Endpoint In Part Research Articles

Safety and antiviral effect of a triple combination of HIV-1 broadly neutralizing antibodies: a phase 1/2a trial.

Human immunodeficiency virus type 1 (HIV-1)-specific broadly neutralizing monoclonal antibodies (bNAbs) have to date shown transient viral suppression when administered as monotherapy or as a cocktail of two antibodies1-4. A combination of three bNAbs provides improved neutralization coverage of global viruses, which may more potently suppress viral escape and rebound5-7. Here we performed an open-label, two-part study evaluating a single intravenous dose of HIV-1 bNAbs, PGT121, PGDM1400 and VRC07-523LS, in six adults without HIV in part 1 and a multicenter trial of up to six monthly infusions of these three bNAbs in 12 people living with HIV with an antiretroviral therapy (ART) interruption in part 2. The primary endpoints were safety, tolerability and pharmacokinetics, and the secondary endpoints in part 2 were antiviral activity following ART discontinuation, changes in CD4+ T cell counts and development of HIV-1 sequence mutations associated with bNAb resistance. The trial met its prespecified endpoints. The bNAb treatment was generally safe and well tolerated. In part 2, 83% of participants (10 of 12) maintained virologic suppression for the duration of antibody therapy for at least 28 weeks, and 42% of participants (5 of 12) showed virologic suppression for at least 38-44 weeks, despite the decline of serum bNAb concentrations to low or undetectable levels. In exploratory analyses, early viral rebound in two individuals correlated with baseline resistance to PGT121 and PGDM1400, whereas long-term virologic control in five individuals correlated with reduced immune activation, T cell exhaustion and proinflammatory signaling following bNAb therapy. Our data show the potential of a triple bNAb cocktail to suppress HIV-1 in the absence of ART. ClinicalTrials.gov registration: NCT03721510 .

REZILIENT3: Phase 3 study of zipalertinib plus chemotherapy in patients with previously untreated, advanced nonsquamous non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertions (ex20ins) mutations.

TPS219 Background: Despite recent advances, tolerable and effective treatments for patients with NSCLC harboring EGFR ex20ins mutations are needed, particularly in the first-line setting where platinum-based chemotherapy remains the standard of care. Zipalertinib (CLN-081/TAS6417), an oral tyrosine kinase inhibitor (TKI) of EGFR with broad activity against EGFR mutations, showed encouraging antitumor activity in heavily pretreated patients with EGFR ex20ins–mutant NSCLC, leading to ‘Breakthrough Therapy’ designation by the U.S. Food and Drug Administration in January 2022. Data suggest that combining EGFR TKIs with chemotherapy can improve antitumor efficacy versus chemotherapy or TKI treatment alone in patients with EGFR-mutated nonsquamous NSCLC. REZILIENT3 is a pivotal phase 3 study designed to compare the efficacy and safety of zipalertinib plus first-line standard-of-care platinum-based chemotherapy versus chemotherapy alone in previously untreated patients with nonsquamous NSCLC harboring EGFR ex20ins mutations. Methods: This randomized, controlled, open-label, phase 3 study (NCT05973773) will be conducted in two parts. Part A (safety lead-in) will confirm the safety of zipalertinib 100 mg twice daily as the recommended dose in combination with chemotherapy in patients with locally advanced or metastatic nonsquamous NSCLC harboring EGFR ex20ins mutations or other uncommon single/compound EGFR mutations. In Part B (randomized part), patients with EGFR ex20ins mutations and at least one measurable lesion (per Response Evaluation Criteria in Solid Tumours, version 1.1) will be randomized 1:1 to zipalertinib plus chemotherapy or chemotherapy alone, stratified by Eastern Cooperative Oncology Group performance status (0/1), brain metastases (yes/no), and geography (Asia/rest of world). Zipalertinib will be administered orally at a starting dose of 100 mg twice daily (pending confirmation in Part A). Chemotherapy (pemetrexed 500 mg/m² plus cisplatin 75 mg/m² or carboplatin area under the curve 5 mg/mL/min) will be administered intravenously on Day 1 of each cycle (carboplatin/cisplatin for four cycles). Patients randomized to chemotherapy alone will be allowed to cross over to zipalertinib monotherapy after documented progressive disease. The primary endpoint in Part B is progression-free survival assessed by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, objective response rate, duration of response, disease control rate, safety, intracranial efficacy endpoints, and quality of life. Part A is anticipated to enroll between 6 and 12 patients, while Part B is estimated to enroll approximately 260 patients. Enrollment started in June 2023. Clinical trial information: NCT05973773 .

Cotadutide promotes glycogenolysis in people with overweight or obesity diagnosed with type 2 diabetes

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994.

Will Survival Improve By Treating Multiple Myeloma Patients at MRD Relapse? the Remnant Study

