Expansion Phase Research Articles

Glofitamab Plus R-CHOP Induces High Response Rates with a Manageable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): A 12-Month Analysis from a Phase Ib Study

Background: Over a third of patients (pts) with DLBCL do not respond or relapse after first-line (1L) treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; Sarkozy and Sehn. Ann Lymphoma 2019); these pts have limited curative options. Glofitamab (Glofit) is a T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format that allows bivalent binding to CD20 on B cells; this enables combination with anti-CD20 antibodies, including rituximab. Glofit monotherapy has shown durable responses in pts with relapsed/refractory DLBCL (Dickinson et al. NEJM 2022). In the safety run-in and expansion phases of the ongoing NP40126 trial (NCT03467373), Glofit + R-CHOP demonstrated promising efficacy and manageable safety in pts with 1L DLBCL (Topp et al. ASH 2022). Here, we report durability of response beyond 12 months in Glofit + R-CHOP-treated pts with 1L DLBCL from the NP40126 trial. Methods: Pts received R-CHOP for 6-8 three-weekly cycles. Intravenous Glofit was given with step-up dosing during Cycle (C)2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards. Glofit maintenance was allowed for up to one year. Efficacy was analyzed in all pts who had been on the study long enough to have a protocol scheduled end-of-treatment response assessment. Safety was analyzed in all pts who received at least one dose of any study drug. Response was assessed by PET-CT using Lugano criteria (Cheson et al. JCO 2014). Cytokine release syndrome (CRS) events were graded using the American Society for Transplantation and Cellular Therapy criteria (Lee et al. Biol Blood Marrow Transplant 2019) and other adverse events (AEs) by the Common Terminology Criteria for Adverse Events (v4.0). Hospitalization was not mandated for Glofit. Results: As of April 4, 2023, 56 pts were enrolled in this cohort. Median age was 68 years (range: 21-84), 54 pts (96.4%) had Ann Arbor stage III/IV disease, and median International Prognostic Index (IPI) score was 3 (IPI 1: 3.6% [2/56], IPI 2: 33.9% [19/56], IPI 3: 35.7% [20/56], IPI 4: 23.2% [13/56], IPI 5: 3.6% [2/56]). The cell of origin was germinal center B-cell (GCB) in 25 (44.6%) pts and non-GCB in 11 (19.6%) pts. After 17.1 (range: 0-26) months of median follow-up, the best overall response rate was 92.9% (52/56) and the complete metabolic response (CMR) rate was 83.9% (47/56). Median time to CMR was 1.8 months (95% confidence interval [CI]: 1.6-4.7). Most CMRs (44/47; 93.6%) were ongoing at data cut-off ( Figure). Among complete responders, the Kaplan-Meier estimated probability of ongoing responses at 12 months was 91.5% (95% CI: 82.2-100). Median duration of response and duration of complete response were not reached at data cut-off. The incidence of AEs and serious AEs (SAEs) were similar compared with earlier analyses. Grade (Gr) ≥3 AEs occurred in 42 (75.0%) pts and Gr ≥3 AEs related to Glofit in 14 (25.0%) pts. SAEs were reported in 20 (35.7%) pts and SAEs related to Glofit in six (10.7%) pts. Gr 5 AEs were reported in four (7.1%) pts (COVID-19 pneumonia, n=3; infusion related reaction associated with rituximab, n=1). AEs leading to dose interruption of Glofit occurred in 12 (21.4%) pts. Median dose intensity was 100% for all R-CHOP components. AEs leading to discontinuation of Glofit occurred in one (1.8%) patient. CRS events were reported in six (10.7%) pts: Gr 1, n=4; Gr 2, n=2; no Gr 3/4 CRS events were reported. All CRS events occurred during C2-3. Tocilizumab was used in two (33.3%) pts with CRS. Neurologic AEs (NAEs) occurred in 23 (41.1%) pts (most common NAEs (>5%) were peripheral neuropathy, n=7 [12.5%]; paraesthesia, n=5 [8.9%]; insomnia, n=4 [7.1%]; headache, n=3 [5.4%]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No Glofit-related NAEs consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 26 (46.4%) pts (Gr ≥3 neutropenia: Gr 3, n=5; Gr 4, n=19). Infections and infestations were reported in 27 (48.2%) pts (of which the majority were Gr ≤2 [17/27]); Gr 3, n=7; Gr 5, n=3. Conclusions: Glofit + R-CHOP had a manageable safety profile with a low incidence of CRS, and continued to demonstrate durable responses with an improved CMR rate since the last data cut-off. These findings support the potential for favorable long-term outcomes with Glofit + R-CHOP as 1L treatment of DLBCL. Further analyses, including circulating tumor DNA data, will be presented.

