Recommended Dose For Expansion Research Articles

452O A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumours

BI 907828, a highly potent mouse double minute-2 (MDM2)–p53 antagonist, has demonstrated preclinical antitumour activity, particularly in TP53 wild-type (wt), MDM2-amplified dedifferentiated liposarcoma (DDLPS) models. This phase I study is evaluating BI 907828 in pts with advanced solid tumours. During dose-escalation (phase Ia), the selected recommended dose for expansion (RDE) was 45 mg q3w (Gounder M, 2021).

Abstract CT197: Phase Ib study of LXH254 + trametinib (TMT) in patients (pts) with NRAS-mutant melanoma

Abstract Background: MAPK pathway dysregulation is a characteristic molecular abnormality of melanoma. NRAS mutations in melanoma lead to constitutive MAPK activation and subsequent MEK and ERK activation. Inhibiting the pathway with a combination of BRAF/CRAF and MEK inhibitors (LXH254 and TMT, respectively) has demonstrated synergistic activity in preclinical models of NRAS-mutant melanoma. Methods: We report data from an open-label, Phase Ib study (NCT02974725), that tested LXH254 + TMT combination in a dose-escalation (ESC) part in pts with KRAS- or BRAF-mutant NSCLC or NRAS-mutant melanoma and in a dose-expansion (EXP) part in NRAS-mutant melanoma pts. In ESC, five dose levels were explored: LXH254 200 mg twice daily (BID) + TMT (1 mg or 0.5 mg) daily (QD); LXH254 400 mg BID + TMT (1 mg or 0.5 mg) QD; LXH254 400 mg BID + TMT 1 mg (QD, 2 wk on/2 wk off). Primary objectives were to evaluate safety and tolerability, and determine the recommended dose for expansion (RDE). Secondary objectives were to characterize pharmacokinetics and pharmacodynamics of LXH254 + TMT, and evaluate antitumor activity. Results: As of Dec 9, 2021, 36 and 30 pts were enrolled in ESC and EXP, respectively; median age was 63.5 and 69 y, respectively. Pts in ESC and EXP received a median of 3 (range: 1-6) and 2 (range: 1-7) prior treatments, respectively, including IO (ESC: 88.9% pts; EXP: 96.7% pts). All pts from ESC and 24 pts from EXP discontinued, mainly due to progressive disease (61.1% and 60%, respectively); 6 pts were ongoing in EXP at data cut-off. In ESC, Grade ≥3 (G≥3) DLTs were reported in 6 pts: dermatitis acneiform (n=2), maculopapular rash (n=2), increased lipase (n=1), and Stevens-Johnson syndrome (n=1). The RDEs were LXH254 200 mg BID + TMT 1 mg QD and LXH254 400 mg BID + TMT 0.5 mg QD. Treatment-related adverse events (TRAEs) were reported in 34 pts (94.4%) in ESC and all pts in EXP. G≥3 TRAEs in ESC and EXP were experienced by 19 (52.8%) and 24 (80%) pts, respectively; the most common being rash or dermatitis acneiform (13.9% each) in ESC and rash (33.3%) in EXP. One fatal TRAE (hypovolemic shock) was reported in the LXH254 400 mg BID + TMT 0.5 mg QD group. The ORR in EXP was 46.7% (7 pts; 95% CI: 21.3-73.4) for LXH254 200 mg BID + TMT 1 mg QD and 13.3% (2 pts; 95% CI: 1.7-40.5) for LXH254 400 mg BID + TMT 0.5 mg QD; overall in EXP, 9 pts (30%) achieved PR and 13 pts (43.3%) reported SD. In EXP the median DOR was 3.8 months (95% CI: 2.6-7.4). Exposures of LXH254 (200 mg or 400 mg BID) + TMT (0.5 mg or 1 mg QD) vs LXH254 single agent were comparable, indicating no apparent LXH254-TMT interactions. Limited paired tumor biopsy data (n=8) showed substantial MAPK pathway inhibition (DUSP6). Conclusions: LXH254 in combination with TMT has shown preliminary antitumor activity in the pretreated, NRAS-mutant melanoma population. A Phase II trial of LXH254 combinations in pts with pretreated BRAF- or NRAS-mutant melanoma is currently ongoing (NCT04417621). Citation Format: Filippo de Braud, Christophe Dooms, Rebecca S. Heist, Celeste Lebbe, Martin Wermke, David Planchard, Dirk Schadendorf, Piotr Rutkowski, Jürgen Wolf, Paolo A. Ascierto, Ignacio Gil-Bazo, Shumei Kato, Maria Wolodarski, Meredith McKean, Eva Muñoz Couselo, Martin Sebastian, Armando Santoro, Vesselina Cooke, Luca Manganelli, Kitty Wan, Anil Gaur, Tanay S. Samant, Jaeyeon Kim, Giordano Caponigro, Xuân-Mai Couillebault, Michele Moschetta, Adil Daud. Phase Ib study of LXH254 + trametinib (TMT) in patients (pts) with NRAS-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT197.