Background: Although many new treatment options have become available, multiple myeloma (MM) is still considered an incurable disease. The importance of achieving minimal residual disease (MRD) negativity in MM patients has become clearer in recent years. Multiple studies show that bone marrow based MRD assessment is one of the strongest prognostic factors, and deeper responses correlate with more favorable outcomes. The REMNANT study will evaluate if treating at MRD relapse after first line (1.L) treatment prolongs progression-free survival (PFS) and overall survival (OS) in MM patients. Methods: The REMNANT study (RElapse from Mrd Negativity As iNdication for Treatment) is an academic, multicenter, open-label, randomized phase 2/3 study of newly diagnosed (ND) MM patients eligible for autologous stem cell transplant (ASCT). The study has a population-based approach with few exclusion criteria, implying that patients with kidney failure, amyloidosis, plasma cell leukemia and other comorbidities are enrolled. To increase enrollment in part 2, patients who have received 1.L treatment outside the REMNANT study can be enrolled directly if they are >CR/MRD negative. 391 NDMM patients (age 18-75 years) eligible for ASCT will be enrolled in part 1 (phase 2) of the study and receive standard of care Norwegian 1.L treatment; 4 pre-transplant induction and 4 post-transplant consolidation cycles of bortezomib, lenalidomide and dexamethasone (VRd). After induction, patients will undergo tandem or single transplant, depending on toxicity and response to first transplant. All patients receive lenalidomide maintenance. Following 1.L treatment 176 patients achieving MRD negative (Euroflow NGF 10 -5) complete response will be enrolled in part 2 (phase 3) of the study. Patients will be randomized in a 1:1 ratio to receive second line treatment (2.L) at MRD relapse in arm A or at PD in arm B. At loss of MRD negativity in arm A or at PD in arm B, 2.L treatment will be daratumumab, carfilzomib and dexamethasone until PD. The primary endpoint of part 1 (phase 2) of the study is the number of patients who achieve MRD negative (Euroflow NGF 10 -5) complete response 30-45 days post consolidation. Secondary endpoints includes response rates, safety evaluations and patient-reported outcome. The co- primary endpoints in part 2 (phase 3) are PSF and OS from randomization to progressive disease or death on 2.L treatment. We will also compare different methods for measuring MRD: NGF Euroflow, Next Generation Sequencing, mass spectrometry and PET-CT. We want to evaluate how the different methods compare when it comes to sensitivity and outcome (PFS and OS). Results: As of July 18 th 2023, 291 patients are enrolled in part 1 and 97 in part 2 (23 directly enrolled). Baseline characteristics, safety summary and preliminary results can be found in Table 1. The ORR on first line treatment is 95% and 65 of 152 patients (45%) were >CR and MRD negative at the post-consolidation visit. Patients achieving > VGPR but not CR MRD negativity post consolidation are followed for up to 24 months on lenalidomide maintenance, and 11 of 74 patients (15%) in follow-up have converted to >CR/MRD negativity at a median time of seven months (range 2-16). Nine patients have started 2.L treatment in part 2 (phase 3), eight in arm A (MRD guided) and one in arm B (control arm). Median time to loss of MRD negativity among the eight patients in arm A was four months (range 1-6). The most common adverse events were infections, occurring in 24% of patients (any grade). During 1.L treatment, 61 patients have left the study. Seven patients have died, 27 discontinued due to disease progression, 12 patients have withdrawn from the study and seven discontinued due to adverse events. 59% of the patients who progressed during 1. L treatment had high-risk cytogenetics (with gain1q and/or del17p and/or t(4;14)). Conclusion: Standard of care Norwegian first line treatment has an ORR of 95%. The MRD negativity rate among patients who have finished 1.L treatment was 43% (65 of 152). The median time to loss of MRD negativity in arm A (MRD guided) was 4 months.

Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1)

Background and Significance Smoldering multiple myeloma (SMM) is an asymptomatic clonal plasma cell disorder that precedes the development of multiple myeloma (MM). Traditionally, patients with SMM have undergone observation until progression to MM, but this paradigm can result in poor outcomes for some patients. Phase 3 clinical trials have demonstrated that early treatment with lenalidomide with or without dexamethasone can delay the development of end-organ damage and improve overall survival among SMM patients with high-risk features. Linvoseltamab (REGN5458) is a fully human B-cell maturation antigen (BCMA)×CD3 bispecific antibody that targets BCMA on plasma cells and CD3 on T cells, resulting in targeted T-cell-mediated cytotoxicity. In the Phase 1/2 LINKER-MM1 study, linvoseltamab alone induced deep and durable responses with a generally manageable safety profile in patients with relapsed/refractory MM (Lee et al. EHA. 2023). These data highlight the potential of novel immunotherapies with promising single-agent activity to be attractive therapeutics for early intervention to prevent progression to MM. Study Design and Methods LINKER-SMM1 is an open-label, Phase 2 study (NCT05955508) designed to evaluate the safety and efficacy of linvoseltamab monotherapy in adult participants with SMM who are at a high risk of progression to MM. High-risk criteria include having both ≥95% clonal plasma cells in the bone marrow (BM) and immunoparesis and/or ≥2 of the following: serum M-protein >2 g/dL, free light chain ratio >20, and BM plasma cells >20%. Participants must have a confirmed diagnosis of SMM within 5 years of enrollment, Eastern Cooperative Oncology Group performance status ≤1, and adequate organ function to be eligible. Participants will be excluded from enrollment if they have myeloma-defining events, uncontrolled infection, history of allogeneic stem cell transplantation, or received prior treatment for SMM. The study will take place at approximately 15 sites in Spain and will include two parts: Part 1 (safety run-in) to evaluate the preliminary safety and tolerability of linvoseltamab and Part 2 (expansion) to evaluate the clinical activity of the selected dosing regimen. In Part 1, at least 6 participants will receive linvoseltamab starting with a step-up schedule before reaching the full dose. All subsequent treatment with full-dose linvoseltamab will be given over 28-day cycles until completion of 24 cycles or occurrence of a protocol-defined reason for discontinuation. Assuming that initial safety is shown to be acceptable, an additional 34 participants will be enrolled in Part 2 according to the dosing regimen established in Part 1. Post-treatment safety monitoring will continue for up to 90 days after the last dose of linvoseltamab, and participants with an ongoing response will continue routine efficacy assessments until confirmed biochemical progression, start of non-protocol cancer therapy, or death. Long-term follow-up will continue for up to 5 years after the last dose of linvoseltamab. The primary endpoints in Part 1 are frequency of adverse events (AEs) of special interest, including grade ≥2 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, and frequency and severity of treatment-emergent AEs. In Part 2, the primary endpoints are complete response (assessed by International Myeloma Working Group criteria) and minimal residual disease (MRD) negativity (10 -5 sensitivity) after 12 and 24 months of treatment. Secondary endpoints include cumulative safety, overall response rate, duration of response, sustained MRD negativity, biochemical and clinical progression-free survival (PFS), time to myeloma-defining event, time to initiation of first-line treatment for MM, and overall survival as well as immunogenicity and serum concentration of linvoseltamab over time. Exploratory endpoints include PFS after the start of first-line treatment for MM, adequacy of stem cell collection, patient-reported outcomes, and various biomarker changes. As this is a proof-of-concept study, results will be analyzed using descriptive statistics and no formal hypothesis testing is planned. Study accrual is planned to begin in Q4 2023.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial

Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

A Phase 2b, Randomised, Double-blind, Placebo-controlled, Parallel-arm, Multicenter Study Evaluating the Safety and Efficacy of Tesnatilimab in Patients with Moderately to Severely Active Crohn's Disease.

