Escalation Phase Research Articles

A first-in-human trial of intravesical enfortumab vedotin (EV), an antibody-drug conjugate (ADC), in patients with non-muscle invasive bladder cancer (NMIBC): Interim results of a phase 1 study (EV-104).

4596 Background: A majority of patients (pts) with bladder cancer present with non-muscle invasive disease; for pts with high-risk tumors, standard of care (SOC) is resection of tumor followed by intravesical Bacillus Calmette-Guerin (BCG). Once pts experience recurrence and develop BCG-unresponsive disease, SOC is radical cystectomy (RC), which many pts are unfit for or refuse. EV is an ADC directed to Nectin-4, which is highly expressed in bladder tumors. Intravenous EV has demonstrated survival benefit in pts with previously treated la/mUC. In preclinical models with intravesical administration, EV was well tolerated and showed antitumor activity. Here we present the first clinical data for intravesical administration of EV in pts with NMIBC. Methods: EV-104 (NCT05014139) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study of intravesical EV evaluating the safety, tolerability, PK, and antitumor activity of intravesical EV in pts with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary disease who are ineligible for or refuse RC. Dose escalation phase aims to identify the MTD or recommended dose of intravesical EV at the following dose levels: 125mg, 250mg, 500mg, and 750mg. Pts receive intravesical EV weekly for 6 weeks in the induction phase, followed by 9 monthly maintenance doses. Preliminary safety, PK, and efficacy data for 125mg and 250mg doses are presented in this abstract. Results: As of data cutoff (1 Dec 2022), 6 pts received intravesical EV across 2 dose levels: 4 pts at 125mg completed 6 induction cycles and proceeded to maintenance; 2 pts at 250mg had received at least 3 doses of intravesical EV. Of 6 pts across doses, there were no Grade ≥3 TRAEs, treatment-related SAEs, TRAEs leading to dose reduction or discontinuation. 4 of 6 pts (3 at 125mg and 1 at 250mg) experienced ≥1 treatment-related adverse event (TRAE) of Grade 1 or 2. Most common TRAEs were fatigue (3 of 6) and micturition urgency (2 of 6). As of data cutoff, no DLTs were observed for 125mg; the DLT evaluation period for 250mg was not complete. All blood PK analyses (ADC and unconjugated MMAE) for pts at 125mg were undetectable; no PK data was available for 250mg. Of 4 pts receiving 125mg of intravesical EV, 3 achieved CR and continue in response. The fourth pt discontinued tx due to persistent disease but remains on study. Pts at 250mg had not been evaluated for response at data cutoff. Detailed safety and additional efficacy data will be presented. Conclusions: Preliminary data from EV-104 show intravesical EV is well tolerated with no evidence of systemic exposure at 125mg. Preliminary antitumor activity was observed at 125mg with 3 of 4 pts achieving a CR. Dose escalation is ongoing to identify the MTD or recommended dose for dose expansion. Clinical trial information: NCT05014139 .

Investigating the novel CD16A and epidermal growth factor receptor (EGFR) bispecific innate cell engager, AFM24, to leverage the innate immune system: Interim results from the colorectal cancer (CRC) cohort.

e14508 Background: AFM24 is a tetravalent, bispecific innate cell engager that binds EGFR on solid tumors and CD16A on natural killer (NK) cells. AFM24 redirects NK cells to EGFR-expressing (EGFR+) solid tumors, enhancing antibody-dependent cellular cytotoxicity. AFM24 induced lysis of EGFR+ tumor cell lines in vitro independent of EGFR expression level and mutation status. The dose escalation phase (Phase 1) of the presented study (NCT04259450) previously established the recommended Phase 2 dose at 480 mg based on tolerability, receptor occupancy, and pharmacokinetics. Correlative science data revealed an activation and enrichment of immune cells in the tumor microenvironment. Here we present preliminary data from the Phase 2a CRC expansion cohort. Methods: The Phase 2a expansion phase is evaluating 480 mg AFM24 in patients with histologically or cytologically confirmed microsatellite stable, RAS wild type EGFR+ CRC. Patients have relapsed or refractory disease to ≥2 prior lines of therapy including an EGFR targeted therapy. EGFR+ is defined as positive staining for EGFR in ≥1% of tumor cells per local immunohistochemistry assay. The study follows Simon’s two-stage design. The primary endpoint is the overall response rate per RECIST v1.1 by investigator assessment; secondary endpoints include safety and tolerability; efficacy per iRECIST is exploratory. AFM24 is administered intravenously once weekly in a 28-day cycle. Tumor assessments are performed at screening, cycles 2, 4, 6, 8, and every 3 cycles thereafter. Results: As of December 2022, 16 patients with Stage 4 CRC were enrolled and treated with 480 mg AFM24 in the study. The median (range) age was 66 years (51–77); 11 males and 5 females; 9 Asian, 7 White). The median number of prior therapies was 4 (2–7) and the median treatment duration was 5.1 weeks (1.0–22.0). Treatment-related adverse events (TRAEs) were reported in 14/16 patients; infusion-related reactions (IRRs, 12), pruritus (3), lymphopenia (3), and anemia (2) were the most common. AFM24 TRAEs of Grade ≥3 occurred in 6 patients and included lymphopenia (3), decreased neutrophil count (1), increased blood bilirubin (1) and IRRs (1). To date, no objective responses were observed. Seven patients remain on treatment including 1 patient with confirmed stable disease ongoing for 5 months exhibiting a tumor reduction of –17%. Final interim results will be presented. Conclusions: The novel mechanism of action of AFM24 may provide an alternative treatment approach for patients with EGFR+ solid tumors. In this study, AFM24 monotherapy was adequately tolerated in a heavily pretreated population of patients with EGFR+ CRC. AFM24 is also being investigated in combination with atezolizumab and autologous NK cells in various EGFR+ solid tumors. Clinical trial information: NCT04259450 .

