Determine Dose-limiting Toxicities Research Articles

Phase I/II trial of plinabulin in combination with nivolumab and ipilimumab in patients with recurrent small cell lung cancer (SCLC): Big ten cancer research consortium (BTCRC-LUN17-127) study

BackgroundPlinabulin is a GEF-H1 releasing agent with an immune-enhancing function. We report results from a multicenter Phase I/II study (NCT03575793) assessing plinabulin in combination with nivolumab and ipilimumab for the treatment of recurrent SCLC. MethodsIn Phase I, patients were enrolled using a 3 + 3 design to determine dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg), and plinabulin (in escalating doses) on day 1 of each 21-day cycle for 4 cycles followed by maintenance with plinabulin and nivolumab. In phase II, patients with recurrent PD(L)1 inhibitor resistant SCLC were enrolled. The primary objective was median progression-free survival (PFS). ResultsBetween 9/2018 and 2/2023, 39 patients were enrolled, and 36 patients received study treatment and were evaluable for safety (16 in Phase I; 20 in Phase II). In the phase I dose-escalation, there were 2 DLTs; grade 3 altered mental status lasting <24 h and grade 3 infusion reaction. The Plinabulin RP2D was determined to be 30 mg/m2. Common TRAEs were vomiting (44 %), nausea (42 %), and infusion reaction (36 %); 6 % of patients had a ≥grade 3 TRAE. Five patients (14 %) had ≥grade 3 irAEs; there were no cases of immune-related pneumonitis. In the efficacy analysis in 27 patients, the median PFS was 1.6 months (95 % CI 1.2 to 2.7) and the trial did not meet the pre-specified target median PFS of 3.5 months. Four patients treated at 30 mg/m2 had PR (confirmed 1, unconfirmed 3); 5 patients had SD with a CBR of 33 %. Two of 8 patients treated in phase I at the lower 20 mg/m2 dose had confirmed PR, with 1 patient on the drug regimen for >90 cycles. The median OS and follow-up time were 5.5 months and 2.5 months respectively. ConclusionsPlinabulin in combination with nivolumab and ipilimumab was tolerable at the dose of 30 mg/m2. While the clinical responses in PD-1 resistant SCLC were limited, some patients had a long duration of response. The number of ≥grade 3 irAE with the combination were lower than expected.

Stereotactic central/core ablative radiation therapy: results of a phase I study of a novel strategy to treat bulky tumor

PurposeBulky tumor remains as a challenge to surgery, chemotherapy and conventional radiation therapy. Hence, in efforts to overcome this challenge, we designed a novel therapeutic paradigm via strategy of Stereotactic Central/Core Ablative Radiation Therapy (SCART).), which is based on the principles of SBRT (stereotactic body radiation therapy and spatially fractionated radiation therapy (SFRT). We intend to safely deliver an ablative dose to the core of the tumor and with a low dose at tumor edge. The purpose of the phase 1 study was to determine dose-limiting toxicities (DLT)s and the Maximum Tolerated Dose (MTD) of SCART.Methods and materialsWe defined a SCART-plan volume inside the tumor, which is proportional to the dimension of tumor. VMAT/Cyberknife technique was adopted. In the current clinical trial; Patients with biopsy proven recurrent or metastatic bulky cancers were enrolled. The five dose levels were 15 Gy X1, 15Gy X3, 18GyX3, 21GyX3 and 24GyX3, while keeping the whole tumor GTV’s border dose at 5Gy each fraction. There was no restriction on concurrent systemic chemotherapy agents.Results21 patients were enrolled and underwent SCART. All 21 patients have eligible data for study follow-up. Radiotherapy was well tolerated with all treatment completed as scheduled. The dose was escalated for two patients to 24GyX3. No grade 3 or higher toxicity was observed in any of the enrolled patients. The average age of patients was 66 years (range: 14–85) and 13 (62%) patients were male. The median SCART dose was 18Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.3 months (range: 1 - 25.6). The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.5% (SD: 40.89, p-value:0.009).ConclusionSCART was safely escalated to 24 GyX 3 fractions, which is the maximum Tolerated Dose (MTD) for SCART. This regimen will be used in future phase II trials.

Combination of hSTC810 and capecitabine therapy in metastatic colorectal cancer with resistance or intolerance to oxaliplatin and irinotecan-based chemotherapy: A single arm, phase 1b/2, multicenter study.

TPS223 Background: hSTC810 is a humanized anti-BTN1A1 monoclonal antibody of the IgG4 isotype that binds to human BTN1A1 and blocks the interaction between BTN1A1 and its ligands. Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1. BTN1A1 has been shown to inhibit anti-CD3-induced cytokine production and T-cell proliferation and also inhibit anti-CD3-induced p38 mitogen-activated protein kinase (MAPK), cAMP response element-binding protein (CREB) and target of rapamycin (TOR) phosphorylation in human T-cells. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. In the first in human phase 1 study, investigating the safety and efficacy of hSTC810 in solid tumors, hSTC810 showed acceptable safety profile and the disease control rate (DCR) was 39.3%, which indicates its potential efficacy. Methods: This multi-center, open label phase 1b/2 study evaluates the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of hSTC810 combined with capecitabine in patients with metastasis/recurrent colorectal cancer. The trial is enrolling adults who are (1) histologically or cytologically confirmed colorectal adenocarcinoma (2) resistant or intolerant to oxaliplatin and irinotecan-based chemotherapy (3) adequate hematologic, hepatic, renal function (4) measurable or non-measurable disease by RECIST 1.1 (5) ECOG PS 0~2 (6) resolved acute effects of any prior therapy. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The primary endpoint of phase 1b is to determine dose-limiting toxicity (DLT), and recommended phase 2 dose (RP2D) of hSTC810 combined with capecitabine, each in 21-day cycles. Phase 1 comprises 3 escalation arms, and if the initial dose is deemed unsafe, 2 deescalation arms will be initiated. Once the RP2D is determined, the Phase 2 will enroll up to 39 patients. The primary endpoint of phase 2 is progression free survival (PFS); secondary endpoints include objective response rate, overall survival, disease control rate, duration of response and quality of life. The study began in Q4 2023 and is recruiting patients. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria. An exploratory study is underway to investigate the impact of hSTC810 on the tumor microenvironment and cytokines, utilizing both tissue biopsies and blood sampling. Clinical trial information: NCT05990543 .