Tesnatilimab, a monoclonal antibody targeting NKG2D, was evaluated in Crohn's disease [CD] patients who had failed or were intolerant to biologic or conventional therapy. TRIDENT was a phase 2b, two-part, randomised, double-blind, placebo-controlled, parallel-arm, multicenter study. In Part 1 [proof of concept], 145 patients who were biologic intolerant or refractory [Bio-IR] or had not failed biologic therapy [Bio-NF] were randomised in a 1:1 ratio to placebo subcutaneously [SC] or tesnatilimab 400 mg SC. In Part 2 [dose ranging], 243 Bio-IR and Bio-NF patients were randomised in a 1:1:1:1:1 ratio to placebo, tesnatilimab [50 mg, 150 mg, 400 mg], or intravenous infusion of ustekinumab ~6 mg/kg at Week 0 and 90 mg SC at Weeks 8 and 16. The primary endpoint was mean change from baseline in Crohn's Disease Activity Index [CDAI] at Week 8 [Part 1] and Week 12 [Part 2]. Clinical and endoscopic remission/response were evaluated. Efficacy analyses were also assessed by NKG2D and MICB single nucleotide polymorphism [SNP] status [SNP-positive means positive in at least one of two SNPs]. Safety events were summarised. In Part 1, mean change from baseline in CDAI score was significantly greater with tesnatilimab vs placebo at Week 8 [-103.6 vs -60.0; p < 0.01]. In Part 2, no dose-response signal was detected. Mean changes from baseline in CDAI at Week 12 were -93.2, -72.2, and -84.3 for low, middle, and high doses of tesnatilimab, respectively, vs -59.2 for placebo and -148.8 for ustekinumab. Similar reductions from baseline in CDAI score were observed in patients receiving tesnatilimab, regardless of SNP status. Clinical remission rates were greater with tesnatilimab than placebo in Parts 1 and 2, whereas endoscopic response rates were greater with tesnatilimab only in Part 1. No unexpected safety events occurred. Tesnatilimab was well tolerated. The efficacy of tesnatilimab in patients with CD was significant for the primary endpoint in Part 1; however, no dose-response signal was detected for the primary endpoint in Part 2. Based on these inconsistent findings, tesnatilimab was not considered an effective treatment for patients with CD and no further development is planned. NCT02877134.

Trials in progress: A phase 1, open-label, pharmacokinetic, safety and tolerability study of PF-07265807 (selective TAM kinase inhibitor) alone or with sasanlimab in patients with advanced or metastatic solid tumors.

TPS270 Background: Inhibition of Mer Proto-oncogene tyrosine kinase (MERTK) and AXL may lower the threshold for immune activation thereby promoting anti-tumor activity. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the tumor-associated macrophage kinases MERTK and AXL. In preclinical models, PF-07265807 plus anti-programmed cell death protein 1 (anti-PD-1) antibodies show antitumor activity that results in long-term cures and resistance to tumor re-challenge. Sasanlimab is a monoclonal antibody to PD-1 administered subcutaneously (300 mg every 4 wk or equivalent); it has an acceptable safety profile and is being tested in a Phase 3 trial in non-muscle invasive bladder cancer. This first-in-human study will evaluate safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of PF-07265807 alone and with sasanlimab in patients (pts) with selected advanced or metastatic solid tumors. Study design of PF-07265807 monotherapy dose escalation (Part 1) was presented at ASCO 2021 (TPS2671). Here, we describe dose escalation (Part 2) and dose expansion (Part 4) cohorts for the doublet combination of PF-07265807 + sasanlimab. Methods: This is a Phase 1, open-label, multi-center study (NCT04458259) of PF-07265807. Adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy will enroll into doublet therapy dose escalation (Part 2). Pts who are anti-PD-1/PD-L1 treatment naïve with intermediate tumor mutational burden (defined as ≥6 and &lt; 16 microsatellite stable) colorectal cancer (CRC) or PD-L1+ (defined as combined positive score ≥1) gastric cancer will enroll into doublet therapy dose expansion cohorts (Part 4). Other key eligibility criteria: measurable or non-measurable disease by RECIST 1.1; ECOG PS 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Each cycle will be 21 days. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The doublet maximum tolerated dose (MTD) will be guided by a Bayesian analysis of dose limiting toxicity (DLT) data for doublet therapy (Part 2). The recommended phase 2 dose (RP2D) will then be determined via holistic data review with/without the MTD identification. Primary endpoints in Part 2 include the incidence of DLTs, adverse events and laboratory abnormalities. After doublet MTD/RP2D is identified in Part 2, the preliminary anti-tumor activity of PF-07265807 + sasanlimab will be explored in Part 4. Primary endpoints in Part 4 include objective response and complete response rates; secondary endpoints include disease control rate and response duration, adverse events and laboratory abnormalities. The study began in Q4 2020 and is recruiting pts. Clinical trial information: NCT04458259 .

ALL-269 Safety and Pharmacokinetics of Calaspargase Pegol in Adults With Newly Diagnosed Philadelphia-Negative Acute Lymphoblastic Leukemia: A Phase 2/3 Study