A phase I trial of palbociclib (palbo) and bosutinib (bos) with fulvestrant (fulv) in patients (pts) with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC) refractory to an aromatase inhibitor (AI) and a CDK4/6 inhibitor (CDK4/6i).

1079 Background: Standard therapy for HR+/HER2- MBC includes a CDK 4/6i with endocrine therapy (ET). Eventual resistance results in progression of disease (PD). A potential mechanism of CDK4/6 resistance is through Src activation. Targeting Src and ET suppresses proliferation of ER+ hormone independent breast cancer cells. Therefore, adding bos, a Src inhibitor, to palbo + fulv may overcome this resistance and restore sensitivity to CDK4/6i. Methods: This is a single arm, 3+3 dose escalation phase I trial (NCT 03854903) of bos + palbo + fulv for pts with HR+/HER2- MBC who have PD after ≥ 1 AI, ≥ 1 CDK4/6i, and < 3 lines of chemo for MBC. Pts were enrolled in two cohorts, A and B, with two dose levels in cohort B. Fulv was given at standard dose. Cohort A: bos 300mg (D1-5/wk), palbo 75mg D1-21 q28 days, fulv; cohort B1: bos 300mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv; cohort B2: bos 500mg (D1-5/wk), palbo 100 mg D1-21 q28 days, fulv. Primary objective was safety and tolerability, including MTD and recommended phase 2 dose (RP2D). Secondary objectives included ORR, and CBR 24 wks. Serum, plasma, and peripheral blood mononuclear cells were collected for Src activation, cell cycle profile arrays, and cytokine array screens. Results: 18 evaluable pts were enrolled between 4/2019 – 11/2022. To date, 16pts have completed and 2 pts remain on treatment. All pts had received prior palbo and 15/18 (83%) had received prior fulv. Median number of prior therapies in the metastatic setting was 3.2. The combination in cohort A and B1 was well tolerated. The combination in cohort B2 (bos 500mg D1-D5/wk) was toxic which resulted in bos dose reduction in all pts in the B2 cohort. There were no DLTs. The RP2D was bos 300 mg D1–5/wk, palbo 100 mg D1-21 q28 days, and standard dose fulv. No pts came off treatment due to adverse events (AEs). Most common AEs were G1/2 (9 pts) and G3/4 (7 pts) neutropenia (no neutropenic fever); G1 nausea (8 pts); G1/2 (12pts) and G3 (1pt) diarrhea; G1/2 rash (4 pts), and no G5 events. Median PFS was 5.9 months with 95% CI (3, 10.1). CBR at 6 months was 50% (9/18) (95% CI (0.26, 0.74)). The ORR was 6% (0 CR, 1 PR cohort B2), but best response was SD in 11 pts. Correlative studies underway include assessment pre and post treatment of 1) Src levels and activity to confirm that bos is acting on target and 2) RNA sequencing of Src activation and cell cycle profiles and 3) cytokine array screens to test if Bos affects inflammatory markers. Conclusions: Bos + palbo + fulv was well tolerated at the RP2D. A robust CBR of 50% was seen despite all patients having prior PD on palbo and 83% on fulv. This is an effective combination for HR+/HER2- MBC which warrants further investigation and may represent a mechanism to overcome resistance to CDK4/6i and provide another oral treatment option. Clinical trial information: NCT03854903 .

A phase 1/2 study of the TORC1/2 inhibitor onatasertib combined with toripalimab in patients with advanced solid tumors.

2526 Background: Pre-clinical studies suggest synergistic activity of the combination of inhibitors of mTOR with a PD-1 antibody in solid tumors. Here we report updated results of a phase 1/2 open-label, dose escalation and expansion trial of the oral TORC1/2 inhibitor, onatasertib (ATG-008) in combination with toripalimab (tori), a PD-1 monoclonal antibody, in patients (pts) with advanced solid tumors. Methods: This study consists of dose escalation and dose expansion. The primary objective in the dose escalation phase was to evaluate safety and tolerability of onatasertib combined with tori, followed by a dose expansion phase to assess antitumor efficacy and verify the safety and tolerability profile of the combination therapy. Primary endpoints included maximum tolerated dose (MTD), recommended phase II dose (RP2D) and efficacy of the combination. Other endpoints included pharmacokinetics and exploratory biomarkers of drug activity. Prior PI3K/AKT/mTOR inhibitor therapy was excluded, regardless of PD-L1 expression. Onatasertib was administered orally once a day (QD) at three dose levels (15, 20 and 30mg) in combination with tori at the approved dose of 240 mg, once every 21 days (Q3W). Results: As of Oct 21, 2022 cut-off, 46 advanced solid tumor pts were enrolled with 10 pts in the dose escalation phase and 36 pts in the dose expansion phase. Median age was 53 years. Baseline ECOG scores were 0 (13 pts) and 1 (33 pts) with a median of 2 prior lines of therapy (0-7); 27 pts had stage IV disease. Twenty-one cervical cancer (CC) pts were enrolled in total with the similar baseline characteristics. No dose-limiting toxicity was reported in dose escalation phase. The study did not reach MTD. Forty-five pts (97.8%) had ≥ 1 TEAEs; 32 (69.6%) pts had grade ≥ 3 TEAEs. The most common grade ≥ 3 TEAEs included lymphocyte count decreased (23.9%), rash (19.6%) and hyperglycemia (10.9%). The RP2D for onatasertib was determined to be 15 mg in combination with the recommended dose of tori. Among the 46 treated pts, ORR was 26.1% (12/46, all confirmed), and DCR was 73.9%. In 21 pts with CC, ORR was 52.4%, including 1 CR and 10 PR, and DCR was 90.5%. One CC pt with negative PD-L1 expression achieved CR and remains on treatment after 883 days. The ORR was 75% (6/8) and 41.7% (5/12) for CC pts with PD-L1 positive and negative expressions, respectively. One CC pt with prior anti-PD-1 therapy also reached PR. Another PR was achieved in nasopharyngeal carcinoma (NPC) for over 2 years. Median PFS in all treated pts and CC cohort was 4.3 months(m) and 7.2 m, respectively. Pharmacokinetic profiles of ATG-008 in combination with PD-1 antibody were similar to ATG-008 monotherapy, across Asia Pacific and U.S. patient populations. Conclusions: Onatasertib in combination with tori is tolerable with encouraging response rate and disease stabilisation in pts with advanced solid tumors, especially in CC pts. Expansion enrolment for CC and NPC is ongoing. Clinical trial information: NCT04337463 .

