287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

3040Background: IDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. Unlike other ...

BackgroundBased on results from Japanese post-marketing surveillance, exploratory analyses were performed to investigate real-world outcomes of radium-223 for metastatic CRPC (mCRPC) according to patient characteristics.MethodsThis non-interventional, prospective study enrolled mCRPC patients selected for radium-223 treatment in clinical practice. Six-month safety and effectiveness were evaluated in subgroups who had/had not received prior chemotherapy (prior-chemo/no prior-chemo groups), and a subgroup who had not received concomitant androgen-receptor axis-targeted agents (ARATs).ResultsIn the overall population (n = 296), the prior-chemo group (n = 126) tended to have more bone metastases, more analgesic use, and higher prostate-specific antigen values than the no prior-chemo group (n = 170). Incidences of treatment-emergent adverse events (TEAEs), drug-related TEAEs, and ≥ grade 3 drug-related hematological TEAEs were 47% vs. 53%, 25% vs. 29%, and 4% vs. 7% in the no prior-chemo and prior-chemo groups, respectively. Incidences of TEAEs (61%), drug-related TEAEs (36%), and ≥ grade 3 drug-related hematological events (12%) were numerically higher in 33 patients who had received two lines of prior chemotherapy. Multivariate analysis showed that two lines of prior chemotherapy, and hemoglobin, platelet, and lactate dehydrogenase values were baseline factors significantly related to ≥ grade 2 platelet count decreased. Safety and effectiveness in patients without concomitant ARATs (n = 201) were similar to those in the overall population.ConclusionIn a real-life setting, radium-223 was well tolerated irrespective of prior chemotherapy, but relatively higher incidences of TEAEs and hematotoxicities were suggested in patients with two lines of prior chemotherapy, possibly reflecting more advanced disease. Radium-223 safety and effectiveness in patients without concomitant ARATs were favorable.

2502 Background: AhR activation is involved in tumor growth, immunomodulation, and resistance to immune checkpoint inhibitors. BAY2416964 is a novel, potent, oral AhR inhibitor (AhRi) that antagonizes AhR ligand-induced immunosuppressive effects, resulting in enhanced proinflammatory activity of antigen-presenting cells and T cells and reduced activity of immunosuppressive myeloid cells. Methods: A first-in-human, Phase I clinical trial of AhRi BAY2416964 (NCT04069026) is evaluating its safety, pharmacokinetics, pharmacodynamics, recommended Phase II dose, and anti-tumor activity per RECIST v1.1 and iRECIST. BAY2416964 was administered orally in patients with advanced solid tumors in a dose-escalation cohort using a modified toxicity probability interval (mTPI) design. The initial expansion cohorts enrolled patients with non-small-cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC). Results: As of November 4, 2022, 72 patients had been treated with BAY2416964: 39 patients in dose escalation and 33 patients in the initial dose expansion treated with 500 mg twice daily (25 NSCLC, 8 HNSCC). The most common tumor types enrolled in dose escalation were colorectal cancer ( n= 12), breast cancer ( n= 6), and pancreatic cancer ( n= 4). Median age was 61 years (range 35-80). 51/72 (70.8%) patients had received ≥3 lines of therapy (including 16 [22.2%] who had received ≥6 lines) and 47/72 (65.3%) had received immune checkpoint inhibitors. Drug-related treatment-emergent adverse events (TEAEs) of all grades reported in ≥10% of patients were nausea (13.9%; 1.4% grade 3) and fatigue (11.1%; 1.4% grade 3). Most drug-related TEAEs were grade 1 or 2; 9 (12.5%) patients experienced drug-related grade 3 TEAEs and no patients experienced drug-related grade ≥4 TEAEs. No dose-limiting toxicities were observed. Two patients in dose expansion discontinued treatment due to drug-related TEAEs. Plasma exposure to BAY2416964 increased according to dose and food intake. Analysis of biomarkers demonstrated evidence of target engagement and an increase in immune activation at the doses tested. Of 67 patients evaluable for response by RECIST, 22 (32.8%) had stable disease per RECIST v1.1, including 1 with thymoma in dose escalation achieving an iRECIST partial response. Conclusions: BAY2416964 was well tolerated across all dose levels and regimens tested. Initial evaluation of biomarkers shows BAY2416964 inhibits AhR and modulates immune functions. Encouraging preliminary anti-tumor activity was observed in heavily pretreated patients. The disease-specific dose-expansion part of this study is ongoing. The observed manageable safety profile also supports combination therapies. Clinical trial information: NCT04069026 .