Asparaginase remains an important component in many adult regimens for acute lymphoblastic leukemia (ALL). In pediatric patients (<21 years), calaspargase pegol (Cal-PEG) provides sustained asparagine depletion as compared to pegaspargase, with similar rates of complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS), with a similar safety profile. To confirm the recommended dose of Cal-PEG in adults (age ≥22 years) and to establish safety and PK/PD analysis. Multicenter, phase 2/3 study (NCT04817761) assessing safety and anti-leukemic activity of Cal-PEG. Part 1 enrollment commenced in Q3 2021 and will establish the safety of Cal-PEG in four groups: patients aged 22-39, 40-54, and ≥55, and patients with an elevated BMI >35 kg/m2. A minimum of 4 (initial cohort) and ~8 patients will be enrolled per group. The study will be conducted in ≤25 investigational centers in the US. Part 2 will comprise expansion cohorts after verifying safety and PK/PD analysis. Newly diagnosed patients with Philadelphia-negative B- or T-cell ALL ≥22 years with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis, or severe hepatic impairment. Approximately 114-122 patients are expected to be enrolled in the study, including 16-32 patients in Part 1. Starting doses of Cal-PEG will be based on the patients' age and BMI, with older patient groups assigned to lower doses. Patients aged≥22-39 and 40-<55 will receive Cal-PEG 2000 and 1500 U/m2, respectively. Patients with BMI >35 kg/m2 and those aged ≥55 will receive 1000 U/m2. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403, with an end-of-treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. The primary endpoints in part 1 are the safety of Cal-PEG, the incidence of pre-defined unacceptable toxicities within 30 days after the induction dose and achieving plasma asparaginase activity ≥0.1 U/mL 21 days after the consolidation day 43 dose. Secondary endpoints include immunogenicity, CR, end-of-induction and consolidation MRD, 1-, 2- and 3-year EFS, disease-free survival, and OS.

MagnetisMM-5: An open-label, multicenter, randomized phase 3 study of elranatamab as monotherapy and in combination with daratumumab in patients with relapsed/refractory multiple myeloma.

TPS8074 Background: Elranatamab (PF-06863135) is a humanized bispecific antibody that targets both B cell maturation antigen (BCMA)-expressing multiple myeloma (MM) cells and CD3-expressing T cells, with binding resulting in T cell-mediated cytotoxicity. Elranatamab has demonstrated antitumor activity and delayed tumor progression in preclinical studies, as well as promising efficacy and manageable safety in the ongoing phase 1 MagnetisMM-1 study in patients (pts) with relapsed/refractory MM (Bahlis et al, J Clin Oncol 2021). Methods: MagnetisMM-5 is an open-label, multicenter, randomized phase 3 study designed to evaluate the efficacy and safety of subcutaneous (SC) elranatamab monotherapy and SC elranatamab + SC daratumumab in pts with relapsed/refractory MM who have received prior therapy, including lenalidomide and a proteasome inhibitor (PI). The study consists of 2 parts. In part 1, a minimum of 20 pts will be enrolled to assess the safety of an elranatamab priming regimen and identify the recommended combination dose for SC elranatamab + SC daratumumab for part 2. The primary endpoint of part 1 is dose-limiting toxicities encompassing the elranatamab monotherapy priming duration (14 d) and the first cycle of SC elranatamab + SC daratumumab dosing (28 d). In part 2, ̃450 pts will be stratified by prior lines of therapy (1 vs 2–3 vs ≥4) and prior treatment with anti-CD38 therapy (yes vs no) and enrolled in a 1:1:1 ratio to receive SC elranatamab or SC elranatamab + SC daratumumab or SC daratumumab + oral pomalidomide + oral dexamethasone. The primary endpoint of part 2 is progression-free survival (PFS), according to International Myeloma Working Group (IMWG) response criteria and blinded independent review. Secondary endpoints include PFS and PFS on next-line treatment by investigator per IMWG, overall survival, objective response rate, duration of response, complete response (CR) rate, duration of CR, time to response, overall and sustained minimal residual disease negativity rates, safety, quality of life, immunogenicity, and PK. Key inclusion criteria are age ≥18 y, MM diagnosis with measurable disease according to IMWG criteria, ECOG performance status 0–2, and clinical laboratory values within specified ranges. For part 2, pts should have received ≥1 prior line of anti-myeloma therapy, including treatment with lenalidomide and a PI. Key exclusion criteria include smoldering MM, plasma cell leukemia, amyloidosis, POEMS syndrome, stem cell transplant within 12 wk of enrollment, primary refractory MM, active, uncontrolled bacterial, fungal, or viral infections, previous treatment with BCMA-targeted therapy, anti-CD38 therapy within 6 mo of the first dose of study treatment, and previous pomalidomide therapy. MagnestisMM-5 will include sites in 28 countries. Clinical trial information: NCT05020236.

A two-part, phase II, multi-center study of the ERK inhibitor ulixertinib (BVD-523) for patients with advanced malignancies harboring MEK or atypical BRAF alterations (BVD-523-ABC).

TPS3172 Background: Ulixertinib (BVD-523) is a small molecule inhibitor of extracellular signal-regulated kinases 1/2 (ERK1/2) in development as a novel anti-cancer drug. Early clinical data demonstrated anti-tumor activity, especially for patients with tumors harboring atypical BRAF or MEK1/2 alterations (Sullivan et al., Cancer Discov. 2018;8(2):184-195). Atypical BRAF (non-V600) alterations can be categorized according to characteristics of molecular signaling (Class II or III), are seen in approximately 3% of all human cancers, and there are currently no approved therapies for this indication. Similar to atypical BRAF alterations, the incidence of MEK1/2 alterations are rare in human tumors (&lt; 1 %). Preclinical data have demonstrated activity of ulixertinib in MEK mutant models. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, with specific BRAF mutations (G469A, L485W, or L597Q). Designed with intent to register, the BVD-523-ABC clinical trial will continue evaluation of ulixertinib in patients with tumors harboring any atypical BRAF or MEK1/2 alteration (NCT04488003). Methods: This multi-center, phase II study, will be conducted in two parts and assess the clinical benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib in patients with advanced malignancies. Ulixertinib will be administered at the RP2D of 600 mg BID for 28-day treatment cycles. Eligible patients will have locally advanced or metastatic cancer which progressed following standard systemic therapies, or for which the patient is not a candidate or refused systemic therapy. Planned correlative analyses include reverse phase protein array and transcriptomics of tumor tissue. Part A is open-label and tumor agnostic, except for group 4 and 6 (CRC patients only). Patients will enroll into one of six groups based on BRAF (groups 1-4) or MEK1/2 (groups 5-6) tumor alteration (38 patients per group). Overall response rate (ORR) is the primary endpoint for Part A, with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Part B is tumor histology specific. Patients will be randomized to receive either ulixertinib or physician's choice of treatment in a 2:1 ratio. Up to three specified tumor histologies will be defined, guided by available Part A data (n = 80-100 per histology). The primary endpoint of Part B is PFS, and secondary endpoints include OS, ORR, and DOR. This study has enrolled 43 patients of the planned 228 in Part A at the time of abstract submission. Clinical trial information: NCT04488003.