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies.

TPS7085 Background: Chronic stimulation of both interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to cause a bone marrow proinflammatory environment responsible for persistent cytopenia in patients with low-risk (LR)-MDS. IRAK1 and IRAK4 are serine/threonine kinases that are critical for the downstream signaling of IL-1R and most TLRs resulting in the production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis leading to bone marrow inflammation and cell death. Thus, IRAK1/4 inhibition is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow allowing the restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases and inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 healthy volunteer study (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the trial supported the advancement of R289 into further studies. An open-label Phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The current study (NCT05308264) includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria will include prior treatment for MDS that concluded <4 weeks prior to study treatment. Dose Escalation Phase: Dose escalation will utilize a 3+3 design to determine the maximum tolerated dose (MTD). R289 tablets can be taken orally with or without food. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 28 days. After completion of the DLT evaluation period, patients who do not experience DLTs may remain on treatment at their respective dose level if they continue to demonstrate clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled; the primary endpoint of the study will be the safety and tolerability of R289. The secondary endpoints will include an assessment of preliminary efficacy and characterization of the pharmacokinetics of R289. R289 will be administered to all patients at a dose not to exceed the MTD determined in the Dose Escalation Phase. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264 .

Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]

Phase I/II study of pazopanib and temozolomide in patients with newly diagnosed and resected glioblastoma: Pazoglio trial.

e14024 Background: Pazopanib, an anti-angiogenic tyrosine kinase inhibitor, has shown activity in pre-treated advanced glioblastomas. A clinical-biological rationale defends the evaluation of the activity of Pazopanib in earlier stage of the disease. Methods: Pazoglio (NCT02331498) is a phase I/II, prospective, multicenter, open-label trial to evaluate the safety and efficacy of Pazopanib combined with temozolomide (TMZ) during the maintenance phase as defined by the Stupp protocol in patients with resected glioblastoma. We report the dose escalation phase I (standard 3+3) whose main objective is to determine the MTD and the RP2D of Pazopanib combined with TMZ during the maintenance phase. The DLT was assessed during the first two cycles. Pazopanib was dosed according to four levels: 200 mg (level 1), 400 mg (level 2), 600 mg (level 3) and 800 mg (level 4). Results: From September 2015 to March 2022, 42 patients (pts) were recorded, and 20 pts finally enrolled. Median age was 54 years [min: 25 – max: 69], 14/20 were women, 15/20 had a complete resection. No DLT was observed among the six patients of levels 1 and 2. One DLT was recorded among the three first pts of the level 3 (grade 2 thrombopenia leading to a postponement of the pazopanib of more than 7 days) but this pt was wrongly enrolled and finally not evaluable for DLT. Three additional pts were enrolled in the level 3 and no DLT was recorded. No DLT was recorded in the 3 first pts of the level 4 but the occurrence of a grade 2 thrombopenia lasting more than 7 days and leading to the cancelation of the third cycle of TMZ in the first pt, as well as a grade 3 thrombopenia and grade 3 neutropenia leading to the postponement and decrease of the dosage of the second cycle of TMZ for the third pt, lead to the enrollment of 3 additional pts in the level 3 according to the IDMC recommendation. One DLT was recorded (grade 2 thrombopenia leading to a postponement of the pazopanib of more than 7 days). Overall, one DLT was observed among the 8 evaluable pts of the level 3. Three additional pts were enrolled in the level 4. Overall, two DLT were recorded among the 6 patients enrolled in the level 4: one grade 3 thrombopenia (postponement and decrease of Pazopanib and TMZ dosage) and one grade 3 hypertension (decrease of Pazopanib dosage). Overall, 328 Adverse Events were recorded during the 6 cycles of treatment, most of which being Grade1-2 (hypertension, increase ALT, asthenia, nausea, diarrhea, thrombopenia, neutropenia, anemia). No grade 4 or 5 AE was observed. The RP2D is 600 mg daily pazopanib in combination with TMZ, RP2D was hardly established since several adaptations of dose intensity, not formerly defined as DLT, were recorded during the 6 cycles of maintenance treatment. Conclusions: The addition of Pazopanib to TMZ during the maintenance part of the “Stupp protocol” is feasible in resected and fit glioblastoma pts. The phase II part of Pazoglio is currently enrolling. Clinical trial information: NCT02331498 .

A phase 1/2 study of CFT1946, a novel, bifunctional degradation activating compound (BIDAC) degrader, of mutant BRAF V600 as monotherapy and in combination with trametinib, in mutant BRAF V600 solid tumors.