Abstract CT503: A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies

Abstract Background: The over-expression of CD73 has been linked to many cancers. NZV930, an investigational, CD73-targeting monoclonal antibody (mAb), forms bidentate structures with the CD73 dimer, shutting down the catalytic activity of cell surface and soluble CD73. Taminadenant is an investigational A2AR antagonist and spartalizumab is an anti-PD-1 mAb. Preclinical studies provide compelling antitumor activity when combining CD73, A2AR, and PD-1 blockade. Methods: This first-in-human study (NCT03549000) comprised dose-escalation and dose-expansion parts. Here, we present the dose-escalation results of the four treatment (tx) arms: NZV930 single agent (SA; 60-1000 mg Q2W), NZV930 (200-600 mg Q2W) + spartalizumab (400 mg Q4W) or taminadenant (80-240 mg Q2W), or in combination with spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID). Eligible pts had selected malignancies, and disease progression following standard therapy. Primary objectives included assessing safety and tolerability and determining the recommended dose for expansion (RDE) of NZV930 SA and its combinations. Secondary objectives were to determine efficacy, characterize the pharmacokinetics (PKs) of NZV930 SA and its combinations, and assess the immunogenicity of spartalizumab and NZV930. Biomarker tumor samples were obtained at screening, C2D1, and C4D1. Results: As of June 10, 2021, 105 pts were enrolled for dose escalation, including pts with CRC (n=63), ovarian cancer (n=15), pancreatic cancer (n=11), NSCLC (n=8), TNBC (n=5), RCC (n=2), and prostate cancer (n=1). Most pts (81%) had been treated with ≥3 lines of prior therapy. In total, 98 pts discontinued, mainly due to disease progression (72%); six were ongoing. At least one tx-related adverse event (TRAE) was reported by 89 pts (85%); these were mostly grade 1-2. A triad of headache, fever, and nausea/emesis was observed after the first infusion of NZV930. Most common TRAEs (≥30%) were headache (67%), nausea and vomiting (32% each), and pyrexia (30%). At least one grade ≥3 TRAE was reported in 15 pts (14%); headache (4%) was most common, accounting for 4/7 DLTs (all grade ≥3). There were no tx-related deaths. Overall, no responses were reported; 12 pts (11%) had stable disease and 69 pts (66%) had progressive disease. NZV930 has good PK properties, with target-mediated drug disposition at lower doses, which normalize to typical IgG-like PKs at higher doses. Biomarker data confirm CD73 target engagement in plasma. Adenosine pathway modulation in tumors and plasma was seen post-NZV930 tx. Conclusions: NZV930 reduced adenosine levels in plasma and tumors. The RDE of NZV930 SA or in combination with spartalizumab and/or taminadenant is 600 mg Q2W with a step-up dosing regimen. NZV930 SA and its combinations exhibited a tolerable safety profile in multiple advanced solid tumors and showed good PK properties. Citation Format: Siqing Fu, Udai Banerji, Philippe L. Bedard, Aitana Calvo Ferrándiz, Alberto Chiappori, Jayesh Desai, Rahima Jamal, Desamparados Roda Perez, Noboru Yamamoto, Erica Vieira, Gabrielle Wong, Kulandayan K. Subramanian, Shunguang Wang, Britta Mueller, Javier A. Otero, Si-Lin Koo. A phase I/Ib study of the safety and preliminary efficacy of NZV930 alone and in combination with spartalizumab and/or taminadenant in patients (pts) with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT503.

Abstract CT215: LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL)

Abstract Background: Disease relapse is common with peripheral T-cell lymphomas (PTCL) or cutaneous T-cell lymphomas (CTCL). Adoptive immunotherapy with CD19 directed CAR-T cells is a standard option for B cell lymphoid malignancies in the relapsed setting. This study assesses the safety and preliminary efficacy of CD4 targeting autologous CAR-T, LB1901, in patients (pts) with CD4+ relapsed or refractory (R/R) TCL. A pre-clinical study showed LB1901 exhibited potent anti-tumor activity without off-target effects (Zeng 2021). Methods: This is a phase 1, open-label, multicenter, multicohort study of LB1901 (NCT04712864; currently enrolling). Eligible pts are ≥18 years with histologically confirmed CD4+ PTCL-NOS (not otherwise specified); or CD4+ AITL (angioimmunoblastic T-cell lymphoma); or CD4+ CTCL (either MF [mycosis fungoides] or SS [Sézary syndrome]). In Part A (dose escalation), pts with SS must have ≤2,000 circulating Sézary cells/µL to ensure safety of pts with higher disease burden. In Part B, pts with >2,000 Sézary cells/µL is allowed. CD4 expressed on tumor cells must be confirmed within 3 months prior to apheresis. Other inclusion criteria include: R/R disease with ≥2 prior lines of systemic antineoplastic therapy; for pts with PTCL-NOS or AITL, ≥1 measurable lesion according to IWG Response Criteria (Cheson 2014) and for pts with CTCL, ≥stage IIB on TNMB-ISLC/EORTC staging system; identified HSCT donor available prior to enrollment (in the event of severe recurrent infections and prolonged lymphopenia for which pt may need an allogeneic HSCT as a safety rescue); and ECOG status of 0 or 1. Response will be evaluated based on IWG response criteria for PTCL and Global Composite Response for CTCL (Olsen 2007). The study will be conducted in 2 parts (Part A: dose escalation and Part B: dose expansion). Three dose levels (0.3 X 106, 1.0 X 106, and 3.0 X 106 CAR+ viable T cells/kg) will be evaluated (N=3-6 for each dose level) with an optional dose level minus 1 (0.1 X 106 CAR+ viable T cells/kg). Part B will include 2 cohorts, PTCL and CTCL (N=12-20 for each), after the recommended dose for expansion (RDE) has been identified in Part A. Enrolled pts will undergo apheresis for PBMC collection. LB1901 will be manufactured from autologous CD8+ T cells. Pts may receive optional bridging therapy and receive lymphodepleting chemotherapy with fludarabine 30mg/m2/day and cyclophosphamide 300mg/m2/day (Flu-Cy), for 3 days followed by LB1901. Primary endpoints are incidence, duration, and severity of AEs and laboratory abnormalities (Parts A and B) and DLT at each dose level (Part A). Secondary endpoints include overall response rate; duration of response; CAR-positive T cell counts and CAR transgene level in blood; and presence of anti-CAR antibody response. Exploratory endpoints include preliminary efficacy, pharmacokinetics, and CD4+ T cell counts. Citation Format: Swaminathan P. lyer, David G. Maloney, Nora Bennani, Auris Huen, Muhammad Akram, Soo Kim, Chuan Wang, Zhiyin Liang, Henry Castro, Lida Pacaud, Mehdi Hamadani. LB1901: A phase 1, open-label, multicenter, multicohort study of CD4-targeted chimeric antigen receptor T cells (CD4-CAR-T) in relapsed or refractory T-cell lymphoma (TCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT215.

A first-in-human, phase 1 study of ASTX029, a dual-mechanism inhibitor of ERK1/2, in relapsed/refractory solid tumors.