Comparison between adalimumab introduction and methotrexate dose escalation in patients with inadequately controlled psoriatic arthritis (CONTROL): a randomised, open-label, two-part, phase 4 study.

Many patients with psoriatic arthritis do not reach minimal disease activity (MDA) on methotrexate alone. This phase 4 open-label study aimed to compare attainment of MDA following introduction of adalimumab with methotrexate escalation in patients with psoriatic arthritis who do not reach MDA after an initial methotrexate course (≤15 mg every week). CONTROL was a phase 4, randomised, two-part, open-label study conducted in 14 countries and 46 sites. We recruited patients with confirmed active psoriatic arthritis, naive to biologic disease-modifying antirheumatic drugs, with an inadequate response to 15 mg or less of methotrexate. In part 1, patients were randomly assigned (1:1) to receive either methotrexate 15 mg (oral or subcutaneous) every week with the addition of adalimumab 40 mg (subcutaneously) every other week (adalimumab plus methotrexate group) or methotrexate (oral or subcutaneous) escalation up to 25 mg every week (escalated methotrexate group). Randomisation was done using Interactive Response Technology and stratified by the duration of methotrexate treatment (≤3 months and >3 months). In this open-label study there was no masking; participants, people giving the interventions, those assessing outcomes, and those analysing the data were aware of group assignment. The primary endpoint was the proportion of patients who reached MDA at 16 weeks. After 16 weeks (part 2), patients who reached MDA (responders) had their current therapy maintained or modified, wheras patients who did not reach MDA (non-responders) had their therapy escalated until 32 weeks. The primary endpoint in part 2 was the proportion of patients who reached MDA at 32 weeks, analysed in all patients who received one or more doses of study drug. The study is registered with ClinicalTrials.gov, NCT02814175. Between Aug 5, 2016, and March 19, 2020, 245 of 287 patients initially assessed were enrolled in the study (50% men and 50% women; 92% of patients were White). 123 patients were randomly assigned to receive adalimumab plus methotrexate and 122 patients to receive escalated methotrexate. All 245 patients were included in the primary analysis, and 227 completed part 1 and entered part 2. A significantly higher proportion of patients reached MDA at 16 weeks in the adalimumab plus methotrexate group (51 [41%] patients) compared with the escalated methotrexate group (16 [13%] patients; p<0·0001). Efficacy was generally maintained through 32 weeks for patients who reached MDA at 16 weeks, with 41 (80%) of 51 adalimumab responders and ten (67%) of 15 methotrexate responders maintaining MDA at 32 weeks. Of adalimumab non-responders, 17 (30%) of 57 patients reached MDA at 32 weeks after adalimumab escalation to every week dosing. Among methotrexate non-responders, 50 (55%) of 91 reached MDA after adalimumab introduction. In part 1, two patients in the adalimumab plus methotrexate group reported serious adverse events; and in part 2, one adalimumab responder, three adalimumab non-responders, and three methotrexate non-responders reported serious adverse events. No new safety signals were identified. Results from this novel treatment-strategy trial support the addition of adalimumab over escalating methotrexate in patients with psoriatic arthritis not reaching MDA after an initial methotrexate course. Safety results were consistent with the therapies' known safety profiles. AbbVie.

PIVOT IO 011: A phase 1/2 study of bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab (NIVO) and tyrosine kinase inhibitor (TKI) versus NIVO and TKI alone in patients (pts) with previously untreated advanced or metastatic renal cell carcinoma (mRCC).

TPS403 Background: The current standard of care for advanced RCC (aRCC) utilizes immune checkpoint inhibitors (ICIs) and targeted agents. Novel combinations of these agents, such as NIVO + TKIs, have demonstrated clinical benefit over TKI monotherapy. In CheckMate 9ER, NIVO + cabozantinib (CABO) in aRCC demonstrated clinically meaningful efficacy results and a favorable safety profile, and was FDA approved (01/2021). High-dose interleukin-2 (IL-2) was used historically for durable responses in mRCC but had unfavorable toxicity with complex inpatient treatment regimens. BEMPEG, an immunostimulatory IL-2 cytokine prodrug, is engineered to deliver a controlled, sustained, and preferential signal to the clinically validated IL-2 pathway. Preferential binding of BEMPEG to the IL-2 heterodimeric receptor (IL-2Rβγ) activates and expands CD8+ T cells and NK cells over immunosuppressive Tregs. In the phase 1/2 PIVOT-02 study, BEMPEG + NIVO displayed encouraging antitumor activity in pts with mRCC, with a tolerable safety profile. The clinical activity and the manageable, non-overlapping toxicity profiles of the individual agents in this combination warrants exploration of triplet regimens in previously untreated aRCC. Methods: PIVOT IO 011 (NCT04540705) is a 2-part, phase 1/2, randomized, open-label study assessing the safety and efficacy of BEMPEG + NIVO + TKI triplet in pts with untreated aRCC or mRCC. In Part 1, pts will receive BEMPEG + NIVO + TKI (Part 1A: axitinib [AXI] or Part 1B: CABO; n≈6–24 pts in each TKI arm). While BEMPEG + NIVO dosing will remain consistent across phases, each TKI will have 2 doses evaluated in Part 1, and results will determine the recommended phase 2 dose for AXI/CABO in Part 2. In Part 2, pts will be randomized 1:1 to receive either BEMPEG + NIVO + CABO or NIVO + CABO (N≈250), stratified by IMDC prognostic score and prior nephrectomy status. If the CABO triplet has an unacceptable toxicity profile, Part 2 may be amended to use the AXI triplet. Key inclusion criteria: aRCC or mRCC with clear cell component; no prior systemic therapy for RCC, except 1 prior adjuvant/neoadjuvant therapy for completely resectable RCC (must have included an anti–VEGF agent with recurrence ≥6 months after last dose); and Karnofsky PS ≥70%. Key exclusion criteria: active CNS brain/leptomeningeal metastases; active, known, or suspected autoimmune disease; and inadequately treated adrenal insufficiency. Primary endpoints in Part 1: dose-limiting toxicities and safety; and in Part 2: overall response rate per RECIST v1.1 by investigator. Secondary endpoints in Part 2: progression-free survival, overall survival, safety. Duration of BEMPEG + NIVO will be ≤2 years, and treatment with TKI will continue until disease progression. The study is currently recruiting. Clinical trial information: NCT04540705.