A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background: Autologous CD19 CAR T cell therapies have demonstrated favorable clinical responses in relapsed or refractory (R/R) diffuse large B-cell lymphomas (DLBCL), but only a subset of patients (pts) experience durable remissions. We hypothesized that the redundancy of CD28 and CD3ζ signaling in a CAR design incorporating all 3 CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX, and hypothesized that a 1XX CAR would afford durable responses at lower dose and fewer toxicities compared to CARs comprising 3 ITAMs. We previously presented the data from the dose-escalation portion of the phase I clinical trial of 19(T2)28z-1XX CAR T cells in DLBCL (Park J et al. ASH 2022). We have now completed accrual and report the updated results from both dose escalation and expansion portion of the study with a longer follow-up (NCT04464200). Methods: This is a single-center, phase I, dose-escalation and expansion trial of 19(T2)28z1XX CAR T cells in adult pts with R/R DLBCL conducted at Memorial Sloan Kettering Cancer Center. Pts received fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by a single infusion of CAR T cells. There were 4 dose levels in the dose escalation cohort: dose level (DL) 1 (25x10 6), DL2 (50x10 6), DL3 (100x10 6) and DL4 (200x10 6 CAR T cells). The primary objective of the trial was to evaluate safety and tolerability and determine the recommended phase 2 dose. Key secondary objectives include assessment of overall response and complete response rates. Results: 28 pts have been enrolled and treated; 16 pts on the dose escalation and 12 pts on the dose expansion phase of the study. Median age was 62 (range, 48-86). 20 pts (71%) had primary refractory disease, 3 pts (11%) had prior autologous HSCT, and 2 pts (7%) had prior autologous CD19 CAR T therapy. In the dose-escalation phase (n=16), 15 pts experienced grade 1-2 CRS (94%) and no pt experienced ≥grade 3 CRS. Two pts (13%) experienced ICANS: 1 pt with grade 1 and 1 pt with grade 3 (Table 1). Eight pts received tocilizumab and 5 pts received corticosteroid. Complete response (CR) was observed in 11 of 16 pts (69%) and partial remission (PR) in 1 pt (6%) with overall response rate (ORR) of 75%. Responses were seen across all dose levels (Table 1). The lowest dose (DL1: 25x10 6) was selected for dose-expansion based on exposure-response analysis and 12 additional pts were treated at that dose level. In a pooled analysis of 16 pts who received DL1 dose (4 in dose escalation and 12 in dose expansion), 12 pts and 1 pt experienced grade 1-2 (75%) and grade 3 CRS (6%), respectively. Only 1 pt experienced ICANS (6%) at grade 3 (same pt who had grade 3 CRS), which was reversible and transient (Table 1). 11 pts received tocilizumab and 9 pts received corticosteroids. Twelve pts achieved CR (75%) and 2 pts (12%) PR with the best ORR of 87% (Table 1). A lower metabolic tumor volume (MTV) at screening but not at post-bridging was associated with a higher likelihood of achieving CR (p=0.039). With a median follow-up of 345 days (range, 33-1024), 4 pts experienced relapse (1 CR and 3 PR pts) and 16 pts have ongoing CR > 6 months (Figure 1). While CAR T cell persistence analysis is ongoing, 5 pts have CAR T cells detected beyond one year in ongoing CR including a patient treated at DL1 with detectable CAR T cells at 2 years. Conclusions: Treatment with 19(T2)28z1XX CAR T cells was shown to be safe with durable remissions with low rates of severe CRS (4%) and ICANS (7%). The overall CR rate of 71% is encouraging and appears durable with the majority of CR patients in ongoing remission > 6 months at a median follow-up of 345 days and with persisting CAR T cells. With more patients treated at DL1 with a longer follow-up, the study demonstrates a high efficacy of 19(T2)28z1XX CAR T cells at a dose significantly lower (25x10 6) than those of approved CD19 CAR T cells (100-300x10 6) and support that the 1XX single ITAM signaling domain may lead to enhanced efficacy of CD19 CARs and allow infusion of a lower T cell dose with favorable toxicity profiles.

Preliminary Safety and Efficacy of Venetoclax and Selinexor in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia: Selclax

Background: Survival rates for children and adolescent/young adults (AYAs) with relapsed or refractory acute myeloid leukemia (R/R AML) remain poor. Previous clinical trials have demonstrated that the selective inhibitor of nuclear export selinexor and the BCL2 inhibitor venetoclax are each safe and active when combined with chemotherapy in children with R/R AML (NCT02212561, NCT03194932). However, many patients are refractory to these combinations. Preclinical data indicate that selinexor and venetoclax are synergistic and that selinexor may abrogate resistance to venetoclax. We thus aimed to characterize the toxicity profile and explore preliminary activity of venetoclax and selinexor with chemotherapy in pediatric and AYA patients with R/R AML and report results from the dose escalation phase of the SELCLAX clinical trial (NCT04898894). Methods: SELCLAX is a Phase I and expansion cohort study of selinexor and venetoclax in combination with chemotherapy in pediatric and AYA patients with R/R AML. For the dose escalation phase, eligibility criteria included < 30 years of age, adequate organ function and performance status, primary refractory, early first relapse (< 12 months from initial diagnosis), relapsed and refractory to salvage, post-transplant relapse or second or greater relapse AML or acute leukemia of ambiguous lineage (ALAL). The primary endpoint was determination of the recommended phase 2 dose (RP2D) of venetoclax and selinexor with chemotherapy. In the dose level 1 (DL1) cohort, venetoclax was given at 360 mg/m 2 per dose (max 600 mg) on days 1-21 in combination with selinexor at 40 mg/m 2 on days 1, 8, 15. For dose level 2 (DL2), venetoclax was dosed as in DL1, and selinexor was dosed at 40 mg/m 2 twice weekly on days 1, 3, 8, 10, 15, 17. Chemotherapy (fludarabine 30 mg/m 2, cytarabine 2 g/m 2 ± granulocyte colony stimulating factor 5 mcg/kg [FLA(G)]) was given on days 16-20. Response was evaluated by blast percentage in day 8 and 15 peripheral blood and in day 15 and end-cycle bone marrow. Any patient with a two-log (100-fold) reduction in measurable residual disease (MRD) between baseline and Day 15 was designated an “exceptional responder” (ER). At the discretion of the treating physician, ER patients could continue venetoclax until day 28 with additional selinexor (DL1: day 22; DL2: day 22, 24); FLA(G) could either be omitted or given on days 30-34; omission of FLA(G) deemed a patient non-evaluable (NE) for dose-limiting toxicity (DLT). Evaluable patients were assessed for DLTs, and dosing was escalated according to a rolling-six design. Results: As of July 14, 2023, fifteen patients (aged 3-17 years) with R/R AML (n=14) or ALAL (n=1) were enrolled in the dose escalation phase ( Table 1). Nearly all patients had high-risk cytomolecular features: KMT2A-rearranged (n=5), NUP98-rearranged (n=5), -7/del(7) (n=3), or FUS::ERG (n=1). Seven patients were enrolled on DL1 (one NE, replaced); eight patients were enrolled on DL2 (two NE, replaced). In the DL1 cohort, one DLT was reported of grade 3 anorexia requiring nasogastric feeds; however, this was cofounded by a prior history of anorexia, mucositis, and poor dentition requiring extractions and restorations. At DL2, one patient experienced a hematologic DLT with failure to recover absolute neutrophil count above 500/uL and platelet count above 25,000/uL by day 43 from start of FLA(G). There were no DLTs in the other five evaluable patients in DL2 and no serious adverse events (AEs) reported. The most common Grade 3 or 4 AE was febrile neutropenia (16.7%). Of the evaluable patients, five of twelve (41.7%) achieved complete response (CR) or complete response with incomplete count recovery (CRi). One patient was an ER on Day 15 at DL2 and did not receive FLA(G); thus, this patient was not evaluable for DLT assessment. Six patients proceeded to hematopoietic cell transplant after protocol therapy, five of whom are alive to date. Conclusion: Venetoclax and selinexor with FLA(G) chemotherapy is a tolerable combination in pediatric and AYA patients with R/R AML. Early activity of this combination regimen was observed in some patients, including those with primary refractory or early first-relapsed AML. Enrollment of the dose expansion phase at DL2 is underway in two cohorts: venetoclax-naïve and venetoclax-exposed.