9085 Background: Aberrant activation of the RAS-RAF-MEK-ERK pathway is common in human cancers. This is an open-label Phase 1 study of ASTX029, a dual-mechanism extracellular signal-regulated kinase 1/2 (ERK1/2) inhibitor, in subjects with relapsed/refractory solid tumors (NCT03520075). Methods: The primary objective is to identify a recommended Phase 2 dose. Subjects with relapsed/refractory solid tumors were eligible for Phase 1A with any molecular feature and for Phase 1B if the tumor demonstrated RAS or BRAF mutations. ASTX029 was administered orally daily on a continuous basis in 21-day cycles. Phase 1A was a modified 3+3 dose-escalation design based on dose-limiting toxicity (DLT) events. Phase 1B subjects were treated at the recommended dose for expansion (RDE) based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. Disease response was evaluated by RECIST v1.1. Results: 76 subjects were treated with at least one dose of ASTX029 in Phase 1A (n = 56) and Phase 1B (n = 20). In Phase 1A, ASTX029 was evaluated from 10 mg to 280 mg daily. Two subjects experienced grade 2 central serous retinopathy (CSR) within a few days of dosing at the 280 mg daily dose level (one event was declared a DLT). Both subjects recovered to baseline within days of dose interruption. CSR is an expected AE based on the class of drugs. At the selected RDE dose level of 200 mg daily, the mean PK exposure was 109% of target exposure (13,022 ng*hr/ml), defined as the level expected to have biological activity based on mouse models. As of the data cut-off of February 7, 2022, the most frequent grade ≥2 AEs experienced by subjects (≥5%) assessed as related to ASTX029 included ocular AEs (n = 6: all Grade 2); nausea (n = 7: all Grade 2); diarrhea (n = 6: 5 Grade 2, 1 Grade 3); fatigue (n = 4: all Grade 2); rash (n = 4, 3 Grade 2, 1 Grade 3). There were 52 serious AEs, all unrelated to ASTX029 except for one subject with Grade 3 malaise. Four subjects had a partial response, including KRAS-G12A BRAF-D549N non-small cell lung cancer (NSCLC; Phase 1A: 120 mg treated 20.0 months); KRAS-G12D pancreatic cancer (Phase 1A: 200 mg treated 2.1 months); KRAS-G13D NSCLC (Phase 1B; treated 10.6 months); KRAS-G12S NSCLC (Phase 1B; treated 10.4 months and ongoing). In all, two partial responses were observed out of 3 NSCLC subjects enrolled in Phase 1B. Phospho-ERK and phospho-RSK were evaluated for PD effect on fresh tumor biopsies obtained at baseline and cycle 2. A PD effect and decreased cell proliferation (Ki-67) were observed in 6 of 9 and 3 of 8 evaluable Phase 1B samples, respectively. The most common reason for ASTX029 discontinuation was disease progression. Conclusions: This Phase 1 study of the ERK1/2 inhibitor ASTX029 has identified a dose level of 200 mg daily continuously for investigation in the Phase 2 study. PK and PD data suggest target exposures are achieved with preliminary clinical activity, especially in KRAS-mutated NSCLC. Clinical trial information: NCT03520075.

Phase I, two-part, multicenter, first-in-human (FIH) study of DS-6000a in subjects with advanced renal cell carcinoma (RCC) and ovarian tumors (OVC).

3002 Background: Cadherin 6 (CDH6) is part of the cadherin family, which is involved with cell-cell adhesion, organ development, and epithelial-mesenchymal transition. CDH6 is found to be overexpressed in various cancers, particularly RCC and OVC. DS-6000a is an antibody-drug conjugate, comprised of an humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I (TOP1) inhibitor payload via a cleavable linker. DS-6000a specifically binds to CDH6 on the surface of tumor cells and is internalized upon binding. The payload is then released, resulting in target cell apoptosis. In preclinical studies, DS-6000a inhibited tumor growth and induced tumor regression in CDH6-expressing RCC and OVC. Here, we report initial results from a phase I trial of DS-6000a in patients (pts) with advanced RCC and OVC (NCT04707248). Methods: This dose-escalation (Part A) and expansion (Part B) study will recruit pts with advanced RCC and OVC. DS-6000a is administered IV as monotherapy on Day 1 of 21-day cycles. Part A assesses safety, tolerability, and maximum tolerated dose or recommended dose for expansion (RDE) using Bayesian optimal interval design; additional pts are enrolled to examine safety and efficacy. The starting dose of DS-6000a is 1.6 mg/kg followed by 3.2, 4.8, 6.4, 8, and 9.6 mg/kg. Part B will assess safety, tolerability and efficacy at the RDE. Results: Part A interim results are presented. At data cutoff (19 NOV 2021), 22 pts had enrolled (7 RCC, 15 OVC). All RCC pts had received an immune checkpoint inhibitor and the majority of OVC had platinum resistant (Pt-R) disease; median age was 63.5 years (range, 41-78); median of 4 (range, 1-12) prior lines of therapy were administered; and median treatment duration was 8.0 wks (range, 3-33.14). Fifteen pts (68.2%) were ongoing at the cutoff date. Treatment-emergent adverse events (TEAEs) occurred in 19 pts (86.4%). Related TEAEs occurred in 17 pts (77.3%). The most common related TEAEs (>20%) were fatigue and nausea (45.5% each), and vomiting (27.3%). Grade ≥3 related TEAEs occurred in 4 pts (18.2%); the most common was neutropenia (13.6%). One patient (4.5%) had a Grade 3 febrile neutropenia. One dose-limiting toxicity of Grade 4 thrombocytopenia (9.6 mg/kg) occurred. There was no study drug discontinuation due to a TEAE. Among 15 evaluable pts, 2 partial responses (PRs; 1 confirmed in RCC and 1 unconfirmed PR in Pt-R OVC) were observed; 9 pts had stable disease. Moreover, 5 out of 11 OVC evaluable pts showed CA-125 responses using GCIG criteria and all CA-125 responders had Pt-R disease. Conclusions: The interim data from dose-escalation of this FIH study showed acceptable tolerability with early signals of efficacy in heavily pretreated pts with advanced RCC and Pt-R OVC, which support further clinical evaluation of DS-6000a in the planned dose-expansion cohorts in advanced RCC and OVC. Clinical trial information: NCT04707248.

