Phase Ib Study Research Articles

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine.

To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally. Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235.

Optimizing the dose of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody drug conjugate (ADC): A posthoc analysis of a phase 1b expansion study in ovarian cancer (319)

Optimizing the dose of upifitamab rilsodotin (UpRi; XMT-1536), a NaPi2b-directed dolaflexin antibody drug conjugate (ADC): A posthoc analysis of a phase 1b expansion study in ovarian cancer (319)

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

Phase Ib study of AVB-S6-500 (axl inhibition) in combination with durvalumab (MEDI4736) in patients with platinum-resistant, recurrent epithelial ovarian cancer (NCT04019288) (320)

OS158 - PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma

OS158 - PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma

OS125 - Safety, pharmacokinetics and efficacy of the novel pan-phosphodiesterase inhibitor ZSP1601 in 36 NASH patients: a double-blinded, placebo-controlled, multiple-dose escalation phase Ib study

OS125 - Safety, pharmacokinetics and efficacy of the novel pan-phosphodiesterase inhibitor ZSP1601 in 36 NASH patients: a double-blinded, placebo-controlled, multiple-dose escalation phase Ib study

A Phase IB Trial of the PI3K Inhibitor Alpelisib and Weekly Cisplatin in Patients with Solid Tumor Malignancies.

The PI3K inhibitor alpelisib has limited activity alone, but there is interest in combinations in platinum-resistant tumors. In this phase Ib study of alpelisib with cisplatin, the objective response rate measured 29% but adverse events limited dose intensity. These promising results provide rationale for studying combinations with better tolerated platinum agents.

Anlotinib combined with TQB2450 in patients with platinum-resistant or -refractory ovarian cancer: A multi-center, single-arm, phase 1b trial

SummaryThis is a phase Ib study of anlotinib plus a programmed death-ligand 1 (PD-L1) inhibitor TQB2450 for platinum-resistant or -refractory ovarian cancer. Thirty-four patients are enrolled and receive treatment. The objective response rate (ORR) is 47.1%, and the disease control rate is 97.1%. The median duration of response (DOR) has not been reached, and 61.3% of patients have a DOR of at least 8 months. The median progression-free survival (PFS) is 7.8 months, and the median overall survival (OS) has not been reached. The PD-L1-positive group has an ORR of 25.0%, whereas the PD-L1-negative group has an ORR of 92.9%. Treatment-related grade 3 or 4 adverse events (AEs) occur in 70.6% of patients, with the most common being hypertension (29.4%) and palmar-plantar erythrodysesthesia syndrome (29.4%). Anlotinib plus TQB2450 show promising antitumor activity and manageable toxicities in patients with platinum-resistant or -refractory ovarian cancer. A phase 3 randomized controlled trial to further validate our findings is ongoing.

P582: FIRST RESULTS OF A PHASE II STUDY (STIMULUS-AML1) INVESTIGATING SABATOLIMAB + AZACITIDINE + VENETOCLAX IN PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA

Background: The BCL-2 inhibitor venetoclax (VEN) in combination with a hypomethylating agent (HMA) has improved outcomes for patients with newly diagnosed (ND) acute myeloid leukemia (AML) who are unfit for intensive chemotherapy (IC; DiNardo CD, N Engl J Med, 2020); however, responses are often transient. Sabatolimab is a novel immuno-myeloid therapy targeting TIM-3, an immune regulator expressed on immune cells and myeloid leukemic progenitors but not on normal hematopoietic stem cells. Sabatolimab + HMA has shown promising durable responses in a Phase Ib study in patients with ND-AML and myelodysplastic syndrome (Wei AH, ASH 2021; NCT03066648). Treatment with sabatolimab + VEN + azacitidine (AZA) may also induce different pathways of cancer cell elimination. Aims: In this first presentation of the study, we report findings from the dose-escalation part of STIMULUS-AML1 (NCT04150029), a Phase II, single-arm study of sabatolimab + AZA + VEN in adult patients with AML. Methods: Adult patients with ND-AML ineligible for IC were enrolled. In dose-escalation part 1 (safety run-in), patients received either 400 mg (Cohort 1) or 800 mg (Cohort 2) sabatolimab every 4 weeks (Q4W) plus 400 mg VEN once a day every day, plus 75 mg/m2 AZA on Days (D) 1-7, or D1-5+D8-9, or D1-6+D8 of a 28-day cycle (Zeidan A, ESH-AML 2022). For the safety run-in part, the primary endpoint was assessment of the incidence of dose-limiting toxicities (DLTs) between Cycle 1 D8 and the end of Cycle 2. Results: As of the Sep 6, 2021 data cutoff, 18 patients have been treated in part 1 of the study with sabatolimab + AZA + VEN (Cohort 1, n=5; Cohort 2, n=13). Baseline demographics are shown in Table 1. Treatment was ongoing for 9 (50%) patients (Cohort 1, n=1; Cohort 2, n=8). Reasons for study treatment discontinuation included adverse events (AEs; n=3), progressive disease (n=3, including a case of chloroma), planned stem cell transplant (n=2), and physician decision (n=1). Only 1 DLT (elevated troponin T/asymptomatic myocarditis) was reported in Cohort 2 and no DLTs were reported in Cohort 1. Table 2 summarizes AEs observed in >20% of patients in the study. Consistent with AEs often observed during AZA + VEN therapy (DiNardo CD, N Engl J Med, 2020), the 5 most common AEs regardless of relationship to study treatment were constipation (all grades [gr]: 39%; gr ≥3: 0%) and hematologic events, including anemia (33%; 28%), decreased platelets (33%; 33%), neutropenia (39%; 39%), and febrile neutropenia (gr: 50%). Treatment-related AEs gr ≥3 in >25% of all patients included neutropenia (39%), decreased platelet count (33%), and decreased neutrophil count (28%). Treatment-related AEs led to study treatment discontinuation in 3 patients (platelet count decreased [n=2], troponin level increased/asymptomatic myocarditis [n=1]). AEs led to sabatolimab dose interruption in 6 patients, all in Cohort 2. No sabatolimab dose reduction was observed. Fourteen patients had dose interruption of VEN due to AEs. Five patients had dose reduction of VEN (none due to AEs). Serious AEs were reported in 14 (78%) patients; the most common was febrile neutropenia (44%). No other serious AEs were reported in >1 patient. Efficacy data will be presented at the EHA meeting. Image:Summary/Conclusion: Safety and tolerability of sabatolimab + AZA + VEN were comparable at 2 dose levels (400 and 800 mg) of sabatolimab and were overall comparable to the reported safety profile of VEN + AZA doublet therapy. These findings supported initiation of the expansion cohort of STIMULUS-AML1 at a sabatolimab 800 mg dose.

PB1849: TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY

Background: Treatment options for patients with AML who are not candidates for intensive chemotherapy (IC) are limited. The addition of venetoclax to hypomethylating agents demonstrated improved remission rates and survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive (DiNardo CD, N Engl J Med, 2020). Murine double minute-2 (MDM2) is a key negative regulator of tumor protein 53 (p53). Inhibition of the p53-MDM2 interaction results in up-regulation of the tumor-suppressive effect of p53. Siremadlin is a selective inhibitor of the p53-MDM2 interaction. Siremadlin + venetoclax has shown durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Findings from a first-in-human Phase I study with siremadlin demonstrated a tolerable safety profile and preliminary antitumor activity in patients with AML (Stein EM, Clin Cancer Res, 2021; NCT02143635). Preliminary results from the ongoing Phase Ib study exploring siremadlin in combination with venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Aims: Here we describe the study design of a Phase Ib/II study to assess the safety and efficacy of the novel combination of siremadlin + venetoclax + azacitidine in patients with AML who are unfit for IC (NCT05155709). Methods: The study will enroll approximately 55 adult patients with AML who are unfit for IC due to older age (≥75 y) or presence of comorbidities (cardiac or pulmonary, Eastern Cooperative Oncology Group performance status of 2 or 3). Patients with prior myelodysplastic syndrome, myelofibrosis, essential thrombocythemia, polycythemia, or therapy-related AML may also be eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated in 2 arms: patients with prior suboptimal response (no complete remission [CR], CR with partial/incomplete hematologic recovery [CRh/CRi], or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax + azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk clinical features that confer a low likelihood of response to venetoclax + hypomethylating agents (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). The study will consist of a safety run-in (Part 1) and expansion phase (Part 2; Figure). The safety run-in will evaluate safety across 2 siremadlin dose levels (20 or 30 mg) from Day (D)1 to D5 in each 28-d treatment cycle in combination with venetoclax and azacitidine. In Arm 1, pts will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. In Arm 2, venetoclax will be ramped up over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m2) will be administered from D1–D7 or from D1–D5, and D8 and D9). Upon confirmation of the recommended dose for expansion (RDE, determined for each arm separately), enrollment for the expansion phase (Part 2) will open; patients will be treated with siremadlin at the RDE in combination with venetoclax + azacitidine. The primary endpoints are incidence of dose-limiting toxicities (Arm 1 and Arm 2 separately) and CR rate (Arm 1 only). Secondary endpoints include safety and tolerability; CR rate (Arm 2 only); CR/CRh and CR/CRi rates; duration of CR, CRi, and CRh; overall survival; early mortality; MRD; and pharmacokinetics. Results: None, trial in progress. Image:Summary/Conclusion: None, trial in progress.