Duvelisib for Cytokine Release Syndrome Prophylaxis during CD19-Targeted CAR T Cell Therapy

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of patients with advanced non-Hodgkin lymphoma (NHL). However, treatment toxicity, including cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS), can be significant. Effective prophylactic strategies may reduce the frequency and/or severity of CAR T cell therapy while also expanding the pool of patients eligible for such therapy. Duvelisib is an oral inhibitor of the gamma and delta isoforms of phosphoinositide 3-kinases (PI3K), which is an active therapy for CLL/NHL with an established safety profile. In addition, prior work from our group and others has demonstrated that PI3K inhibition can prevent CRS in an in vitro model (Amatya et al. ASH 2022) and can enhance antitumor cytotoxicity of CAR-T cells. Consequently, we performed a trial of duvelisib for CRS prophylaxis in patients undergoing standard-of-care (SoC) CAR T-cell therapy for NHL (NCT05044039). This was a phase I trial with a 3 + 3 dose escalation and two-arm dose expansion phase. The trial enrolled patients with NHL eligible for SoC CAR T-cell therapy and adequate organ function. Herein, we report data from the dose escalation cohort and the first dose expansion cohort, treated with duvelisib BID from day -2 to +28. The primary outcome was safety and tolerability. Secondary outcomes included the incidence and severity of CRS and ICANS, overall response rate (ORR), and progression-free survival (PFS). 17 patients are included in this analysis, including 6 patients in dose escalation and 11 of 14 planned patients in dose expansion cohort A, with full enrollment of cohort A expected prior to presentation. Median age was 68 years (range: 28 - 79) and 53% were male. Diagnoses included DLBCL (n = 13), MCL (2), FL (1) and PBMCL (1). For CAR-T cell therapy, patients received axi-cel (10), liso-cel (4), brexu-cel (2) and tisa-cel (1). 3 patients were enrolled on dose level 1 (15 mg BID) and 3 patients were enrolled on dose level 2 (25 mg BID). No patients experienced a dose-limiting toxicity (DLT) during dose escalation and consequently, 25 mg BID was selected as the recommended dose for expansion. 75 adverse events (AEs) were considered possibly (73) or probably (2) related to duvelisib by study investigators, including 14 severe (grade ≥3) AEs. The most common AEs were blood count abnormalities (41), liver function test abnormalities (12), fatigue (8) and nausea (6). The majority of severe AEs were cytopenias (13) and one patient had grade 3 hypokalemia. 13 patients (77%) had AEs attributed to duvelisib, including 6 patients (35%) with severe AEs. 76% of patients (13/17) experienced CRS at a median of 5 days following cell infusion (range 2 - 9) (Figure 1A). In 71% of patients (12/17), the onset of CRS was after day 3. Most were grade 1 (65%) and no patients experienced severe (grade 3 - 4) CRS. The median duration of CRS was 1 day (range: 1 - 7). ICANS occurred in 41% of patients (7/17) at a median of 7 days (range 4 - 10) and 12% of patients experienced severe (grade 3-4) ICANS. The median duration of ICANS was 5.5 days (range: 4 - 11 days). Toclizumab was given to 65% of patients for treatment of CRS and 53% received steroids for CRS and/or ICANS. All 17 patients were evaluable for disease response. At day +30, the overall response rate (ORR) was 71% (12/17) with 47% achieving complete response (CR) rate. At day +100, the ORR was 64% (9/14) with 50% CR. Best response was CR in 71% of patients and stable disease in 18% of patients. No patients had progressive disease (PD) as best response. CAR T cell expansion by flow cytometry was robust at all dose levels, consistent with prior reports (Figure 1B). With a median follow up of 93 days (range: 28 - 406), 53% of patients were alive and in remission. PD occurred in 6/17 (35%) patients with a median time to progression of 89 days (range: 28 - 182). Three patients enrolled on the study have died. One died from disease progression on day +266. Two died in remission from neutropenic sepsis (day +50) and vaping-induced lung injury (day +144). Data from this ongoing phase I study suggests that duvelisib with SoC CAR T-cell therapy is safe and tolerable. Preliminary data from this study suggest that the addition of duvelisib to CAR T-cell therapy may prevent grade 3-4 CRS and also delay the onset of CRS. Although limited follow-up is available, the depth and duration of response is similar to published data for CAR T-cells in this setting.