BackgroundIndoleamine 2,3‐dioxygenase 1 (IDO1) is a heme‐containing enzyme that degrades tryptophan (Trp) to kynurenine (Kyn), which suppresses effector T cells and reduces antitumor activity. KHK2455 is a long‐acting selective IDO1 inhibitor that blocks the heme component of the IDO holoenzyme. Mogamulizumab is a humanized immunoglobulin G1 monoclonal antibody targeting CCR4. KHK2455 + mogamulizumab demonstrated enhanced antitumor activity in preclinical studies, which led to a first‐in‐human, two‐part, multicenter, open‐label, phase 1, dose‐escalation, cohort‐expansion trial (ClinicalTrials.gov identifier NCT02867007) evaluating the safety/tolerability, pharmacokinetics, and IDO1 activity of KHK2455 alone and in combination with mogamulizumab in patients with treatment‐refractory advanced solid tumors.MethodsPatients received oral KHK2455 at fixed doses of 0.3, 1, 3, 10, 30, and 100 mg once daily as run‐in monotherapy for 28 days (cycle 0), and then in combination with 1 mg/kg intravenous mogamulizumab given weekly for cycle 1 and every 2 weeks from cycle 2 onward.ResultsThirty‐six patients were enrolled. One patient with an initial diagnosis of lower esophageal cancer (100‐mg cohort) experienced grade 3 gastrointestinal necrosis, and did not receive mogamulizumab. Overall, KHK2455 + mogamulizumab was well tolerated, with manageable adverse events at all doses. KHK2455 + mogamulizumab demonstrated dose‐dependent plasma concentration increases and suppression of IDO1 activity. One patient with advanced bevacizumab‐resistant glioblastoma demonstrated a durable confirmed Response Evaluation Criteria in Solid Tumors, version 1.1, partial response, and nine patients achieved a durable disease stabilization of ≥6 months. On the basis of the preliminary antitumor response, the cohort expansion was not initiated.ConclusionsKHK2455 + mogamulizumab was safe and well tolerated with manageable toxicities, and resulted in dose‐dependent suppression of IDO1 activity; signals of antitumor activity were observed.

