Phase Ib Study of Navicixizumab Plus Paclitaxel in Patients With Platinum-Resistant Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Abstract

Purpose: This phase Ib study evaluated the safety and efficacy of paclitaxel plus navicixizumab, a bispecific antiangiogenic antibody to vascular endothelial growth factor and delta-like ligand 4, against platinum-resistant ovarian cancer.

Patients and methods: This open-label, nonrandomized, dose-escalation and -expansion study included 44 patients with previously treated, recurrent, platinum-resistant grade 2/3 ovarian cancer. Treatment was intravenous navicixizumab (3 mg/kg or 4 mg/kg once every 2 weeks) plus paclitaxel (80 mg/m2 intravenously on days 0, 7, and 14 of 28-day cycles). The primary and secondary objectives were to evaluate the safety and efficacy of navicixizumab plus paclitaxel. An RNA-based diagnostic panel was retrospectively used to test the hypothesis that tumors with high angiogenesis or immune-suppressed tumor microenvironment (TME) subtypes (biomarker-positive) are more likely to respond to navicixizumab than those with immune-active/-desert TME subtypes (biomarker-negative). RNA expression was analyzed in available pretreatment tumor tissue to classify 33 patients' TME subtypes, and TME panel findings were correlated with tumor response.

Results: The dose-escalation cohorts enrolled patients at navicixizumab doses of 3 mg/kg once every 2 weeks (n = 3) and 4 mg/kg once every 2 weeks (n = 2); 3 mg/kg was selected for expansion (n = 39). No dose-limiting toxicities occurred. The most common grade 3/4 treatment-related adverse events were hypertension (40.9%), neutropenia (6.8%), and thrombocytopenia (4.5%). Pulmonary hypertension occurred in 18.2% (grade 1-2). The overall objective response rate was 43.2% (95% CI, 28.3 to 59.0): 33.3% (95% CI, 17.3 to 52.8) in patients previously treated with bevacizumab, 64.3% (95% CI, 35.1 to 87.2) in bevacizumab-naive patients, and 62% (95% CI, 31.6 to 86.1) in biomarker-positive patients. The median duration of response was 6 months (95% CI, 5.4 months to not estimable).

Conclusion: Navicixizumab plus paclitaxel demonstrated promising clinical activity in bevacizumab-treated and -naive patients with platinum-resistant ovarian cancer, with manageable toxicity.

Trial registration: ClinicalTrials.gov NCT03030287.

Conflict of interest statement

Kathleen N. Moore

Leadership: GOG Partners, NRG Oncology (Inst)

Honoraria: Research To Practice, Prime Oncology, Physicans' Education Resource, Great Debates and Updates

Consulting or Advisory Role: Genentech/Roche, Immunogen, AstraZeneca, TESARO (Inst), VBL Therapeutics, Merck, Aravive, Eisai, Vavotar Life Sciences, Mersana (Inst), Myriad Genetics, Alkemeres (Inst), Blueprint Pharmacetuicals (Inst), GlaxoSmithKline/Tesaro (Inst), I-Mab (Inst), InxMed (Inst), Mereo BioPharma (Inst), OncXerna Therapeutics, Onconova Therapeutics, Mereo BioPharma, Novartis

Research Funding: PTC Therapeutics (Inst), Lilly (Inst), Merck (Inst), Tesaro (Inst), Genentech (Inst), Clovis Oncology (Inst), Lilly Foundation (Inst), Regeneron (Inst), Advaxis (Inst), Bristol Myers Squibb (Inst), Verastem (Inst), Novartis Pharmaceuticals UK Ltd (Inst), AstraZeneca (Inst), Agenus (Inst), Takeda (Inst), Forty Seven (Inst), Stem CentRx (Inst), Immunogen (Inst), Bayer (Inst), Novogen (Inst), AbbVie/Stemcentrx (Inst), artios (Inst), Bolt Biotherapeutics (Inst), Amgen (Inst), Daiichi Sankyo/Lilly (Inst), Cyteir (Inst), Immunocore (Inst)

Patents, Royalties, Other Intellectual Property: UpToDate

Other Relationship: GOG Partners (Inst)

No other potential conflicts of interest were reported.

Figures

FIG 1.

Tumor response per RECIST 1.1 and duration of treatment. Waterfall plots showing percentage change from baseline in sum of largest tumor diameter (A) overall and (B) according to prior bevacizumab treatment status. (C) Swimlane plot showing duration of treatment. aPatients in the 4 mg/kg dose escalation cohort; all other patients received 3 mg/kg in the dose escalation or expansion cohorts. bOngoing response at the end of the study. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of longest diameters.

FIG 2.

Efficacy according to biomarker status. (A) Tumor response per RECIST 1.1. (B) PFS. aPatients in the 4 mg/kg dose escalation cohort; all other patients received 3 mg/kg in the dose escalation or expansion cohorts. CR, complete response; NE, not estimable; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; SLD, sum of longest diameters.