Bayesian Optimal Interval Research Articles

A Bayesian optimal interval design for dose optimization with a randomization scheme based on pharmacokinetics outcomes in oncology.

The primary objective of an oncology dose-finding trial for novel therapies, such as molecularly targeted agents and immune-oncology therapies, is to identify the optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. Pharmacokinetic (PK) information is considered an appropriate indicator for evaluating the level of drug intervention in humans from a pharmacological perspective. Several novel anticancer agents have been shown to have significant exposure-efficacy relationships, and some PK information has been considered an important predictor of efficacy. This paper proposes a Bayesian optimal interval design for dose optimization with a randomization scheme based on PK outcomes in oncology. A simulation study shows that the proposed design has advantages compared to the other designs in the percentage of correct OD selection and the average number of patients allocated to OD in various realistic settings.

TITE-gBOIN-ET: Time-to-event generalized Bayesian optimal interval design to accelerate dose-finding accounting for ordinal graded efficacy and toxicity outcomes.

One of the primary objectives of an oncology dose-finding trial for novel therapies, such as molecular-targeted agents and immune-oncology therapies, is to identify an optimal dose (OD) that is tolerable and therapeutically beneficial for subjects in subsequent clinical trials. These new therapeutic agents appear more likely to induce multiple low or moderate-grade toxicities than dose-limiting toxicities. Besides, for efficacy, evaluating the overall response and long-term stable disease in solid tumors and considering the difference between complete remission and partial remission in lymphoma are preferable. It is also essential to accelerate early-stage trials to shorten the entire period of drug development. However, it is often challenging to make real-time adaptive decisions due to late-onset outcomes, fast accrual rates, and differences in outcome evaluation periods for efficacy and toxicity. To solve the issues, we propose a time-to-event generalized Bayesian optimal interval design to accelerate dose finding, accounting for efficacy and toxicity grades. The new design named "TITE-gBOIN-ET" design is model-assisted and straightforward to implement in actual oncology dose-finding trials. Simulation studies show that the TITE-gBOIN-ET design significantly shortens the trial duration compared with the designs without sequential enrollment while having comparable or higher performance in the percentage of correct OD selection and the average number of patients allocated to the ODs across various realisticsettings.

A phase 1/2 open-label, multicenter, dose escalation and expansion study of AVB-001, an intraperitoneally administered, cell-generated, human IL-2 immunotherapy in patients with platinum-resistant, high-grade, serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube.

TPS5616 Background: The potential of cytokines as cancer therapeutics has been limited by short half-life and severe adverse effects associated with high systemic exposure when delivered intravenously. Many strategies are being explored to overcome these limitations. A locoregional delivery approach to achieve high sustained local concentrations in the tumor microenvironment with minimal systemic exposure could widen the therapeutic window. Early experience with free recombinant human IL2 (rhIL-2) given intraperitoneally (IP) showed meaningful clinical activity in relapsed ovarian cancer. Still, the cumbersome delivery procedure requiring indwelling catheters and need for high volume IP infusions leading to frequent complications and poor patient compliance limited the utility of this approach. To overcome these shortcomings, we developed a clinically translatable localized delivery LOCOcyte platform composed of polymer encapsulated allogeneic epithelial cells engineered to produce immune effector molecules for local delivery with temporal regulation. The first product, AVB-001, produces native hIL-2, for the treatment of ovarian cancer and other peritoneal malignancies. IP AVB-001 inhibited tumor growth and improved survival in an in vivo ID8 ovarian cancer murine model. Sustained IL-2 production with well tolerated high IP concentrations were achieved, with >100x differential concentration vs. systemic blood levels in both mice and non-human primates. Strong local and systemic immune activating effects, optimized T cell profile and immune memory were observed without concomitant increase of T regs. The first in human study of AVB-001 in patients with advanced ovarian cancer (NCT05538624) is described here. Methods: Part 1 dose escalation exploring 4 ascending dose levels (capsules target production of 0.6, 1.2, 2.4, and 3.6 ug hIL2/kg/d) with a Bayesian Optimal Interval 3+3 design, in patients with recurrent high grade serous adenocarcinoma of the ovary, primary peritoneum, or fallopian tube. A minimum of 12 and up to 24 patients will be enrolled to receive one dose of AVB-001 administered IP. The primary objective is to evaluate safety (Incidence and severity of adverse events per NCI CTCAE v5.0), tolerability, and feasibility of delivering AVB-001 IP, and establish the RP2D. Secondary objectives include assessment of antitumor activity (RECIST v1.1, iRECIST), pharmacokinetics, and pharmacodynamic correlates of immune activation. Part 2 will enroll 20 patients at the RP2D with efficacy as the primary objective. This multicenter study will be conducted at 5 sites, currently two sites are open. The first patient was dosed in December 2022. Recruitment in dose level 1 cohort continues. Clinical trial information: NCT05538624 .

Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors.

