A phase I dose escalation and cohort expansion study of T-cell redirecting bispecific antibody against Glypican 3 in patients with advanced solid tumors.

BackgroundXmAb20717 is a humanized bispecific monoclonal antibody that simultaneously targets PD-1 and CTLA-4. We report updated data on patients treated at the recommended expansion dose from an ongoing, multicenter, Phase 1, dose-escalation and -expansion study of intravenous XmAb20717 in patients with selected advanced solid tumors that progressed after treatment with all standard therapies or with no standard therapeutic options.MethodsA maximum tolerated dose was not reached in dose escalation. XmAb20717 10 mg/kg every 2 weeks (Q2W) was selected as the expansion dose, based on consistent T-cell proliferation in peripheral blood indicative of dual PD-1/CTLA-4 checkpoint blockade, and response to treatment (RECIST[1.1]).1 Parallel expansion cohorts included ~20 patients each with melanoma, renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and a basket of tumor types without an FDA-approved checkpoint inhibitor (CI). Patients treated with 10 mg/kg in dose escalation were pooled with expansion cohorts for analysis of clinical activity and safety.ResultsAs of 9 June 2021, 110 patients, ranging in age from 39 to 89 years and 66.4% male, were treated, and 5 were continuing treatment. Patients had received a median of 4 prior systemic treatment regimens, including CI therapy for 64.5%. The objective response rate was 13.0% (10/77 patients evaluable for efficacy), including 1 complete response (melanoma [confirmed]) and 9 partial responses (confirmed: 1 melanoma, 2 RCC, 2 CRPC, 1 ovarian cancer; unconfirmed: 1 melanoma, 2 NSCLC). The CRPC responders (2/7 with RECIST-measurable disease) had confirmed PSA decreases ≥ 50% from baseline (to 0.02 and 0.3 ng/mL); neither had progression on bone scans. All responders had prior CI exposure, except those with CRPC. Robust CD4 and CD8 T-cell activation was seen. Low baseline tumoral expression of myeloid recruitment genes, including IL-8, was associated with clinical benefit. Grade ≥ 3 immunotherapy-related adverse events in ≥ 3 patients included rash (16.4%), transaminase elevations (9.1%), hyperglycemia (4.5%), acute kidney injury (3.6%), amylase and lipase increased (2.7%), and lipase increased (2.7%).ConclusionsPreliminary data indicate 10 mg/kg XmAb20717 Q2W was associated with complete and partial responses in multiple tumor types and was generally well-tolerated in these heavily pretreated patients with advanced cancer. Changes in T-cell populations in the periphery and tumor are consistent with robust dual checkpoint blockade. These findings support further development of XmAb20717 in advanced solid tumors, including metastatic prostate cancer.Trial RegistrationNCT03517488ReferencesShum E, Daud A, Reilley M, et al. Preliminary safety, pharmacokinetics/pharmacodynamics, and antitumor activity of XmAb20717, a PD-1 x CTLA-4 bispecific antibody, in patients with advanced solid tumors. JITC 2020;8(3):A247-8.Ethics ApprovalThe study was approved by each institution’s IRB.

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Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps3112 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS3112-TPS3112 ◽

Cited By ~ 1

Author(s):

Laura Quan Man Chow ◽

Michael S. Gordon ◽

Theodore F. Logan ◽

Scott J. Antonia ◽

Shailender Bhatia ◽

...

Keyword(s):

T Cell ◽

Antitumor Activity ◽

Phase I ◽

Solid Tumors ◽

Clinical Outcomes ◽

Dose Escalation ◽

Fixed Dose ◽

Weekly Schedule ◽

Advanced Solid Tumors ◽

Biologic Activity

TPS3112 Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N=160) includes a dose escalation phase (Part 1) using a 3 + 3 design followed by an expansion phase (Part 2). In Part 1 (N=60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 µg/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1–4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N=50) or non-small cell lung carcinoma (N=50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 + nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.

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Phase I study of ABBV-428, a mesothelin-CD40 bispecific, in patients with advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002015 ◽

2021 ◽

Vol 9 (2) ◽

pp. e002015 ◽

Cited By ~ 1

Author(s):

Jason J Luke ◽

Fabrice Barlesi ◽

Ki Chung ◽

Anthony W Tolcher ◽

Karen Kelly ◽

...

Keyword(s):