Phase 1b/2 Trial of Enasidenib in Lower-Risk MDS and Nonproliferative CMML without Isocitrate Dehydrogenase Type 2 Mutations

Introduction: Enasidenib is an FDA approved selective-inhibitor of mutant IDH2 ( mIDH2) enzyme commonly found in acute myeloid leukemia (AML). Previous studies found enasidenib unexpectedly improved red blood cell and platelet transfusion needs in mIDH2 AML patients without a reduction in AML disease burden (Pollyea DA, et al. Leukemia 2019; 33(11):2575-2584; DiNardo CD, et al. Lancet Oncol 2021; 22(11):1597-1608). We subsequently demonstrated enasidenib robustly enhanced human erythropoiesis from umbilical cord-blood and bone marrow-derived CD34+ hematopoietic progenitor cells independent of IDH2 status and the oncometabolite R-2-hydroxyglutarate (R-2-HG), thus prompting us to investigate enasidenib as an erythropoiesis-stimulating agent (Dutta R, et al. J Clin Invest 2020; 130(4):1843-1849). Aim: To evaluate the safety, tolerability, and efficacy of daily enasidenib in patients with lower-risk MDS or nonproliferative CMML without IDH2 mutations. Methods: In this ongoing two-part phase 1b/2 single-center, investigator-initiated, open-label trial, patients with a diagnosis of IDH2 wildtype lower risk MDS and nonproliferative CMML self-administered continuous daily dosing of enasidenib. Two dose levels were planned at 100mg and 200mg daily for Cohort A and B, respectively based on a standard 3 x 3 dose escalation schema. All patients were evaluated for adverse events (AEs) to determine dose-limiting toxicities (DLTs) and establish the recommended phase 2 dose (RP2D). Patients were screened in a consecutive manner to reduce selection bias by the investigators and all consents were translated into participant's native language to ensure full understanding and voluntary participation. Eligible patients are 18 years or older, ECOG ≤3, negative for IDH2 mutation, have adequate organ function, and symptomatic anemia (hemoglobin &amp;lt;10.5g/dL). Other causes such as iron/nutritional deficiencies and bleeding were ruled out during screening. Prior treatment with ESA, G-CSF, and luspatercept was allowed with a 30-day washout period. Each cycle is 28 days. Patients were evaluated by the PI on Day 1 (±3 days), and laboratory evaluation was conducted every 15 ±3 days. Results: Seven patients were enrolled between July 6, 2022 and December 21, 2022 with three patients in Cohort A receiving 100mg and 4 patients in Cohort B receiving 200mg (Table 1A). No DLTs were seen during the first 6 cycles of treatment. One treatment was discontinued due to the need for treatment of vasculitides related to a new diagnosis of VEXAS made during cycle 2 of the trial (unrelated to study drug). Another patient discontinued treatment after 1 cycle to pursue allogeneic stem cell transplant. All patients experienced at least one treatment-related adverse event (TRAE) which were limited to grade 1 or 2. TRAEs noted were consistent with those previously reported with enasidenib use (Stein EM, et al. Lancet Haematol 2020; 7(4):e309-e319), most commonly hyperbilirubinemia observed in 6 patients (85.7%), nausea in 4 patients (57.1%), and rash (inflammatory dermatoses, previously well-described) in 5 patients (71.4%) (Table 1B) (Parisi R, et al. Leuk Res 2022; 123:106970). No grade 3 or higher TRAE were observed. Two patients (28.7%) experienced a Grade 3 adverse event of pneumonia. Four patients developed an infection (57.1%) with only one requiring a hospitalization. One grade 4 event occurred (duodenal hemorrhage) in a patient with history of duodenal ulcers and concurrent aspirin use. As above, a patient in Cohort A was diagnosed with VEXAS syndrome after enrollment and experienced a complicated course of vasculitis and opportunistic infections in the setting of high dose steroid use. Interestingly, one newly diagnosed patient in the 200mg Cohort B without prior growth factor or ESA is enjoying a sustained trilineage improvement with increase of absolute neutrophil count, hemoglobin, and platelets from baseline (10 cycles at the time of data cutoff of June, 16, 2023). Conclusions: Enasidenib at 200mg dose was safe and well tolerated in patients with lower-risk MDS. Thus far, one patient has seen trilineage improvement in blood counts and continues on study. The Phase 2 portion of the study is ongoing to further characterize safety and evaluate for efficacy to improve anemia and decrease transfusion needs.