e17546 Background: ARTS-021 is an investigational, reversible, orally available CDK2 selective inhibitor that inhibits CDK2 at nanomolar potency and with over 600-fold selectivity against CDK1 (Liang J et al. AACR 2022). ARTS-021 has shown promising preclinical data, including strong single agent antitumor activity in CCNE1 amplified patient derived xenografts (PDX). Furthermore, consistent with the hypothesis that CDK2 activity may mediate resistance to CDK4/6 inhibitors, ARTS-021 significantly enhanced Palbociclib anti-tumor activity in an estrogen positive (ER+) breast cancer xenograft model. Taken together, these data support the clinical development of ARTS-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6 inhibitors in ER+ breast cancer. Methods: A first in human, open label, multicenter phase1/2 dose escalation and dose expansion study will be conducted to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and anti-tumor activity of ARTS-021 1) as a single agent in advanced or metastatic solid tumors harboring CCNE-1 gene amplification; 2) in combination with carboplatin to treat refractory/resistant CCNE-1 amplified ovarian cancer that has failed standard therapies; 3) in combination with endocrine therapy and CDK4/6 inhibitor to treat ER+/HER2- breast cancer patients have failed standard therapies. The phase 1 (dose-escalation) portion of the trial will have an accelerated dose escalation followed by a Bayesian Optimal Interval (BOIN) design. After the monotherapy recommended phase 2 dose (R2PD) is identified, the combination arms will be initiated at one dose level below the monotherapy R2PD. Phase1 primary endpoints are assessment of safety, tolerability, and pharmacokinetics (PK). The secondary endpoint is preliminary efficacy. Once the RP2D is defined for both monotherapy and in combination, the trial will be advanced into three Phase 2 expansion cohorts: monotherapy cohort (basket cohort), combination with carboplatin (ovarian cohort), and combination with endocrine therapy + CDK4/6 inhibitor (ER+ breast cancer cohort). The phase 2 primary end point is to estimate the anti-tumor efficacy in CCNE1 amplified cancer patients or CDK4/6 inhibitor resistant breast cancer patients. Objective tumor response rate will be measured per RECIST v1.1. The secondary endpoint of Phase 2 study will be safety/tolerability. Archival tumor and paired fresh tumor biopsy will be collected throughout the study for exploratory pharmacodynamics (PD) and biomarker evaluation. Results: ARTS-021 clinical study is ongoing. Conclusions: ARTS-021 shows potential anti-tumor activities.

Preliminary results from a first-in-human study of ESG401, a trophoblast cell-surface antigen 2 (TROP2) antibody drug conjugate (ADC), in patients with locally advanced/metastatic solid tumors.

1100 Background: ESG401 is an innovative ADC composed of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to topoisomerase I inhibitor SN-38 via a proprietary stable-cleavable linker with DAR of 8. Methods: Patients (pts) aged ≥18 years with locally advanced/metastatic solid tumors refractory to/relapsed from standard treatment with measurable disease (RECIST v1.1) were eligible. ESG401 is administered intravenously by designated dose and regimen until unacceptable toxicity or progressive disease. The Bayesian Optimal Interval (BOIN) design was used to establish the MTD. Results: As of Feb 3, 2023, 35 pts with a median age of 53 were treated with ≥1 dose of ESG401 during escalation at doses of 2-20 mg/kg once Q3W (Regimen A), or 12-16 mg/kg D1,8,15 in a 4-week cycle (Regimen B). 80% of pts were ECOG = 1, 63% of pts were 3L+; median 4 (2-10) prior lines, 94% of pts had visceral metas (11% brain, 63% liver, 60% lung) at baseline. Only one patient treated with 20 mg/kg experienced DLT. The MTD has not reached either regimen. The most common TRAEs were leukopenia (80%), neutropenia (69%), anemia (66%), fatigue (54%), nausea (51%), and vomiting (46%). The most common ≥ Grade 3 TRAEs were leukopenia (29%) and neutropenia (31%). There was no ≥ Grade 3 thrombocytopenia, diarrhea, skin rash, or oral mucositis. No Interstitial Lung Disease (ILD) was observed. Of 33 efficacy evaluable (EE) pts, 12 partial responses (PR) were observed and 4 pts had achieved SD ≥24 wks. The first dose level found PR (16 mg/kg Q3W) and afterward were taken as therapeutically relevant doses (TRD). The ORR and DCR were 36% (4/11) and 64% (7/11) in 11 TRD pts with TNBC, while 62% (8/13) and 77% (10/13) in 13 TRD pts with HR+/HER2-BC. Two pts with brain metas both got an obvious intracranial response (one pt whose intracranial lesion was significantly reduced to too small to measure). Until the cut-off date, 11 (31%) pts remained on treatment. Three pts were treated over 12 mons and the longest on-treatment duration was 12.9 mons. One pt had consistent PR up to 10.8 mons. Conclusions: The preliminary data demonstrated that ESG401 is safe and well-tolerated with promising signals of efficacy in heavily pretreated pts. These encouraging findings warrant further clinical evaluation. Clinical trial information: NCT04892342 . [Table: see text]

XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers.

TPS3154 Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. High B7-H4 expression has been observed in several cancers including breast, endometrial, and ovarian, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in preclinical models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In parallel with DES, optional backfill cohorts will enroll patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a selected dose level from DES and can be initiated at multiple dose levels simultaneously. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and assessment of antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996. Clinical trial information: NCT05377996 .

Phase 1 multicenter dose escalation and dose expansion study of antibody-drug conjugate (ADC) MYTX-011 in subjects with non-small cell lung cancer.

TPS9147 Background: cMET is a receptor tyrosine kinase and proto-oncogene whose activity is upregulated across a wide range of cancers. In NSCLC, expression of cMET is upregulated by DNA amplification (2% to 5%), exon 14 skipping mutations (2% to 4%), and overexpression (30% to 60%). In NSCLC, cMET upregulation has also been demonstrated to be a resistance mechanism for several approved EGFR-targeted kinase inhibitors, and this may limit their effectiveness. Despite the approval of MET tyrosine kinase inhibitors, almost half of patients do not respond to these inhibitors and resistance is inevitable. MYTX-011 is an ADC incorporating the clinically validated vcMMAE linker-payload conjugated to a novel, pH-dependent anti-cMET antibody. In preclinical studies, MYTX-011, compared to a surrogate of an advanced clinical stage cMET ADC, showed markedly higher ( > 3 fold) internalization and increased cytotoxicity in cMET+ tumor cells in vitro, which translates to greater (≥3 fold) efficacy in high or moderate c-Met+ xenograft models in vivo. PK and toxicity studies revealed that MYTX-011 exhibited favorable PK characteristics, and a toxicity profile similar to previously described MMAE-based ADCs. Methods: MYTX-011-01 (ClinicalTrials.gov Identifier: NCT05652868) is a first-in-human Phase 1 dose escalation and dose expansion study. MYTX-011 will be administered intravenously every 21 days for a maximum of 2 years. Part 1 (dose escalation) will assess the safety and tolerability of MYTX-011 in patients with advanced NSCLC and identify the recommended Phase 2 dose (RP2D). Part 2 (dose expansion) will include subjects with NSCLC with cMET overexpression or MET amplification/exon 14 skipping mutations. In Part 1, subjects will be enrolled to evaluate the safety of escalating doses of MYTX-011 as a single-agent and to establish the RP2D and/or MTD. The dose escalation scheme is based on a 3-subject cohort minimum Bayesian Optimal Interval (BOIN) design. The RP2D will be selected as a biologically active dose at or below the MTD (or the highest dose tested if an MTD is not identified during the study) and will be informed by safety, tolerability, pharmacokinetic data, and preliminary anti-tumor activity of MYTX-011 based on RECIST 1.1. Part 2 of the study will be initiated once the RP2D has been determined and will enroll subjects into different cohorts based on cMET IHC positivity cutoff and/or presence of MET genetic alterations ( MET amplification or exon 14 skipping). All cohorts are defined to explore preliminary antitumor activity in populations with different thresholds of cMET positivity that were selected based on data for cMET expression and efficacy observed with MYTX-011 in preclinical models, published data for responses to cMET targeting agents, and on the prevalence of subject tumors with different expression levels. Enrollment in the MYTX-011-01 study is ongoing. Clinical trial information: NCT05652868 .