A Phase 1, Open-Label, Dose Escalation and Dose Expansion Study of CLN-978 (CD19XCD3XHSA) in Patients with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (B-NHL)

Background: Patients with B-cell non-Hodgkin lymphoma (B-NHL) who are refractory to/or have relapsed (R/R) after treatment with anti-CD20 monoclonal antibodies, either alone or in combination with standard-of-care chemotherapy, have a poor prognosis. Response rates tend to decrease and duration of response shortens with each successive line. CD19 represents a significant target for the development of novel immunotherapies for the treatment of patients with R/R B-NHL, many of whom develop disease that is refractory to CD20-containing regimens. CD19-directed therapies approved for B-NHL include an Fc-enhanced anti-CD19 monoclonal antibody, a CD19-directed antibody-drug conjugate, and several CD19-directed CAR-T cell products. While CAR-T approaches are an important alternative for some B-NHL subtypes, many patients still relapse, and challenges remain with toxicity and accessibility in the community setting. Consequently, substantial unmet needs remain for effective treatments with broad applicability across B-NHL subtypes and practice settings. CLN-978 is a fully human, half-life extended, single-chain T cell engaging construct targeting CD19 and CD3, with a human serum albumin (HSA) binding moiety for half-life extension. Preclinically, CLN-978 effectively redirects T cells to kill CD19-expressing malignant cells and has demonstrated potent in vitro and in vivo efficacy against cancer cells expressing very low levels of human CD19. Study Design and Methods: This is a phase 1, open-label, multi-center, first-in-human, dose escalation, and dose expansion study of CLN-978 in patients with R/R B-NHL. Adult patients (≥ 18 years of age) with one of the following CD19+ B-cell histologies: diffuse large B-cell lymphoma - de novo or transformed, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, or marginal zone lymphoma (nodal, extranodal, or mucosa-associated) for whom there is no available approved standard therapy will be recruited. Other key eligibility criteria include: ≥ 2 lines of prior chemotherapy, Eastern Cooperative Oncology Group Performance Status 0-2. Key exclusion criteria include prior treatment with allogeneic hematopoietic stem cell transplantation or any other investigational CD19 x CD3 T cell engager. Prior CAR-T therapy, unconjugated or radio-conjugated CD19 mAb, and CD19 antibody-drug conjugate are allowed. The study consists of 2 parts: 1) a dose escalation phase commencing with accelerated titration in single-patient cohorts followed by a conventional 3+3 dose escalation design to identify the recommended phase 2 dose (RP2D) and 2) a dose expansion phase to further characterize the safety and preliminary efficacy of CLN-978 in disease-specific cohorts at the RP2D. CLN-978 will be subcutaneously (SC)-administered once weekly (QW) in 28-day cycles until progressive disease, intolerable toxicity, or a maximum of 24 cycles of treatment. Initial administration of CLN-978, inclusive of potential priming doses and the first target dose, will be administered on an inpatient basis. Subsequent doses may be given in the outpatient setting. Based on emerging data, less frequent administration schedules may be implemented in Cycle 4 and beyond as approved by the Safety Review Committee. Safety, pharmacokinetic (PK), pharmacodynamic, and preliminary efficacy assessments will guide the selection of the dose and schedule for further evaluation. The primary endpoint is safety. Key secondary endpoints include PK, anti-drug antibodies, overall response rate, duration of response, time to response, time to subsequent anti-lymphoma therapy, progression-free survival, and overall survival. Approximately 90 patients (30 in dose escalation and 60 in dose expansion) will be enrolled at approximately 6 sites in the U.S., reflecting both community and academic centers. The study is currently enrolling (NCT05879744).

Effective and Safe Molecular-Pharmacodynamic Once Weekly Dosing of Decitabine and Venetoclax Is a Highly Effective and Well-Tolerated Induction Therapy for AML: Interim Results of a Phase 2 Trial

Background: Hypomethylating agents (HMAs) (5-azacytidine or decitabine) combined with venetoclax (Ven) have become the new standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. However, myelosuppression and infectious complications are common adverse events of currently approved HMA/Ven regimens, requiring dose interruptions/delays that often undermine treatment goals. Previous studies have identified the minimum dose of decitabine needed to deplete DNA methyltransferase-1 (DNMT1) without causing cytotoxicity. Administration of a single venetoclax dose synergizes with low dose weekly decitabine by inhibiting de-novo pyrimidine synthesis - a major mechanism of resistance to HMAs. A recently reported retrospective experience has shown proof of concept for a regimen of once weekly low dose decitabine combined with a single weekly dose of venetoclax in MDS and AML. Here, we report the feasibility portion of an ongoing Phase II clinical trial evaluating tolerability and efficacy of a metronomic dosing of decitabine and venetoclax for treatment of older patients with AML. Aims: The primary endpoint of this study is percentage of patients who are able to continue on treatment during the 12-week induction period without dose interruptions or delays. The key secondary endpoints include best overall response, rate of Grade >3 adverse events, infections, and hospitalizations. Correlative studies evaluate DNMT1 depletion in bone marrow at the time of diagnosis and at week 12. Methods: This is a single arm open-label Phase II clinical trial (NCT05184842). Patients >18 years old with a diagnosis of AML, MDS, CMML, MDS/MPN, and MDS/AML not fit for intensive chemotherapy are eligible. Subcutaneous decitabine and oral venetoclax are administered on the same day, once a week at 0.2mg/kg and 400mg, respectively. A bone marrow exam and measurable residual disease (MRD) assessment by multiparametric flow cytometry (MFC) are performed following 12-week induction period. Results: Between June 2022 and April 2023, twenty patients on this study have completed the 12-week induction period, these included AML (n=14), MDS (n=2), MF (n=1), MDS/MPN (n=1), CMML (n=2). Median age was 75 and 50% of patients were minorities (Table 1). Seventeen patients (85%) were able to complete all 12 weeks of induction treatment without dosing interruptions or delays and only one patient (5%) had a dose interruption post-induction. There were no Grade > 3 non-heme therapy-related adverse events. Eight patients (40%) required hospitalization during the induction period and no patient required hospitalization post-induction. Of the 14 AML patients who have completed the 12-week induction period, the median age was 75 years old (63-87). At the end of induction, the ORR was 71% with 8 patients (57%) achieving a CR, 1 CRI and 1 PR; 5/8 CRs were MRD negative by MFC. At a median followup of 10.9 months, 7/14 (50%) responses are ongoing and 11/14 patients (79%) remain alive. Of the six patients with TP53 mutations, four achieved MRD-negative CR with transfusion independence and two with no response (one post-MPN AML and other with erythroid leukemia). During the induction period, four patients (29%) had progression of disease (POD). The primary refractory cases included one patient with post-MPN AML, one patient with FLT3-ITD and two patients with monocytic-M5 AML with RAS mutations. One of two patients with MDS, had an MRD negative CR and achieved transfusion independence while the other transformed to erythroid leukemia. Of the two patients with CMML, one had a CR with transfusion independence, and one with stable disease. The 30 and 60-day mortality was zero. Studies evaluating DNMT1 staining on bone marrow samples from patients treated on this study are ongoing. Summary/Conclusion: In this preliminary analysis we demonstrate safety and efficacy of weekly, low-dose, metronomic dosing of decitabine and venetoclax, by allowing frequent sustained drug exposure often not possible with standard HMA/Ven regimens. The minimal cytotoxic nature of this regimen allowed for blood count recovery without drug interruptions with a high rate of clinical responses. (Figure 1). Additional cohorts are being enrolled in an expansion phase of the study in order to more fully assess the efficacy of this regimen in subsets of AML and MDS patients, including patients with p53 mutations.