Phase I / II Study on Infusion of Alloreactive or Ex Vivo il-15 Stimulated Natural Killer Cells after Haploidentical Stem Cell Transplantation in Pediatric Patients with Acute Leukemia (PHINK): A Study of the Spanish Hematopoietic Stem Cell Transplantation Group (GETH)

Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is a highly complicated but effective procedure for high-risk pediatric leukemia in the absence of an HLA-identical donor. Post-transplant relapse is the main problem for patient survival. According to literature, Natural Killer (NK) cells play a potent role as inducers of the graft-versus-leukemia (GvL) effect in haplo-HSCT. The presence of alloreactive NK cells correlates with a lower relapse rate, improved engraftment, decreasing graft-versus-recipient disease (GvHD) and viral infection risk. In the absence of donor-recipient NK cell alloreactivity, other NK cell activation strategies are necessary. We propose a phase I/II clinical trial with dose escalation, multicenter, framed in the GETH, to determine dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of a single infusion of alloreactive NK cells (Allo-NK) or NK cells stimulated ex vivo with IL-15 (IL15-NK) after haplo-HSCT in pediatric patients with high-risk leukemias. Methods: Eighteen pediatric patients with high-risk leukemia were recruited between September 16, 2020, and May 12, 2023, at 5 hospitals in Spain, Hospital Universitario La Paz, Hospital Universitario Gregorio Marañón, Hospital Universitario Niño Jesús, Hospital Universitario Central of Asturias and Hospital Santa Creu and Sant Pau. Patients were stratified in 2 treatment groups: Allo-NK (n=9) or IL15-NK (n=9), depending on the KIR disparity between donor and recipient. Our phase I/II clinical trial presents a dose-escalation design (3+3). The treatment cohorts are divided into cohort 1 (up to 2x10 7 cells/kg), cohort 2 (2-5x10 7 cells/kg) and cohort 3 (5-10x10 7 cells/kg). We have monitored infections reactivation, as well as, chimerism and engraftment after transplantation. In Allo-NK group, the KIR clone that provides alloreactivity in the NK cell was also tracked. The phenotypic profile and functional capacity of NK cells present in the patient up to 360 days after transplantation have also been analyzed. Results: Nine patients (4 in Allo-NK and 5 in IL-15NK) were included in cohort 1, 7 patients (4 in Allo-NK and 3 in IL-15NK) in cohort 2 and 2 patients (1 in Allo-NK and 1 in IL-15NK) in cohort 3. We were unable to complete the dose escalation design initially proposed due to the high weight of some patients and the unavailability of ex vivo expanded NK cells. In IL15-NK group patients presented a higher prevalence of B-ALL (p=0.018) and had received a previous transplant (p=0.082). NK cell infusions of IL15-NK group showed higher expression of CD25 and CD69 receptors and higher functional capacity. In the Allo-NK group, the most prevalent KIR-reactive clone was KIR2DL1 (55.6%). We also observed a tendency for KIR2DL1 alloreactive clone to increase from 30 (8,18%) to 360 (25,63%) days after transplantation. Regarding clinical outcomes in 2 study arms, the incidence of severe (Grades III-IV) acute GvHD was 22.2% and severe chronic GvHD was only observed in 1 (5.6%) patient (Table 1). The incidence any infection or endothelial vascular complications were 72% and 33% respectively. No statistical differences were observed in GvHD, infections and endothelial vascular complications. We found 2 relapses, 1 in each study arm (11.1%). Five patients died, 1 (5.6%) because of disease progression and 4 (22.2%) because transplant related complications (TRM) (Table 1). Dividing patients into the 3 dose-escalation cohorts, we found no significant differences between cohorts in the primary clinical outcomes analysed. One-years overall survival (OS) and disease-free survival (DFS) was 72.22% (CI95% 51.93-100) and GvHD-free/relapse-free survival (GRSF) was 64.1% (CI95% 44.62-92.1), finding no significant differences between either 2 study arms or the 3 dose-escalation cohorts. Regarding the analysis of the NK phenotype, we observed a tendency to increase the expression of CD16 and CD57 receptors between 30 to 360 days after transplantation in both groups. Conclusions: Two study arms shows similar data respect to clinical outcome. Patients infused with IL-15-stimulated NK cells showed similar toxicity to the alloreactive NK group. According to dose escalation, we observed no association between increased toxicity and increased number of infused NK cells. We were unfortunately unable to complete cohort 3 because of the cells/kg ratio in some patients.

The Safety and Efficacy of SCART for Bulky Metastatic or Recurrent Cancer, a Phase I Study

We are proposing a new treatment methodology, (called Stereotactic Centralized Ablative Radiation Therapy, (SCART), for bulky or metastatic tumors, which is based on the principles of SFRT, by using SBRT methods to deliver an ablative radiation dose to the central portion of the target while keeping the dose to surrounding normal tissue to a relatively low level. We performed a prospective dose escalation study of SCART for bulky metastatic or recurrent cancer. The purpose of the study was to determine dose-limiting toxicities (DLTs) and the Maximum Tolerated Dose (MTD) of SCART. This study was registered at ClinicalTrials.gov Identifier: NCT0488198, and approved at Foshan Chancheng Hospital. Patients with unresectable solid "bulky" nonhematological malignancies with limited treatment options were enrolled and received SCART with a prescription to the central spot in the tumor with a peripheral dose to the tumor edge at around 20% isodose line of the prescription dose. Five dose levels were proposed. The primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose where zero of three or one of six patients experienced grade 3 dose-limiting toxicity (DLT), scored according to the Common Toxicity Criteria for Adverse Events v. 4.03, up to 6 months after SCART. A total of 21 patients received SCART and have eligible data for study follow-up. The dose was escalated for two patients to 24 GyX3. No grade 3 toxicity was observed in any of the enrolled patients. The median SCART dose was 18 Gy (range: 15 - 24). Six out of the 18 patients with data for overall survival (OS) died, and the median time to death was 16.29 months (range: 0.99 - 25.58). Three patients out of the 15 patients with available data for local recurrence (LR) were found to have an LR and the median time to LR was 16.01 months (range: 0.99 - 25.58). There appears to be a trend of tumors decreasing from the patient's first visit date, or pre-SCART, to their final volume post-SCART. The mean percent change for tumor shrinkage between first visit volumes and post-SCART volumes was 49.49% (SD: 40.89, p-value:0.009). Of 15 patients with available data for progression free survival, 9 had a local recurrence or were deceased. Estimated median survival (i.e., when survival is 50%) was equal to16.80 months (95% CI = 13.90, NA). The survival rate at 12 months and 24 months were72.22% and 24.07%, respectively. Of 15 patients with available data for time to local recurrence, 3 people had a local recurrence. The percent of patients that were free from local recurrence at one and two years after the beginning of SCART treatment was 85.56% for both. Despite the high dose delivered and the excellent local control achieved; the incidence of Any toxicity was unexpectedly low. Multiple courses of SCART are possible. The optimal dose, volume and timing of SCART still need more study.