P-123 A phase Ia/Ib, open-label, dose-escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy in patients with advanced gastrointestinal cancers

Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 is therefore an attractive therapeutic strategy in oncology, but some early TRAILR2 agonists showed limited clinical success due to low efficacy or severe hepatotoxicity. The tetravalent bispecific antibody BI 905711 represents a novel, liver-sparing, TRAILR2 agonist, which cross-links TRAILR2 with cadherin 17 (CDH17) to induce CDH17-dependent TRAILR2 oligomerisation. CDH17, a membrane protein highly expressed in gastrointestinal (GI) cancers, is not expressed in normal hepatocytes. Thus, using CDH17 as a liver-sparing anchor may avoid hepatotoxicity while increasing selectivity to cancer cells. In preclinical models of GI cancer, including colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), BI 905711 showed activity both as a single agent and in combination with chemotherapeutic agents (Garcia-Martinez et al., Mol Cancer Ther 2021;20:96–108). Preclinical studies also showed synergism of BI 905711 and SoC chemotherapy, particularly irinotecan. This phase Ia/Ib open-label, multicentre study (NCT05087992) aims to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE), pharmacokinetics (PK), and preliminary efficacy of BI 905711 in combination with chemotherapy (FOLFIRI; irinotecan, leucovorin, and fluorouracil) with or without bevacizumab in patients with advanced, refractory GI cancers. Up to 100 patients with histologically or cytologically confirmed, advanced, unresectable or metastatic GI cancers will be enrolled. In phase Ia, approximately 20 patients with CRC will receive intravenous BI 905711 at escalating doses (starting dose 0.6 mg/kg) on day 3 of 14-day cycles, plus FOLFIRI and bevacizumab (5 mg/kg IV infusion over 30 mins) on day 1. BI 905711 dose escalation will be guided by a Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first two 14-day cycles). BI 905711 will be administered until disease progression, unacceptable toxicities or another reason requiring treatment discontinuation. In phase Ib, patients with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, patients who have progressed after prior oxaliplatin-based therapy will be randomised in a 2:1 ratio to receive FOLFIRI and bevazicumab with or without BI 905711. In the PDAC cohort, patients with CDH17-positive PDAC who have progressed after prior platin/gemcitabine-based first-line therapy will receive FOLFIRI plus BI 905711. In both cohorts, BI 905711 will be administered at the RDE determined in phase Ia. A safety run-in will be included in the PDAC cohort to confirm the RDE defined in phase Ia prior to enrolling further patients. Primary endpoints are the MTD based on the occurrence of DLTs (phase Ia), and confirmed objective response (OR) according to RECIST 1.1 (phase Ib). Secondary endpoints include PK assessments (phase Ia), progression-free survival, tumour shrinkage, duration of OR and disease control (phase Ib). Further endpoints include assessment of immunogenic response and pharmacodynamic biomarker modulation (including caspase activation and changes in circulating tumour DNA levels). Patient recruitment is active and the study is ongoing. NCT05087992. Medical writing assistance, supported financially by Boehringer Ingelheim Pharmaceuticals Inc., was provided by Jane Saunders of Ashfield MedComms, an Ashfield Health Company, during the preparation of this abstract. The authors received no direct payment. Boehringer Ingelheim.

A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 (ezabenlimab) and BI 754111 in patients (pts) with advanced solid tumors.

3095 Background: Preclinical data show that combining a murine double minute 2–tumor protein 53 (MDM2–p53) antagonist with immune checkpoint inhibitors produces anti-tumor effects in multiple tumor types. This Phase Ia/Ib study (NCT03964233) is assessing BI 907828, a MDM2–p53 antagonist, combined with immune checkpoint inhibitors in TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), pts with advanced/metastatic solid tumors received escalating doses of BI 907828 guided by a Bayesian Logistic Regression Model (starting dose 10 mg orally) plus ezabenlimab 240 mg (anti-PD-1 antibody) and BI 754111 600 mg (anti-LAG-3 antibody) every 21 days (q3w). Primary endpoint was the maximum tolerated dose (MTD) of BI 907828 based on the number of pts with dose-limiting toxicities (DLTs) during cycle one. During Phase Ia, other studies indicated a lack of added efficacy when BI 754111 was combined with ezabenlimab; therefore, the study design was updated to switch the dose escalation to the doublet combination of BI 907828 plus ezabenlimab. Results: A total of 11 pts received the triplet combination at 10/20/30/45 mg dose levels (DL; n = 3/3/3/2 respectively); all have discontinued treatment. No DLTs were reported in cycle one; MTD was not reached. As of 20th January 2022, 15 pts have received the doublet combination at 30/45 mg DLs (n = 10/5 respectively). One pt (45 mg) had a DLT during cycle one: G2 neutropenia. Four DLTs were reported after cycle one: G3 anemia (30 mg); G2 thrombocytopenia (45 mg); and G3 neutropenia and G4 thrombocytopenia (45 mg). G≥3 adverse events occurred in eight pts; most commonly anemia (n = 6), thrombocytopenia (n = 4) and lymphopenia (n = 3). There were no notable safety findings with BI 907828 45 mg q3w, the recommended dose for expansion (RDE) for BI 907828 monotherapy. Nine of the 15 pts who received doublet therapy were evaluable for response; four had a confirmed partial response (PR; 30 mg, n = 1; 45 mg, n = 3), two biliary tract carcinoma, one urothelial carcinoma, and one myxoid liposarcoma; one had an unconfirmed PR (30 mg) with adenocarcinoma (primary site intrahepatic cholangiocarcinoma). Four pts with liposarcoma and gastric cancer had stable disease. MTD will be reported. In Phase Ib, pts will receive the RDE of BI 907828 plus 240 mg ezabenlimab (q3w). Pts will be recruited to two cohorts: soft tissue sarcomas (liposarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma, synovial sarcoma and leiomyosarcoma) and selected MDM2-amplified tumors (NSCLC, gastric adenocarcinoma, urothelial carcinoma, and biliary tract carcinoma). Primary endpoints are progression-free survival and objective response (RECIST 1.1). Conclusions: The doublet combination of BI 907828 plus ezabenlimab showed a manageable safety profile and early signs of anti-tumor activity. Eleven pts remain on treatment; recruitment is ongoing. Clinical trial information: NCT03964233.

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).