Phase 1/2, first-in-child study of sonodynamic therapy (SDT) using low intensity focused ultrasound and 5-aminolevulinic acid (ALA) for patients with diffuse intrinsic pontine glioma.

TPS10070 Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with poor prognosis. Sonodynamic therapy (SDT) with ALA is a non-invasive strategy that sensitizes target tissues with a non-toxic chemical agent followed by exposure to low intensity MR-guided focused ultrasound (MRgFUS). Preclinical studies have shown that ALA is preferentially taken up by glioma cells and metabolized to protoporphyrin IX (PpIX). SDT activates protoporphyrin IX and induces tumor cell death via photodynamic effect (lipoperoxidation, apoptosis). Suheiro et al and Wu et al demonstrated that SDT killed tumors via apoptosis and lipoperoxidation in rodent glioma models with minimal damage to surrounding normal brain.1,2 ALA SDT was well-tolerated in an ongoing first-in-human trial in adults with recurrent high-grade gliomas and demonstrated biomarker evidence of the photodynamic effect3. Methods: A Phase 1/2, multicenter, open label study (NCT05123534) is enrolling patients at Children’s National Hospital. The study employs the Bayesian optimal interval (BOIN) algorithm to evaluate safety and tolerability of treatment with SDT in newly diagnosed DIPG subjects to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of MRgFUS energy in combination with ALA. The study will evaluate 3 ALA doses and 3 acoustic energy doses. ALA is administered IV six to nine hours prior to MRgFUS with the Exablate type-2 device. The first cohort, B1C1, evaluates the lowest drug-device dose combination and if no dose-limiting toxicity (DLT) is encountered after 3 patients, ascending dose-escalation will proceed to the second cohort, B2C1, treated with lowest dose of ALA with the second level of MRgFUS energy. Again, if no DLT is experienced, the next cohort will receive a higher dose combination. The initial patient in each cohort is treated in 2 sessions 21 to 28 days apart, each covering one-half of the pons. Subsequent patients are treated in 1 session to the whole pons. The primary objective is to evaluate the safety and tolerability of SDT in DIPG subjects. Secondary outcomes include preliminary efficacy assessments, pharmacokinetics of ALA and PpIX, mechanical performance of the Exablate Type-2 device, and radiographic evidence of tumor physiological changes associated with SDT. All patients at least 5 years of age with newly diagnosed, radiographically typical DIPG between 4-24 weeks after completion of standard radiotherapy are eligible for the trial. Patients with evidence of disease progression, diagnosis of porphyria, or prior or concurrent therapy with any other anticancer or investigational intervention will be excluded. Cohort 1 has been completed without DLT.

Phase 1/2 study of tiragolumab and atezolizumab in patients with relapsed or refractory SMARCB1 or SMARCA4 deficient tumors.

TPS10066 Background: The SMARCB1/A4 gene products are core subunits of the SWItch/Sucrose Non-fermentable (SWI/SNF) chromatin remodeling complex. Tumors with defects in SWI/SNF are histologically distinct aggressive cancers occurring in children and young adults. SMARCB1/A4 deficient tumors, particularly rhabdoid tumors, poorly differentiated chordoma, epithelioid sarcoma, and medullary renal cell carcinoma, have immune cell infiltrates and programmed death ligand 1 (PD-L1) expression. Response to immune checkpoint inhibition (CI) has been observed in SMARCB1/A4 deficient tumors; however, responses are not durable. T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel inhibitory receptor expressed on multiple immune cells. TIGIT inhibits T and NK cells by binding to its ligand poliovirus receptor (PVR) and Nectin2 on tumor cells and antigen-presenting cells. Utilizing RNAseq data, SMARCB1/A4 deficient tumors demonstrate high expression of PVR and Nectin2. Tiragolumab is an antibody to the TIGIT receptor. In patients with non-small cell lung cancer, tiragolumab with atezolizumab increased survival compared to atezolizumab alone. Thus, data suggest that SMARCB1/A4 deficient tumors are susceptible to CI; however, monotherapy is unlikely to achieve durable responses; the addition of tiragolumab may enhance response rates. Methods: This is a phase 1/2 trial of tiragolumab monotherapy and in combination with atezolizumab in patients ≥ 12 months of age with SMARCB1/A4 deficient tumors administered IV on Day 1 of 21-day cycles. Part A will evaluate the safety of tiragolumab monotherapy (300 mg if ≤ 15 kg; 420 mg if >15 to ≤ 40 kg; 600 mg if > 40 kg or ≥ 18 yrs) based on cycle 1 DLTs in up to 6 evaluable patients <18 yrs of age. Part B will estimate the antitumor activity of tiragolumab in combination with atezolizumab (15 mg/kg [max 1200 mg]) if < 18 yrs or 1200 mg if ≥ 18 yrs) in 6 histology-specific cohorts (renal medullary carcinoma, malignant rhabdoid tumor, atypical teratoid rhabdoid tumor, poorly differentiated carcinoma, epithelioid sarcoma, and other) Each cohort will be conducted using a 6+4 Simon’s two stage design. Up to 13 patients may enroll in each cohort allowing for inevaluable patients (maximum n=78). Enrollment of patients ≥ 18 yrs on Part B may occur concurrently with enrollment of patients < 18 yrs on Part A. If the pediatric dose of tiragolumab is deemed safe, patients <18 yrs old may be enrolled on Part B. Cycle 1 toxicities of the combination therapy will be monitored in Part B using a Bayesian Optimal Interval Design in patients < 12 yrs of age. The secondary objectives are to characterize pharmacokinetics/anti-drug antibody and estimating progression free survival, overall survival, and duration of response. Enrollment is open for all Pediatric Early Phase Clinical Trial Network sites. Clinical trial information: NCT05286801 .

