Final Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with Relapsed or Refractory AL Amyloidosis

Analysis of the Phase 1a/b Study of Chimeric Fibril-Reactive Monoclonal Antibody 11-1F4 in Patients with AL Amyloidosis

Organ Biomarker Responses in Patients with Light Chain Amyloidosis Treated with NEOD001 Are Independent of Previous Hematologic Response

Organ Biomarker Responses in Patients With Light Chain Amyloidosis Treated With NEOD001 Are Independent of Previous Hematologic Response

Safety, Tolerability and Efficacy of Cael-101 in AL Amyloidosis Patients Treated on a Phase 2, Open-Label, Dose Selection Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis

Interim Results from the Phase 1a/1b Dose-Finding Study of CWP232291 (CWP291) in Relapsed or Refractory Myeloma (RRMM) Alone or in Combination with Lenalidomide and Dexamethasone

ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor: Interim Results Of Combination Therapy With Bortezomib In Patients With Multiple Myeloma (MM)

NEOD001 Demonstrates Organ Biomarker Responses in Patients with Light Chain Amyloidosis and Persistent Organ Dysfunction: Results from the Expansion Cohort of a Phase 1/2 Study

BL-B01D1, a first-in-class EGFR–HER3 bispecific antibody–drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study

Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors. To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors. The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022. Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity. The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables. Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months). In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC. ClinicalTrials.gov Identifier: NCT02794571.

Updated Organ Response Results of an Open-Label Study to Evaluate the Safety and Tolerability of Cael-101 in Patients with AL Amyloidosis Receiving Anti-Plasma Cell Therapy

Background: Bruton’s tyrosine kinase inhibitors (BTKi) have received regulatory approvals and are standard of care for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and WaldenstrÖm macroglobulinemia (WM). However, BTKi-resistant disease remains a clinical challenge with limited options for subsequent therapy. Immunomodulatory drugs (IMiDs, e.g., lenalidomide) are approved as monotherapy for follicular lymphoma (FL), MZL, and MCL, in combination with other therapies for diffuse large B-cell lymphoma (DLBCL) and have shown synergy with BTK-targeted therapy. Dual activity of BTK protein degradation with IMiD-like activity offers a unique approach to overcome known resistance to BTKi. NX-2127 is an oral small molecule that induces BTK degradation via recruitment of cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NX-2127 has shown preclinical activity similar to IMiDs by catalyzing the ubiquitination of Ikaros (IKZF1) and Aiolos (IKZF3), ultimately leading to increased T-cell activation. NX-2127 was shown to degrade both wild-type (WT) and C481-mutated (ibrutinib-resistant) BTK protein in vitro. Robust BTK degradation was also shown in non-human primate studies. Further, NX-2127 demonstrates potent tumor growth inhibition in BTK-dependent mouse xenograft tumor models expressing either WT or ibrutinib-resistant C481S BTK-mutant protein. This dual activity of BTK degradation and IMiD-like activity offers a promising treatment for patients who have failed prior therapy. Aims: The primary objectives are to evaluate safety and tolerability and to determine the maximum tolerated dose (Phase 1a), and to evaluate the early clinical activity of NX-2127 in expansion cohorts (Phase 1b). Methods: NX-2127-001 is a first-in-human, dose escalation (Phase 1a) and cohort expansion (Phase 1b) study designed to evaluate the safety, tolerability, and preliminary efficacy of NX-2127 in adult patients with relapsed/refractory B-cell malignancies with once daily oral dosing. Dose escalation will proceed using a modified Fibonacci design with 1 patient per cohort, proceeding to a standard 3 + 3 design based on protocol specified criteria. There will be up to 5 expansion cohorts in Phase 1b enrolling patients with CLL/SLL, DLBCL, FL, MCL, MZL, and WM. Key eligibility criteria include ≥2 two prior lines of therapy (≥1 prior for WM); measurable disease; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Approximately 130 patients (30 in Phase 1a, 100 in Phase 1b) will be enrolled and treated until disease progression or unacceptable toxicity. The primary endpoint are dose-limiting toxicities and maximum tolerated dose (Phase 1a), objective response (Phase 1b), and safety (Phase 1a and Phase 1b) of NX-1607. Secondary endpoints (Phase 1a and Phase 1b, unless otherwise indicated) include pharmacokinetics, pharmacodynamics, duration of response, progression-free survival, overall survival (Phase 1b), safety (Phase 1b), and complete response rate/complete response rate with incomplete marrow recovery. Results: The Phase 1a part of this study is currently enrolling in the United States. Summary/Conclusion: Accrual is ongoing. Clinical trial information: NCT04830137.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren’t reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