3004 Background: The highly potent MDM2–p53 antagonist BI 907828 showed antitumor efficacy in vivo, particularly in TP53 wild-type, MDM2-amplified de-differentiated LPS (DDLPS) patient-derived xenografts and syngeneic models. This phase I study (NCT03449381) is assessing BI 907828 monotherapy in patients with advanced solid tumors, including LPS. In Part A (dose escalation), patients received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. Based on previously reported results from Part A (LoRusso ASCO 2021), the MTD was 60 mg q3w and the recommended dose for expansion (RDE) was selected as 45 mg q3w. Methods: In Part B (dose expansion), patients received BI 907828 45 mg q3w. The primary endpoint was PFS. Secondary endpoints/objectives included objective response rate, overall survival, the number of patients with grade ≥3 treatment-related AEs, and PK parameters. Here, we report overall safety data and efficacy data in the subgroup of patients with advanced LPS. Results: As of January 10, 2022, 90 patients had been enrolled; 49 (54.4%) were male, 55 (61.1%)/34 (37.8%) were ECOG PS 0/1, the median number of prior systemic therapies was 2 (range, 0–11), 44 had advanced LPS (28 DDLPS, 16 well-differentiated LPS [WDLPS]). At data cut-off, 31/90 patients (34.4%) had received treatment for ≥6 months. In the 41 evaluable patients with advanced LPS, best response of PR or SD was observed in 24/27 patients with DDLPS (88.9%) and 13/14 patients with WDLPS (92.9%). Two DDLPS and 4 WDLPS patients achieved a PR; all had MDM2-amplified disease. In Part A, 5/11 DDLPS patients and 4/8 WDLPS patients have achieved PFS ≥10.5 months. In the 42 patients who received the RDE of 45 mg q3w, 18 patients (42.9%) had grade ≥3 AEs; the most common grade ≥3 AEs were neutropenia (23.8%), thrombocytopenia (21.4%), and anemia (11.9%). Seven patients (16.7%) had SAEs; the most common were thrombocytopenia (4.8%) and pyrexia (4.8%). PK analysis showed that mean plasma exposures (Cmax and AUC0-inf) increased with dose and showed no significant deviation from linearity in the dose range 10–60 mg. A correlation was observed between exposure and GDF-15 levels in plasma, as a target engagement marker. Conclusions: BI 907828 showed a manageable safety profile, high plasma exposure, target engagement and encouraging signs of antitumor activity in patients with advanced DDLPS and WDLPS. The Part B dose expansion is ongoing. Clinical trial information: NCT03449381.

Model-based dose selection to inform translational clinical oncology development of WNT974, a first-in-class Porcupine inhibitor.

WNT974 is a potent, selective, and orally bioavailable first‐in‐class inhibitor of Porcupine, a membrane‐bound O‐acyltransferase required for Wnt secretion, currently under clinical development in oncology. A phase I clinical trial is being conducted in patients with advanced solid tumors. During the dose‐escalation part, various dosing regimens, including once or twice daily continuous and intermittent dosing at a dose range of 5–45 mg WNT974 were studied, however, the protocol‐defined maximum tolerated dose (MTD) was not established based on dose‐limiting toxicity. To assist in the selection of the recommended dose for expansion (RDE), a model‐based approach was utilized. It integrated population pharmacokinetic (PK) modeling and exposure–response analyses of a target‐inhibition biomarker, skin AXIN2 mRNA expression, and the occurrence of the adverse event, dysgeusia. The target exposure range of WNT974 that would provide a balance between target inhibition and tolerability was estimated based on exposure–response analyses. The dose that was predicted to yield an exposure within the target exposure range was selected as RDE. This model‐based approach integrated PK, biomarker, and safety data to determine the RDE and represented an alternative as opposed to the conventional MTD approach for selecting an optimal biological dose. The strategy can be broadly applied to select doses in early oncology trials and inform translational clinical oncology drug development.

Abstract P5-16-06: A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian cancer

Abstract Introduction: Despite initial efficacy, most patients (pts) with HR+/HER2– advanced breast cancer (BC) eventually progress on endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). In preclinical models, resistance to ET + CDK4/6i can be overcome by concomitant inhibition of CDK2. Therefore, simultaneous inhibition of CDK2/4/6 may provide a new therapeutic strategy to prolong clinical benefit. This first-in-human dose escalation/expansion study (NCT03519178) is evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of the first-in-class selective CDK2/4/6 inhibitor PF-06873600 (PF-3600) as monotherapy and combined with ET. The results of Part 1 monotherapy dose escalation and initial combination with ET are presented.Methods: This is a phase 1/2a, open-label, non-randomized, study of PF-3600 as monotherapy and combined with letrozole or fulvestrant (F). Pts with locally advanced/metastatic HR+/HER2– BC whose tumor progressed on previous ET + CDK4/6i and with ≤2 prior lines of chemotherapy (Cx), triple-negative breast cancer (TNBC) with ≤2 prior lines of Cx, and platinum-resistant ovarian cancer (OVCA) with ≤3 prior lines of treatment (Tx) were eligible for Part 1 dose escalation. Pts received escalating doses of PF-3600 (1–50 mg) BID orally. Dose escalation followed the modified toxicity probability interval method. Tx continued until disease progression, toxicity requiring discontinuation or pt withdrawal. Primary objectives for Part 1 were to evaluate safety including dose-limiting toxicities (DLTs) in the 1st 28-day cycle, adverse events (AEs), and laboratory abnormalities; and to select the recommended dose for expansion (RDE) in combination with ET. Results: As of 24 June 2021, 67 pts (HR+/HER2– BC, n=59; TNBC, n=2; OVCA, n=6) received PF-3600 (n=58) or PF-3600 + F (n=9). In the PF-3600 group, 22 (38%) and 36 (62%) pts had ECOG performance status (PS) 0 and 1, respectively. In the PF-3600 + F group, 6 (67%) and 3 (33%) pts had ECOG PS 0 and 1, respectively. The median (range) number of prior Tx in the metastatic setting was 4.0 (1, 8) for PF-3600 and 4.0 (3, 6) for PF-3600 + F. The most frequently reported treatment-related AEs (all grade/grade ≥3) for PF-3600 alone and PF-3600 + F, respectively, were nausea (50%/0% and 67%/0%), anemia (38%/14% and 44%/11%) and neutropenia (29%/16% and 22%/11%). Six (13%) of 48 DLT-evaluable pts treated with monotherapy had DLTs; all occurred at the highest doses (35 and 50 mg BID). At the RDE of 25 mg BID (PF-3600 alone, n=17; PF-3600 + F, n=9), there were no DLTs. PF-3600 exposure increased with dose, was not significantly impacted by F and at the RDE remained above the preclinical efficacious concentrations in most of the tested models for >70% of the dosing interval. The disease control rate was 48% (28/58, PF-3600) and 67% (6/9, PF-3600 + F) including 3 pts who remained stable for >13 mos with one ongoing for >28 mos. Three heavily pre-treated pts with HR+/HER2– BC (including prior ET + CDK4/6i and Cx) treated with PF-3600 alone had partial responses (2 confirmed), including 1 pt who remained on Tx for >13 mos. Modulation of cell cycle PD biomarkers (pRb and Ki-67) in paired tumor biopsies was observed. Data are not final and subject to change. Updated data will be presented.Conclusions: PF-3600 can be combined with ET with a manageable AE profile and demonstrates promising preliminary antitumor activity in heavily pretreated pts, including those with HR+/HER2– BC progressing on ET + CDK4/6i and Cx. Dose expansion in combination with ET in pts with HR+/HER2– BC with and without prior CDK4/6i Tx is ongoing. Citation Format: Timothy A. Yap, Cynthia Basu, Jonathan W. Goldman, Michael Gordon, Erika Hamilton, Adrianne Kelly, Feng Liu, Allison R. Moreau, Heather Neumann, Kyriakos Papadopoulos, Hope S. Rugo, Geoffrey I. Shapiro, Shaveta Vinayak, Li Zhou, Komal Jhaveri. A first-in-human phase 1/2a dose escalation/expansion study of the first-in-class CDK2/4/6 inhibitor PF-06873600 alone or with endocrine therapy in patients with breast or ovarian 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 P5-16-06.