TPS3163 Background: BRAF is a protein kinase that acts as a signal transducer in the MAPK pathway. Mutant BRAF V600 is capable of uncontrolled signaling and is constitutively active and signals as a monomer, leading to hyperactivation of MEK, ERK, and dysregulation of cellular proliferation. Mutant BRAF V600 is a clinically-validated target in a variety of cancers including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and anaplastic thyroid carcinoma (ATC). Currently approved BRAF inhibitors (BRAFi) result in paradoxical RAF activation as the mutant BRAF protein is still able to dimerize with WT BRAF, resulting in a dimeric signaling complex. CFT1946 is a novel, orally bioavailable BiDAC degrader that inhibits and degrades mutant BRAF V600 protein. Distinct from approved BRAFi, CFT1946 avoids paradoxical RAF activation as the degraded BRAF V600 mutant protein can no longer incorporate into a dimeric signaling complex. CFT1946 is selective for the mutant protein and spares WT BRAF V600. CFT1946 has demonstrated preclinical activity in BRAF V600 mutant in vitro and in vivo models, including models resistant to BRAFi. These preclinical data provide rationale for a first-in-human (FIH) study to evaluate CFT1946 in BRAF V600 mutant solid tumors. Methods: This is a FIH, open-label, multicenter, Phase 1/2 clinical trial to characterize the initial safety, tolerability, and preliminary efficacy of CFT1946 and CFT1946+trametinib in BRAF V600 mutant melanoma, NSCLC, CRC, ATC, and other non-CNS BRAF V600 mutant solid tumors. This study includes 2 phases: dose escalation Phase 1 comprising CFT1946 (Arm A) with a starting oral dose of 20 mg twice daily and CFT1946+trametinib (Arm B) as well as dose expansion Phase 2 comprising CFT1946 (Arm A1) and CFT1946+trametinib (Arms B1 and B2). Arm A1 and B1 will include BRAF V600 mutant melanoma and NSCLC with prior BRAFi therapy while Arm B2 will enroll BRAF V600 mutant NSCLC who are BRAFi-naïve. Phase 2 will be initiated once the RP2D has been identified. Eligible subjects are ≥18yo with documented BRAF V600 mutant cancers who have received ≥1 prior therapy. CFT1946 will be administered orally in 28-day cycles until disease progression or intolerable toxicity. Primary objectives include safety, tolerability, RP2D and preliminary antitumor activity of CFT1946 monotherapy and in combination with trametinib. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics. Key inclusion criteria include documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy; at least 1 prior line of standard-of-care therapy for locally advanced or metastatic disease. The study is anticipated to enroll 101-122 patients across 11 participating US and European sites and is currently open to enrollment (NCT05668585). Clinical trial information: NCT05668585 .

Phase 1/2 study of PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, in patients with locally advanced and/or metastatic solid tumors.

TPS3157 Background: PRO1184 is an antibody-drug conjugate (ADC) directed to folate receptor alpha (FRα), a cell surface antigen overexpressed in multiple cancers including ovarian, endometrial, lung, mesothelioma, and breast cancer. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetic (PK) profiles across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance efflux pumps. It may thus lend a robust bystander effect and induce deeper or more durable responses in refractory tumors. Preclinical studies further established that PRO1184 exerts potent antitumor activity in mouse xenograft models with high, moderate, and low FRα expression, consistent with the inherent potency and expected bystander activity of the exatecan payload. PRO1184 is stable in plasma and retains the excellent PK properties and bioactivity of the unconjugated parent antibody. The preliminary safety profile of PRO1184 was more favorable than a benchmarking deruxtecan-based ADC in cynomolgus monkeys. PRO1184 is thus a promising development candidate with a potentially large therapeutic index to benefit a broad population of patients with FRα-expressing solid tumors. Methods: PRO1184-001 is an ongoing, phase 1/2, open-label dose escalation and expansion study. Eligible patients are adults with metastatic or unresectable solid tumors, including ovarian, endometrial, non-small cell lung, breast cancer, or mesothelioma. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or mRECIST 1.1 for pleural mesothelioma. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1184 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1184 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). Part A of the study consists of a dose escalation phase and Part B consists of 4 FRα-expressing tumor specific expansion cohorts treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Clinical trial information: NCT05579366 .

GNC-038, a tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale.

TPS2668 Background: Bispecific T cell engagers can mediate single antigen-specific cell cytolysis, but cannot preempt clonal relapse, or modify the immunosuppressive cancer cell surfaceome. The first-in-class octavalent, CD19xCD3x4-1BBxPD-L1 tetra-specific antibody, GNC-038, functions as a CD19-specific T cell engager by mediating direct antitumor activity, but further, GNC-038 overcomes inhibition of T cells by PD-L1 based on its 4 binding sites. The antitumor activity of GNC-038 is mediated by activating CD3 and 4-1BB signaling on T cells and targeting high expression of CD19 or PD-L1 on tumor cells. Preclinical studies showed GNC-038 has robust anti-tumor activity. Considering its favorable tolerance and pharmacokinetics in cynomolgus monkeys, we developed a phase I study to investigate GNC-038 for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) and relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: Patients diagnosed with relapsed/refractory non-Hodgkin lymphoma or acute lymphoblastic leukemia are currently being enrolled in this phase I study to evaluate the safety, tolerability and pharmacokinetics of GNC-038. This study will be conducted in two phases, dose-escalation (Ia) and dose-expansion (Ib). During the dose escalation phase, R/R-NHL patients will receive GNC-038 (0.016-6 μg/kg/d) as continuous intravenous (cIV) infusion for 8 weeks. Further escalation will be conducted with step-up dosing: cIV infusion of 3.6 μg/kg/d GNC-038 will be administered during week 1 followed by higher doses on subsequent weeks (9, 13.5, 20.25 or 30 μg/kg/d). R/R-ALL patients will receive GNC-038 by cIV infusion for 8 weeks (0.016-16 μg/kg/d). During the dose-expansion phase, one or more dosages will be chosen for further investigation in specific indications. The primary endpoints are dose limiting toxicity (DLT), maximum tolerated dose (MTD), treatment emergent adverse events (TEAE) and recommended phase 2 dose (RP2D). Secondary endpoints are adverse events (AEs), pharmacokinetics, objective response rate (ORR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Exploratory endpoints are biomarker assessment, anti-drug antibody (ADA) and pharmacodynamics. The dose expansion phase (Ib) has been initiated. Clinical trial information: NCT04606433 .

Results from a phase (Ph) 1 clinical study of the all-oral regimen of CC-486 and venetoclax for acute myeloid leukemia (AML).