A phase 1, multi-center, open-label, dose-escalation and dose expansion study of CBP-1018, a bi-ligand-drug conjugate, in patients with heavily treated advanced solid tumors.

e15007 Kaiwen Li and Junyan Wu contributed equally to this work. Yehui Shi and Hai Huang are the corresponding authors. Background: Prostate-specific membrane antigen (PSMA) or folate hydrolase 1 (FOLH1) is highly expressed on prostate cancer and folate receptor α (FRα) overexpressed in various malignant tissues which both related to tumor invasiveness. CBP-1018 is a first-in-class bi-ligand-drug conjugate targeting both PSMA and FRα with monomethyl auristatin E (MMAE) as payload. Methods: This phase 1 study included both a dose-escalation and expansion stage. In the dose-escalation stage, an accelerated titration was conducted in single patient at 0.03mg/kg followed by an i3+3 design for dose levels (DLs) ≥ 0.06 mg/kg, Q2W in a 4-week cycle. This stage mainly enrolled patients (pts) with metastatic castration resistant prostate cancer (mCRPC) received a median 3.5 prior lines of treatment. The primary objectives were to evaluate the safety and tolerability, determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD). Additionally, pharmacokinetics (PK) and preliminary efficacy will also be evaluated. Results: As of 24 Nov 2022, 14 pts (12 mCRPC, 1 bladder cancer and 1 ureteral carcinoma) were enrolled at 5 DLs (1 pt at 0.03 mg/kg, 3 pts each at 0.06, 0.08, 0.10 mg/kg, 4 pts at 0.12 mg/kg). No DLTs or drug-related deaths were observed. For 9 pts (64.3%) experienced treatment-related adverse events (TRAEs) ≥ grade 3, most common were neutrophil decrease (35.7%), WBC decrease (28.6%), lymphocyte decrease (14.3%), elevated GGT (14.3%) and hypertriglyceridaemia (14.3%). Among 10 efficacy evaluable pts with mCRPC, 3 SD were observed at DLs of 0.08, 0.10, and 0.12mg/kg, 4 non-PD at 0.06, 0.10, and 0.12 mg/kg, and 3 PD at 0.06 and 0.08 mg/kg. Decrease of prostate-specific antigen (PSA) was detected in 3 pts at 0.10 mg/kg. Overall median PFS was 7.2 months (95%CI, 1.7-9.3) and not reached in mCRPC pts. For PK profile of CBP-1018 and free MMAE, t1/2z was ranged 0.54-1.15 h and 40.28-57.27 h, respectively, no accumulation of both substances after multiple doses. Conclusions: CBP-1018 was well-tolerated at DLs of 0.03-0.12 mg/kg Q2W with no DLTs. Multiple SD were observed at DLs of 0.08-0.12 mg/kg, conferred a promising preliminary antitumor activity in pts with mCRPC. MTD was not reached and dose-escalation to establish the RP2D is continuing. Clinical trial information: NCT04928612 .

First-in-human, phase I study of KC1036, a multiple kinase inhibitor, as a single agent in patients with advanced solid tumors.

e15000 Background: KC1036 is a novel and selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, metastasis and drug resistance by inhibiting receptor tyrosine kinases (AXLs and VEGFRs) involved in the tumor microenvironment. KC1036 has demonstrated anti-tumor activity in preclinical models of solid tumors, including non-small cell lung cancer (NSCLC). Methods: This phase I, first-in-human study of KC1036 (NCT04387916) enrolled adult patients (pts) with advanced or metastatic solid tumors. This study was comprised of dose escalation (Part A: With the accelerated titration of the 10 mg QD, in which only one patient was enrolled, a standard 3+3 design was applied for 20, 40, 60, and 80 mg QD) followed by dose expansion (Part B) and recommended phase II dose (RP2D) expansion (Part C). The primary safety endpoints were to determine dose limiting toxicities (DLTs) and RP2D. Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of November 30, 2022, a total of 41 pts had received at least 1 dose of KC1036 orally with 13 pts in Part A (10 mg [n = 1], 20 mg [n = 3], 40 mg [n = 3], 60 mg [n = 4], 80 mg [n = 3]) and 28 pts in Part B (60 mg [n = 21], 80 mg [n = 7]). In Part A, no DLTs were observed, and the maximum tolerated dose (MTD) has not been reached. Consequently, 60 mg and 80 mg were recommended for Part B. Pts most commonly had NSCLC (31.7%, 13/41), esophageal cancer (14.6%, 6/41), colorectal cancer (12.1%, 5/41). All pts were heavily pre-treated with 65% (27/41) receiving three or more lines of therapy, and average targeted tumor size was 58.7 mm with the largest 162 mm. Of the 41 pts, the median duration of KC1036 exposure was 105.0 days (range, 51.0-168.0). Any-grade TRAEs occurred in 39 pts (95.1%), with 16 pts (39.0%) reported with ≥ Grade 3. The most commonly reported ≥ Grade 3 TRAEs at 60 mg was hypertension (16.7%, 4/24), and that at 80 mg was diarrhea (30.0%, 3/10). PK analysis showed that KC1036 exhibited with dose-proportional increases in exposure over the range of 10 to 40 mg, but increased less proportionally within the range of 40-80 mg. Of 36 pts who had at least one efficacy evaluation, 5 (13.9%) had a best response of partial response (PR) and 24 (66.7%) had stable disease (SD). Thus, ORR was 13.9% (95% CI: 4.7, 29.5) and DCR was 80.6% (95% CI: 64.0, 91.2). Among the 9 evaluable pts with lung adenocarcinoma (6 on 60 mg and 3 on 80 mg), 2 pts had PR, 5 had SD and 2 had progressive disease (PD) as best response. Sustainable PR for 42 weeks was observed in 1 patient with lung adenocarcinoma on 60 mg. Conclusions: KC1036 demonstrated a manageable safety profile and preliminary antitumor activity in pts with advanced solid tumors. Taking safety, efficacy and clinical PK into consideration, 60 mg QD was recommended as RP2D for Part C, and this part was ongoing. Further studies in pts with lung adenocarcinoma would be considered promising. Clinical trial information: NCT04387916 .