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 5176: Tumor dynamic model-based decision support for phase Ib immunotherapy combination studies

Abstract Background: Tumor growth inhibition (TGI)-overall survival (OS) models predict OS distributions and study outcomes (OS hazard ratio (HR)) in a number of cancers and settings (Bruno, Clin Cancer Res 2020;26:1787-95). Model-derived TGI metrics such as tumor growth rate (KG) have been considered as a promising early endpoint compared to classical response criteria (Gong J Clin Oncol 2020; doi: 10.1200/JCO.2020.38.15_suppl.9541). This work is assessing the validity of tumor growth rate estimates to inform GO/noGO decisions for Phase Ib studies. Methods: We resampled baseline characteristics and longitudinal sum of longest diameters (SLD, RECIST 1.1) from a positive Phase III study (IMpower150, Socinski, N Engl J Med 2018;378:2288-301) to mimic a Phase Ib study of 15, 30, or 40 patients per arm (atezolizumab +bevacizumab+carboplatin+paclitaxel (A+BCP) vs. BCP) with 10 months recruitment and 6 or 3 months follow-up (FU) after the last patient recruited. Effect sizes across A+BCP vs. BCP or BCP vs. BCP were calculated as geometric mean ratio (GMR) for KG, difference (d) in objective response rate (ORR), and HR for progression-free survival (PFS) and simulated OS. For this, individual KG were estimated using a bi-exponential model (Claret, Clin Cancer Res 2018;24:3292-8); ORR and PFS were estimated per RECIST 1.1, OS was simulated using a previously published TGI-OS model (Chan CPT:PSP 2021; doi.org/10.1002/psp4.12686) with 400 patients per arm bootstrapped from the 15, 30 or 40 patients of the resampled subsamples. Correct and incorrect Go decisions were based on the probability (prob) to achieve target effect sizes in A+BCP vs. BCP and BCP vs. BCP, respectively, across 500 replicated subsamples. Results: To not exceed an incorrect Go decision of 20% and for 40 patients/6 months FU, correct Go based on prob(KG GMR<0.90), prob(dORR>0.10), prob(OS HR<0.85) and prob(PFS HR<0.70) were 83%, 69%, 67% and 58%, respectively. For 40 patients/3 months FU, 30 patients/6 or 3 months FU, the ranking did not change and prob(KG GMR<0.90) correct Go decision rate remained around 80%. Conclusions: This evaluation suggests that model-based estimates of on-treatment tumor growth rate could be used as an exploratory endpoint to inform early clinical decisions. Expansion of this work is planned in other settings e.g. single-arm studies commonly used in early oncology clinical development. Citation Format: René Bruno, Mathilde Marchand, Kenta Yoshida, Phyllis Chan, Haocheng Li, Wei Zou, Francois Mercier, Pascal Chanu, Benjamin Wu, Anthony Lee, Chunze Li, Jin Y. Jin. Tumor dynamic model-based decision support for phase Ib immunotherapy combination studies [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 5176.

Abstract 5454: Amdizalisib (HMPL-689), a highly selective PI3Kδ inhibitor, exhibits potent anti-tumor activity in pre-clinical B-cell lymphoma models