Abstract OT2-11-02: Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer

Abstract Background Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. Amcenestrant, as monotherapy or in combination with palbociclib, has shown antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. Published data support the addition of targeted therapy to endocrine therapy for patients with ER+/HER2- advanced breast cancer. The objective of Arm 4 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 4 investigates dose escalation (Part H) and dose expansion (Part I), of amcenestrant in combination with everolimus. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 4 (Parts H and I), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Patients must have progressed on a non-steroidal aromatase inhibitor plus cyclin-dependent kinase 4/6 inhibitor as first-line therapy for advanced disease. Prior treatment with fulvestrant or any other SERD is not allowed. Part H allows ≤ 1 prior chemotherapy for advanced disease; no prior chemotherapy for advanced disease is allowed in Part I. Exclusion criteria in Arm 4 include prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; history of severe cutaneous reactions; type 1 diabetes; uncontrolled type 2 diabetes; uncontrolled hypercholesterolemia, hypertriglyceridemia, and hyperglycemia; any uncontrolled infection; uncontrolled stomatitis, angioedema due to angiotensin-converting enzyme inhibitors, and impaired wounds. Part H evaluates the selected amcenestrant dose for combination therapy plus everolimus 10 mg once daily (QD) (the approved standard dose) or everolimus 5 mg QD, taken in 28-day cycles. Additional amcenestrant doses may be explored based on safety and pharmacokinetics (PK). The objective of Part H is to determine the recommended dose (RD) of everolimus in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part H is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of everolimus in combination with amcenestrant in Part H. In Part I, approximately 12 patients will be treated at the RD of everolimus for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Patrick Neven, Katarina Petrakova, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Valentina Boni. Ameera-1 Arm 4: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with everolimus in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-02.

Abstract OT2-11-04: Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer

Abstract Background Endocrine therapy in combination with a targeted cyclin-dependent kinase (CDK) 4/6 inhibitor is the clinical standard for treatment of ER+/HER2- advanced breast cancer. Amcenestrant (SAR439859) is an optimized oral SERD with potent dual activity that antagonizes and degrades the ER, resulting in inhibition of the ER signaling pathway. In previous arms of the AMEERA-1 study, amcenestrant, as monotherapy or in combination with the CDK4/6 inhibitor palbociclib, demonstrated antitumor activity and a favorable safety profile in postmenopausal women with heavily pretreated ER+/HER2- advanced breast cancer. The objective of Arm 5 of the AMEERA-1 study is to evaluate safety and antitumor activity of amcenestrant in combination with the CDK4/6 inhibitor abemaciclib for patients with ER+/HER2- advanced breast cancer. Methods AMEERA-1 (NCT03284957) is an open-label, non-comparative, dose escalation and dose expansion Phase 1/2 study of amcenestrant as monotherapy, then in combination with other anti-cancer targeted therapies. Arm 5 investigates dose escalation (Part J) and dose expansion (Part K), of amcenestrant in combination with abemaciclib. Postmenopausal women with ER+/HER2- advanced breast cancer, ECOG performance status 0-1, and ≥ 6 months prior endocrine therapy are eligible. In Arm 5 (Parts J and K), ≤ 1 prior line of a single endocrine therapy for advanced disease is allowed. Prior treatment with fulvestrant or any other SERD is not allowed; in addition, prior therapy with CDK4/6 inhibitors for advanced disease is not allowed. Part J allows ≤ 1 prior chemotherapy for advanced disease, while prior chemotherapy for advanced disease is not allowed in Part K. Additional exclusion criteria in Arm 5 are prior drugs targeting the phosphoinositide 3-kinase axis; history of or concurrent pneumonitis; and history of or concurrent venous thromboembolism (i.e., deep vein thrombosis, pulmonary embolism, or cerebral venous sinus thrombosis). Part J evaluates the selected amcenestrant dose for combination therapy plus abemaciclib 150 mg twice daily (BID) (the approved standard dose) or abemaciclib 100 mg BID, taken in 28-day cycles. Additional dose levels of amcenestrant may be explored based on safety and pharmacokinetics (PK). The objective of Part J is to determine the recommended dose (RD) of abemaciclib in combination with the selected amcenestrant dose for combination therapy, based on preliminary safety, PK, and antitumor activity data. The primary endpoint in Part J is the incidence of treatment-related dose-limiting toxicities (DLTs) at Cycle 1. Approximately up to 12 DLT-evaluable patients will be needed to establish the RD of abemaciclib in combination with amcenestrant in Part J. In Part K, approximately 20 patients will be treated at the RD of abemaciclib for combination therapy with amcenestrant, the primary endpoint being safety and tolerability. Secondary endpoints include PK and antitumor activity. Funding: Sanofi. Citation Format: Mario Campone, Sarat Chandarlapaty, Aditya Bardia, Patrick Neven, Katarina Petrakova, Peter Kabos, Valentina Boni, Sofia Braga, Marina Celanovic, Patrick Cohen, Alice Gosselin, Sylvaine Cartot-Cotton, Vasiliki Pelekanou, Hannah Linden. Ameera-1 Arm 5: Phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), with abemaciclib in postmenopausal women with ER+/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-11-04.