Safety and clinical efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies in a phase I study.

e14601 Background: This is a first phase I study investigating the safety and efficacy of sintilimab in pediatric patients with advanced or recurrent malignancies. Methods: During dose escalation, patients received a single-dose intravenous infusion of sintilimab. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received sintilimab every three weeks. Primary endpoints were determination of dose-limiting toxicities at the maximum administered dose, safety and tolerability, and the proportion of patients with objective response to sintilimab according to the Response Evaluation Criteria in Solid Tumours version 1.1. PD-L1 expression of tumor in subjects were identified by immunohistochemistry (DACO,22C3). Whole exome sequencing (WES) was performed in 15 patients to characterize the mutational landscape and CNV status. Results: 29 patients were enrolled, including 10 patients with Hodgkin lymphoma (HL), 19 patients with other tumor types. Some special pathological types, including thymoma, choroid plexus carcinoma, and NK-T cell lymphoma are included. Patients were pretreated with a median of 3 prior lines of systemic treatment. Sintilimab was well tolerated without dose-limiting toxicity. By the safety data cutoff date, all patients experienced treatment related adverse events (TRAE) with most adverse events being grade 1 or 2, and ≥ grade 3 TRAEs occurred in 10%. Among all 27 subjects evaluated, 4 confirmed complete response (2HL, 1 NK/T lymphoma, 1 anaplastic ependymoma), 7 confirmed partial responses (4 HL, 1 Ewing sarcoma, 1 diffuse large-B lymphoma and 1 thymoma), and 7 stable disease were observed, for an objective response rate of 40.7%, and a disease control rate of 66.7%. Subjects with PD-L1-positive expression benefited more from sintilimab treatment than PD-L1-negative subjects (66.7% ORR versus 33.3% ORR, p=0.314) although statistically insignificant. The genomic profiling of WES indicatedpatients with a specific genomic mutation type predict the response of PD-1 therapy. Conclusions: Sintilimab was well tolerated and demonstrated promising anti-tumor activity in pediatric HL. The completion of the current phase I study has led to the initiation of the first prospective anti-PD-1 registration trial in Asia focusing on pediatric patients and serve as the basis for its potential study in combinatorial regimens for childhood cancer. Clinical trial information: NCT04400851 . [Table: see text]

Abstract CT014: Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer

Abstract Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr &amp;gt;2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by &amp;gt;2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) &amp;gt;1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with &amp;gt;2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

Tislelizumab combined with anlotinib and chemotherapy (XELOX) in the treatment of advanced gastric carcinoma: Preliminary results of a single-arm, open-label phase I/IIa trial (TALENT study).

396 Background: PD-1 inhibitor combined with chemotherapy is one of the standard regimens for first line gastric. The addition of anti-vascularization agents has been reported to help improve the overall survival (OS) in GC/GEJC patients (pts) through vascular-normalization in the microenvironment. In this phase I/IIa study, we aim to explore the safety and efficacy of tislelizumab combined with anlotinib and XELOX (TAXE regimen) as first line treatment for advanced GC/GEJC. Methods: This prospective, multicenter, phase I/IIa study planned to enroll 9 patients in phase I and 57 patients in Phase IIa. The aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of 8 mg, 10 mg or 12 mg anlotinib in combination with XELOX and tislelizumab. The maximum tolerable dosage (MTD) would be administered to all pts in phase II. The primary and objective response rate(ORR). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), OS, and safety. The exploring endpoint was to evaluate the association between the efficacy and the expression of biomarkers including PD-L1, microsatellite instability profile, and genome stability (GS). Results: From march 2021 to August 2022, 38 pts were enrolled (9 pts in phase 1). Phase 1 was completed without dosage limiting toxicities (DLTs). 12mg anlotinib was recommended for phase 2. Thirty two (84.21%) pts had at least one treatment-related adverse events (TRAEs), and 7 patients (18.42%) had at least one grade 3/4 TRAEs. Anemia (15 pts, 39.47%), leukopenia (12 pts, 31.58%) and fatigue (10 pts, 26.32%) were the most common TRAEs. Two pts achieved complete response (CR), 20 pts achieved partial response (PR), and 7 pts achieved stable disease (SD). The ORR was 75.86% (95% CI: 57.89%-87.78%), and the DCR was 100%. Conclusions: The preliminary results of this Phase I/IIa trial by using tislelizumab combined with anlotinib and XELOX had shown great potential in improving the response rate in advanced GC/GEJC patients with manageable toxicity. Clinical trial information: NCT04963088 .