Mosunetuzumab Plus Polatuzumab Vedotin Demonstrates a Favorable Safety Profile and Efficacy in Patients (Pts) with Relapsed or Refractory (R/R) Large B-Cell Lymphoma (LBCL): Primary Analysis of a Phase Ib/II Study

Background: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. The ongoing Phase Ib/II GO40516 study (NCT03671018) investigates Mosun in combination with polatuzumab vedotin (Pola; M-Pola) in pts with B-cell non-Hodgkin lymphoma (B-NHL). The Phase II expansion phase of the M-Pola regimen (with conventional Mosun and Pola dose and dose schedule), showed an acceptable safety profile and promising anti-tumor activity in pts with R/R B-NHL at interim analysis (Budde et al. ASH 2021). With enrollment complete, we present full dose-expansion cohort results. Methods: Eligible pts had confirmed R/R LBCL (including diffuse LBCL not otherwise specified, high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma [tFL], and follicular lymphoma [FL] grade [Gr] 3b) and had received ≥1 prior line of therapy (including an anti-CD20 antibody). Treatment cycles were 21 days. Pola (1.8mg/kg; intravenous [IV]) was administered on Day (D) 1 of Cycles (C) 1-6. Mosun IV was administered with C1 step-up dosing to mitigate cytokine release syndrome (CRS), with the following dose and dose schedule: 1mg on C1D1, 2mg on C1D8, 60mg on C1D15 and C2D1, and 30mg on D1 of C3+. Pts with a complete response (CR) completed Mosun after C8, and pts with stable disease or partial response at the end of C8 continued Mosun for a total of 17 cycles. Primary endpoint was best overall response rate (ORR) by independent review committee (IRC) using Lugano 2014 criteria (Cheson et al. J Clin Oncol 2014). CRS events were reported using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: As of April 7, 2023, 98 pts received M-Pola in the dose-expansion cohort. Median age was 68.0 years (range: 20-88), 71.4% were male, 87.8% had de novo DLBCL, 8.2% had tFL, 4.1% had Gr 3b FL, 18.4% had HGBCL (including double/triple-hit lymphoma), 7.1% had bulky disease (≥10 cm), 51.0% had an International Prognostic Index score 3-5, and 85.7% had Ann Arbor stage III/IV disease. The median number of prior lines of therapy was 2 (range: 1-8), 35.7% had prior CAR-T therapy, and 11.2% had prior ASCT. Most pts (80.6%) were refractory to prior anti-CD20 therapy, 58.2% were primary refractory, 77.6% were refractory to their previous therapy, and 26.5% were refractory to CAR-T therapy. The median number of cycles received was 8 for Mosun (range: 1-17) and 6 for Pola (range: 1-6). Adverse events (AEs) occurring in ≥15% of pts were fatigue (42.9%), neutropenia (28.6%), nausea (26.5%), diarrhea (23.5%), pyrexia (23.5%), headache (21.4%), CRS (18.4%), chills (17.3%), and peripheral sensory neuropathy (16.3%). Gr 3/4 AEs that occurred in ≥5% pts were neutropenia (20.4%) and fatigue (7.1%). Gr 5 AEs occurred in 3 (3.1%) pts, of which 2 were due to COVID-19 pneumonia and 1 was due to pneumonia. None were considered related to treatment. CRS events were observed in 18.4% of pts: Gr 1 n=11, Gr 2 n=4, Gr 3 n=3. All CRS events were resolved by data cut-off. Three pts received tocilizumab, 2 pts had a vasopressor, 2 pts received high flow oxygen, and 2 pts required ICU admission for CRS. Mosun-related neurologic AEs potentially consistent with immune effector cell-associated neurotoxicity syndrome occurred in 5 pts (5.1%); all were Gr 1/2 except 1 Gr 4 encephalopathy event. Treatment-related neuropathy occurred in 25.5% of pts (all Gr 1/2). Eleven pts (11.2%) discontinued treatment due to AEs, of which 5 (5.1%) were treatment-related: 1 (1.0%) due to encephalopathy (Mosun-related) and 4 (4.1%) due to peripheral neuropathy (Pola-related). Investigator-assessed ORR and CR rate were 62.2% and 50.0%, respectively ( Table). Median duration of response was not reached (NR; 95% confidence interval [CI]: 11.6-NR); median duration of CR was NR (95% CI: 20.5-NR). Median progression-free survival was 9.6 months (95% CI: 5.6-18.6) and overall survival was 23.3 months (95% CI: 15.2-NR), with a median follow-up of 18.6 months (95% CI: 17.7-23.7). In pts with prior CAR-T therapy (n=35), the ORR and CR rates were 60.0% and 45.7%, respectively. In primary refractory pts (n=57), the ORR and CR rates were 56.1% and 40.4%, respectively. Conclusions: M-Pola continues to show a favorable safety profile and compelling efficacy in highly refractory pts, including those with prior CAR-T therapy and/or primary refractory disease. Primary analysis data, including IRC responses and biomarker analyses, will be presented.

Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Patients with Relapsed or Refractory CD20+ B Cell Lymphoma

The antibody-coupled T cell receptor (ACTR) platform is an autologous engineered T cell therapy combining the cell-killing ability of T cells and the tumor-targeting ability of coadministered antibodies. Activation of the T cell product ACTR707 is dependent on the engagement of antibody bound to target cells via the CD16 domain of the chimeric receptor (CD16V-CD28-CD3ζ). ACTR707 in combination with the anti-CD20 monoclonal antibody rituximab was evaluated in the ATTCK-20-03 study, a multisite, single-arm, open-label phase I trial in B cell non-Hodgkin lymphoma (NHL). The primary objectives of this study were to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Secondary objectives included evaluation of antitumor activity and ACTR T cell persistence. The study design included an ACTR707 cell dose escalation phase and an expansion phase at the RP2D. Escalating dose levels of ACTR707 in combination with rituximab were explored in 5 dose cohorts, with 25 subjects receiving study treatment. Subjects received lymphodepleting chemotherapy (cyclophosphamide 400 mg/m2/day and fludarabine 30 mg/m2/day) for 3 days, followed by rituximab 375 mg/m2 and, 24 to 48 hours later, a single dose of ACTR707. Additional doses of rituximab were administered every 3 weeks until disease progression, unacceptable toxicity, or investigator decision. Blood samples were collected at various time points to assess levels of rituximab, cytokines, inflammatory markers, and ACTR707 T cells. The overall response rate of ACTR707 plus rituximab was 56% (14 of 25) across all dose levels. Ten subjects (40.0%) achieved a complete response, with the longest duration of 586 days (range, 85 to 586 days), and 4 subjects (16.0%) experienced a partial response, with the longest duration of 130 days (range, 44 to 130 days). Only 1 case of cytokine release syndrome (grade 2) and no events of neurotoxicity were reported. There were no dose-limiting toxicities or events leading to death. ACTR707 plus rituximab resulted in only 1 adverse event (neutropenia), leading to study discontinuation of rituximab. The ATTCK-20-03 trial serves as proof of principle regarding the ACTR approach that potentially could be used with other antibodies targeting other markers in other malignancies. Although the ACTR707 program has been discontinued, these results may support other programs in the use of similar novel approaches of antibody-coupled T cell activation.

Research on two-phase thermo-hydrodynamic lubrication performance considering bubble dynamics

Gas-liquid two-phase fluid in the lubrication gap exist in many important engineering tribo-pairs. Based on the Reynolds equation, the bubble dynamics equation, and the full energy equation for two-phase fluids, the thermo-hydrodynamic lubrication problem in the lubrication gap is investigated. The evolution of the fluid phase composition with operating time and its impact on the thermodynamic properties are studied using the developed model. The mechanisms by which sliding velocity, clearance, surface dilatational viscosity, surface tension, and initial gas volume fraction affect two-phase fluid lubrication behavior are evaluated. The results show that hydrodynamic pressure-driven bubbles eventually condense in the dispersion area and have a major impact on the temperature distribution. Velocity and clearance affect the gas-phase expansion region and initial formation location in the steady state, respectively. The pressure amplitude, bubble expansion, and horizontal and vertical gas phase expansion in the dispersion zone were affected differently by surface dilatational viscosity and surface tension. It becomes difficult to preserve the initial gas-phase composition inside the pressure convergence zone when bubble migration is taken into account, which may be crucial for establishing gas-liquid two-phase lubrication.

A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors

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

Balancing urban expansion with a focus on ecological security: A case study of Zhaotong City, China

The conflict between socio-economic development and ecological environmental protection presents a significant challenge to achieving regional and urban sustainable development. In Zhaotong City, Yunnan Province, China, this conflict arises from the interplay between urban expansion and ecological environmental protection land, creating a fundamental tension between built-up and non-built-up ecosystems. This study focuses on investigating the spatial characteristics of expansion, constructing an ecological security pattern based on ecosystem service functions and sensitivity, and utilizing integrated models to simulate urban expansion paths and analyze their formation mechanisms. The results highlight that Zhaotong City has undergone rapid urban expansion, characterized by linear growth surrounding the central city, specifically in the east, north, and west directions. The expansion between urban areas exhibits a discontinuous dotted-star distribution, with concentrated urbanization and a distinct urban boundary observed in Zhaoyang District. In contrast, other areas experience scattered expansion, indicative of random land encroachment. Through simulation, three primary urban expansion axes are identified: the western town sprawl belt, central town development axis, and resource-rich town corridor. Ecological conflicts primarily arise in Zhaoyang District, Zhenxiong County, and Yanjin County. By combining these findings, the study analyzes the scenario pattern of urban expansion evolution in Zhaotong City, revealing a transition from the spreading spillover expansion of a single center (Zhaoyang and Ludian) during the circle expansion phase to a polycentric expansion and spreading spillover pattern centered around Zhaoyang District along three primary axial radial paths. In conclusion, this study contributes to our understanding of the challenges posed by the conflict between socio-economic development and ecological environmental protection in Zhaotong City. The findings underscore the importance of integrating ecological considerations into urban planning processes and highlight the need for sustainable development practices to achieve a harmonious coexistence between urban expansion and ecological security. The insights gained from this research offer guidance for fostering sustainable urban development in Zhaotong City and beyond.