Abstract Background: The delta isoform of PI3K (PI3Kδ) plays an important role in B-cell development and function by mediating the signaling of key receptors on B cells. Aberrant activation of PI3Kδ signaling pathway promotes the survival and proliferation of malignant B cells, making selective inhibition of this isoform a promising therapeutic approach for the treatment of B cell malignances. Amdizalisib (HMPL-689, Amdiz), discovered and being currently developed in a pivotal phase II clinical trial (NCT04849351) by HUTCHMED, is a highly potent and selective PI3Kδ inhibitor. Based on encouraging clinical data from the phase Ib study (2021 ESMO, abstract# 8330), Amdiz is a designated breakthrough therapy in China for treatment of relapsed and refractory follicular lymphoma. Herein, we report the pre-clinical anti-tumor activity of Amdiz. Methods: Kinase activity was measured by Transcreener™ Fluorescence Polarization assay. The kinome selectivity profile of Amdiz was evaluated in Eurofins KinaseProfiler™ panel containing 323 kinases. Cell based phosphorylation of AKT was determined by using Acumen Explorer system. CD63 expression in basophils was evaluated by FACS assay. Inhibitory effects of Amdiz alone or in combination with other agents on cell viability were investigated in a panel of B cell lymphoma cell lines by CellTiter-Glo luminescent or CCK-8 assay. The ability of Amdiz to inhibit the activation of B cells in animals was evaluated in naïve rats using an ex vivo assay, and B cell activation was determined by evaluating CD86 expression using FACS analysis. Human B cell lymphoma cell line derived xenograft models were used to determine the anti-tumor activity of Amdiz in combination with other agents such as rituximab, BTK inhibitor, and venetoclax. Results: Amdiz is a highly selective inhibitor of PI3Kδ, showing more than 250-fold selectivity over other PI3K isoforms and no significant inhibition over other 319 protein kinases at the concentration of 1 µM. Amdiz potently inhibited PI3Kδ in biochemical, cellular and human whole blood assays with IC50s ranging from 0.8-3 nM. Its inhibitory effects on cell viability were also evaluated in a panel of B -cell lymphoma cell lines. Results showed that Amdiz potently inhibited cell survival with IC50s from 0.005 to 5 μM. Amdiz showed a long-lasting and strong inhibition on B cell activation in a rat pharmacodynamics (PD) study at a dose as low as 0.1 mg/kg. Moreover, Amdiz significantly improved anti-tumor activity of standard-of-care agents as well as targeted agents in multiple B-cell lymphoma models both in vitro and in vivo. Conclusion: Amdiz is a highly potent and selective PI3Kδ inhibitor with strong activity against B-cell lymphoma in pre-clinical studies, supporting clinical evaluation as either a single agent or in combination with other therapeutic agents for the treatment of B-cell malignancies. Citation Format: Jia Hu, Jianhan Wang, Xiaoming Dai, Jianlin He, Junqing Liang, Ying Yu, Juntao Yu, Na Yang, Linfang Wang, Yu Cai, Xiong Li, Weiguo Qing, Yongxin Ren, Weiguo Su. Amdizalisib (HMPL-689), a highly selective PI3Kδ inhibitor, exhibits potent anti-tumor activity in pre-clinical B-cell lymphoma models [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 5454.

Abstract 1025: Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm

Abstract Background: Innovations in data science and trial design have catalyzed novel clinical research methods which may inform the future success of new experimental therapies more efficiently than previously believed. To guide development of the novel immune agent GEN-1, we compared endpoints experienced by patients from a recent neoadjuvant single-arm phase Ib study of GEN-1 plus standard chemotherapy to those of similar historical clinical trial patients in receipt of standard chemotherapy alone. Methods: To compare safety and efficacy endpoints following first-line neoadjuvant weekly GEN-1 immunotherapy and carboplatin and paclitaxel to standard first-line neoadjuvant carboplatin and paclitaxel in women with advanced ovarian cancer, we first applied key OVATION-1 trial (NCT02480374) inclusion and exclusion criteria to the Medidata Enterprise Data Store (MEDS) data to identify candidate historical clinical trial patients for comparison. We standardized and integrated patient-level MEDS data (N=41) from distinct phase I-III trials (enrollment years 2015-2016) with patient-level OVATION-1 data (N=18). Standard propensity score methods were used to identify MEDS patients who appeared similar to OVATION-1 patients to create a synthetic control arm (SCA). Results: Fifteen OVATION-1 patients (15/18, 83%) were matched to 15 (37%, 15/41) MEDS historical trial control patients. Matching attenuated pre-existing differences in attributes between the OVATION-1 and MEDS patients. The median progression-free survival time was not reached by the OVATION-1 group and was 15.8 months for the SCA. The hazard of progression for the OVATION-1 group relative to the SCA was 0.53 (95% CI 0.16, 1.73). Fourteen of 15 OVATION-1 patients (93.3%) and 15 of the SCA patients (100%, 15/15) had at least one MedDRA toxicity. Compared to SCA patients, OVATION-1 patients had a slightly higher incidence in nausea (OVATION-1 73.3%; SCA 53.3%), fatigue (OVATION-1 73.3%; SCA 33.3%), anorexia (OVATION-1 46.7%; SCA 13.3%), chills (OVATION-1 26.7%; SCA 6.7%), and infusion-related reaction (OVATION-1 26.7%; SCA 0%). Conclusions: The comparison of patient endpoints from a single-arm phase Ib trial to a historical clinical trial SCA provided informative and relatively reliable estimates of efficacy endpoints which were used to inform GEN-1’s expected effect study size in the phase II setting. This information led to a decrease in the number of planned patients for the subsequent randomized phase II trial. More broadly, this approach supports the ability of historical clinical trial patient comparisons to inform drug development via trial design, something which may further increase the scientific value of early phase trials. Citation Format: Xiang Yin, Ruthanna Davi, Elizabeth B. Lamont, Premal H. Thaker, William H. Bradley, Charles A. Leath, Kathleen M. Moore, Khursheed Anwer, Lauren Musso, Nicholas Borys. Phase Ib trial single-arm efficacy estimates via comparison to a historical clinical trial synthetic control arm [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 1025.