7034 Background: Venetoclax (Ven) with azacitidine (Aza) is the standard of care for newly diagnosed AML patients who are unfit for intensive induction chemotherapy. It is well known that this treatment also has activity in the relapsed and refractory (R/R) setting. However, this regimen requires seven consecutive daily SQ or IV doses of Aza each month. The relative inconvenience of this, and its negative impact on quality of life, may lead to its early discontinuation, possibly decreasing the overall efficacy of this regimen. An all-oral regimen may decrease infusion center visits, and potentially increase the efficacy of the regimen due to improved compliance. CC-486 is the oral formulation of Aza that is currently approved for post-induction chemotherapy maintenance in AML. Methods: This is a single center open label, Ph 1 study investigating CC-486 and Ven in R/R AML patients. In the dose escalation phase, subjects received CC-486 at one of two cohorts (200 mg PO days 1-14 and 300 mg PO days 1-14). Ven was given at the 400 mg/day PO regimen, for 28 days, after an initial intra-patient dose escalation per the standard of care. Using a 3+3 study design for the two cohorts, we aimed to determine the maximum tolerated dose (MTD) of CC-486 in combination with Ven. An expansion cohort is planned for 10 patients treated at the MTD. Results: As of February 1, 2023, 8 patients have been accrued. The average age at the time of enrollment was 64, and median prior treatment regimens was 1 (range 1-3). Four patients had received Ven in prior treatments. In cohort 1, there were no DLT events. There have been no DLT events in 5/6 patients enrolled in cohort 2. The most common hematologic toxicities were Gr 3-4 neutropenia (n = 7, 88%), Gr 3-4 anemia (n = 6, 75%), and Gr 3-4 thrombocytopenia (n = 4, 50%). The most common non-hematologic toxicities were Gr 1-2 nausea (n = 4, 50%), Gr 1-2 fatigue (n = 2, 25%), and Gr 1-2 diarrhea (n = 2, 25%). Best responses were complete remission (CR) (n = 2, 25%), partial remission (PR) (n = 1, 13%), and stable disease (SD) (n = 2, 25%). Three patients proceeded to an allogeneic stem cell transplant. Conclusions: CC-486 and Ven is an all-oral regimen being investigated for the treatment of R/R AML. Our Ph 1 dose escalation thus far has demonstrated a favorable safety profile for this regimen. Full Ph 1 findings and the MTD will be presented at the meeting. Responses have been seen in both dose cohorts, and patients have been bridged to hematopoietic stem cell transplant. Clinical trial information: NCT05287568 . [Table: see text]

Results from a first-in-human phase I study of F182112, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma.

8038 Background: F182112 is a BCMA x CD3 bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells.NTP-F182112-001 is a First-in-human, Open-label, Multiple center Phase 1 Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetic, Immunogenicity, and Preliminary Efficacy of F182112 in Patients with Relapsed or Refractory Multiple Myeloma. Clinical trial information: NCT04984434. Methods: Eligible patients aged ≥ 18 years had received at least 2 prior multiple myeloma treatment regimens (not including autologous stem cell transplant) including a proteasome inhibitor, an immunomodulatory agent. Three dose cohorts (0.01, 0.1, and 0.3μg/kg) were planned for accelerated titration phase and the following dose cohorts (3, 10,20, and 30 μg/kg) were planed for the i3+3 dose escalation phase. F182112 were administered as QW or Q2W IV infusion. The primary endpoint was safety and tolerability assessed throughout the study by monitoring AEs per the CTCAE 5.0, except CRS per ASTCT 2018. Results: As of Feb 2,2023, 16 pts in the first 7 cohorts received F182112 (0.01-20 μg/kg). Median follow-up was 3.1 mo (range 0.9–11.7; median age 64 y [range 52–74]; 68% female). 9 (56%) pts had received ≥4 prior lines of therapy and 12 (75%) pts were refractory to last lines of therapy. The ORR was 43.8% (95% CI 19.8-70.1) among all enrolled patients (7/16). Of the 9 pts treated with ≥ 10 μg/kg F182112, 6 pts achieved a partial response (PR) or better (overall response rate; 66.7%), including 2 (22.2%) with a very good partial response or better.The most common treatment-related AEs were CRS (81%), lymphopenia (75%; grade 3/4: 69%), neutropenia (63%; grade 3/4: 44%), leukopenia (56%; grade 3/4: 50%), and anemia (31%). CRS and anemia events were all grade 1–2 and median duration time to CRS was 2 days (1-5). One dose-limiting toxicities (transient ALT elevation, grade 3) occurred at the dose group of 10 μg/kg. No pts required a F182112 dose reduction due to AEs. Conclusions: F182112 provides a novel immunotherapy approach for the treatment of Relapsed/ Refractory Multiple Myeloma that may yield improved clinical efficacy in heavily pretreated pts. Clinical trial information: NCT04984434.

A first-in-human phase I, dose-escalation and dose-expansion study of SY-5007, a highly potent and selective RET inhibitor, in Chinese patients with advanced RET positive solid tumors.