Background Ixazomib is an oral proteasome inhibitor under phase 3 investigation in pts with multiple myeloma and AL amyloidosis. Ixazomib citrate, a prodrug, rapidly hydrolyzes to the active moiety, ixazomib, in plasma. Metabolism appears to be the major route of elimination for ixazomib. This phase 1, open-label, multicenter, parallel-group study (NCT01454076) investigated the effect of rifampin, an established strong CYP3A inducer, on the pharmacokinetics (PK) of ixazomib. Methods Adult pts with advanced solid tumors (Eastern Cooperative Oncology Group Performance Status 0 or 1), for which no effective standard treatment was available, were enrolled. Pts in the ixazomib + rifampin arm received a single 4 mg dose of ixazomib on day 8, plus rifampin 600 mg PO on days 1-14 of a 21-day PK cycle. On day 8, ixazomib and rifampin were administered concomitantly and PK samples were collected over 168 hours post-dose. Pts in the reference arm received a single 4 mg dose of ixazomib on day 1 with PK samples collected over 168 hours post-dose. After completion of the 21-day PK cycle, pts could continue in the study and receive ixazomib on days 1, 8, and 15 of 28-day cycles. Plasma PK parameters were estimated by non-compartmental methods. Geometric mean ratios and 90% confidence intervals (CIs) of PK parameters in the ixazomib + rifampin versus ixazomib alone arms were calculated using an ANOVA model. Treatment-emergent adverse events (TEAEs) were assessed using NCI CTCAE version 4.03. Results Eighteen and 20 pts were enrolled to the ixazomib + rifampin and ixazomib alone arms, respectively. To assess the impact of rifampin on ixazomib PK, data from 16 PK-evaluable pts who received ixazomib + rifampin were compared with data from 14 PK-evaluable pts who received ixazomib alone. Demographics and PK parameters are shown in the Table. At data cut-off (4 August 2014), 15 pts (83%) in the ixazomib + rifampin arm had ≥1 TEAE related to study medication. The most common (≥20%) drug-related TEAEs, regardless of grade, were nausea (39%) and fatigue (28%). Three pts (17%) in the ixazomib + rifampin arm experienced ≥1 grade 3 TEAE. Conclusions The strong CYP3A inducer rifampin produced a 74% decrease in ixazomib total systemic exposure. Systemic treatment with strong CYP3A inducers should be avoided in pts receiving ixazomib. ParameterIxazomib + rifampin (test)Ixazomib alone (reference)LS geometric mean ratio (90% CI) (test / reference)N (PK evaluable)18 (16)20 (14)-Age, yearsa62 (39-81)61 (29-76)-Male,%5645-Weight, kga80.2 (58.9-109.3)69.8 (46.9-93.5)-Tmax, hoursb1.45 (0.5-4.12)1.49 (0.5-7.5)-Cmax, ng/mLc25.7 (50)55.8 (57)0.46 (0.29, 0.73)AUC0-last, ng•hr/mLc232 (50)907 (44)0.26 (0.18, 0.37)aMean (range); bmedian (range); cgeometric mean (% coefficient of variation). AUC, area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration; CI, confidence interval; Cmax, maximum plasma concentration; LS, least square; PK, pharmacokinetic; Tmax, time to first maximum plasma concentration. Citation Format: Neeraj Gupta, Michael J. Hanley, Karthik Venkatakrishnan, Alberto Bessudo, Sunil Sharma, Bert O'Neil, Bingxia Wang, Ai-Min Hui, John Nemunaitis. A phase 1 drug-drug interaction study between ixazomib, an oral proteasome inhibitor, and rifampin in patients (pts) with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B147.

Lasmiditan is the first 5-HT1F receptor agonist with potential to address the huge unmet medical needs for the treatment of migraine in China. The CENTURION study was the first phase3 study of lasmiditan in Caucasian and Chinese patients with migraine. This posthoc analysis further demonstrates the safety profile of lasmiditan in the Chinese population and was urgently needed. Patients were randomized 1:1:1 to lasmiditan 200mg lasmiditan 100mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed. A total of 281 Chinese patients were included in this posthoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200mg (73.9%) and 100mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy. In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population. NCT03670810.