TPS4620 Background: Bladder cancer is the most common malignancy involving the urinary system, resulting in approximately 18,000 deaths each year in the US. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guérin (BCG) shortage and limited effective alternate therapies, there continues to be a significant unmet need for treatment options for patients with NMIBC. TARA-002 is being developed for the treatment of high-grade (HG) NMIBC (consisting of HG Ta, T1, and carcinoma in situ [CIS]). TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. TARA-002 is manufactured using the same master cell bank as OK-432 (Picibanil) and is approved in Japan and Taiwan for the treatment of several oncology indications. Nonclinical toxicology studies with TARA-002 and nonclinical and clinical studies with OK-432 (a comparable product to TARA-002) support the starting dose for the planned Phase 1a/b study. Methods: ADVANCED-1 is a Phase 1a/b, dose finding, open-label study of intravesical instillation of TARA-002 in adults with HG NMIBC. The study includes a dose escalation phase (Phase 1a) and a dose expansion phase (Phase 1b). The objective of the study is to evaluate the safety and tolerability of TARA-002, to establish the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) in the treatment of subjects with HG Ta or CIS ± Ta NMIBC during Phase 1a, and to further assess the safety and preliminary efficacy of TARA-002 in the treatment of subjects with CIS NMIBC with active disease during Phase 1b. For this first-in-human study, stage T1 is excluded. The study includes eligible male and female subjects ≥ 18 years of age who are unable to obtain BCG or have received at least one dose of intravesical BCG or chemotherapy. Those with current or a history of penicillin allergy or current evidence of any condition, therapy, or laboratory abnormality that might confound the results are excluded. The overall study duration for each subject includes 28 days of screening period, 6-week treatment period, and 6-week follow-up period. During the dose escalation phase (1a), up to 18 subjects with HG Ta or CIS ± Ta NMIBC are enrolled. Up to 3 dose levels are tested sequentially with 6 weekly intravesical doses, starting with the lowest dose using a 3+3 design in a dose escalation manner. At the established RP2D, the dose expansion phase (1b) will enroll approximately 12 new subjects with CIS ± Ta NMIBC with active disease and treat in the same manner to further assess the safety and preliminary efficacy of TARA-002. Phase 1a is currently open for enrollment. Clinical trial information: NCT05085977; NCT05085990.

4606 Background: BCG is the standard therapy after transurethral resection of bladder tumor for high-risk NMIBC. IL-15 agonists can enhance the immune response induced by BCG via stimulating the proliferation and activation of natural killer cells and CD8+ cytotoxic T cells, without inducing regulatory T cells. SHR-1501 is an IL-15 agonist fusion protein, composed of a humanized antibody Fc region fused with IL-15 and IL-15Rα sushi domain. In this phase 1/2 study, we assessed the safety, tolerability, and efficacy of SHR-1501 in patients (pts) with high-risk NMIBC. Methods: The study comprised dose-escalation phase 1a and 1b parts of SHR-1501 alone or in combination with BCG in pts with high-risk NMIBC, followed by a phase 2 part of SHR-1501 plus BCG in multiple cohorts, including pts with BCG-naive NMIBC (cohort A), BCG-unresponsive NMIBC carcinoma in situ (CIS; cohort B), and BCG-unresponsive high-grade Ta/T1 NMIBC without CIS (cohort C). All pts received intravesical study treatment weekly for 6 weeks during induction period. During maintenance period, instillations occurred weekly for the first 3 weeks at 3, 6, 12, 18, and 24 months after the initial induction instillation. Primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase 2 dose in phase 1a and 1b parts; and was complete response (CR) rate for cohort B and 12-mo disease-free survival (DFS) rate for cohorts A and C in phase 2 part. Results: As of Sep 7, 2024, 84 pts were enrolled (n = 8 in phase 1a; n = 6 in phase 1b; n = 29, 17, and 24 in cohorts A, B, and C in phase 2). In phase 1a part of SHR-1501 alone (200, 400, and 600 μg) and phase 1b part of SHR-1501 (600 μg) plus BCG (120 mg), no DLTs were observed, and MTD was not reached. Thus, 600 μg of SHR-1501 plus 120 mg of BCG was used in phase 2 part. Treatment-related adverse events (TRAEs) occurred in 4 (50.0%) of 8 pts with SHR-1501 and 53 (69.7%) of 76 pts with SHR-1501 + BCG. Grade 3 TRAEs were reported in 1 (12.5%) pt with SHR-1501 (urinary tract infection) and 7 (9.2%) pts with SHR-1501 + BCG (urinary tract infection and hypertension occurred in > 1 pt). No grade 4 or 5 TRAEs were reported. No serious TRAEs occurred. Of the efficacy evaluable pts in cohort B, the CR rate at 3 or 6 months was 90.9% (10/11). In cohorts A and C, the 12-month DFS rate was not reached. The 9-month DFS rate was 94.4% (95% CI, 66.6-99.2) in cohort A and 53.9% (95% CI, 15.5-81.4) in cohort C. Conclusions: SHR-1501 alone or in combination with BCG was well-tolerable and demonstrated a favorable efficacy in BCG-naive and BCG-unresponsive high-risk NMIBC pts, supporting further investigations. Clinical trial information: NCT05410730 .

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