9111 Background: RET gene fusions have been identified as oncogenic drivers in 1-2% of non-small-cell lung cancer (NSCLC) and 10-20% of papillary thyroid carcinomas. Activating RET mutations occur in 50-60% of medullary thyroid cancer (MTC). Recently, selective RET TKIs, selpercatinib and pralsetinib, were approved for RET positive solid tumors by FDA. SY-5007 is a highly potent RET inhibitor that selectively targets RET fusions and mutations. This study is to investigate the safety, PK characteristics and preliminary efficacy of SY-5007 in Chinese patients with advanced RET-altered solid tumors. Methods: In this first-in-human phase I study, eligible patients previously treated and with positive RET were enrolled. In the dose escalation phase, following 3+3 design, the patients were administered orally with SY-5007 20 mg once daily, or 20, 40, 80, 120, 160, 200 mg twice daily in a 28-day cycle. The expansion doses (160 and 200 mg twice daily) were executed in a dose expansion phase to determine a recommended phase II dose (RP2D). Then three cohorts ( RET fusion-positive NSCLC or thyroid cancers and RET mutant MTC) at RP2D were expanded in eligible patients. Primary endpoints included safety, tolerability, MTD, DLTs. Secondary endpoints included PK and preliminary antitumor activity of SY-5007 per RECIST v1.1. Results: As of Feb.06, 2023, a total of 60 patients including 55 RET fusion NSCLC and 5 RET mutant solid tumors were enrolled into dose escalation cohorts (n = 17) and dose expansion cohorts (n = 43).Totally, 55 (91.7%) patients experienced treatment-related adverse events (TRAEs) including increased aspartate aminotransferase (50.0%), increased alanine aminotransferase (41.7%), diarrhea (41.7%), etc. Grade ≥3 TRAEs were observed in 22 (36.7%) patients including hypertension (15%), diarrhea (5%), increased alanine aminotransferase (3.3%), etc. PK study showed SY-5007 was absorbed rapidly, exposure of SY-5007 increased in a dose-dependent manner at doses between 20 and 160 mg twice daily, and it was saturated at 160 mg twice daily. In 50 evaluable patients, the overall ORR and DCR was 62.0% (95% CI, 47.2-75.4) and 94.0 % (95% CI, 83.5-98.8), respectively. 29 patients (24 NSCLC, 4 MTC) received SY-5007 at 160 mg twice daily, 27 of 28 (96.4%) evaluable patients showed tumor regression, ORR and DCR was 72.4% (95% CI, 52.8-87.3) and 89.7% (95% CI, 72.7-97.8), respectively. For NSCLC patients, the ORR and DCR was 75.0% (95% CI, 53.3-90.2) and 91.7% (95% CI, 73.0-99.0), respectively. Conclusions: SY-5007 was well tolerated in patients. Preliminary antitumor activity was also observed in patients with advanced RET-fusion positive NSCLS and RET mutant MTC. The pivotal Phase II clinical study of SY-5007 in NSCLC patients is ongoing. Research Sponsor: Shouyao Holdings (Beijing) Co., Ltd. Clinical trial information: NCT05278364 .

OniLon: Phase II trial of trifluridine/tipiracil (TAS-102) and nanoliposomal irinotecan (nal-IRI) in advanced colorectal cancer.

3580 Background: TAS-102 (FTD/TPI) is a combination of a nucleoside analogue and a thymidine phosphorylase inhibitor, and has showed activity in 5FU-resistant CRC. Nal-IRI achieves higher intra-tumor concentrations than irinotecan (Iri; 142-fold) and its major metabolite, SN-38 (9-fold). This resulted in superior anti-tumor activity compared to free Iri in multiple tumor xenografts. Furthermore, multiple clinical trials have established the activity of nal-IRI in combination with 5FU in pancreaticobiliary cancers. The combination of nal-IRI with the more potent nucleoside analogue TAS-102 may thus result in a more effective systemic therapy. We conducted this study to define the safety and efficacy of the combination of TAS-102 and nal-IRI in advanced CRC. Methods: Eligible patients (pts) on this investigator-initiated phase II study had advanced CRC and must have had disease progression on at least one prior therapy. Additional inclusion criteria - measurable disease, ECOG PS 0-1 & adequate organ function. Based on previously published dose escalation phase I data, the pts were treated at the recommended phase II dose of TAS-102 (given orally at 35mg/m2 bid on days 1-5) and nal-IRI (60mg/m2 IV on day 1) in 14-day cycles. The primary endpoint was objective response rate (ORR) = complete (CR) + partial (PR) response per RECIST v1.1. Multiple secondary endpoints included safety/tolerability, progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DoR). Results: Twenty-two pts were enrolled, of whom 20 were evaluable for response. Male - 50%; ECOG PS 1 – 75%; African Americans – 38%; median age - 58yrs (interquartile range [IQR] 49-67). Median line of prior therapy was 1 (IQR 1-2) and 13.6% (3 pts enrolled during the dose escalation phase) had received prior Iri. 47.6% received concurrent Bevacizumab. ORR was 15% (3 PR, 0 CR). 60% had stable disease (SD) as best response; DCR of 75%. mPFS - 9.7 mos (95% CI: 5.6, 14.2); mOS - 10.1 mos (95% CI: 7.3, 15.9). 12-month PFS and OS rates were 34.6% and 39.5% respectively. At a median follow up of 11.9 mos, DoR was yet to be determined and 50% of the pts had maintained response for 12 mos. Median duration of progression free among pts with SD was 7.6 mos (95% CI: 4.6, 13.2), with a 12-month survival rate of 47.7% (95% CI: 15.5%, 74.5%). Median time to response (TTR) was 4.8mos. Most common treatment related toxicities included fatigue and neutropenia (G3; 27.3% each); anemia and leucopenia (G3; 18.2% each). Other G3 AEs included febrile neutropenia, diarrhea, hypokalemia, lymphopenia and nausea (4.5% each). Conclusions: We demonstrated that the combination of TAS-102 and nal-IRI had an acceptable safety profile, and showed antitumor activity in patients with advanced CRC. Additional biomarker analyses such as survival correlation with UGT1A1 phenotype and RAS mutational status are ongoing. (NCT03368963). Clinical trial information: NCT03368963 .

Phase 1b/2 dose expansion, open-label study to evaluate safety and anti-tumor activity of intravesical instillation of TARA-002 in adults with high-grade non-muscle invasive bladder cancer.

