Nonuniform dose distributions among disseminated tumor cells can be a significant limiting factor in targeted α therapy. This study examines how cocktails of radiolabeled antibodies can be formulated to overcome this limitation. Methods: Cultured MDA-MB-231 human breast cancer cells were treated with different concentrations of a cocktail of 4 fluorochrome-conjugated monoclonal antibodies. The amount of each antibody bound to each cell was quantified using flow cytometry. A spreadsheet was developed to "arm" the antibodies with any desired radionuclide and specific activity, calculate the absorbed dose to each cell, and perform a Monte Carlo simulation of the surviving fraction of cells after exposure to cocktails of different antibody combinations. Simulations were performed for the α-particle emitters 211 At, 213 Bi, and 225 Ac. Results: Activity delivered to the least labeled cell can be increased by 200%-400% with antibody cocktails, relative to the best-performing single antibody. Specific activity determined whether a cocktail or a single antibody achieved greater cell killing. With certain specific activities, cocktails outperformed single antibodies by a factor of up to 244. There was a profound difference (#16 logs) in the surviving fraction when a uniform antibody distribution was assumed and compared with the experimentally observed nonuniform distribution. Conclusion: These findings suggest that targeted α therapy can be improved with customized radiolabeled antibody cocktails. Depending on the antibody combination and specific activity of the radiolabeled antibodies, cocktails can provide a substantial advantage in tumor cell killing. The methodology used in this analysis provides a foundation for pretreatment prediction of tumor cell survival in the context of personalized cancer therapy.

Background: Combining endocrine therapy (ET) with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor significantly improves progression-free survival (PFS) over ET alone in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC). However, optimal management of disease that progresses on this therapy is not established. In Phase 1 of the TRINITI-1 study (ClinicalTrials.gov identifier: NCT02732119), continuous ribociclib 300 mg/d + everolimus (EVE) 2.5 mg/d + exemestane (EXE) 25 mg/d, the recommended Phase 2 dose, resulted in 1 dose-limiting toxicity. Clinical benefit at week 24 was found in 3 of 6 patients whose disease had progressed on a CDK4/6 inhibitor. Here we report Phase 2 efficacy and safety in patients whose disease progressed on a CDK4/6 inhibitor. Methods: Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on ≤3 lines of therapy for ABC (1-3 lines of ET and ≤1 line of chemotherapy) and had measurable disease and/or lytic/mixed bone lesions were eligible. Progression on 1 CDK4/6 inhibitor, as the last therapy before enrollment, after ≥4 months of treatment for ABC was required. Dexamethasone mouthwash was required for the first 8 weeks. The primary objective of clinical benefit at 24 weeks in Phase 2 would be met if ≥9 of 42 patients had clinical benefit at 24 weeks. Secondary objectives included PFS, tumor response, safety, and tolerability. Results: Of 46 enrolled patients, 44 were evaluable; among 42 evaluable for efficacy, 6 had prior chemotherapy, 13 had ≥2 prior lines of therapy (median, 1 line), and 13 were on therapy on December 15, 2017. At week 24, 17 patients (40.5%) had clinical benefit by local assessment; the overall response rate was 7.1% (n=3; all had partial response at week 24). Median PFS was 8.8 months (95% CI, 1.9 months-not evaluable). In the safety set (n=44), there was 1 on-treatment death unrelated to study drug; 1 patient discontinued with Grade 4 hypophosphatemia. Common (≥25%) any-grade adverse events were neutropenia (68.2%), stomatitis (45.5%), fatigue (38.6%), nausea (34.1%), thrombocytopenia (34.1%), diarrhea (29.5%), and anemia (25.0%). Seven patients (15.9%) had Grade 1/2 pneumonitis, 23 (52.3%) had Grade 3/4 neutropenia, 2 (4.5%) had Grade 3/4 increased aspartate aminotransferase, and 1 (2.3%) had Grade 3/4 increased alanine aminotransferase. Febrile neutropenia, Grade 3/4 stomatitis or pneumonitis, and corrected QT interval (Fridericia's formula) >480 ms were not observed. Conclusion: TRINITI-1 is the first trial to demonstrate promising clinical benefit and tolerability of continuous ribociclib 300 mg/d, EVE 2.5 mg/d, and EXE 25 mg/d following progression on a CDK4/6 inhibitor, warranting further evaluation of this combination. Citation Format: Stacy Moulder, Megan Karuturi, Denise A. Yardley, Gail Shaw Wright, Sara Hurvitz, Rebecca Moroose, Tara Sanft, Cynthia Ma, Amelia Zelnak, Angela DeMichele, Amy Clark, Das Purkayastha, Alisha Khullar, Nicola Caria, Aditya Bardia. Ribociclib in combination with everolimus and exemestane in men and postmenopausal women with HR+/HER2− advanced breast cancer after progression on a CDK4/6 inhibitor: Efficacy and safety results from phase II of the TRINITI-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT107.