Background: For patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and certain B-cell neoplasms, resistance to Bruton tyrosine kinase inhibitors (BTKi) develops primarily through mutations at the cysteine binding site (C481) or PLCγ2 mutations. Nemtabrutinib (MK-1026, formerly ARQ-531) is a non-covalent, potent inhibitor of both wild type and C481-mutated BTK. Aims: In the phase 1/2 dose-escalation and dose-expansion BELLWAVE-001 study (NCT03162536), the preliminary recommended phase 2 dose (RP2D) of nemtabrutinib was determined to be 65 mg once daily. The efficacy and safety of nemtabrutinib in patients (pts) with CLL/SLL and B-cell non-Hodgkin lymphoma (NHL) were also evaluated at a higher dose during the dose-expansion phase. Methods: In this open-label, single-arm phase 2 study, 9 expansion cohorts were initiated following determination of preliminary nemtabrutinib RP2D. Approximately 10-25 eligible pts were enrolled into Cohort A (relapsed/refractory (r/r) CLL/SLL, with ≥2 prior therapies including covalent BTKi, with documented C481 mutation), Cohort B (r/r CLL/SLL progressed on/intolerant to a BTKi, with ≥2 prior therapies without C481 mutation), Cohort C (Richter transformation with ≥1 prior therapy), Cohort D-H (follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, high-grade B cell lymphoma with known MYC, BCL-2 or BCL-6 translocations, and Waldenström macroglobulinemia [WM], respectively, who received ≥2 prior therapies), Cohort I (food-effect cohort including pts with B-cell NHL, CLL/SLL, and WM). Primary end point was ORR (per iwCLL criteria, by investigator) for participants with CLL/SLL. Secondary end points included DOR and safety and tolerability. Results: Among 118 pts enrolled, 44 had B-cell NHL, 68 CLL/SLL, and 4 WM. Of these, 94 (79.6%) were treated at the preliminary RP2D, including 51 (54.3%) participants with CLL/SLL. Pts with CLL/SLL had a median (range) number of prior therapies of 4 (1-18), 43 (84%) had prior BTKi therapy, 12 (23%) had del17p, 30 (59%) had IGHV unmutated status, and 32 (63%) had C481S BTK mutation. At data cut-off (April 7, 2021), median (range) follow-up was 4.6 mo (0.1-26.7) for all treated pts. ORR was 57.9% (22/38; 1 CR, 21 PR/PRL) per iwCLL criteria in the efficacy-evaluable population of pts with CLL/SLL treated at preliminary RP2D. Median duration of response was not estimable [NE] (range, 8.3 mo-NE). Among all treated participants, 114 (97%) had a treatment-emergent adverse event (TEAE), with 78 (66%) having a drug-related TEAE, and 9 (8%) having a drug-related TEAE that led to discontinuation. Common TEAEs (≥ 20%) included fatigue (33%), constipation (31%), dysgeusia (28%), cough (25%), nausea (25%), pyrexia (25%), dizziness (23%), hypertension (23%), peripheral edema (22%), diarrhea (21%), and arthralgia (20%). Grade ≥3 TEAEs occurred in 80 (68%) participants. Grade 5 TEAEs occurred in 7 (6%) participants and included death following disease progression 3 (3%), sepsis 1 (1%), dyspnea 1 (1%), and respiratory failure 2 (2%). Common drug-related TEAEs (≥10%) included dysgeusia (15%), nausea (11%), fatigue (11%), and decreased neutrophil count (10%). Grade 3-4 drug-related TEAEs occurred in 31 (26%) participants. No drug-related TEAEs led to death. Summary/Conclusion: Nemtabrutinib has promising antitumor activity with a manageable safety profile in pts with CLL/SLL exposed to multiple lines of therapy, including in those who had progression of disease on prior covalent BTKi. Further evaluation of nemtabrutinib in B-cell malignancies is ongoing.

Preliminary Efficacy and Safety of MK-1026, a Non-Covalent Inhibitor of Wild-Type and C481S Mutated Bruton Tyrosine Kinase, in B-Cell Malignancies: A Phase 2 Dose Expansion Study

303 Background: Enzalutamide (ENZA), an androgen receptor (AR) inhibitor that blocks multiple steps in the AR signaling pathway, is approved for patients (pts) with metastatic castration-resistant prostate cancer. This Phase 2, open-label, extension study (NCT01534052) evaluated long-term safety of continued ENZA administration. Methods: Prostate cancer pts previously treated with ENZA in Phase I studies (NCT01902251; NCT01911728; NCT02225093) continued to receive ENZA 160 mg/day until the investigator considered it no longer beneficial or consent was withdrawn. The primary end point was safety. Baseline data from the parent studies were used. Results: 52 pts were enrolled and received ENZA treatment (median age, 67 years [range, 54–88]). Median treatment duration was 443 days (range, 63–2010) since first administration and 392 days (range, 3–1926) in the extension study. In the extension, 43 pts (82.7%) experienced ≥1 any grade treatment-emergent adverse event (TEAE) with the most common (≥10% of pts) being fatigue (26.9% all grades, 13.5% grade 1, 7.7% grade 2, and 5.8% grade 3); arthralgia and back pain (13.5% each); and diarrhea, hot flush, and decreased appetite (11.5% each). Drug-related TEAEs (investigator assessed) were reported in 27 pts (51.9%) with the most common (≥5% of pts) being fatigue (17.3%); hot flush (11.5%); and diarrhea, hypophosphatemia, and muscle weakness (5.8% each). 17 pts (32.7%) had ≥1 serious TEAE. Eight drug-related serious TEAEs were reported in five pts (malignant neoplasm progression [3.8%]; acute pancreatitis, rectal haemorrhage, cerebrovascular accident, dysarthria, hemiparesis, and hypertensive crisis [1.9% each]). One (1.9%) death due to acute myocardial infarction (not drug-related) and four (7.7%) due to malignant neoplasm progression (two drug-related) were reported. No notable changes from baseline in clinical laboratory parameters or clinically meaningful abnormalities in vital signs, physical examinations, or electrocardiogram were found. Conclusions: Long-term continued ENZA treatment is generally well tolerated, with a safety profile consistent with that previously reported. Clinical trial information: NCT01534052.