Abstract P044: A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas

Abstract Background: PRMT5 catalyzes symmetric arginine dimethylation of protein substrates with important roles in cancer cell growth/survival, including glioblastoma (GBM) cells. PRT811 is a brain penetrant, potent, selective, oral PRMT5 inhibitor with preclinical efficacy in a GBM orthotopic model (Zhang AACR 2020). An open-label Phase I study of PRT811 in patients (pts) with advanced solid tumors and recurrent high-grade glioma (NCT04089449) is ongoing. Dose escalation results are presented herein. Materials and Methods: This study assesses the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary anti-tumor activity (RECIST v1.1, Lugano, & RANO) of PRT811 administered at varying doses/schedules (15-600 mg daily [QD]; 300 mg twice daily [BID]). Serum symmetric dimethylarginine (sDMA) and intron retention, a marker of PRMT5-mediated mRNA splicing fidelity, were assessed as measures of PRMT5 target engagement and function, respectively. Results: As of 18 June 2021, 38 unselected pts with recurrent or refractory disease had enrolled (22 solid tumor, 16 GBM). Median number of prior lines of systemic therapies was 2. No dose-limiting toxicities have been identified. Most frequent treatment-related adverse events (TRAEs), any grade, were nausea (n=10, 26%), vomiting (n=7, 18%), diarrhea (n=4, 11%), fatigue (n=4, 11%), constipation (n=3, 8%), and pruritis (n=3, 8%). Decreased lymphocyte count (n=1, 3%) and vomiting (n=1, 3%) were the only Grade ≥3 TRAEs. 28 pts discontinued treatment, mainly due to disease progression. No pts discontinued due to treatment-emergent AEs (TEAEs). PRT811 exhibited linear PK characteristics. At the highest evaluated dose (600 mg QD), Cmax,of 3777 nM, AUC of 12,487 nM.hr, and T½ of 5.8 hrs were observed. Comparison of PK parameters of 300 mg administered either QD or BID demonstrated similar PK with no accumulation with the BID schedule. Serum sDMA levels decreased by 80% with 600 mg QD. PRMT5-mediated mRNA splicing fidelity in peripheral blood mononuclear cells showed increased intron retention in specific transcripts at the higher PRT811 doses, indicating PRMT5 functional activity was decreased. A partial response was observed in 1 pt with GBM (>9 months duration) who remains on study. In addition, a pt with uveal melanoma (spliceosome SF3B1 mutation) achieved a 25% decrease in tumor burden per RECIST v1.1. An additional 3 pts with solid tumors had stable disease ≥6 mo. Conclusions: PRT811 was well tolerated with a favorable safety profile when administered at either QD or BID schedules. Target engagement and inhibition of PRMT5 functional activity were observed across multiple dose levels. Preliminary evidence of antitumor activity was observed in GBM and uveal melanoma. The expansion phase of the study will be initiated in select tumor types upon establishing the recommended expansion dose. Citation Format: Gerald S. Falchook, Jon Glass, Varun Monga, Pierre Giglio, David Mauro, John Viscusi, Peggy Scherle, Neha Bhagwat, William Sun, Rachel Chiaverelli, Eric Mintah, Lydia Clements, Tanner M. Johanns, Meredith McKean. A phase 1 dose escalation study of protein arginine methyltransferase 5 (PRMT5) brain penetrant inhibitor PRT811 in patients with advanced solid tumors, including recurrent high-grade gliomas [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P044.

Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study

Investigating the Addition of Ianalumab (VAY736) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL) on Ibrutinib Therapy: Results from a Phase Ib Study

ARC-12: Phase 1/1b Study to Evaluate Safety and Tolerability of AB308 + Zimberelimab (AB122) in Advanced Malignancies

Background: PD-(L)1 pathway inhibitors have demonstrated durable clinical benefit in both solid tumors and hematologic malignancies; however, as less than 1/3 of patients respond to anti-PD-(L)1 monotherapy, combination therapies may be needed for improved response rates and survival. T cell Immunoglobulin and ITIM domain (TIGIT) is expressed on activated T cell and natural killer (NK) cell subsets; TIGIT-CD155 binding suppresses T and NK cell function and inhibits the antitumor immune response. AB308, an Fc-enabled anti-TIGIT humanized IgG1 monoclonal antibody (mAb), has reversed TIGIT-CD155-mediated T cell inhibition in preclinical models. ARC-12 will assess whether TIGIT pathway blockade by AB308 can augment zimberelimab (zim; anti-PD-1 mAb) activity in patients with solid and hematologic malignancies.Study Design and Methods: ARC-12 is a phase 1/1b, first-in-human, open-label, dose-escalation study of AB308 + zim in patients with advanced solid tumors or hematologic malignancies. Dose expansion cohorts include relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). For the dose-escalation, eligible adults have solid tumors for which no standard-of-care therapy exists or have pathologically-confirmed R/R non-Hodgkin lymphoma (NHL) and have not received or are ineligible for allogeneic stem cell transplant or adoptive cell transfer; ≤5 lines of prior systemic therapy; ≥1 measurable lesion per RECIST (solid tumors) or Lugano Classification (NHL) criteria; and ECOG performance score of 0-1. As shown in the figure, patients will receive AB308 + zim intravenously (IV) once every 3 weeks (Q3W; Part A) or once every 4 weeks (Q4W; Part B). In Part A, the first 6 patients of Cohort 1 will follow 3+3+6 rules, allowing for AB308 dose adjustment if dose-limiting toxicities (DLTs) warrant; all other dose-escalation cohorts will use 3+3 rules. After the Cohort 2 DLT period has been cleared, Part B enrollment will begin in parallel with Part A to determine the recommended dose for expansion (RDE) for AB308 + zim for both the Q3W (Part A) and Q4W (Part B) schedules. Each part can independently proceed to dose-expansion once the RDE is determined for that dose schedule. In the dose-expansion, patients will be enrolled into disease-specific cohorts for non-small cell lung cancer (NSCLC), melanoma, gastrointestinal cancer, cervical cancer, and hematologic malignancies (DLBCL or MM). AB308 + zim may be dosed on either a Q3W or Q4W schedule; all patients in each expansion cohort will receive the same dose schedule. For both the dose-escalation and dose-expansion, the primary endpoints assess safety and tolerability of AB308 + zim; secondary endpoints include pharmacokinetics (PK), immunogenicity, and objective response rate for AB308 + zim. Additional secondary endpoints in the dose-expansion are disease control rate and duration of response. Safety and efficacy data will be analyzed using summary statistics and Kaplan Meier estimates as appropriate; PK parameters will be estimated using noncompartmental methods. ARC-12 is actively recruiting at sites in the United States (NCT04772989). [Display omitted] DisclosuresAilawadhi: Pharmacyclics: Consultancy, Research Funding; Takeda: Consultancy; Sanofi: Consultancy; Amgen: Consultancy, Research Funding; Ascentage: Research Funding; Genentech: Consultancy; AbbVie: Consultancy; BMS: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Medimmune: Research Funding; Cellectar: Research Funding; Karyopharm: Consultancy; Beigene: Consultancy; GSK: Consultancy, Research Funding. Foster: Arcus Biosciences, Inc.: Current Employment. Ryba: Arcus Biosciences, Inc.: Current Employment. Scharville: Arcus Biosciences, Inc.: Current Employment. El-Baghdady: Arcus Biosciences, Inc.: Current Employment. OffLabel Disclosure:AB308 and zimberelimab (AB122) are in clinical development and are not approved in the United States for the use under discussion.

A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies

Background: BR101801 not only blocks the signaling responsible for cell growth caused by PI3K, but also efficiently induces cell cycle arrest and apoptosis through inhibition of DNA-PK activation and stimulates decreasing stability of the oncogenic protein, c-Myc(AACR2020 abstract #655). This phase I study evaluated safety, tolerability, pharmacokinetics and preliminary activity of the BR101801 (PI3Kγ/δ and DNA PK inhibitor) in patients with advanced hematologic malignancies.Method: This is a Phase I, multi-center, open-label, first-in-human study. The Phase Ia (dose escalation) part of the study was designed to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of BR101801. BR101801 was administered orally once daily in 28-day cycles. The dose escalation part was initiated with a dose titration in the initial cohort, followed by a 3 + 3 design.Results: 11 patients were enrolled and have been treated at 4 dose levels: 50mg, 100mg, 200mg, 325mg and expanded 200mg through fifth cohort escalation. Pathological subtypes include 7 PTCL, 2 DLBCL, 1 MZBL and 1 composite CTCL/MF. 3 females and 8 males have been treated to date. Median age is 58 (range 30-71) and ECOG PS is in the range of 0-1. All patients had taken at least one prior chemotherapy. 10 of total patients have completed at least one cycle except 1 premature drop-out case due to disease progression. First interim analysis after completion of cycle 3 of the last patient of 200mg QD cohort had been conducted, which was to include 5 patients (1 DLBCL and 4 PTCLs). No DLT had been identified in Cohorts 1-3, and 2 patients discontinued the study treatment due to adverse event (G4 thrombocytopenia, not related to IP) and disease progression, respectively. The PK values from multiple dosing range of 50mg to 200mg cohort resulted in an approximate 2.92-fold and 4.97 fold increase in exposure based on Cmax and AUCtau, respectively. BR101801 PK profile showed that the exposure of concentration increased in a dose dependent manner and there was no accumulation observed in the dose range of 50mg to 200mg. 2 DLTs was observed at 325mg QD cohort. The dose was de-escalated to the previous lower dose level (200mg QD) and was expanded to 3 additional patients. The expansion cohort is ongoing at present. 2 of 11 patients had G3 skin reaction and 3 had G3 hepatotoxicites. All adverse effects were manageable and recovered to grade 0-1 upon BR1010801 discontinuation. Total 5 patients have been currently ongoing. For overall tumor response assessment, 4 SDs and 2 PRs have been obsereved.Summary/Conclusion: 200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL. This study is registered at clinicaltrials.gov identifier NCT04018248. DisclosuresKim: AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees. Curran: Servier pharmaceuticals and Amgen: Consultancy. Kim: Boryung pharmaceuticals: Current Employment.