Identification of Waterlogging-Prone Areas in Nanning from the Perspective of Urban Expansion

The objective of this study was to discern the spatial and temporal patterns of areas in Nanning that are susceptible to waterlogging, particularly during various phases of urban expansion. Furthermore, this study presents a proposal outlining strategies aimed at preventing and controlling waterlogging. These strategies are based on the integration of the concepts of sponge city and resilient city construction. This study employed remote sensing (RS) and geographic information system (GIS) techniques to provide technical support. The supervised classification method and normalized difference index method were utilized to compare and extract impervious surfaces in Nanning from 2013 to 2020. The present investigation utilized the acquired impervious surfaces to compute the fractal dimension as a weighting factor, incorporating a digital elevation model (DEM) for the purpose of conducting a hydrological analysis in ArcGIS. Based on the findings of the study, several conclusions can be derived. The following conclusions can be drawn from the study: (1) The fractal dimension of Nanning varied over the study period, with values of 1.32, 1.41, and 1.58 in 2013, 2017, and 2020, respectively. The distribution of impervious surfaces showed a decreasing trend from the city center to the periphery. Urban planning and construction activities have significantly influenced the distribution of impervious surfaces, resulting in a progressively more complex and unstable structure. (2) From 2013 to 2020, the urban expansion fractal dimension increased from 1.32 to 1.58, indicating a decrease in the stability of impervious surfaces. The areas with higher concentrations of impervious surfaces coincided with frequent waterlogging-prone areas. Furthermore, the distribution of waterlogging-prone points transformed from a concentrated pattern to a scattered one. (3) In terms of waterlogging prevention and control strategies, the old urban areas are recommended to be transformed into sponge city projects, and the new development areas are planned, designed and implemented with the concept of “resilience”.

New records of non-native Coleoptera in Italy.

In the last decades, climate change and globalisation have been exacerbating the introduction of non-native beetles worldwide. Due toits peculiar territory, climate and geographical position in the middle of the Mediterranean Basin, Italy is one of the European countries with the highest number of intercepted, adventive and established non-native beetles, some of which are invasive. In this perspective, producing new faunistic records and continuously updating reliable and easily accessible distributional data is a fundamental step in investigating and potentially preventing further species introduction. The aim of this contribution is to report and discuss new faunistic records of non-native Coleoptera in Italy. For some species, new records enlarge the previously-known distribution (e.g. the ambrosia beetles Anisandrusmaiche (Kurentzov, 1941) and Cnestusmutilatus (Blandford, 1894) or the click beetle Monocrepidiusposticus (Eschscholtz, 1829)), while for others (e.g. the scarab beetle Archophileurusspinosus Dechambre, 2006), data confirm their establishment and highlight a possible expansion phase. The false powderpost beetles Ptilineurusmarmoratus (Reitter, 1877) and the longhorn beetle Xylotrechuschinensis (Chevrolat, 1852) are two new additions to the Italian fauna, while the establishment of the monotomid beetle Monotomaamericana Aubé 1837 is confirmed.

A possible mechanism for the formation of an eastward moving auroral spiral

The generation process of auroral spirals is described by different theories varying for their morphology and surrounding conditions. Here, a possible mechanism is proposed for an eastward moving auroral spiral, which was observed in Tromsø, Norway, during the expansion phase of a substorm on 18 September 2013. Measurements from the THEMIS-A and Cluster spacecraft were analyzed, which were located up to ∼10 RE duskward from the spiral generator region in the magnetosphere. Precursory to the spiral observation, concurrent magnetic field dipolarizations, flow bursts and electron injections were measured by the Cluster satellites between 13.6 and 14.2 RE radial distance from Earth. A local Kelvin-Helmholtz-like vortex street in the magnetic field was detected at the same time, which was likely caused by bursty bulk flows. The vortex street was oriented approximately in the X-Y (GSE) plane and presumably propagated towards the source region of the spiral due to a high dawnward velocity component in the flow bursts. The observations suggest that the spiral can have been generated by an associated vortex in the magnetotail and then mapped along the magnetic field lines to the ionosphere. To better understand the role of the ionosphere in auroral spiral generation, in future more mesoscale observations are required.

Integration of a Gamma-Type Stirling Engine with LPG Cooking Stove for Micro-Scale Combined Heat and Power Generation

The Stirling engine is one of the most versatile micro-scale prime movers for combined heat and power applications, adaptable to different levels of heat sources. This study started a unique journey that included developing, experimenting, and analyzing the Gamma-type Stirling engine. Notably, the engine design ingeniously harnesses heat from a customized cooking stove burner powered by liquefied petroleum gas. The engine fabrication resulted in a compression ratio 2.014, accommodating a volumetric capacity of 181 cc. The Stirling engine test used air as the working gas, and the initial conditions were at atmospheric pressure. Stirling engine performance was analyzed using an ideal thermodynamic cycle model and burner efficiency using the water boiling method. The modified burner attains an average temperature of 699.5°C, producing a burner power output of 5.702 kW and a thermal efficiency of 32.7% or around 1.867 kW of heat for operating the engine and cooking activities. Simultaneously, tests of the Stirling engine revealed an average air temperature difference of 146.2°C between the expansion and compression phases. The flywheel rotation speed ranges from 158 to 369 rpm. During testing, the Stirling engine obtained an average thermal efficiency of 31.08%, accompanied by an ideal power spectrum ranging from 0.3 W to 42.6 W. The highlight of this study was the maximum pressure achieved at the end of the heat absorption stage, recorded at 296.1 kPa. Importantly, these findings underscore the promising potential of micro-Combined Heat and Power systems. Integrating the gamma-type Stirling engine with the LPG stove represents novelty and paves the way for further development and advancement in sustainable energy solutions.