A Phase 2, Open-Label Study to Evaluate the Efficacy and Safety of Mgta-145 in Combination with Plerixafor for the Mobilization of Hematopoietic Stem Cells in Patients with Sickle Cell Anemia

Background: IDO1 is a mediator of tumor immune suppression through alteration of tryptophan metabolism. Indoximod (1-methyl-tryptophan) is an IDO1 pathway inhibitor. There is preclinical evidence that indoximod acts synergistically with chemotherapy such as taxanes (Uyttenhove, 2003) in an immune dependent fashion. Previous studies demonstrated the safety and activity of indoximod combined with docetaxel in patients with advanced solid tumors, including breast cancer (Soliman, 2014). A phase 2 clinical trial was designed to study the efficacy of indoximod plus taxanes in metastatic breast cancer (MBC) patients (pts). Method: This is a phase II randomized, 1:1 placebo controlled clinical trial, that enrolled MBC pts in multiple centers in the US and Poland. Eligibility criteria included ER+ or ER- HER2- MBC, ability to receive taxane therapy, PS 0-1, normal organ function and absence of autoimmune disease. Pts were randomized to taxane (either weekly paclitaxel 80mg/m2 3 on 1 off or q3wk docetaxel at 75mg/m2 per treating physician’s discretion) + placebo (TP) or taxane + indoximod 1200mg PO BID (TI) as first line treatment for MBC. Primary endpoint was PFS. The sample size of 154 patients was designed to detect a HR of .64 with one sided α=.1 and β=.2 after 95 events. Archival tumor tissue was stained with IHC for IDO1 expression when available. Aperio digital pathology positive pixel algorithm was used for scoring, with manual verification. Median value was used as cut-off for IDO positivity. Results: 164 pts were randomized and treated (85 TI, 79 TP). Demographics and tumor features are shown in table 1. Treatment discontinuation was due to disease progression (60%), adverse events (10%), other (30%). Objective response rate was 40% in TI and 37% in TP arm (p=.74). The median PFS was 6.0 (95% CI, 4.5, 8.1) months in the TI arm and 8.4 (95% CI, 5.6, 9.8) in the TP arm, HR of 1.14 (0.81, 1.60). The median OS was 21.6 months (CI 95%, 16, 39.1) in the TI arm and 21.2 (CI 95%, 19.1, 32.1) in the TP arm. The median follow up was 17.4 (range 0.1, 39.4) months. Grade ≥3 treatment emergent adverse events were observed in 60% of patients in both arms with neutropenia, fatigue, anemia, diarrhea being most common but not significantly different between arms. An exploratory analysis of IDO staining with outcomes in 42 samples (22 in TI and 20 TP) suggested a difference in median PFS in pts with high IDO expression assigned to TI vs. TP (10.3 vs 4 months, p=.047). No other prognostic or predictive associations were observed based on IDO status in the analysis. Conclusions: The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies. Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2) Citation Format: Veronica Mariotti, Shou-Ching Tang, Patrick Dillon, Alberto Montero, Andrew Poklepovic, Susan Melin, Ibrahim Nuhad, Petros Nikolinakos, Eugene Kennedy, Hyo Han, Roohi Ismail-Khan, Daniel Bruetman, Oana Danciu, Paul Gilman, Boguslawa Karaszewska, Krzysztof Lesniewski-Kmak, Timothy Panella, Dhimant Patel, Malgorzata Suszko-Kazarnowicz, Fabio Volterra, Hatem Soliman. Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-04.