A phase 1/2 dose escalation study of the BCL-2 inhibitor ZN-d5 and the WEE1 inhibitor azenosertib (ZN-c3) in patients (Pts) with acute myeloid leukemia (AML).

TPS7077 Background: B-cell lymphoma 2 (BCL-2) is an anti-apoptotic protein and pathway inhibition combined with chemotherapy and/or targeted therapeutics has led to significant clinical benefit in pts with AML. Disruption of cell cycle regulation may complement BCL-2 inhibition as many malignant cells are dependent on proteins that regulate cell cycle progression. The cell cycle checkpoint protein, WEE1, is highly expressed in genomically unstable malignancies and inhibition of WEE1 induces tumor cell apoptosis. It has been previously reported that the combination of ZN-d5 (an oral, selective BCL-2 inhibitor) and azenosertib (an oral, highly potent WEE1 inhibitor) synergistically enhance killing of AML cells both in vitro and in vivo, as well as in TP53-mutated models (Izadi, AACR 2022). Based on this strong pre-clinical rationale, a Phase 1/2 study was designed to evaluate the novel combination of ZN-d5 and azenosertib in pts with relapsed/refractory (R/R) AML. Methods: This phase 1/2 open-label study (ZN-d5-004C, NCT05682170) is determining the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and clinical activity of ZN-d5 + azenosertib in pts with AML. The phase 1 dose-escalation stage is based on a Bayesian Optimal Interval design. Phase 2 is an open-label expansion to be conducted if supported by safety and efficacy data from the dose-escalation stage. Prior to initiating dose-escalation for the ZN-d5 + azenosertib combination, an azenosertib monotherapy cohort is being enrolled, as it has not been previously administered to pts with hematologic malignancies. For the dose-escalation azenosertib monotherapy (n≈15) and ZN-d5 combination (n≈40) cohorts, pts must have relapsed/refractory (R/R) disease after ≥1 line of AML therapy that may include the BCL-2 inhibitor, venetoclax. In phase 1, an azenosertib monotherapy cohort will be opened prior to investigation of ZN-d5 + azenosertib in combination. In phase 2, ZN-d5 + azenosertib will be given at the RP2D. Alternative dosing schedules may also be investigated based on emerging clinical data. The primary endpoints are adverse events and dose-limiting toxicities. Secondary endpoints include the rate and duration of remission according to the European LeukemiaNet 2017 criteria, including complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), stable disease, progressive disease, relapse after remission (including molecular relapse), remission rate (CR + CRi), overall response rate (CR + CRi + MLFS + PR), and rate of and time to relapse. Pts will remain on study until disease progression, failure to respond, remission if additional therapy is clinically indicated, withdrawal of consent, loss to follow-up, or death. Clinical trial information: NCT05682170 .

Phase 1 study to determine the safety and efficacy of onvansertib, a novel, oral, PLK1 inhibitor in patients with proliferative chronic myelomonocytic leukemia relapsed/refractory or intolerant to available therapies.

TPS7089 Background: Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN) that can be further divided into MD (WBC < 13 x 109/L) and MP (≥13 x 109/L) subtypes. MP-CMML is enriched in RAS pathway mutations ( NRAS, CBL, KRAS, PTPN11 and NF1), has a shorter median survival (19 vs 36 months), has a higher rate of acute myeloid leukemia (AML) transformation (40% vs 10%) and has a unique transcriptomic and epigenetic composition. These RAS pathway mutations promote selective PLK1 overexpression, a mitotic checkpoint kinase. Given the relative inefficacy of hypomethylating agents (HMA) in MP-CMML and previously demonstrated in vitro and in vivo efficacy data for PLK1 inhibition on MP-CMML with RAS pathway mutations, we designed a phase 1 clinical trial testing the safety of onvansertib, a novel, orally bioavailable, PLK1 inhibitor in relapsed/refractory MP-CMML. Methods: This is an investigator-initiated, prospective, open-label, phase I study of onvansertib in MP-CMML relapsed/refractory (RR) or intolerant to existing therapies including HMA and hydroxyurea. The primary endpoint is characterization of safety. Secondary endpoints include efficacy as defined by the 2015 MDS/MPN International Working Group criteria, volumetric spleen response and symptom response via assessment with MPN-SAF-TSS. Inclusion criteria include MP-CMML RR following hydroxyurea or at least 4-cycles of HMA or intolerance of treatment with either, platelets ≥ 20,000/m3 and Cockcroft-Gault creatinine clearance ≥ 60 mL/min/m2. Hydroxyurea may continue for the first 28 days on study. Onvansertib will be given orally on days 1 through 21 of a 28-day cycle with a Bayesian optimal interval design to assess the safety and recommended phase II dose. Exploratory end points include targeting efficacy, impact of PLK1 and KMT2A expression and interactions with ASXL1 and TET2 mutations. Twenty-five patients will be enrolled at Mayo Clinic in Minnesota, with enrollment open since November 2022. Clinical trial information: NCT05549661 .

ACTION-1 phase Ib/3 trial of RYZ101 in somatostatin receptor subtype 2–expressing (SSTR2+) gastroenteropancreatic neuroendocrine tumors (GEP-NET) progressing after 177Lu somatostatin analogue (SSA) therapy: Initial safety analysis.