Intravenous tocilizumab for the treatment of giant cell arteritis: a phase Ib dose-ranging pharmacokinetic bridging study

BackgroundSubcutaneous tocilizumab (TCZ SC) is approved globally for giant cell arteritis (GCA). This phase Ib study investigated the pharmacokinetics, pharmacodynamics, safety, and exploratory efficacy of intravenous (IV) TCZ 6 and 7 mg/kg in patients with GCA. This study explored an IV dose resulting in a minimum exposure level within the range of effective trough concentrations achieved with TCZ SC dosing in GCA and not exceeding the exposure of the well-tolerated 8 mg/kg IV every 4 weeks (Q4W) in rheumatoid arthritis (RA).MethodsPatients with GCA who had received ≥ 5 doses of TCZ IV 8 mg/kg Q4W and achieved remission were enrolled. Patients received 5 doses of TCZ IV 7 mg/kg Q4W in period 1 and, if still in remission, 5 doses of 6 mg/kg Q4W in period 2. Pharmacokinetic endpoints were maximum concentration (Cmax), minimum concentration (Ctrough), area under the curve over a dosing interval (AUCτ), and mean concentration (Cmean) of TCZ after the last dose of each period. Other endpoints included pharmacodynamic markers, safety, and exploratory efficacy.ResultsIn 24 patients, the median (range) age was 65.5 (57–90) years, and 62.5% were female. TCZ exposures (Cmax and AUCτ) were 11.2% and 20.0% lower at the 6- than 7-mg/kg dose. The mean interleukin 6 (IL-6) serum concentrations were elevated at baseline and remained elevated, with slightly higher concentrations in period 1 than in period 2. The mean serum soluble IL-6 receptor concentrations were elevated at baseline and comparable between the 2 doses at steady state. C-reactive protein levels and most erythrocyte sedimentation rates were within normal ranges throughout the study. Overall, 22 patients (91.7%) had ≥ 1 adverse event, and 4 (16.7%) had a serious adverse event. No patients experienced a GCA flare, and all remained in remission throughout the study.ConclusionsBoth doses of TCZ IV Q4W were generally well tolerated in patients with GCA. The Cmax and Cmean achieved with 6 mg/kg IV Q4W in patients with GCA were similar to those in patients with RA treated with 8 mg/kg IV Q4W, and Ctrough was within the range observed in patients with GCA treated with SC dosing every week or every 2 weeks.Trial registrationClinicalTrials.gov, NCT03923738

EPCT-05. Phase Ib study of unesbulin (PTC596) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG): A report from the COllaborative Network for NEuro-Oncology Clinical Trials (CONNECT)

BACKGROUND: The B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) protein, implicated in self-renewal and DNA-damage signaling, is highly expressed in DIPG and HGG. Preclinically, BMI-1 modulation by unesbulin (PTC596 [which mediates hyperphosphorylation and subsequent degradation of BMI-1]) leads to DIPG/HGG cell proliferation blockade, mitotic abnormalities, and tumor cell sensitization to radiation-induced DNA damage. METHODS: This phase Ib study sought to determine the maximally tolerated dose/ recommended phase 2 dose (RP2D) of unesbulin administered concurrently with radiotherapy and adjuvantly in children with newly diagnosed DIPG or HGG. Patients were enrolled according to a Rolling-6 design and received oral unesbulin twice weekly during radiotherapy and as maintenance therapy. RESULTS: Twenty-seven patients enrolled (median age: 8.5 years [range: 2-18]), including 18 patients with DIPG and nine patients with HGG. Unesbulin was administered in capsule formulation in the first nine patients, then tablet formulation for subsequent patients. Within the capsule formulation group, three dose-limiting toxicities (DLTs) were observed in two patients on dose level 2 (grade 4 neutropenia). Within the tablet formulation group, four DLTs were experienced by three patients on dose level 2 (grade 3 ALT elevation, grade 3 dehydration/vomiting, grade 3 decreased ejection fraction, grade 4 neutropenia). Dose level 1 was declared the RP2D, and six additional patients enrolled in the expansion cohort at this dose without DLTs. Most common drug-related grade 3/4 toxicities were neutropenia (48%), leucopenia (35%), and elevated ALT (26%). Similar pharmacokinetic profiles were observed for capsule and tablet formulations, consistent with adult data. Survival outcomes and genomics results will be shared at time of presentation. CONCLUSIONS: The RP2D of unesbulin in children newly diagnosed with DIPG or HGG is 200mg/m2 twice weekly, concurrent with and following radiotherapy. The recently opened surgical cohort will assess intratumoral pharmacokinetics and inhibition of tumor BMI-1 signaling, with results forthcoming.