Abstract OT1-14-01: Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204)

Abstract Background: HER2-targeted therapies have led to marked improvements in survival for patients with HER2-positive breast cancer. Despite the gains obtained with current HER2-targeted therapies, an unmet medical need remains for patients with HER2-expressing (high or low expression) advanced breast cancer that has progressed after prior treatments. Zanidatamab is a novel HER2-targeted bispecific antibody that has multiple mechanisms of action, including immune clearance of HER2-expressing tumor cells through antibody-dependent cellular phagocytosis. Zanidatamab has been shown to be well-tolerated and has demonstrated antitumor activity, both as monotherapy and in combination with chemotherapy, across HER2-expressing solid tumors in a Phase 1 study. ALX148 is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of anticancer therapies, including antibodies, with minimal added hematologic toxicity. Treatment with zanidatamab in combination with ALX148 has the potential to augment the immune clearance of HER2-expressing cancer cells by blocking the CD47-SIRPa interaction that inhibits phagocytosis of the same cancer cells. In a Phase 1 study, ALX148 demonstrated antitumor activity when combined with trastuzumab in patients whose disease had progressed on prior HER2-targeted therapies. Here, we describe a Phase 1b/2 study to investigate the safety and antitumor activity of a chemotherapy-free combination of zanidatamab plus ALX148 in advanced HER2-expressing cancers, including breast cancer. Methods: ZWI-ZW25-204 is a Phase 1b/2, 2-part, open-label, multicenter study to evaluate the safety and antitumor activity of zanidatamab administered in combination with ALX148 in patients with locally advanced/inoperable and/or metastatic HER2-expressing cancer. Part 1 of this study will evaluate safety and tolerability and will establish the recommended doses (RDs) of zanidatamab plus ALX148. It will include patients with either HER2-positive (defined per ASCO/CAP guidelines) or HER2-low (defined as immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization (ISH) negative) breast cancer. Part 2 will evaluate the antitumor activity of zanidatamab plus ALX148 (at their combination therapy RDs) in 3 expansion cohorts: HER2-positive breast cancer (Cohort 1), HER2-low breast cancer (Cohort 2) and other HER2-overexpressing advanced malignancies (Cohort 3). Other key eligibility criteria include: prior use of approved agents known to confer clinical benefit, disease progression on or after the most recent systemic therapy, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Patients will receive zanidatamab and ALX148, each administered intravenously once every 2 weeks in a 28-day treatment cycle. Response assessments will be performed every 8 weeks. Primary endpoints include safety and tolerability assessments (Part 1) and confirmed objective response rate per RECIST 1.1 (Part 2). Secondary endpoints in Part 2 include disease control rate, clinical benefit rate, duration of response, progression-free survival, overall survival, safety, pharmacokinetics, and immunogenicity assessments. The study is currently open for enrollment in the United States and may enroll up to 93 patients (NCT: 05027139). Citation Format: Sara A. Hurvitz, Jorge Chaves, Adam Brufsky, Alberto J. Montero, Bruno Fang, Kay Yeung, Manish R. Patel, Ritesh Parajuli, Adam Omidpanah, Elaina Gartner, Abraham Fong, Sophia Randolph, Funda Meric-Bernstam. Zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: A phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-14-01.

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study

Abstract CT029: Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan: A Children's Oncology Group Study (ADVL1312)

Abstract Background: Inhibition of the WEE1 kinase by adavosertib (AZD1775) potentiates replicative stress from genomic instability or chemotherapy, and demonstrated anti-tumor activity in preclinical models of pediatric cancer. This study reports the phase 2 expansion of the ADVL1312 phase I/II trial combining irinotecan and adavosertib in children and adolescents with relapsed/refractory solid and CNS tumors. Methods: Patients (&amp;lt; 21 yrs old) with measurable or MIBG-evaluable relapsed/refractory neuroblastoma (Part B), medulloblastoma/CNS embryonal tumors (Part C) or rhabdomyosarcoma (Part D) were treated with irinotecan (90 mg/m2/dose) and adavosertib (85 mg/m2/dose) orally for 5-days every 21-days. Any patient who received at least one dose was considered evaluable for response. Using a Simon's two stage design the combination was considered effective if there were three out of twenty responses in parts B and D or six out of nineteen responses in part C. Tumor tissue was analyzed for ATRX deficiency by multiplex immunofluorescence of ultrabright telomere foci and ATRX, and where available, prior tumor genomic analyses. Results: Twenty eligible patients with neuroblastoma, with a median age of nine years old (6-19) were included in Part B. They had a median of three prior chemotherapy regimens (1-7); nineteen patients (95%) had prior irinotecan and seventeen (85%) received prior radiation therapy. The combination therapy resulted in three objective responses confirmed by central review (estimated response rate of 16.7%) meeting the protocol defined efficacy endpoint for Part B. The responses included a measurable partial response (11 cycles), MIBG evaluable complete response (9 cycles) and MIBG and marrow evaluable partial response (18 cycles). In addition, there were three patients with prolonged stable disease of 8, 11 and 13 cycles. Two of the three patients with objective responses had tumors with predicted ATRX deficiency, while the third did not have available archival tumor. Of the nine neuroblastoma patient tumors with predicted ATRX deficiency, 4 (44%) had objective responses or prolonged stable disease. In part C, of 9 patients eligible for response, 1 patient with pineoblastoma had a confirmed partial response (9 cycles) and another with medulloblastoma had prolonged stable disease (11 cycles). In part D, of 10 eligible patients, 2 had stable disease of 8 and 10 cycles. Part C and D did not meet the protocol defined efficacy endpoint. The combination was well tolerated with one patient experiencing a dose limiting toxicity that resolved with dose reduction. Conclusion: This the first phase 2 clinical trial of adavosertib in pediatrics and the first in combination with irinotecan. The combination was of sufficient activity to support further study in neuroblastoma, and possibly other pediatric tumor types with recurrent ATRX mutation. Citation Format: Kristina A. Cole, Heba Ijaz, Lea Surrey, Mariarita Santi-vicini, Xiaowei Liu, Charles G. Minard, John M. Maris, Stephan Voss, Elizabeth Fox, Brenda Weigal. Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan: A Children's Oncology Group Study (ADVL1312) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT029.