4132 Background: RYZ101 (225Ac-DOTATATE) is a first-in-class, highly potent alpha-emitting radiopharmaceutical in development for treating SSTR2+ solid tumors. Alpha-particles (as emitted by 225Ac) have a shorter path length (40–100 μm) and higher linear energy transfer (80–100 keV/μm) than beta-particles, causing more frequent double-strand DNA breaks and potentially higher cancer cell kill rates and less damage to healthy tissues. ACTION-1 (NCT05477576) is a 2-part, global, randomized, controlled, open-label, phase 1b/3 trial of RYZ101 in patients (pts) with advanced well-differentiated SSTR+ GEP-NETs progressing after 177Lu-SSA therapy. Part 1 (phase 1b) aims to determine safety, pharmacokinetics, and recommended phase 3 dose (RP3D) of RYZ101. Methods: Part 1 is an uncontrolled dose de-escalation study with a Bayesian optimal interval design. Escalation (0.197) and de-escalation (0.298) boundaries based on a target dose-limiting toxicity (DLT) rate of 25% were applied. Pts received RYZ101 IV every 8w for up to 4 cycles. Planned dose levels (n=6/level): Level 0 (starting dose), 120 kBq/kg (3.2 µCi/kg); if necessary, Level –1, 90 kBq/kg (2.4 µCi/kg); Level –2, 60 kBq/kg (1.6 µCi/kg). No dose escalation above starting dose was permitted. DLT was assessed for 56d after the first RYZ101 treatment. Treatment-emergent adverse events (TEAEs) were graded by NCI-CTCAE v5.0. Dose de-escalation decisions and safety data review were overseen by a Data Review Committee. Data cut-off: 26 Oct 2022. Results: At data cut-off, 9 pts had received RYZ101 at 120 kBq/kg (median dose 8.9 MBq); 7 pts were DLT-evaluable. No DLTs occurred and no dose de-escalation steps were implemented. Baseline characteristics: median age 70y; male (n=6)/female (n=3); ECOG PS 0 (n=4)/1 (n=5); median disease duration 6.9y; primary tumor site GI (n=6)/pancreas (n=3). A safety summary is shown. No treatment-related serious AEs were observed. TEAE requiring dose reductions occurred in 2 pts (Grade 2 platelet count decreased, n=1; Grade 2 thrombocytopenia, n=1). Grade 3 or 4 TEAEs occurred in 3 pts (lymphocyte count decreased, n=2; skin infection, n=1; weight decreased, n=1). One serious adverse event (skin infection) was unrelated to treatment. Conclusions: RYZ101 was well tolerated at 120 kBq/kg, which was declared the RP3D. Part 2 (Phase 3) will commence after Part 1 and will compare RYZ101 at the RP3D with standard of care in pts with advanced SSTR2+ GEP-NETs with disease progression following prior 177Lu-labeled SSAs. Clinical trial information: NCT05477576 . [Table: see text]

Updated dose escalation results for ReFocus, a first-in-human study of highly selective FGFR2 inhibitor RLY-4008 in cholangiocarcinoma and other solid tumors.

4009 Background: Oncogenic FGFR2 alterations (fusions/rearrangements (f/r), amplifications, mutations) represent a broad therapeutic opportunity as they drive multiple solid tumors, particularly cholangiocarcinoma (CCA). However, off-isoform toxicity and on-target resistance limit the benefit of approved pan-FGFR inhibitors (FGFRi). RLY-4008 is the first potent, highly selective, oral FGFR2 inhibitor designed to overcome these limitations by targeting FGFR2 driver alterations and resistance mutations. Here, we present updated dose escalation results from ReFocus (NCT04526106), a seamless Phase I/II, open label study evaluating the safety and preliminary efficacy of RLY-4008 in patients (pts) with advanced, FGFR2-altered solid tumors. Methods: Adult pts received RLY-4008 BID, QD, QD discontinuous on a 4-week (wk) cycle following a Bayesian Optimal Interval design. Treatment-related adverse events (TRAEs), PK, ctDNA and anti-tumor activity (RECIST v1.1) were assessed. Results: As of 30 Jan 23, 116 pts (82 f/r, 27 mutation, 6 amplification) received RLY-4008 at doses of 20-200 mg/day, including 91 with CCA. 50% had prior FGFRi, and median lines of prior therapies was 3 (1-15). 28/46 ct-DNA-evaluable pts with CCA with prior FGFRi had ≥1 baseline resistance mutation, most commonly at FGFR2 N549X (23/46) or V564X (17/46). RLY-4008 had favorable PK with doses ≥40 mg QD providing FGFR2 occupancy ≥90%. 70 mg QD was the RP2D based on PK, safety, anti-tumor activity and exposure-dependent tumor regressions in FGFRi-naïve CCA f/r pts. Anti-tumor activity was observed in CCA and solid tumors across doses and FGFR2 alterations with radiographic tumor reductions in 74 (64%), SD/PR in 83 (72%), including 4/4 (100%) FGFRi-naïve CCA f/r pts at RP2D achieving confirmed PR. Clinically meaningful disease control and durable responses were observed in pts with FGFR2 f/r CCA. Overall, median treatment duration was 24 wks (range <1-108 wks). 105 pts discontinued (PD (81%), AE (3%), other (7%)). Across doses, most common TRAEs were low-grade PPE (57%), stomatitis (56%), dry mouth (38%), alopecia (28%), and dry eye (22%). No grade 4/5 TRAEs were observed. Conclusions: These encouraging dose escalation data confirm the broad therapeutic potential of highly selective FGFR2 targeting with RLY-4008 by demonstrating encouraging initial efficacy across FGFR2-altered solid tumors and genomic alterations, with a differentiated safety profile that avoids FGFR1- and FGFR4-related toxicity. Phase 2 of ReFocus continues across solid tumors and with registrational intent in FGFRi-naïve, FGFR2 f/r CCA. Clinical trial information: NCT04526106 . [Table: see text]

Phase 1b/2 trial of pepinemab plus avelumab as second line combination immunotherapy for patients with metastatic pancreatic adenocarcinoma.