Efficacy and safety of IBI110 in combination with sintilimab in first-line advanced HER2-negative gastric cancer or gastroesophageal junction cancer: Preliminary results from a phase Ib study.

e16097 Background: Sintilimab plus XELOX has been proven to be efficacious in the first line treatment of gastric cancer. Dual inhibition of PD-1 and lymphocyte-activation gene 3 (LAG-3) may improve anti-tumor effect synergistically. IBI110 (anti-LAG-3 mAb) plus sintilimab (anti-PD-1 mAb) has shown preliminary antitumor activity in advance solid tumors. This phase Ib cohort study evaluated the safety and efficacy of IBI110 in combination with sintilimab and XELOX regimen for advanced HER2-negative gastric or gastroesophageal junction adenocarcinoma (G/GEJ AC) in first-line setting. Methods: This phase Ib study enrolled patients with previously untreated, unresectable, locally advanced or recurrent/metastatic HER2-negative GC/GEJAC. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W plus oxaliplatin and capecitabine (XELOX) until disease progression, unacceptable toxicity or death. The primary objective was to evaluate the safety and tolerability, and efficacy of the combination therapy. Results: As data cutoff January 20th 2022, 18 patients were enrolled, 6 patients had locally advanced/recurrent tumors, and 12 had metastatic tumors. The median follow up time was 4 weeks (range, 0-20). The median exposure of combination therapy was 9.4 weeks (range, 3-24). Any grade TRAEs occurred in 16 pts (88.9%); most commonly white bloo4d cell count decreased (n = 6; 33.3%), neutrophil count decreased (n = 6; 33.3%), and aspartate aminotransferase increased (n = 6; 33.3%). Grade ≥ 3 TRAEs occurred in 5 pts (27.8%), including neutrophil count decreased (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%), platelet count decreased (n = 2; 11.1%) and hepatic function abnormal (n = 2; 11.1%). Immune-mediated AEs occurred in 7 pts (38.9%); most commonly amylase increased (n = 2; 11.1%). One patient discontinued treatment because of the coronary artery disease. There were no treatment-related death. For 15 evaluable patients, the ORR and DCR were 60% (9 PR) and 100% (9 PR,6 SD), respectively. The median duration of response (DOR) and median progression free survival (PFS) were not reached. As data cutoff, 17 patients were still in treatment. Conclusions: In this phase Ib study, IBI110 in combination with sintilimab and chemotherapy was well tolerated in the first line treatment of G/GEJ AC and the clinical benefit need more follow up time to be elucidated. Clinical trial information: NCT04085185.

Sintilimab plus bevacizumab as maintenance therapy for patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization: A phase Ib study.