A Phase 1a/b Dose Escalation Study of the Mutation Agnostic BTK/FLT3 Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory B-Cell Malignancies

A Phase 1a/b Dose Escalation Study of the Mutation Agnostic BTK/FLT3 Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory B-Cell Malignancies

A Phase 1a/b Dose Escalation Study of the Mutation Agnostic FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

A Phase 1a/b Dose Escalation Study of the Mutation Agnostic FLT3/BTK Inhibitor Luxeptinib (CG-806) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Abstract CT216: A Phase 1/2 Study of INCB000928 as Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104)

Abstract Background: Anemia represents a therapeutic challenge in patients with myelofibrosis (MF). ALK2 activation is associated with elevated hepcidin, which may contribute to anemia of chronic disease and anemia due to hematologic malignancies, and is associated with increased transfusion rate and reduced overall survival. This phase 1/2, open-label, multicenter, dose-escalation/dose-expansion study will evaluate the safety and tolerability of INCB000928, a potent, highly selective, ALK2 inhibitor, as monotherapy or combined with ruxolitinib in patients with anemia due to MF (INCB 00928-104; NCT04455841). Methods: Patients with histologically confirmed primary/secondary MF presenting with transfusion-dependent or symptomatic anemia will receive oral INCB000928 either alone (treatment group [TG] A) or combined with ruxolitinib (TGB). In TGA, patients must have intermediate (INT)-2 or high-risk (per Dynamic International Prognostic Scoring System [DIPSS]) disease that is intolerant, resistant, refractory, or has lost response to prior JAK inhibitor therapy (≥12 weeks). In TGB, patients must have received stable ruxolitinib therapy for ≥12 consecutive weeks before first dose and have INT-1/INT-2, or high-risk disease. Eligibility also requires age ≥18 y, ECOG PS 0-1 (dose-escalation) or 0-2 (dose-expansion), life expectancy >6 months, no other hematologic malignancy, no prior stem cell transplantation, no major surgery within 28 days, and no prior disease-directed therapy within 5 half-lives or 28 days of first dose. In Part 1 (dose escalation), TGA will receive INCB000928 monotherapy starting at 50 mg/day (28-day cycles). Dose-escalation will follow a Bayesian optimal-interval design to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE). Dose increases not exceeding 2-fold will continue until Grade ≥2 treatment-related toxicity occurs. TGB will receive INCB000928 plus ruxolitinib; INCB000928 dose escalation will start 2 dose levels below the highest dose determined to be safe and tolerable in TGA. In Part 2 (dose expansion), the RDE in TGB will be evaluated in combination with ruxolitinib in ~25 patients; treatment will continue for ≤12 months, and may continue if clinically beneficial and no progression occurs. Primary objective is to determine the safety and tolerability of INCB000928 as monotherapy or combined with ruxolitinib. Secondary objectives are to determine the efficacy of INCB000928 as monotherapy or combined with ruxolitinib (anemia response, duration of anemia response, mean change from baseline in hemoglobin, and RBC transfusion rate through weeks 24 and 48); evaluate INCB000928 pharmacokinetics; and evaluate effects of INCB000928 as monotherapy or combined with ruxolitinib on hepcidin levels and other measures of iron homeostasis and erythropoiesis. Citation Format: Stephen T. Oh, Jean-Jacques Kiladjian, Francesca Palandri, Jason R. Gotlib, Sanjay Mohan, Haris Ali, Ekatherine Asatiani, Francis Seguy, Feng Zhou, Srdan Verstovsek. A Phase 1/2 Study of INCB000928 as Monotherapy or in Combination with Ruxolitinib in Patients with Anemia Due to Myelofibrosis (INCB 00928-104) [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 CT216.

Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study

Novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population. This was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 μg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235. Between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 μg/kg and 45 μg/kg for patients with classical Hodgkin lymphoma and 80 μg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81). These results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma. ADC Therapeutics.

A first-in-human phase I study of ATR inhibitor M1774 in patients with solid tumors.

TPS3153 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response by sensing and responding to DNA replication stress, and by inducing cell cycle arrest to prevent aberrant replication and mitotic catastrophe. Based on extensive preclinical and limited clinical evidence, ATR inhibition is a promising treatment strategy as monotherapy for patients with advanced tumors harboring synthetically lethal conditions, such as alternative lengthening of telomeres (ALT) and inactivating mutations in ARID1A and ATM. M1774 is a potent, selective, orally administered ATR inhibitor that has been shown to exert antitumor activity in patient-derived xenograft tumors and acute myeloid leukemia xenograft tumors that express the ATR inhibition sensitizing mixed lineage leukemia fusion protein. This study (NCT04170153) aims to evaluate the safety and tolerability, maximum tolerated dose, recommended dose for expansion (RDE) and pharmacokinetics (PK) of M1774 (part A1), the effect of food on M1774 PK (part A2), and the efficacy of M1774 in patients with tumors harboring selected mutations (part A3). An additional objective is to assess the pharmacodynamics of M1774 by measuring relative changes in baseline p-CHK1 and γ-H2AX expression in paired tumor biopsies and serial blood samples. Methods: Patients aged ≥18 years, with an Eastern Cooperative Oncology Group performance status ≤1, adequate baseline hematological, renal and hepatic function, and with locally advanced or metastatic disease refractory to standard therapy are eligible. Patients with tumors bearing loss-of-function (LoF) mutations (determined by site testing or a central trial assay) in ARID1A, ATM, or ATRX and/or DAXX as ALT status surrogate markers; and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, will be enrolled in part A3. In the dose escalation phase (part A1 [open]), 18–24 patients are due to receive M1774 at a starting dose of 5 mg once daily. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. The preliminary food assessment (part A2) will follow a randomized two-sequence two-period crossover design in which ≤12 patients will be randomized (1:1) to receive a single dose of M1774 on Day –7 at the RDE (determined in part A1) in either a fed or fasted condition. After the food assessment, patients will subsequently receive M1774 according to the part A1 dosing schedule. In the preliminary efficacy study (part A3), patients (n = 20–24 for each of the three planned cohorts) with tumors harboring LoF mutations in the genes for ARID1A, ATM, ATRX and/or DAXX, will receive M1774 at the RDE. The primary efficacy endpoint is overall response (RECIST). The study is open and currently recruiting. Patients have been enrolled to seven cohorts in part A1 with no DLTs observed; dose escalation is ongoing. Clinical trial information: NCT04170153.