Background: B-cell receptor (BCR) signaling pathway plays crucial roles in the pathobiology of non-Hodgkin's lymphomas (NHL). Despite available agents targeting the BCR pathway, no agents are yet curative, remissions are usually not durable, and toxicities are often serious. Hence, there continues to be unmet medical needs for more effective and less toxic therapies in patients with relapsed/refractory (R/R) lymphoma. HMPL-689 is a small molecule, orally available, highly selective inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ), a key kinase, and therapeutic molecular target in the BCR signaling pathway. There are currently ongoing global clinical studies with HMPL-689, in Australia, China, the EU (Italy, Spain & Poland), and the United States (US). Preliminary results from dose escalation and expansion stage for HMPL-689 are expected soon. Herein is the description of ongoing phase I open-labelled dose-escalation study including dose expansion stage. Methods: Study Population: The target population is adult patients with histologically confirmed relapsed or refractory HL or NHL. To be eligible for enrollment, pts must have exhausted all approved therapy options available. Objectives: The primary objective is to assess the safety and tolerability of HMPL-689 in patients with R/R lymphoma, and to determine the maximum-tolerated dose (MTD)/ recommended phase II dose (RP2D). Preliminary efficacy in pts with R/R lymphoma will be evaluated as a secondary objective. Study Design: Open-labelled, dose-escalation in R/R NHL patients, following a traditional 3+3 design. Anticipate up to 30 patients will enroll until MTD/RP2D is reached. The proposed doses are 5, 10, 15, 20, 25, 30, 35 mg, oral, daily in a 28-day cycle. until disease progression, intolerable toxicity, no further benefit from treatment, withdrawal, end of study, or death. Expansion stage will further evaluate clinical benefit of the study drug at MTD/RP2D in ~60 patients, with ~10 patients in each cohort of: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), Mantle cell lymphoma (MCL), Follicular lymphoma (FL) Marginal zone lymphoma (MZL) Peripheral T-Cell lymphoma (PTCL) Waldenström's macroglobulinemia/ lymphoplasmacytic lymphoma (WM) Conclusions: Ongoing global studies are still open and enrolling patients with R/R lymphoma. Validated data / results from this study will be made available at the end of dose escalation and or at the conclusion of dose expansion stage. Citation Format: Tunde Lawrence, Alisha Khullar, Weiss Yang, Marjo Hahka-Kemppinen, Marek Kania, Weigou Su. A phase I study of HMPL-689, a small molecule selective inhibitor of phosphoinositide 3-kinase-delta, inpatients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5234.

Background: B-cell receptor (BCR) signaling pathway plays crucial roles in the pathobiology of non-Hodgkin's lymphomas (NHL). Despite available agents targeting the BCR pathway, no agents are yet curative, remissions are usually not durable, and toxicities are often serious. Hence, there continues to be unmet medical needs for more effective and less toxic therapies in patients with relapsed/refractory (R/R) lymphoma. HMPL-523 is a small molecule, orally available, highly selective inhibitor of spleen tyrosine kinase (SYK), a key kinase, and therapeutic molecular target in the BCR signaling pathway. There are currently ongoing global clinical studies with HMPL-523, in Australia, China, the EU (Italy, Spain & Poland), and the United States (US). Preliminary results from dose escalation and expansion stage for HMPL-523 are expected soon. Herein is the description of ongoing phase I open-labelled dose-escalation study including dose expansion stage. Methods: Study Population: The target population is adult patients with histologically confirmed relapsed or refractory HL or NHL. To be eligible for enrollment, patients must have exhausted all approved therapy options available. Objectives: The primary objective is to assess the safety and tolerability of HMPL-523 in patients with relapsed or refractory lymphoma, and to determine the maximum-tolerated dose (MTD)/ recommended phase II dose (RP2D). Preliminary efficacy in patients with relapsed or refractory lymphoma will be evaluated as a secondary objective. Study Design: Open-labelled, dose-escalation in R/R NHL pts, following a traditional 3+3 design. Anticipate up to 30 pts will enroll until MTD/RP2D is reached. The proposed doses are 100, 200, 400, 600 and 800 mg, oral, daily in a 28-day cycle. until disease progression, intolerable toxicity, no further benefit from treatment, withdrawal, end of study, or death. Expansion stage will further evaluate clinical benefit of the study drug at MTD/RP2D in ~60 patients, with ~10 patients in each cohort of: • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), • Mantle cell lymphoma (MCL), • Follicular lymphoma (FL) • Marginal zone lymphoma (MZL) • Peripheral T-Cell lymphoma (PTCL) • Waldenström's macroglobulinemia/ lymphoplasmacytic lymphoma (WM) Conclusions: Ongoing global studies are still open and enrolling patients with R/R lymphoma. Validated data / results from this study will be made available at the end of dose escalation and or at the conclusion of dose expansion stage. Citation Format: Tunde Lawrence, Alisha Khullar, Weiss Yang, Marjo Hahka-Kemppinen, Marek Kania, Weigou Su. A phase I study of HMPL-523, a small molecule, selective inhibitor of spleen tyrosine kinase, inpatients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5239.