e16165 Background: Sintilimab (a PD-1 inhibitor) plus bevacizumab (Sin-Bev) has been demonstrated to confer a significant survival benefit over sorafenib in patients with unresectable hepatocellular carcinoma (uHCC). This phase Ib study (NCT04592029) aimed to evaluate the safety and efficacy of Sin-Bev for patients with uHCC who received transarterial chemoembolization (TACE). Methods: The key eligibility criteria were: age ≥ 18 years; BCLC B/C stage uHCC; no prior systemic therapy and non-curative local treatments; Child-Pugh score ≤7; ECOG PS ≤1. This study included dose escalation and dose expansion stages. In the dose escalation stage, a 3+3 design was employed to determine the safety of a standard dose of sintilimab (200 mg Q3W) plus two possible doses of bevacizumab (group A: 7.5 mg/kg Q3W; group B: 15.0 mg/kg Q3W) after TACE. In the dose expansion stage, additional 30 patients were randomized 1:1 to each group. Sintilimab and bevacizumab was started at 3-7 days after the first TACE (TACE was repeated on demand). The primary endpoints were the incidence of adverse events (AEs) and progression free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At the time of data cutoff (January 20th, 2022), 36 patients were enrolled (18 in each group). One patient in group A withdrew from the study after the first cycle of treatment. Of the remaining 35 patients, 20 (57.1%) had disease at BCLC C stage, 15 (42.9%) had macroscopic vascular invasion and 11 (31.4%) had extrahepatic metastasis. The mean largest tumor size was 10.5±5.2 cm. The median follow-up was 9.57 (range, 4.4-15.6) months. Thirty-one patients (86.1%, n=36) had treatment-related AEs (83.3% in group A vs. 88.9% in group B, P=1.000). All the AEs were mild (<grade 2) and manageable. During follow-up, 19 patients (54.3%) experienced disease progression (per RECIST 1.1 or mRECIST). The median PFS was 7.2 (95% CI 3.6-10.8) months (6.7 [95% CI 4.7-8.8] months in group A vs. 8.4 [95% CI 3.9-12.8] months in group B, P=0.832). The median PFS in this report was immature due to some later enrolled patients were censored. Thus, it is likely to improve with longer follow-up. The ORR per RECIST 1.1 and mRECIST was 37.1% (41.2% in group A vs. 33.3% in group B, P=0.733) and 80.0% (88.2 in group A vs. 72.2% in group B, P=0.402), respectively. The DCR per RECIST 1.1 or mRECIST was 91.4% (94.1% in group A vs. 88.9% in group B, P=1.000). The median OS was not reached. Conclusions: Sin-Bev showed preliminary clinical benefits and an acceptable safety profile in uHCC patients treated with TACE. The study is still ongoing and further follow-up is required to obtain the final survival results. Clinical trial information: NCT04592029.

Mitoxantrone hydrochloride liposome injection in the treatment of recurrent/metastatic head and neck cancers: A multicenter, open-label, single-arm, phase Ⅰb study.

e18028 Background: Mitoxantrone is an anthraquinone antibiotic antitumor agent, and mitoxantrone hydrochloride liposomes have been approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) in China. The current study aimed to evaluate the safety and efficacy of mitoxantrone hydrochloride liposome in patients (pts) with recurrent/metastatic head and neck cancers. Methods: This study is a multicenter, open-label, single-arm, phase Ⅰb study. The pts with histologically confirmed diagnosis of head and neck squamous cell carcinoma (including nasopharyngeal carcinoma) were enrolled. Mitoxantrone hydrochloride liposome was administered at 20 mg/m2 by an intravenous infusion, every 21 days (q3w, 1 cycle) until disease progression, intolerable toxic reaction, death, or withdrawal by investigator or patient decision (a maximum of 8 cycles). The primary objective was to determine the safety of mitoxantrone hydrochloride liposome. Secondary objective was to assess the efficacy of mitoxantrone hydrochloride liposome in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Efficacy assessment was performed every 2 cycles after dosing as per RECIST v1.1. Results: From July 8, 2021 through November 5, 2021, 34 pts with median age of 48 years (range 20-69 years) were enrolled, including 23 with nasopharyngeal cancer and 11 with non-nasopharyngeal cancer (5 with tongue cancer, 2 with hypopharynx, 2 with tonsil cancer, and 1 each with larynx and gum cancer). The most common treatment-emergent adverse events (TEAEs) were white blood cell decreased (41.2%), anemia (41.2%) and lymphocyte count decreased (29.4%). TEAEs were generally Grade (G) 1-2; 13 pts reported G3 TEAE. The summary of all-grade TEAEs (≥ 10%) are shown in the table below. Nineteen pts had undergone at least 1 efficacy evaluation (including 18 pts with nasopharyngeal cancer and 1 with non-nasopharyngeal cancer). The overall objective response rate (ORR) was 42.1% (8/19) and disease control rate (DCR) was 78.9% (15/19). ORR for nasopharyngeal cancer was 38.9% (7/18) and DCR was 77.8% (14/18). One case of hypopharyngeal cancer was evaluated as partial remission (PR). Conclusions: The preliminary data of mitoxantrone hydrochloride liposome has showed manageable safety and evidence of efficacy in pts with recurrent/metastatic head and neck squamous cell carcinoma. An expanded sample size is still needed for further validation in the future study. Clinical trial information: NCT04902027. [Table: see text]

Efficacy and safety of IBI110 (anti-LAG-3 mAb) in combination with sintilimab (anti-PD-1 mAb) in first-line advanced squamous non-small cell lung cancer (sqNSCLC): Initial results from a phase Ib study.