TPS4195 Background: Monotherapy with immune checkpoint inhibitors (ICIs) is not effective in metastatic pancreatic adenocarcinoma (PDAC), likely due to the unique immunosuppressive tumor microenvironment (TME) of PDAC, thus safe and novel strategies to overcome resistance and facilitate adaptive immune responses are a major unmet need. Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumoral infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs without increasing toxicity. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC (NCT03268057). Pepinemab is also being evaluated in combo with pembrolizumab in patients with metastatic squamous cell carcinoma of the head and neck (NCT04815720). The principal goals of this proof-of-concept study are to investigate the safety, efficacy, and TME biomarker changes of treatment with the combo of pepinemab plus avelumab in patients with metastatic PDAC. Methods: This single-arm, open-label study (NCT05102721) is evaluating the safety, tolerability, and efficacy of pepinemab in combo with avelumab in patients diagnosed with metastatic PDAC who have either progressed on or are otherwise intolerant to first line chemotherapy. Patients must have received 5FU or gemcitabine-based first line therapy with evidence of intolerance or treatment failure, including progression both during or after completing first-line treatment. Accrual for the Phase 1b portion follows a Bayesian Optimal Interval Design (BOIN), beginning at the highest dose combo; 20 mg/kg pepinemab and 800 mg avelumab Q2W. Phase 2 begins after 16 subjects are enrolled at MTD, permitting a Simon’s two stage assessment of futility prior to closing the Phase 1b period. The primary objective for Phase 1b is tolerability, and the primary objective for Phase 2 is therapeutic efficacy compared to historical second-line systemic chemotherapy. The trial anticipates a total evaluable cohort of 40 subjects and is powered to detect a response rate of 23% or greater, with alpha set at 0.1 and 80% power. Exploratory objectives include robust correlative analysis of immune, stromal, and genomic profiling of baseline and on-treatment tumor biopsies to ascertain mechanisms of treatment response and failure. Patient reported outcomes are incorporated throughout the trial to assess disease specific symptoms associated with pancreatic cancer and cancer cachexia. One patient has been enrolled as of Feb 14, 2023. Clinical trial information: NCT05102721 .

A phase 1, open-label, first-in-human study of TAS2940 in patients with advanced solid tumors.

TPS3165 Background: Aberrant expression and signaling of the ERBB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), has a role in the pathogenesis of solid tumors such as breast cancer (BC), non–small cell lung cancer (NSCLC), and glioblastoma (GBM). Although therapies that target HER2 are effective in early and advanced HER2-overexpressing BC, many patients develop resistance despite tumor dependence on HER2 at the time of progression. Approximately 4% of patients with NSCLC have HER2 mutations, mostly presenting as exon 20 insertions (ex20ins); however, approved HER2/EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy in patients with NSCLC and HER2 ex20ins. Many patients with NSCLC or BC develop brain metastases, and EGFR alterations, including EGFRvIII mutations, are common in GBM. There is therefore a need for a brain-penetrable TKI with activity against tumors harboring HER2/EGFR alterations. TAS2940 is a potent, selective, and orally bioavailable pan-ERBB inhibitor that has shown promising preclinical efficacy against cancers with a variety of HER2/EGFR mutations and amplifications. Further, TAS2940 inhibited tumor growth and induced tumor regression in a dose-dependent manner in nude mice intracranially implanted with NCI-N87, a HER2-overexpressing human gastric cancer cell line. Methods: TAS2940-101 (NCT04982926) is an open-label, phase 1, first-in-human trial to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TAS2940 in patients with advanced solid tumors and HER2/ EGFR aberrations. Eligible patients are aged ≥18 years, have non-measurable (Part 1) or measurable (Part 1 and 2) disease per RECIST 1.1 or RANO criteria, ECOG performance status 0/1, and adequate organ function. Patients with non-stable brain metastases are excluded. Part 1 (dose escalation) will use a Bayesian optimal interval design with a starting dose of 15 mg/kg orally QD (planned dose levels: 15, 30, 60, 120, 240 and 480 mg). Once the recommended phase 2 dose is determined, Part 2 (dose expansion) will enroll patients with NSCLC (Cohort A), HER2+ BC (Cohort B), recurrent/refractory GBM (Cohort C), or other solid tumors with EGFR/ HER2 aberrations (Cohort D). The primary objectives are the maximum tolerated dose of TAS2940 in Part 1 and antitumor activity in Part 2. Secondary objectives include antitumor activity in Part 1. The safety and PK profile of TAS2940 will be assessed in both parts. Approximately 142 patients will be enrolled, comprising ~42 in Part 1 and ~100 in Part 2. As of January 24, 2023, 15 patients have been enrolled. No dose-limiting toxicities have been reported with dose escalation up to 240 mg QD. Recruitment is ongoing. Clinical trial information: NCT04982926 .

A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer.

e17532 Background: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this single-center Phase I trial, time-to-event Bayesian Optimal Interval Design (TITE-BOIN) was used. The starting dose for docetaxel was 60 mg/m2, with escalation in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The target dose-limiting toxicity (DLT) rate was 25%, and the total sample size was 30 patients. HIPEC was delivered immediately following the debulking surgery using the closed technique with a target temperature of 43 ℃ for 90 minutes. Results: A total of 30 patients were enrolled from August 2022 to November 2022. Among patients who received a docetaxel dose level ≤ 65 mg/m2, no DLT was reported. DLTs were observed in one patient at 70mg/m2 docetaxel (grade 3 anemia) and three patients at 75mg/m2 docetaxel (one grade 3 anemia, one grade 3 hepatic impairment and one grade 4 thrombocytopenia). When patients were treated with docetaxel at a dose of 75 mg/m2 in combination with 75 mg/m2 cisplatin, the estimated DLT rate was 25% which was closest to the target DLT rate and therefore selected as the MTD. Conclusions: For ovarian cancer patients who receive HIPEC following debulking surgery, docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be safely used at intraperitoneal doses of 75 mg/m2(ClinicalTrials.gov identifier, NCT05410483).