Abstract OT-03-05: Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: A phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08)

Abstract Background In patients (pts) with HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) metastatic breast cancer (mBC), HER2-targeted therapies have greatly improved survival. However, for pts with HER2-low mBC (IHC 1+ or IHC 2+/ISH−), there are no approved HER2-directed therapies. In pts with hormone receptor (HR)+, HER2-low mBC whose disease progresses on standard first-line treatment (endocrine therapy [ET] and CDK4/6 inhibitors), median progression-free survival (PFS) with continued ET alone is ≈ 2 months, and with mTOR or PI3K inhibitors (in PIK3CA-mutant tumors) in the second-line setting, PFS ranges from 3.5 to 7.3 months, respectively (André F, et al. ESMO 2018; Dhakal A, at al. ASCO 2018; Rugo R, et al. ASCO 2020). For ET-refractory pts, chemotherapy (CTX) is the standard of care and has a poor benefit-risk ratio. The treatment landscape for pts with HR−, HER2-low mBC is even more limited, consisting largely of CTX (with or without PD-1/PD-L1 inhibitors in the first-line setting). T-DXd is an antibody-drug conjugate composed of a humanized HER2 antibody attached to a membrane-permeable topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker at a drug to antibody ratio of ≈ 8. In a recent phase 1b study, pts with heavily pretreated (median, 7.5 prior therapies) HER2-low advanced or metastatic breast cancer treated with T-DXd 5.4 or 6.4 mg/kg had a confirmed objective response rate (ORR) of 37.0% (20/54) by independent central review and a median PFS of 11.1 months, and the safety profile was generally manageable (Modi S, et al. J Clin Oncol. 2020;38:1887-1896). Here, we describe a phase 1b trial evaluating the safety, tolerability, and pharmacokinetics (PK) of T-DXd in combination with other anticancer agents in pts with HER2-low, HR+ or HR− mBC. Study Description DESTINY-Breast08 is a multicenter, open-label, 2-part study evaluating T-DXd combinations in pts with HER2-low mBC. The 5 treatment modules comprise T-DXd in combination with (1) capecitabine, (2) durvalumab + paclitaxel, (3) capivasertib, (4) anastrozole, and (5) fulvestrant. Part 1 (dose finding): Each treatment module will enroll 3 to 12 pts per dose level to determine the recommended phase 2 dose (RP2D) in combination; modules 1 through 3 will enroll irrespective of HR status, whereas modules 4 and 5 will be restricted to only HR+ pts. HR+ pts should have received ≥ 1 prior line of ET and ≥ 1 prior line of CTX; HR− pts should have received ≥ 1 prior line of CTX. Part 2 (dose expansion): Modules 1, 4, and 5 will enroll 20 pts, and modules 2 and 3 will enroll 40 pts using the RP2D determined in part 1 of each module. Patient eligibility per module in part 2 is as follows: Module 1 (HR+ or HR−): HR−, only 1 prior line of CTX for mBC; HR+, only 1 prior line of ET but no prior CTX for mBCModule 2 (HR−): no prior CTX for mBCModule 3 (HR−): only 1 prior line of CTX for mBCModules 4 and 5 (HR+): only 1 prior line of ET but no prior CTX for mBC The primary endpoint in part 1 is safety and tolerability and determination of RP2Ds. In part 2, the primary endpoint is safety and tolerability, and secondary endpoints include ORR, duration of response, and PFS (all by investigator assessment according to RECIST 1.1) as well as overall survival, PK, and immunogenicity. Citation Format: Komal Jhaveri, Erika Hamilton, Sherene Loi, Peter Schmid, Annie Darilay, Chen Gao, Gargi Patel, Magdalena Wrona, Fabrice Andre. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: A phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-05.

Phase I study of BI 754091 plus BI 754111 in Asian patients with gastric/gastroesophageal junction or esophageal cancer.

212 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, has been proposed to restore T-cell function and thus enhance antitumor responses. This Phase I trial evaluated BI 754091 (anti-PD-1) with BI 754111 (anti-LAG-3) antibodies in Asian pts with advanced solid tumors (NCT03433898). Here, we present results from pts with anti-PD-(L)1 inhibitor-naïve gastric/gastroesophageal junction or esophageal cancer (Cohorts A and B). Methods: In Parts 1 and 2 (dose escalation), the recommended dose for the combination was determined as BI 754091 240 mg + BI 754111 600 mg IV Q3W. In Part 3, the combination was assessed in expansion cohorts including pts with gastric/gastroesophageal junction cancer (Cohort A) and esophageal cancer (Cohort B). Eligible pts had received ≥1 line of prior systemic therapy but no prior anti-PD-(L)1 therapy. The primary endpoint in Part 3 was objective response (OR; confirmed complete response or partial response [PR]) per RECIST 1.1. Results: In Cohort A/B, 36/37 pts were treated:26/31 (72/84%) male, median age 60/63 years. Patients were enrolled in Taiwan (1/7 pts, 3/19%), Japan (12/27 pts, 33/73%) or Korea (23/3 pts, 64/8%). The median number of regimens of prior systemic therapy was 2/2 (Cohorts A/B, range: 1–6/1–4). All pts in Cohort B had squamous cell carcinoma. At the time of analysis, pts in Cohort A/B had undergone a median of 84/73 days on treatment (range: 31–346/8–325), from the start of treatment until the date of snapshot, death or discontinuation. Confirmed OR (PR) was observed in 4/7 pts in Cohorts A/B; overall response rate (ORR) was 11% and 19%. Stable disease (SD) was observed in 10/8 (28/22%) pts in Cohorts A/B and overall disease control rate was 39/41%. In Cohorts A/B, adverse events (AEs) and treatment-related AEs were experienced by 30/34 (83/92%) and 12/22 (33/59%) pts, respectively. The most commonly reported AEs were pyrexia (25/19%), decreased appetite (17/19%), increased aspartate aminotransferase (11/14%), anemia (11/11%) and nausea (6/14%). In Cohort A/B, 9/15 (25/41%) pts experienced immune-related AEs, most commonly rash in Cohort A (4 pts; 11%) and hyperthyroidism in Cohort B (4 pts; 11%). In Cohorts A/B, 2/6 (6/16%) patients experienced AEs leading to discontinuation of treatment. Conclusions: Treatment was well tolerated and preliminary antitumor activity was seen. Addition of LAG3 did not improve ORR beyond that expected for an anti-PD-1 monotherapy in gastric and esophageal cancer without patient selection. Clinical trial information: NCT03433898. [Table: see text]