Trial in Progress: Phase 1b/2 Study of Alrizomadlin (APG-115), Alone or Combined with 5-Azacitidine (AZA), in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML), or Myelodysplastic Syndrome (MDS)

Background AML, CMML, and MDS are rare and often clinically challenging hematologic malignancies. Alrizomadlin is an investigational, novel, orally active, potent, small-molecule selective inhibitor that destabilizes the MDM2-p53 complex and activates p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. This multicenter trial is evaluating alrizomadlin alone or in combination with AZA in patients with AML, CMML, or MDS in order to determine dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase 2 dose (RP2D). Methods This multicenter study is investigating the safety and tolerability of alrizomadlin as monotherapy (Part 1), and when combined with AZA (Part 2), in adults with histologically confirmed relapsed or refractory AML, CMML, or high-risk MDS for which no available standard treatments are either indicated or likely to elicit a durable response. Part 1 (phase 1) is a standard "3+3"-designed dose escalation in which alrizomadlin is administered orally once daily (QD) on Days 1 to 5 of every 28-day cycle. The starting dose is 100 mg QD, which is then increased to 150, 200, and 250 mg in each subsequent cohort. An additional 3 to 6 patients will be treated at RP2D in the dose expansion phase. In Part 2 (phase 2), alrizomadlin, with a different assigned dose, is combined with AZA 75 mg/m2 subcutaneously on Days 1 to 7 of a 28-day cycle. An additional 12 to 15 patients will be treated with alrizomadlin at the RP2D plus AZA in the dose expansion cohort. The primary outcome measure comprises safety and tolerability, including DLT as well as the severity and frequency of adverse events (AEs) and serious AEs based on NCI CTCAE v5.0. The study is actively enrolling patients, and the overall estimated enrollment is 70 subjects. Internal study identifier: APG115-AU101. ClinicalTrials.gov identifier: NCT04358393.

Abstract CT565: Clinical and translational results of a phase I study, tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer

Abstract Background: Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC) refractory to gemcitabine + nab-paclitaxel (GN) due to suppression of cancer associated fibroblast (CAF) and increase of drug infiltration in tumor. We sought to determine the safety, recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with GN-refractory MPC. Methods: This phase 1, dose finding trial was conducted following preclinical study of IL-6 signaling blockade in genetically engineered mouse model of pancreatic cancer (pGEMM) and patients-derived CAF, enrolled 10 patients with MPC that had progressed after GN. During the dose-finding part to determine dose-limiting toxicity (DLT), patients initially received TCZ 8 mg/kg on Day 1 and nab-paclitaxel 100 mg/m2 + gemcitabine 750 mg/m2 on Days 2, 9, and 16. The subsequent dose-expansion part used the TCZ dose identified in the dose-finding study. Before Cycle 1 and at the end of Cycle 1, biopsy of liver metastasis was performed 3 to 5 hours after levofloxacin (LVXF) administration to measure LVFX infiltration in tumor using matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). Results: In pGEMM tumor, mouse IL-6 receptor antibody plus GN led pathological response. The growth of CAFs from patients with pancreatic cancer was inhibited by TCZ. In this phase I study, no DLTs occurred and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events (TEAEs) occurred in 80% of patients (Grade ≥3 in 60%) with decreased neutrophil count (n=5, 7 events) being the most common TEAE. Disease control rate was 80·0% (95%CI: 44·4-97·5) and tumor reduction during cycle 1 was observed in 4 patients who were defined as responder. In paired-biopsied samples, decrease of phosphorylated (p) STAT3 expression in tumor was observed in 7 of 8 patients (88%). Responder-related biological activities were increase of cleaved PARP expression of tumor nuclei (P = 0.01), decrease of proliferative CAF (P = 0.08), and increase of LVFX infiltration in tumor (P = 0.04). Decrease of pSTAT3 expression (P = 0.02) was favor to increase of LVFX infiltration against increase of gamma-H2AX, an index of gemcitabine exposure (P = 0.20). Conclusion: TCZ+GN-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and gain of intratumoral drug infiltration in MPC. Citation Format: Shuichi Mitsunaga, Masafumi Ikeda, Kazunori Aoki, Kyoko Yamaguchi, Noriaki Sawada, Etsuko Fujii, Masanobu Nishidate, Takashi Fujitomo, Hideaki Mizuno, Yoko Kayukawa, Atsuhiko Kato, Mayu Makikawa, Hiroshi Imaoka, Mitsuhito Sasaki, Kazuo Watanabe, Hiroyuki Tsunoda, Kimio Terao, Atsushi Ochiai. Clinical and translational results of a phase I study, tocilizumab plus gemcitabine/nab-paclitaxel in patient with gemcitabine/nab-paclitaxel-refractory metastatic pancreatic cancer [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 CT565.

Phase I/II trial of BMS-986205 and nivolumab as first line therapy in hepatocellular carcinoma.

