Compass Therapeutics Opens First-in-Human CTX-10726 Clinical Trial, Testing a PD-1 × VEGF-A Bispecific Antibody in Four Advanced Cancers
Compass Therapeutics (NASDAQ: CMPX) has registered a Phase 1 CTX-10726 clinical trial (NCT07419841) that will mark the first time the tetravalent PD-1 × VEGF-A bispecific antibody enters human testing. The open-label, multiple-ascending-dose study plans to enroll approximately 70 patients with advanced gastroesophageal cancer, hepatocellular carcinoma, endometrial cancer, or renal cell carcinoma — all of whom must have progressed on prior PD-1 or PD-L1 therapy. Dosing is expected to begin in Q2 2026, with primary completion projected for Q2 2028.
The trial is structured as a two-cohort study. Cohort 1 uses a conventional 3+3 dose-escalation design to evaluate four dose levels of CTX-10726 monotherapy (0.3 to 10.0 mg/kg), delivered as an intravenous infusion once every two weeks. Cohort 2 will expand enrollment at dose levels selected from the escalation phase. Primary endpoints center on safety: incidence of dose-limiting toxicities, treatment-emergent adverse events, and laboratory abnormalities. Secondary endpoints include a full pharmacokinetic profile (Cmax, AUC, t½, clearance, volume of distribution), immunogenicity screening for anti-drug antibodies, and preliminary efficacy signals measured by objective response rate, progression-free survival, duration of response, disease control rate, clinical benefit rate, and overall survival — all assessed per RECIST 1.1.
Why Dual PD-1 and VEGF-A Blockade in a Single Molecule
The biological premise of CTX-10726 rests on a well-established but incompletely exploited observation: PD-1-mediated immune suppression and VEGF-A-driven angiogenesis cooperate to shield tumors from immune attack. VEGF-A does more than build blood vessels. It promotes an immunosuppressive microenvironment by impairing dendritic cell maturation, expanding regulatory T cells, and creating a disorganized vasculature that physically limits T-cell infiltration. Blocking VEGF-A can therefore normalize the tumor vasculature and render the microenvironment more permissive to immune-mediated killing — a rationale validated clinically by the atezolizumab-plus-bevacizumab combination approved for first-line hepatocellular carcinoma.
What distinguishes CTX-10726 from that two-drug regimen, and from other PD-1 × VEGF bispecifics in development, is its tetravalent architecture — four antigen-binding sites (two for PD-1, two for VEGF-A) — and a reported mechanism involving cleavage of cell-surface PD-1 rather than simple receptor blockade. Compass Therapeutics has stated that preclinical models showed this cleavage-based approach produced more durable removal of PD-1-mediated suppression than conventional anti-PD-1 antibodies. The company presented data at the Society for Immunotherapy of Cancer (SITC) 2025 annual meeting indicating that CTX-10726 outperformed both bevacizumab and ivonescimab in humanized mouse tumor models, though these results have not yet been published in a peer-reviewed journal.
CTX-10726 Phase 1 Eligibility and Patient Population
The Compass Therapeutics clinical trial casts a deliberately wide net across four tumor types, but the eligibility criteria are tightly defined within each indication. All patients must be adults (≥18 years) with an ECOG performance status of 0 or 1, measurable disease per RECIST 1.1, and adequate organ function including left ventricular ejection fraction ≥50% and creatinine clearance ≥30 mL/min.
For renal cell carcinoma, patients must have clear cell histology, prior exposure to both a PD-1/PD-L1 inhibitor (minimum two doses) and at least one tyrosine kinase inhibitor. Hepatocellular carcinoma patients must have progressed after one of three specific first-line regimens — ipilimumab plus nivolumab, tremelimumab plus durvalumab, or atezolizumab plus bevacizumab — and must have Child-Pugh A or B7 hepatic function. The inclusion of Child-Pugh B7 patients is notable; most HCC trials exclude patients beyond Child-Pugh A, limiting the generalizability of their results. Gastroesophageal cancer patients require prior platinum-based chemotherapy and PD-1/PD-L1 exposure. Endometrial cancer patients must have received at least one cycle of platinum-based chemotherapy, and those with microsatellite instability-high or mismatch repair-deficient tumors must additionally have progressed on PD-1/PD-L1 therapy.
Exclusion criteria reflect the anti-angiogenic component of the molecule. Patients with a history of arterial or venous thrombosis within six months, poorly controlled hypertension (>140/90 mmHg despite treatment), tumors encasing major blood vessels, or active bleeding tendencies are ineligible. The protocol also bars patients who experienced clinically meaningful immune-related adverse events leading to discontinuation of prior PD-1/PD-L1 therapy.
The CMPX First-in-Human Study in Context: A Crowded Post-Immunotherapy Landscape
The decision to position the CMPX first-in-human study in the post-PD-1/PD-L1 setting reflects a genuine clinical gap. Across all four indications, frontline treatment now routinely includes a checkpoint inhibitor, yet no consensus standard of care exists for patients who progress. In hepatocellular carcinoma after atezolizumab-bevacizumab, available second-line agents — cabozantinib, regorafenib, ramucirumab — were studied primarily in the post-sorafenib era and carry median overall survival estimates of roughly six to ten months. In renal cell carcinoma after IO-TKI combinations, subsequent single-agent TKIs yield median progression-free survival of approximately five to seven months. In gastroesophageal cancer, second-line ramucirumab plus paclitaxel delivers a median overall survival near eight months. In pMMR/MSS endometrial cancer, lenvatinib plus pembrolizumab is approved but limited by high rates of grade ≥3 adverse events and frequent dose reductions.