Ovarian Cancer ◽

Phase I ◽

Solid Tumors ◽

Phase Ii ◽

Dose Escalation ◽

Phase I Study ◽

Bispecific Antibody ◽

Advanced Solid Tumors ◽

Recommended Phase Ii Dose ◽

Dose Proportional

BackgroundCD40 agonist immunotherapy can potentially license antigen-presenting cells to promote antitumor T-cell activation and re-educate macrophages to destroy tumor stroma. Systemic administration of CD40 agonists has historically been associated with considerable toxicity, providing the rationale for development of tumor-targeted immunomodulators to improve clinical safety and efficacy. This phase I study assessed the safety, tolerability, preliminary antitumor activity, and preliminary biomarkers of ABBV-428, a first-in-class, mesothelin-targeted, bispecific antibody designed for tumor microenvironment-dependent CD40 activation with limited systemic toxicity.MethodsABBV-428 was administered intravenously every 2 weeks to patients with advanced solid tumors. An accelerated titration (starting at a 0.01 mg/kg dose) and a 3+3 dose escalation scheme were used, followed by recommended phase II dose cohort expansions in ovarian cancer and mesothelioma, tumor types associated with high mesothelin expression.ResultsFifty-nine patients were treated at doses between 0.01 and 3.6 mg/kg. The maximum tolerated dose was not reached, and 3.6 mg/kg was selected as the recommended phase II dose. Seven patients (12%) reported infusion-related reactions. Treatment-related grade ≥3 treatment-emergent adverse events were pericardial effusion, colitis, infusion-related reaction, and pleural effusion (n=1 each, 2%), with no cytokine release syndrome reported. The pharmacokinetic profile demonstrated roughly dose-proportional increases in exposure from 0.4 to 3.6 mg/kg. Best response was stable disease in 9/25 patients (36%) treated at the recommended phase II dose. CD40 receptor occupancy >90% was observed on peripheral B-cells starting from 0.8 mg/kg; however, no consistent changes from baseline in intratumoral CD8+ T-cells, programmed death ligand-1 (PD-L1+) cells, or immune-related gene expression were detected post-ABBV-428 treatment (cycle 2, day 1). Mesothelin membrane staining showed greater correlation with progression-free survival in ovarian cancer and mesothelioma than in the broader dose escalation population.ConclusionsABBV-428 monotherapy exhibited dose-proportional pharmacokinetics and an acceptable safety profile, particularly for toxicities characteristic of CD40 agonism, illustrating that utilization of a tumor-targeted, bispecific antibody can improve the safety of CD40 agonism as a therapeutic approach. ABBV-428 monotherapy had minimal clinical activity in dose escalation and in a small expansion cohort of patients with advanced mesothelioma or ovarian cancer.Trial registration numberNCT02955251.

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Safety and efficacy of AK112, an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors in a phase I dose escalation study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2515 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2515-2515

Author(s):

Jermaine Coward ◽

Anna Rachelle Austria Mislang ◽

Sophia Frentzas ◽

Charlotte Rose Lemech ◽

Adnan Nagrial ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Dose Escalation ◽

Bispecific Antibody ◽

Advanced Solid Tumors ◽

Antitumor Effects ◽

Dose Escalation Study ◽

Safety And Efficacy ◽

Anti Vegf ◽

Anti Tumor Activity

2515 Background: AK112 is a tetrameric bispecific antibody targeting PD-1 and VEGF-A. Published data suggests that the combination of anti-VEGF-A with immune checkpoint inhibitor (ICI) therapy produces complementary and synergistic antitumor effects. Given the strong correlation between VEGF-A and PD-1 expression in the tumor microenvironment, it is postulated that the simultaneous blockade of these 2 targets by AK112 as a single agent might achieve higher target binding specificity and produce enhanced antitumor activity, with an improved safety profile, compared to the co-administration of anti-PD-(L)1 and anti-VEGF therapies. Here, we present preliminary safety and efficacy data from a dose escalation study of AK112. Methods: A multicenter, phase I, open-label dose escalation and expansion study in advanced solid tumors that are resistant/refractory to standard therapies, began in December 2019 to determine the safety and efficacy of AK112 (0.3 mg/kg to 30 mg/kg) administered IV every 2 weeks (Q2W) using an accelerated titration followed by 3+3+3 dose escalation design. Selected dose escalation cohorts were expanded to a maximum of 18 subjects with selected solid tumor types for further evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and anti-tumor activity. Pts with prior exposure to ICI were eligible. PD studies examined serum VEGF levels and PD-1 receptor occupancy (RO) on circulating T-cells as an indication of target engagement. Results: As of 13 Jan 2021, 29 pts, median age 60 years [30-76], have received AK112 at doses of 0.3 mg/kg (n = 1), 1.0 mg/kg (n = 3), 3.0 mg/kg (n = 3), 10.0 mg/kg (n = 13), 20.0 mg/kg (n = 8), and 30.0 mg/kg (n = 1) Q2W. Treatment-related adverse events (TRAEs) occurred in 55.2% of pts. G3 TRAEs occurred in 10.3% [3/29] and treatment-related SAEs occurred in 3.4% [1/29] of pts. There was no G4 TRAE. No DLT occurred. TRAEs leading to treatment discontinuation occurred in 6.9% of pts [2/29]. Most frequent TRAEs were arthralgia (17%), diarrhea (14%), rash (10%), and fatigue (10.3%). Of the 17 evaluable pts treated at doses ≥ 3 mg/kg Q2W, the ORR was 23.5% (4/17) and disease control rate (DCR) was 64.7% (11/17). Among the 4 responders, a responder (endometrial ca) had not received prior ICI or bevacizumab, 2 responders (ovarian ca, mesothelioma) had received prior ICI therapy; and a responder (microsatellite stable colorectal ca) was previously treated with bevacizumab. Conclusions: AK112, up to 20 mg/kg Q2W (inclusive), can be given safely to pts and demonstrated encouraging anti-tumor activity with an ORR of 23.5% when dosed ≥ 3 mg/kg Q2W in a pt population with various solid tumors resistant/relapsed to standard therapies. Enrolment is currently ongoing at 30.0 mg/kg Q2W and in dose escalation cohorts selected for expansion. Updated data, including PK, serum VEGF, and RO will be presented. Clinical trial information: NCT04047290.

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