e16200 Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Indoleamine-2,3-dioxygenase (IDO) is an intracellular enzyme expressed by HCC which helps to orchestrate immune suppression within the tumor microenvironment (TME) and may contribute to primary and acquired resistance of PD-(L)1 inhibitors. BMS-986205 is a novel oral drug that potently and selectively inhibits IDO1. This Phase I/II study is evaluating the safety and tolerability of the combination of BMS-986205 and nivolumab as first-line therapy in HCC. Methods: Patients (pts) ≥18y with untreated, unresectable/metastatic HCC received BMS-986205 in combination with nivolumab. A fixed dose of Nivolumab 240mg/m2 IV was administered on Day 1 of each 14-day cycle. BMS-986205 was an oral tablet administered daily; a total of two dose levels (50-100mg) were given to determine dose limiting toxicities (DLT) during the dose-escalation Phase I of the study. Safety was assessed using CTCAE v5.0 criteria, and efficacy was assessed by objective response rate (ORR) using RECIST v1.1 criteria. Secondary objectives included preliminary data on disease control rate (DCR), duration of response (DOR), ORR using immune RECIST criteria (iRECIST), progression free survival (PFS) and overall survival (OS). Results: Here we report the results of the dose escalation cohort. Eight pts were treated with median age 69y [60-76]; 75% male; and PS 0 (3 pts) or 1 (5 pts). Pts were White (62.5%), Asian (25%), and African American (12.5%). Six of 8 pts had underlying viral hepatitis (5 hepatitis C, 1 hepatitis B), and all pts were Child Pugh A at enrollment with median baseline alpha-fetoprotein (AFP) level 41.8 [3.8–917.2]; 4 pts received prior local therapies. A total of 91 cycles of therapy were administered; 2 pts received 27 and 43 cycles of treatment each. Six pts were evaluable for DLT; 2 pts were replaced for DLT assessment due to insufficient dose administered, unrelated to toxicity. No DLTs were observed at either the 50 or 100mg dose of BMS-986205. There were 24 treatment-related adverse events (TRAEs), 4 of which were Grade 3 events; there were no Grade 4-5 events. The most common TRAEs of all grades were AST elevation and ALT elevation in 3 pts, and diarrhea, maculopapular rash and increased alkaline phosphatase in 2 pts each. Grade 3 events were diarrhea and AST elevation (1 pt), and hyperglycemia and pancreatitis requiring treatment discontinuation (1 pt). Eight pts were evaluable for efficacy with best response of partial response in 1 pt (12.5%) and stable disease in 3 pts (37.5%), yielding a DCR of 50%. Median PFS was 8.5 weeks; median OS has not been reached. Conclusions: Combination BMS-986205 and nivolumab showed a manageable safety profile with durable benefit as 1st line therapy in a meaningful subset of patients with unresectable/metastatic HCC. Clinical trial information: NCT03695250.

First-in-human, phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

3013 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: This phase I, first-in-human, dose escalation and expansion study of TT-00420 ( NCT03654547 ) enrolled adult patients with advanced or metastatic solid tumors. Capsules in 1 mg or 5 mg formulation were administered orally once daily in 28-day cycles. Dose escalation was guided by Bayesian modeling with overdose control. The primary safety endpoints were to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of February 7, 2022, 48 advanced solid tumor patients were enrolled in the study, and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N = 1), 3 mg q.d. (N = 1), 5 mg q.d. (N = 4), 8 mg q.d. (N = 10), 10 mg q.d. (N = 6), 12 mg q.d. (N = 20), and 15 mg q.d. (N = 6). DLTs were observed in 3 out of 40 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had Grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Among the twenty (20) safety evaluable patients treated at 12 mg, the DRDE, drug-related TEAEs included hypertension (n = 11, 55.0%; Gr 3: n = 6, 30%); diarrhea (n = 7, 35%, Gr 3: n = 1, 5%); mucosal inflammation (n = 7, 35%; Gr 3: n = 1, 5%); palmar-plantar erythrodysaesthesia syndrome (n = 6, 30%; Gr 3: n = 0, 0%); and vomiting (n = 4, 20%; Gr 3: n = 0, 0%). No grade 4 suspected adverse events were reported. Out of 42 patients who had at least one post-baseline scan, 7 (16.7%) had a best response of partial response (PR) and 22 (52.4%) had stable disease (SD). Among 7 PRs, 3 were CCA patients (one for each treated at 8 mg, 10 mg, or 12 mg), 2 were TNBC patients (one for each at 10 mg, or 12 mg), 1 was HER2-negative BC patient at 12 mg, and 1 was CRPC patient at 12 mg. Sustainable stable disease for six months or longer was observed in patients with colon cancer (n = 1), head and neck cancer (n = 1), and peritoneal mesothelioma (n = 1). Conclusions: TT-00420 monotherapy was well tolerated and had favorable PK characteristics. The TEAEs observed in dose escalation and dose expansion cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420 and reversible upon the discontinuation of TT-00420 treatment. Taking safety, efficacy and clinical PK into consideration, 10 mg p.o. q.d. was recommended for phase II study of TT-00420 in patients with advanced CCA. Clinical trial information: NCT03654547.

First-in-man, first-in-class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered intravenously in adult patients with advanced, metastatic solid tumours

BackgroundS81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients. Patients and methodsThis trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion. Results38 patients were treated at doses ranging from 4 to 135 mg/m2/week; 144 cycles were administered (median 2/patient; range 1–32 cycles). Patients discontinued treatment for disease progression (78.9%), adverse events (AE; 18.4%) or withdrawal of consent (2.6%). Treatment modifications occurred in 22 patients (57.9%; 49 cycles). Common treatment-emergent AEs were fatigue (22 patients;57.9%), anaemia (17;44.7%) and nausea (12;31.6%). Haematological toxicity was mild, with Grade 3 anaemia observed in three patients and neutropenia mainly seen at the 135 mg/m2 dose level. Three first cycle DLTs included G3 anaemia (4 mg/m2 dose), G4 hypertension (20 mg/m2), G3 fatigue (135 mg/m2). MTD was not reached due to premature discontinuation of enrolment based on a sponsor decision. Among 35 patients evaluable for response, one (renal cell carcinoma) had a complete response, one (hepatocellular carcinoma) had a transient decrease of target lesions and 13 had stable disease. Seven patients remained on study for ≥6 cycles, two at the 135 mg/m2 dose. ConclusionsS81694 can be administered safely as a single agent in adults with solid tumours on days 1,8,15 of a 28-day cycle up to a dose of 135 mg/m2/week without reaching MTD. The RP2D was not defined due to the prioritization of the use of S81694 in combination with cytotoxic agents, based on emerging preclinical data. Trial registrationEudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.