The idea of a democratic university

This article sets the current crisis of universities in the UK in its recent historical, post–1960s context. It argues that an expansionary and initially broadly progressive phase of development from the 1960s onwards, lasting for twenty-five or so years, has come in the recent neoliberal decades to be seen as a threat to the dominant social order, in the context of a broader resistance to the egalitarian and democratic trends of post-war British society. Since the 1980s this now large sector of social and cultural production and reproduction has been subject to a purposeful restructuring, to render it consistent with the norms of a society dominated by capital. This restructuring can be broadly understood as taking place within a neoliberal framework of assumptions. Unless this wider situation, and the changes which have led to them, is understood, in historically and theoretically coherent terms, resistance to what is happening is unlikely to succeed. The article first discusses the phase of university expansion, the forces which brought it about, and the social and cultural changes and opportunities to which it gave rise. It then discusses the counter-reaction, and the attempts to remodel the practices and institutions of higher education that constitute its active elements. Finally it explores what might be involved in resetting this path of development in a more positive direction, and considers the many theoretical and political difficulties involved in imagining this and making it possible. Here it argues the need for a dismantling of the graduate meritocracy over society, and for bringing into being an educated democracy. It is crucial to create the conditions for a broad debate on the place and function of universities in our society, in which these larger issues of direction and purpose can be debated. The author notes, however, that only in a society that becomes less grossly unequal than ours is it possible to imagine education being designed or indeed allowed to serve these generally democratic and enabling purposes.

Envelope ejection and the transition to homologous expansion in common-envelope events

ABSTRACT We conduct a long-time-scale ($5000\,$ d) 3D simulation of a common-envelope event with a $2\, {\rm M}_{\odot }$ red giant and a $1\, {\rm M}_{\odot }$ main-sequence companion, using the moving-mesh hydrodynamic solver manga. Starting with an orbital radius of $52\, \mathrm{ R}_{\odot }$, our binary shrinks to an orbital radius of $5\, \mathrm{ R}_{\odot }$ in $200\,$ d. We show that over a time-scale of about $1500\,$ d, the envelope is completely ejected, while 80 per cent is ejected in about $400\,$ d. The complete ejection of the envelope is solely powered by the orbital energy of the binary, without the need for late-time reheating from recombination or jets. Motivated by recent theoretical and observational results, we also find that the envelope enters a phase of homologous expansion about $550\, \rm d$ after the start of our simulation. We also run a simplified 1D model to show that heating from the central binary in the envelope at late times does not influence the ejection. This homologous expansion of the envelope would likely simplify calculations of the observational implications such as light curves.

Investigation of the Multimechanism Laser Cleaning Dynamics for Rough Fused Silica Surfaces with Organic Contaminants: A Computational Simulation and Atomic Analysis.

The detrimental impact of organic contaminants on optical components poses a significant obstacle to high-energy laser systems. However, irregularities or defects on the surface of optical components during manufacturing can affect the process of organic contaminant removal. Thus, a comprehensive understanding of the intricate interplay among surface roughness, contaminant absorption, and ablation is essential to effectively address the challenges of laser-induced damage. In this study, a molecular dynamics approach was employed to investigate the interaction between laser-fused silica and contaminants and to analyze the influence of surface roughness on the removal of contaminants from fused silica. Research findings demonstrate that during laser irradiation, organic contaminants on the surface of mechanical components diffuse into the optical elements. As the laser flux increases, the contaminants gradually decompose into smaller molecular clusters. Additionally, the phenomenon of contaminant ablation is observed to consist of two distinct phases: the "Thermal expansion phase" and the "Thermal ablation phase." The study examines the impact of substrate roughness on the contaminant removal in these two phases. It is found that a higher surface roughness leads to stronger thermal expansion and vaporization of contaminants. With increasing roughness of the fused silica substrate, the corresponding van der Waals energy and pressure decrease under the same laser fluence, making the removal of contaminants easier. These results provide valuable insights into the interaction between laser irradiation and organic contaminants.

Nanotopographical Cues Tune the Therapeutic Potential of Extracellular Vesicles for the Treatment of Aged Skeletal Muscle Injuries.

Skeletal muscle regeneration relies on the tightly temporally regulated lineage progression of muscle stem/progenitor cells (MPCs) from activation to proliferation and, finally, differentiation. However, with aging, MPC lineage progression is disrupted and delayed, ultimately causing impaired muscle regeneration. Extracellular vesicles (EVs) have attracted broad attention as next-generation therapeutics for promoting tissue regeneration. As a next step toward clinical translation, strategies to manipulate EV effects on downstream cellular targets are needed. Here, we developed an engineering strategy to tune the therapeutic potential of EVs using nanotopographical cues. We found that EVs released by young MPCs cultured on flat substrates (fEVs) promoted the proliferation of aged MPCs while EVs released by MPCs cultured on nanogratings (nEVs) promoted myogenic differentiation. We then employed a bioengineered 3D muscle aging model to optimize the administration protocol and test the therapeutic potential of fEVs and nEVs in a high-throughput manner. We found that the sequential administration first of fEVs during the phase of MPC proliferative expansion (i.e., 1 day after injury) followed by nEV administration at the stage of MPC differentiation (i.e., 3 days after injury) enhanced aged muscle regeneration to a significantly greater extent than fEVs and nEVs delivered either in isolation or mixed. The beneficial effects of the sequential EV treatment strategy were further validated in vivo, as evidenced by increased myofiber size and improved functional recovery. Collectively, our study demonstrates the ability of topographical cues to tune EV therapeutic potential and highlights the importance of optimizing the EV administration strategy to accelerate aged skeletal muscle regeneration.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial

Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. Akeso Biopharma. For the Chinese translation of the abstract see Supplementary Materials section.