TPS4618 Background: Bladder cancer is the most common malignancy involving the urinary system, with over 700,000 individuals living with bladder cancer in the US in 2019. In the US, approximately 80,000 new cases and 18,000 deaths occur each year due to bladder cancer. Approximately 70% of new urothelial bladder cancer cases are classified as non-muscle invasive bladder cancer (NMIBC). With the current Bacillus Calmette-Guerin (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 intravesical instillation for the treatment of high-grade (HG) NMIBC. TARA-002 is a lyophilized biological preparation for instillation containing cells of Streptococcus pyogenes (Group A, type 3) Su strain treated with benzylpenicillin. The chemical characteristics of TARA-002 are intended to be comparable to OK-432. Therefore, nonclinical and clinical evidence with OK-432 and TARA-002 support the ADVANCED-1 study (dose escalation Phase 1a [NCT05085977] and dose expansion Phase 1b/2 [NCT05085990]). The dose for the planned Phase 1b/2 study (ADVANCED-1-Ph1b/2) will be based on the recommended Phase 2 dose (RP2D) established in the Phase 1a study. Methods: ADVANCED-1-Ph1b/2 is a Phase 1b/2, dose expansion, open-label study of intravesical instillation of TARA-002 in adults with HG carcinoma in situ (CIS) NMIBC. The purpose of this study is to evaluate the safety and anti-tumor activity of TARA-002 administered intravesically for the treatment of subjects with CIS NMIBC (± Ta/T1) with active disease. The study includes approximately 102 eligible male and female subjects ≥ 18 years of age enrolled in 2 cohorts based on their prior BCG experience. Cohort A includes subjects unable to obtain BCG or subjects who have not received BCG in the last 24 months prior to CIS diagnosis, and Cohort B includes subjects with CIS who are BCG unresponsive after completion of adequate BCG therapy (at least 5 of 6 doses of an initial induction course plus either at least 2 of 3 doses of maintenance therapy or at least 2 of 6 doses of a second induction course). 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 is 6 months/24 weeks per subject for Ph1b/2-Cohort A (includes induction, reinduction [if applicable]), and 24 months/96 weeks per subject for Ph1b/2-Cohort B (includes induction, reinduction [if applicable], maintenance until 18 months). The ADVANCED-1 study started in March 2022. Phase 1a is open for enrollment. Phase 1b/2 is expected to begin enrollment in May 2023. Clinical trial information: NCT05085977 ; NCT05085990 .

Leveraging innate immunity with AFM24, a novel CD16A and epidermal growth factor receptor (EGFR) bispecific innate cell engager: Interim results for the non-small cell lung cancer (NSCLC) cohort.

2533 Background: Patients with EGFR mutant NSCLC who progress on or after small molecule EGFR inhibitors have only limited treatment options. AFM24 is a tetravalent, bispecific innate cell engager that binds EGFR on solid tumor cells and CD16A on NK cells to redirect and enhance antitumor antibody-dependent cellular cytotoxicity, thus acting independently of the EGFR downstream signaling pathway and EGFR expression levels. The Phase 1 dose escalation phase of the presented study (NCT04259450) established the recommended Phase 2 dose of AFM24 monotherapy at 480 mg based on tolerability, receptor occupancy, and pharmacokinetics (PK). Correlative science data revealed an activation and enrichment of immune cells in the tumor microenvironment. Methods: The Phase 2a expansion phase is evaluating 480 mg AFM24 in patients with EGFR mutant NSCLC, relapsed or refractory to ≥1 prior lines of therapy; EGFR-positivity is defined as positive staining for EGFR in ≥1% of tumor cells per local immunohistochemistry assay. The study follows Simon’s two-stage design. The primary endpoint is overall response rate per local RECIST v1.1; secondary endpoints include safety, PK, and immunogenicity. Efficacy per iRECIST is an exploratory endpoint. AFM24 is administered intravenously once weekly in a 28-day cycle. Tumor assessments are performed at initial screening, cycles 2, 4, 6, 8, and every 3 cycles thereafter. Results: As of December 2022, 14 patients (median [range] age 55 [37–82]; 12 male; 11 Asian, 3 White) were enrolled; the median number of prior therapies was 2.5 (1–12). Median treatment duration with AFM24 was 6.7 weeks (1.0–26.1). Best objective response in 10 evaluable patients was confirmed partial response in 1 patient (change from baseline –45%); 4 patients exhibited stable disease, 1 was confirmed. Tumor shrinkage occurred in 2 patients with stable disease (–6%, –18%). The tumor control rate was 50%. Treatment-related adverse events (TRAEs) were reported in 13 patients; infusion related reactions (IRRs, 12), dermatitis acneiform, neutrophil count decreased, decreased appetite, and myalgia (2 each) were most common. Grade ≥3 TRAEs occurred in 4 patients and included decreased neutrophil count (2), lymphopenia, and IRR (1 each). Grade 5 pneumonitis was observed in 1 patient with disease progression and multiple comorbidities; relation to AFM24 could not be ruled out. As of January 2023, enrollment is ongoing; results of the interim analysis will be presented. Conclusions: AFM24 demonstrated clinical activity and acceptable safety in heavily pretreated patients with EGFR mutant NSCLC. The novel mechanism of action of AFM24 could add to the therapeutic options for patients with EGFR expressing tumors and is under clinical evaluation as a single agent and in combination with atezolizumab or autologous NK cells. Clinical trial information: NCT04259450 .

Safety and efficacy of HB0025, an anti-PD-1/VEGF bispecific antibody fusion protein, in patients with advanced solid tumors: Preliminary results from an FIH trial.

