, 0.17, 0.18mg/kg d1,15; q28d) and a dose expansion period. Phase Ib clinical expansion study included 3 cohorts, platinum-resistant ovarian cancer (OC), metastatic triple negative breast cancer (TNBC) and other solid tumors. The primary objective was to assess the safety and preliminary efficacy. Results: As of January 13, 2022, 106 patients received at least one dose of study drug were enrolled (phase Ia: n = 30; phase Ib: n = 76) and received median 3 prior regimens. Included tumor species were OC (n = 52), TNBC (n = 20), ER+/Her2+ breast cancer (BC) (n = 16), lung cancer (n = 3), pancreatic cancer (n = 2) and others (n = 13). In phase Ia study, DLTs were observed in 3 patients (0.12, 0.15, 0.18mg/kg, n = 1 each), including grade 4 hypophosphatemia, neutropenia, febrile neutropenia, and grade 3 hyperglycemia, alanine aminotransferase (ALT). MTD was not yet reached. Majority of adverse events were mild to moderate. The most common grade 3/4 treatment-emerging adverse events (TEAEs) were neutropenia (37.7%), AST elevation (6.6%), ALT elevation (5.7%), hyperglycemia (2.8%), hypohemoglobinemia (2.8%) and nausea (1.9%). Drug-related death was not observed. A total of 69 patients at dose of 0.15mg/kg or above were evaluable for efficacy assessment. There were 11 patients achieved partial response (PR) (OC n = 8, ER+/Her2+ BC n = 2, TNBC n = 1) and 30 patients achieved stable disease (SD). In 32 advanced platinum-resistant OC patients with FRα and/or TRPV6-positive expression, 6 PR and 16 SD were observed. Moreover, 6/18 PR (33.3%) and 8/18 SD (44.4%) were observed in enriched OC patients who showed high score of FRα/TRPV6 receptor. Conclusions: The preliminary results showed that CBP-1008 has manageable safety profile. Antitumor activity was observed in patients with FRα/TRPV6 receptor expression, especially in platinum-resistant OC cohort with high score of the two receptors. Clinical trial information: NCT04740398.

A phase Ia/Ib study evaluating the safety and efficacy of intratumorally administrated OH2, an oncolytic herpes simplex virus 2, in unresected stage IIIC to IV melanoma patients.

e21537 Background: OH2 is a herpes simplex virus type 2-derived oncolytic virus. It was engineered to selectively replicate within tumors and express granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance tumor-specific immune responses. We conducted a phase Ia/Ib clinical trial to evaluate the safety and preliminary efficacy in unresected stage IIIC to IV melanoma patients (pts). Methods: In this phase Ia/Ib trial, we enrolled pts aged between 18-75 with histologically confirmed unresectable stage III or distant metastatic melanoma failed with prior therapies. In phase Ia, nine pts were in the single-dose group, where 3 dose levels (106, 107, and 108 CCID50/mL) of OH2 were assessed. And six pts were in the multi-dose group testing multiple administration regimens. The recommended doses were then expanded in phase Ib. The primary objective was the safety and tolerability of OH2 injection as defined by the dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) in phase Ia. Antitumor activity was assessed per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and immune-RECIST in phase Ib. The clinical trial information: NCT04386967. Results: 35 pts were enrolled between November, 2018 and December, 2021. Among this, 37.1% were stageIVM1b-M1c; 88.6% had received of previous treatments: In the phase Ia study, OH2 was well-tolerated, neither serious AEs (SAEs) nor death were reported. No patient experienced TEAE leading to early withdrawal. Most TRAEs were Grade 1 in severity. There were no Grade 3 or above TRAEs. No DLTs were recorded, and the most frequent TRAEs were pyrexia (80%), Skin depigmentation (26.7), Oedema peripheral (26.7%), which were similar in three different doses of the single-dose group. The one-year survival rate was 93.3 % with median overall survival (mOS) being 20.8 months (still ongoing). In the phase Ib study, five pts achieved immune-partial response/partial response. The overall response rate (ORR) was 25.0 % and the five pts had ongoing responses. Six pts experienced stable disease (SD) with a disease control rate (DCR) being 55 %. The durable response rate (partial or complete response for ≥ 6 months) was 60 %. There were seven III-IV1a pts prior treated with anti-PD-1 antibodies. Three of the seven pts achieved iPR/PR (42.9 %), with DCR being 85.7 %. Conclusions: OH2 oncolytic virotherapy showed a favorable safety profile with no DLTs. And exhibited durable antitumor activity in pts. It warrants further investigation for the treatment of pts with unresectable melanoma. Clinical trial information: NCT04386967.