Trial in Progress: Phase 1b/2 Open-Label Study of Lisaftoclax (APG-2575) Monotherapy or in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM)

Background: Multiple myeloma (MM) is a hematologic malignancy (HM) caused by proliferation of plasma cells in bone and extramedullary sites, with frequent symptoms including hypercalcemia, renal impairment, anemia, and bone lesions. High-dose therapy and autologous hematopoietic stem cell transplantation have been treatment mainstays. More recent introduction of the proteasome inhibitor bortezomib and other agents offers promise. Bortezomib can prevent breakdown of proapoptotic factors by malignant cells, triggering apoptosis, and lenalidomide can stimulate programmed death of malignant cells both directly and indirectly. Despite these and other treatment advances, relapse is virtually inevitable, and MM remains incurable. Lisaftoclax is a novel, potent, selective BCL-2 inhibitor that is under clinical development for HMs. In chronic lymphocytic leukemia, lisaftoclax requires a short ramp-up to help mitigate tumor lysis syndrome and is associated with a potentially lower incidence of neutropenia (Ailawadhi et al. J Clin Oncol 2021;39: abstract 7502).Methods: This open-label, multicenter study is assessing the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of lisaftoclax alone or combined with lenalidomide and dexamethasone. The primary aim is to determine dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase 2 dose (RP2D) of lisaftoclax when administered alone (Arm A) or in tandem with lenalidomide and dexamethasone (Rd; Arm B), each in 28-day cycles. The trial is enrolling adults who have (1) R/R MM with measurable sites and received ≥ 1 prior therapy; (2) ECOG performance status of 0 to 2; and (3) adequate hematologic, hepatic, renal, and coagulation function. Excluded were individuals with (1) lenalidomide intolerance; (2) recent monoclonal antibody (≤ 8 weeks before study onset), CAR-T (≤ 3 months), and other MM treatments (≤ 2 weeks); (3) history of allogenic stem cell transplantation or BCL-2 treatment; (4) other systemic conditions, including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), amyloidosis, Fahrenheit macroglobulinemia, non-secretory MM, and plasma cell leukemia; (5) known CNS involvement; and (6) serious and potentially uncontrolled medical disorders, including cardiovascular disease, chronic inflammatory disorders, and active infection warranting systemic treatment (e.g. HIV, hepatitis). Lisaftoclax is administered as monotherapy orally once daily at 3 dose levels (400, 600, and 800 mg) without ramp-up, every 28 days as a cycle in a “3+3” dose escalation in Arm A and similarly in Arm B, which also includes Rd: lenalidomide 25 mg (10 mg for patients with baseline creatinine clearance ≥ 30 mL/min but < 60 mL/min) orally on Days 1 through 21 of each 28-day cycle and dexamethasone 40 mg (or 20 mg for patients aged > 75) orally on Days 1, 8, 15, and 22 of a repeated 28-day cycle. The primary outcome measure is DLT, defined by the rate of some predefined treatment-related adverse events (measured by NCI CTCAE v5) within the first 28 days of study treatment. As of July 19, 2021, three of fifty-seven patients have been enrolled. Internal study identifier APG2575MC101. Clinicaltrial.gov identifier: NCT04674514. DisclosuresChen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Li: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Phase I dose escalation safety and feasibility study of autologous WT1-sensitized T cells for the treatment of patients with recurrent ovarian cancer

BackgroundThis phase I dose escalation trial evaluated the feasibility of production, safety, maximum tolerated dose, and preliminary efficacy of autologous T cells sensitized with peptides encoding Wilms’ tumor protein 1...

Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

3090 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: The phase I, first-in-human dose escalation and expansion study of TT-00420 is enrolling adult patients with advanced or metastatic solid tumors. TT-00420 capsules in 1 mg or 5 mg formulation are administered orally once daily in 28-day cycles. Dose escalation is guided by Bayesian modeling with overdose control. The primary safety endpoints are to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints include pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criteria. Results: As of February 17, 2021, 40 advanced solid tumor patients were enrolled in dose escalation cohorts and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N=1), 3 mg q.d. (N=1), 5 mg q.d. (N=4), 8 mg q.d. (N=10), 10 mg q.d. (N=6), 12 mg q.d. (N=12), and 15 mg q.d. (N=6). DLTs were observed in 3 out of 32 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Suspected adverse events (AEs) reported in ≥ 20% of patients across all tested dose levels include hypertension (any grade: n=17, 42.5%; Gr 3: n=8, 20.0%), diarrhea (n=10, 25.0%; Gr 3: n=1, 2.5%), vomiting (n=9, 22.5%; Gr 3: n=0), palmar-plantar erythrodysaesthesia syndrome (n=9, 22.5%; Gr 3: n=1, 2.5%), and nausea (n=8, 20.0%; Gr 3: n=1, 2.5%). No Gr 4 AEs, regardless of causality, were reported. Out of 26 patients who had at least one post-baseline scan, 4 (15.4%) had a best overall objective response of partial response (PR) and 13 (50.0%) had stable disease (SD). Of the patients who achieved PRs are 2 CCA patients (8 mg q.d., n=1; 10 mg q.d., n=1), 1 HER2-negative breast cancer patient (12 mg q.d.), and 1 TNBC (10 mg q.d.). Both CCA patients with PRs had disease control for ≥ 8 months. Of the patients who achieved SD, 1 salivary gland patient (5 mg q.d.) and 1 CCA patient (10 mg q.d.) had disease control for 8 months, and 2 TNBC patients (5 mg q.d., n=1; 8 mg q.d., n=1) had disease control for 6 months prior to disease progression. Conclusions: Toxicities observed in dose escalation cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420. 12 mg p.o. q.d. was recommended as the dose for dose expansion cohort for further safety and efficacy evaluation of TT-00420 capsules with focus on enrollment of TNBC and CCA patients. Clinical trial information: NCT03654547.