2589 Background: HB0025 is a recombinant humanized anti-PD-L1 monoclonal antibody-VEGFR1 fusion Protein. Nonclinical data both in vitro and vivo have shown high-affinity binding to both targets as well as the inhibition of tumor growth in animal models. Here, we present preliminary safety and efficacy data from a dose escalation phase I study of HB0025. Methods: Eligible patients(pts) were ≥18 years old (ECOG PS 0–1) who had advanced solid tumors (NSCLC, gynecological tumors, digestive system tumors, etc.) and failed standard treatment. This phase 1 dose escalation includes accelerated titration (0.01, 0.03, 0.1 and 0.3mg/kg) and conventional 3+3 dose escalation (1.0, 3.0, 6.0, 10, 12, 20, and 30.0 mg/kg). HB0025 is administered intravenously every 14 days (Q2W). Objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and antitumor activity. Adverse events (AEs) were reported with CTCAE v5.0 and DLTs were evaluated within a 28-day window. Results: As of Aug 30th 2022, 30 pts including 8 male and 22 female from Caucasian and Mongoloid have received HB0025 at doses of 0.01 mg/kg (n=1), 0.03 mg/kg (n=2), 0.1 mg/kg (n=1), 0.3 mg/kg (n=1),1.0 mg/kg (n=3), 3.0 mg/kg (n=7), 6.0mg/kg (n=7), 10.0 mg/kg (n=5), and 12.0mg/kg (n=3) Q2W. Overall, the median age was 55 years and the median lines of previous treatment was four. Of the 22 evaluable pts dosed at ≥ 3 mg/kg Q2W, the ORR was 9.1% (2/22) and the disease control rate (DCR) was 50% [11/22]. Among the 2 responders, a CR (colorectal ca) pt whose prior therapy was no immune checkpoint inhibitor (ICI) or bevacizumab have continued more than 36 weeks; and a PR (NSCLC) pt with duration more than 18 weeks whose tumor was 60.2% regression and prior ICI failure. Till the date of submission, the therapy was continuing for the CR and PR pts. Treatment-related adverse events (TRAEs) occurred in 83.3% of pts. The grade 3 TRAEs occurred in 20% [6/30] and treatment-related SAEs occurred in 13.3% [4/30]. One DLT occurred in the 12.0mg/kg cohort. No death occurred related to HB0025. TRAEs leading to treatment discontinuation occurred in 13.3% of pts [4/30]. The most frequent TRAEs were hypertriglyceridemia (23.3%), hypercholesterolemia (23.3%), anemia (16.7%), alanine aminotransferase increase (16.7%), and proteinuria (13.3%). Conclusions: HB0025 shows manageable safety and promising anti-tumor activity in pts with various solid tumors. To better characterize the risk-benefit profile, HB0025 is currently enrolled at 20.0 mg/kg Q2W and is being explored at doses 10 mg/kg in expansion cohorts. The future data, including PK, PD and ADA will be presented. Clinical trial information: NCT04678908 .

Preliminary results of a phase 1/2, first-in-human, open-label, dose escalation study of ZL-1211 (anti-Claudin 18.2 mAb) in patients with unresectable or metastatic solid tumors.

2537 Background: ZL-1121 is a humanized immunoglobulin G1 monoclonal antibody targeting Claudin18.2. Site mutations (S239D and I332E) were introduced in the Fc portion of ZL-1211 to enhance antibody dependent cellular cytotoxicity. Herein, we present the preliminary results from the ongoing dose escalation part of the study. Methods: This is a first-in-human, phase 1/2, multicenter, dose escalation/cohort expansion study of ZL-1211 administered intravenously to adult patients with Claudin 18.2-positive advanced solid tumors. A Bayesian optimal interval design with 3+3 run-in was adopted to assess 5 dose levels of ZL-1211 monotherapy (1 to 40 mg/kg biweekly) for phase 1 dose escalation, followed by phase 2 cohort expansion. The primary objectives were to determine the maximum tolerated dose and/or the recommended phase 2 dose, assess the safety/tolerability, and evaluate the preliminary antitumor activities of ZL-1211. Tumor assessments were performed every 8 weeks per RECIST v1.1. Blood samples were collected for pharmacokinetic (PK) analyses. Results: As of Dec 12, 2022, 19 patients (11 pancreatic cancer, 6 gastric cancer, 1 esophageal cancer, and 1 bile duct cancer) had been enrolled in the dose escalation phase to receive ZL-1211 at 1 mg/kg (n = 3), 5 mg/kg (n = 7), 10 mg/kg (n = 4), and 20 mg/kg (n = 5). The median age was 60 years and the majority of the patients (78.9%) received ≥2 lines of prior systemic therapy. No dose limiting toxicities (DLT) had been observed as of the cut-off date. The most common treatment-related adverse events (TRAEs) were gastrointestinal disorders, including nausea (11/19, 57.9%), vomiting (6/19, 31.6%), and abdominal pain (3/19, 15.8%). Other common TRAEs (≥15%) were hypoalbuminaemia (3/19, 15.8%) and infusion-related reactions (3/19, 15.8%). Grade 3 TRAEs occurred in 3 patients, 1 with nausea and vomiting, 1 with platelet count decreased, and 1 with anaemia, leukopenia, platelet count decreased, and weight decreased. No Grade ≥ 4 TRAEs were reported. Two patients experienced serious TRAEs: 1 reporting 2 cases each of grade 3 vomiting and nausea and 1 reporting a grade 3 platelet count decreased and a grade 2 abdominal pain, all of which had recovered. TRAEs led to treatment interruption in 5 patients (26.3%) and treatment withdrawal in 1 patient (5.3%). No TRAEs leading to death were reported. Six of 9 tumor-evaluable patients achieved stable disease as the best overall response. Three patients had tumor regression: 17.1% in a pancreatic cancer patient of the 5 mg/kg cohort; 14.5% in a pancreatic cancer patient and 24.9% in a gastric cancer patient in the 10 mg/kg cohort. Preliminary PK analyses revealed linear PK of ZL-1211 over the dose range tested. Conclusions: ZL-1211 displayed an acceptable safety/tolerability profile to date and demonstrated preliminary antitumor effects. Clinical trial information: NCT05065710 .

Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma

PurposeGenomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib.MethodsThis two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics.ResultsTovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400–800 mg.ConclusionsThe safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings.ClinicalTrials.gov identifierNCT01425008.

Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study

Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours. In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186. Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039). Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation. None.