BLU-222, an oral, potent, and selective CDK2 inhibitor, in patients with advanced solid tumors: Phase 1 monotherapy dose escalation.

3095 Background: Cell growth regulation and proliferation is dependent on cyclins and CDKs. Cyclin E1 ( CCNE1) is a cell cycle regulator that activates CDK2. A broad range of aggressive cancers overexpress cyclin E and/or harbor CCNE1 gene amplifications. Inhibition or loss of CDK2 impairs the growth of CCNE1-amplified cell lines and cyclin E overexpression represents one of several CDK4/6 inhibitor resistance mechanisms, including in hormone receptor–positive/human epidermal growth factor receptor-2–negative (HR+/HER2−) breast cancer, making CDK2 inhibition a promising novel therapeutic approach. BLU-222 is an investigational, oral, potent, and selective CDK2 inhibitor in early clinical development with best-in-class potential. Methods: VELA (NCT05252416) is an international, open-label, phase 1/2 study evaluating the safety, PK, pharmacodynamics, and efficacy of BLU-222. In monotherapy dose-escalation, adult patients (pts) enrolled regardless of CCNE1 status, but CCNE1 amplification or progression after a CDK4/6 inhibitor were of specific interest. Pts with ECOG PS 0–2 and confirmed nonresectable tumors who had progressed following standard of care for advanced relapsed/recurrent disease were enrolled. BLU-222 was administered BID in continuous 28-day cycles, with dose escalation employing a Bayesian Optimal Interval design to identify the maximum tolerated dose. Blood samples were collected for PK and circulating biomarker analysis. Results: By Jan 29, 2023, 27 pts were enrolled in 6 escalating BID dose cohorts and included in the safety population. Median age was 64 y (range, 29–85); 85% were female. The most frequent cancer types were breast (44%, 12/27), endometrial (15%, 4/27), ovarian (11%, 3/27), and prostate (11%, 3/27). No pts discontinued treatment due to AEs. The most common (≥15%) AEs (all-cause AE; treatment-related AE) were nausea (33%; 26%), vomiting (22%; 11%), anemia (22%; 19%), diarrhea (22%; 22%), and fatigue (18%; 15%). Transient visual AEs (including blurred vision, photophobia, vision change) were seen in 5 pts (19%). These visual symptoms were mild except in 1 pt with Grade (Gr) 3 blurred vision/photophobia; all had fully resolved by/after the data cut-off. There were 2 dose limiting toxicities reported at the 2 highest dose levels: nausea (Gr 3; n=1) and blurred vision/photophobia (Gr 3; n=1). Translational pharmacodynamic data has shown early evidence of pathway modulation. One partial response was seen in a pt with HR+/HER2− metastatic breast cancer previously treated with 5 lines of therapy, including palbociclib, abemaciclib, and capecitabine. Conclusions: As of the cutoff date, BLU-222 monotherapy was generally well tolerated in pts at the BID doses tested. Dose escalation is ongoing to determine the recommended phase 2 dose. Preliminary evidence of cell cycle pathway modulation and clinical activity have been observed. Clinical trial information: NCT05252416 .

BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study.

9011 Background: Despite improved frontline OSI treatment outcomes, patients (pts) with advanced EGFRm NSCLC inevitably progress, with worse outcomes in the EGFR L858R subgroup (median PFS of 14.4 vs 21.4 mo in pts with exon 19 deletions). BLU-945 is an investigational, next-generation, oral tyrosine kinase inhibitor (TKI) that targets common EGFR-activating and T790M and C797X resistance mutations, while being selective against EGFR wild type (WT). Preclinically, BLU-945 in combination (combo) with OSI had enhanced potency on L858R and extended antitumor response durability versus OSI alone. SYMPHONY (NCT04862780) is an ongoing first-in-human phase 1/2 study of BLU-945 monotherapy (mono) or combo with OSI. Methods: In the phase 1 dose escalation, pts (aged ≥18 y; metastatic EGFRm NSCLC; ECOG PS 0–1; treated with ≥1 EGFR TKI) received BLU-945 mono starting at 25 mg QD. Pts progressing on OSI could receive BLU-945 with 80 mg OSI starting at 50% of the highest safe BLU-945 mono dose. Each dose escalation followed a Bayesian Optimal Interval design. Safety, including dose-limiting toxicities (DLT), PK, and circulating tumor DNA (ctDNA) mutational status were assessed. Results: As of Jan 6, 2023, 108 pts received BLU-945 mono (25–600 mg QD; 100–300 mg BID). Pts had a median of 3 lines of prior therapy and were genomically complex with ctDNA detectable EGFR on-target and/or off-target resistance alterations (46%) at baseline. DLTs included alanine transaminase (ALT) and aspartate transaminase (AST) elevation, hepatic cytolysis, fatigue, nausea, vomiting, and hyponatremia, occurring at doses of ≥400 mg/d. The maximum tolerated dose was 500 mg/d. The most common AEs were nausea (42%), headache (40%), increased ALT (38%), increased AST (37%), and vomiting (32%). Robust on-target EGFR activity was observed with ctDNA reduction on day 15 in 90%, 85% and 70% of EGFR T790M, C797S, and L858R alleles at ≥400 mg/d doses, respectively. At ≥400 mg/d, 48% had tumor shrinkage, including partial responses (PRs). Twenty-five pts received BLU-945 (200–400 mg QD; 100–200 mg BID) combo with OSI. Pts had a median of 2 lines of prior therapy. The most common combo AEs were fatigue (36%), diarrhea (32%), headache (32%), and nausea (28%). Other EGFR WT AEs were dry skin (20%) and rash (8%). One DLT (Grade 4 pneumonitis) was reported in the BLU-945 300 mg QD with OSI group. Tumor reductions, including PRs in 2 pts progressing on OSI, were observed at ≥300 mg/d. Dose escalation is ongoing. Conclusions: BLU-945 mono and combo with OSI were generally well tolerated and showed robust on-target EGFR ctDNA reduction, with tumor shrinkage in genomically heterogeneous, heavily pretreated pts. Combo showed responses at BLU-945 doses lower than in mono, consistent with additive benefit. The combo safety profile and on-target activity provide rationale for further development in front line. Clinical trial information: NCT04862780 .

A phase I trial of dose-adjusted EPOCH plus inotuzumab ozogamicin (InO) in adults with relapsed/refractory (R/R) B lymphoblastic leukemia/lymphoma (B-ALL).

7007 Background: Outcomes for adults with R/R B-ALL remain poor, with existing options limited by efficacy and safety. InO has been combined with low-intensity chemotherapy, the benefit of which is unclear. DA-EPOCH is safe and active as frontline therapy in adults with ALL, so we combined this with InO in adults with R/R B-ALL (NCT03991884). Aims: The primary objective was to estimate the maximum tolerated dose (MTD) of InO when added to DA-EPOCH. Methods: Eligible patients (pts) were adults with R/R CD22+ B-ALL with ≥5% blood or marrow (BM) blasts or ≥1 site of measurable extramedullary disease (EMD); other eligibility criteria included ECOG ≤2 and no history of sinusoidal obstructive syndrome (SOS) or chronic liver disease. DA-EPOCH was given on days (d) 1-5 with GCSF. After cycle 1, dose adjustments to EPOCH were made based on hematologic nadirs from the prior cycle. Three dose levels (DL) of InO were studied, with InO given on d 8 + 15 as follows (respectively): 0.3 + 0.3 mg/m2 (DL1); 0.6 + 0.3 mg/m2 (DL2); and 0.6 + 0.6 mg/m2 (DL3). Up to 4 28-d cycles were given. The MTD was the highest DL of InO that yielded ≤33% rate of dose limiting toxicity (DLT), defined as grade 4+ non-heme treatment-related adverse events (TRAEs), any SOS regardless of timing, unable to complete 1 cycle due to TRAE, and treatment delays > 3 weeks. After the first 5 pts received DL1, a Bayesian Optimal Interval Design was used. Target accrual was 24 pts. BM and EMD response was assessed by NCCN criteria, with measurable residual disease (MRD) evaluated by multiparameter flow cytometry (MFC) and clonoSEQ. Results: 24 pts were screened: all were enrolled and evaluable for DLT and response. Median age was 46 (range: 28-76) years; median prior lines of therapy was 3 (range: 1-16); 13 pts (54%) had previously received allograft (HCT). 5 pts were enrolled at DL1, 8 pts at DL2, and 11 pts at DL3. There were 4 total DLTs: 1 at DL1 (grade 4 sepsis) and 3 at DL3 (grade 4 hyponatremia; delay for pancytopenia; grade 5 SOS after post-study HCT). DL3 was thus determined to be the MTD. No deaths occurred on study. Three pts (12%) had Grade 3 AST/ALT elevation; the SOS rate was 4%. Other grade 3+ non-heme TRAEs seen in >1 pt included infections (6 pts; 9 events), neutropenic fever (7; 8), and oral mucositis (3; 4). In the pts with ≥5% blood/BM blasts (n=20), the CR/CRi rate was 85%. By MFC, 70% achieved MRD- (45% after 1 cycle); using clonoSEQ, 33% were MRD-. Of the 6 pts with EMD, 83% responded (4 CR; 1 PR). The per-protocol and intent-to-treat (ITT) overall response rate was 83%. With median follow-up of 12 months (m), the median overall and relapse-free survival were 19 m and 12 m. Nine (38%) pts received post-study HCT. Conclusions: The addition of InO to DA-EPOCH in adults with heavily-pretreated R/R B-ALL is safe, with ITT response rates among the highest reported to date. Many pts proceeded to HCT. Further investigation of this combination is warranted. Clinical trial information: NCT03991884 .

A phase 1, first-in-human, open label, escalation and expansion study of ORM-5029, a highly potent GSPT1 degrader targeting HER2, in patients with HER2-expressing advanced solid tumors.

TPS1114 Background: Targeted protein degradation (TPD) molecules have expanded the therapeutic options through their catalytic mechanism of action (MOA) and ability to degrade “undruggable” proteins. To increase the efficacy versus tolerability window of protein degradation and improve drug delivery, ORM-5029 uses a Dual-Precision TPD (TPD2) approach combining the catalytic mechanism of TPDs with the precision of tumor-targeting therapeutic antibodies. ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody. HER2 is overexpressed in cancers such as breast, ovarian and gastric, and associated with early-onset aggressive disease. ORM-5029 is in development for treatment of HER2-expressing solid tumors. The MOA is mediated by targeted uptake of the ADC, release of the TPD payload, and cell death by GSPT1 degradation. ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models. Methods: This phase 1 first-in-human study evaluates the safety, tolerability, and efficacy of ORM-5029 administered by intravenous infusion in patients (pts) with HER2-expressing advanced solid tumors (NCT05511844). The escalation, guided by the Bayesian Optimal Interval design, explores cohorts of ORM-5029 to identify the maximum tolerated dose (MTD) and/or expansion dose level (EDL). Each cohort will enroll ≥3 breast cancer pts with at least HER2 1+ (HER2 low) or greater by immunohistochemistry or positive by in situ hybridization. Expansion cohort A (HER2+ breast cancer) may enroll in parallel to escalation evaluating doses showing pharmacodynamic activity or efficacy. Up to 10 pts may be enrolled at each dose explored in cohort A. Enrollment into expansion cohort B (up to 21 pts) and cohort C (up to 22 pts) will begin once the EDL has been determined to further assess the safety, tolerability and efficacy of ORM-5029 using a Simon’s optimal 2-stage design. Cohort B will enroll pts with HER2+ breast cancer refractory or intolerant to standard treatment after ≥2 HER2 therapies in the metastatic setting. Cohort C will enroll pts with advanced solid tumors that are refractory or intolerable to standard treatment or for which no standard treatment is available, including HER2+ gastric or gastroesophageal junction adenocarcinoma or tumors with HER2 expression, amplification or mutations (e.g., colorectal, bile duct, ovarian, bladder, non-small cell lung). Study enrollment began in October 2022 in the United States. Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844 .