e21145 Background: Although PD-1/L1 inhibitors have shown efficacy in advanced/metastatic sqNSCLC, many patients do not respond to this treatment. More effective combination therapies are needed. The efficacy and safety of IBI110 in combination with sintilimab as first-line therapy for advanced sqNSCLC was evaluated in a phase Ib study. Here, we report the initial results. Methods: Eligible patients with previously untreated, unresectable, locally advanced or metastatic NSCLC were enrolled in cohort D. Patients received IBI110 200mg IV Q3W and sintilimab 200mg IV Q3W until disease progression, unacceptable toxicity or death, in combination with chemo regimen (paclitaxel 175 mg/m2 plus carboplatin) IV Q3W for 4 cycles. The primary objective was to evaluate the safety, tolerability and efficacy of the combination therapy. Results: Totally, 20 patients were enrolled (median age: 63 [range: 52-74]; male: n = 19; ECOG 1: n = 16). As of data cutoff date, Jan 20, 2022, median follow up was 3.3 months (range: 2.6-7.0). The median exposure of combination therapy was 15.1 weeks (range: 6-52). The objective response rate was 80% (16/20, 9 patients with ≥2 efficacy assessments were confirmed PR and 7 needed further confirmation). The median progression-free survival and overall survival were not reached. The most common treatment-related adverse events (TRAEs) included white blood cell count decreased (50%), alopecia (50%), anaemia (45%), asthenia (40%), neutrophil count decreased (35%), rash (35%), and hyperglycaemia (30%); most common TRAEs ≥ grade 3 were neutrophil count decreased (30%), and white blood cell count decreased (20%). Immune-related AEs occurred in 11 patients (55%) and most were grade 1-2. The biomarker analysis including LAG-3 and PD-L1 expression in tumor specimen was ongoing. Conclusions: IBI110 in combination with sintilimab in first-line advanced sqNSCLC showed promising anti-tumor activity with acceptable safety. The study is still ongoing. Clinical trial information: NCT04085185.

P-95 Bevacizumab, irinotecan and biweekly trifluridine/tipiracil for pretreated metastatic colorectal cancer: MODURATE, a phase Ib study

Treatment of refractory metastatic colorectal cancer (mCRC) with trifluridine/tipiracil yields some survival benefits. Trifluridine/tipiracil combined with bevacizumab or irinotecan suggested enhanced therapeutic effects in preclinical models. A phase Ib study combining standard trifluridine/tipiracil regimens with irinotecan resulted in better antitumor activity, accompanied by a high degree of febrile neutropenia. This phase Ib study of trifluridine/tipiracil, irinotecan, and bevacizumab in previously treated mCRC was conducted at two centers, Shizuoka Cancer Center and Aichi Cancer Center in Japan, and consisted of dose escalation (3+3 design) and expansion cohorts. Key eligibility criteria included histologically confirmed colorectal adenocarcinoma, failure or intolerant to fluoropyrimidine and oxaliplatin, no prior therapy with trifluridine/tipiracil and irinotecan, age of 20–75 years, and ECOG PS of 0–1. Patients received trifluridine/tipiracil (25–35 mg/m2 twice daily on days 1–5), irinotecan (150–180 mg/m2; day 1), and bevacizumab (5 mg/kg; day 1) every 2 weeks. The recommended phase II dose (RPTD) in the dose escalation cohort was administered to at least 15 patients in both cohorts. A total of 28 patients from two centers were enrolled between August 2016 and January 2020, comprising 18 in dose escalation cohort and 10 additional patients in expansion cohort. Five dose-limiting toxicities were observed in dose escalation cohort. RPTD was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of the 16 patients who received RPTD, patients characteristics were as follows; median age (range), 64 (38-73) years; male/female, 11/5; PS 0/1, 13/3; right-/left-sided tumor, 1/15; median number of metastatic site (range), 2 (1-5); RAS mutant/wild-type, 9/7; uridine diphosphate glucuronosyltransferase 1A1 genotype wild/single hetero/double hetero or homo, 7/8/1; prior history of bevacizumab/anti-EGFR antibody, 6/4. The most common grade 3/4 adverse events were neutropenia (86%) and leukopenia (63%) without febrile neutropenia. No treatment-related death was observed. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. At a median follow-up time (range) of 417 (346–611) days, the overall response rate was 19%, with 3 patients achieving a partial response. The disease control rate was 75%, with an additional 9 patients exhibiting stable disease for >4 months duration in 5 patients. The median progression-free survival and overall survival were 7.1 (95% confidence interval [CI], 3.7–not reached [NR]) months and 21.7 (95% CI, 11.3–NR) months, respectively. Biweekly administration of trifluridine/tipiracil, irinotecan, plus bevacizumab may decrease febrile neutropenia with moderate antitumor activity in previously treated mCRC patients. Further investigation of this combination therapy is required.