7051 Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients (pts) who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/d in the phase 3 BFORE trial were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure-adjusted TEAE rate was defined as the number of pts with TEAEs / total pt-yr (pt-yr = sum of total time to first TEAE for pts with TEAEs and treatment duration for pts without TEAEs). Results: After ≥36 mo follow-up, 65% vs 62% of pts in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals and drug-related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%) and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%) and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3% and 4% vs 1%, 0.4% and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of pts in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs, respectively, were 0.04, 0.03 and 0.04 vs 0.03, 0.01 and 0.04 (grade 3/4/5 only: 0.01, 0.01 and 0.02 vs 0.01, 0.002 and 0.02) for bosutinib vs imatinib. Conclusions: Cardiac, vascular and hypertension TEAE rates were low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. Clinical trial information: NCT02130557. [Table: see text]

Background: AZD1775 is a first-in-class, potent, selective WEE1 inhibitor that has shown acceptable toxicity, linear PK, target engagement, and antitumor activity in combination with chemotherapy (phase I and II studies, both Leijen S et al., J Clin Oncol 2016). In Western patients (pts), the recommended phase II dose with paclitaxel (P) and carboplatin (C) is AZD1775 225 mg bid for 2.5 days per 21-day cycle, which was used successfully in a phase II study (Oza A et al., ASCO 2015). We evaluated AZD1775 with P/C in Asian pts. Methods: In this phase Ib study (NCT02341456, D6011C00003), eligible pts had advanced solid tumors with no existing standard therapy and measurable disease by RECIST 1.1. Pts received a single oral AZD1775 dose with a 5 ± 2-day washout, then five AZD1775 doses (bid for 2.5 days per 21-day cycle) plus P (175 mg/m2) and/or C (AUC 5). In a 3+3 dose-escalation design, AZD1775 was given with P/C at 175 mg (Cohort 1, n=7) or 225 mg (Cohort 2, n=6) for six cycles, or with C at 175 mg (Cohort 1a, n=6) until disease progression. Objectives were assessment of safety/tolerability (primary), PK profile, and antitumor activity (secondary). Results: 19 pts were treated; 58% were female, median age was 55 years, and 21% had breast cancer. 4/18 evaluable pts reported DLTs: two in Cohort 2 (grade 4 sepsis and grade 5 acute respiratory distress syndrome), one in Cohort 1, and one in Cohort 1a (both grade 4 platelet count decreased). Most common grade ≥3 treatment-emergent adverse events (TEAEs; all pts) were anemia, white blood cell (WBC) count decreased (both 58%), platelet count decreased (47%), neutrophil count decreased (42%), neutropenia (26%), thrombocytopenia (21%), febrile neutropenia, diarrhea, nausea, and hypophosphatemia (16% each). Most common TEAEs (all grades, all pts) were nausea (84%), vomiting, anemia (79% each), diarrhea, and WBC count decreased (68% each). For 18 pts evaluable for efficacy, ORR was 28% (table). Table.Pharmacokinetics and antitumor activity of AZD1775 in combination with chemotherapyCohort 1Cohort 2Cohort 1aAZD1775 175 mg, paclitaxel, carboplatin n=7AZD1775 225 mg, paclitaxel, carboplatin n=6AZD1775 175 mg, carboplatin n=6n=6n=6n=6AZD1775 AUC0-t, nM·h*8300 (33)14870 (34)†7154 (32)AZD1775 Cmax, nM*1271 (31)2289 (33)†1129 (26)AZD1775 tmax, h‡4 (2.1-4.1)4 (1.0-8.0)3 (2.0-4.1)n=6n=6n=6Complete response000Partial response131Stable disease222Progressive disease201Not evaluable112*Cycle 1, day 3, Gmean (CV %); †n=5; ‡Cycle 1, day 3, median (range). AUC0-t, area under the plasma concentration-time curve from zero to time of last measurable concentration; Cmax, maximum concentration; CV, coefficient of variation; Gmean, geometric mean; tmax, time to maximum concentration Conclusions: As there were two DLTs in Cohort 2 (AZD1775 225 mg bid plus P/C), the safety profile at this dose was not considered tolerable. The safety profile of the combination at the lower AZD1775 dose, 175 mg bid for 2.5 days plus P/C, was considered acceptable, and this is the recommended phase II dose for Asian pts. Exposure at the 225-mg combination dose was higher in Asian than in Western pts. The safety profile was comparable in the two pt populations. Citation Format: Yung-Jue Bang, Paul De Souza, Sang-We Kim, Jason Lickliter, Yoichi Naito, Keunchil Park, Sanjeev Kumar, Ganesh M. Mugundu, Hidenori Kato. The WEE1 inhibitor AZD1775 in combination with chemotherapy in Asian patients with advanced solid tumors: a phase Ib study [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B183.

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial