A novel dual-pathway inhibitor of tumor angiogenesis passed a preliminary clinical test, demonstrating manageable toxicity and biomarker evidence of engagement with the drug's targets, as reported at the 2016 ASCO Annual Meeting in Chicago.
Michael S. Gordon, MD
A novel dual-pathway inhibitor of tumor angiogenesis passed a preliminary clinical test, demonstrating manageable toxicity and biomarker evidence of engagement with the drug’s targets, as reported at the 2016 ASCO Annual Meeting in Chicago.
Preliminary evidence of clinical activity also emerged from the phase I trial of ABT-165, as 5 of 55 evaluable patients had partial responses (PRs), including 4 of 16 patients with treatment-refractory ovarian cancer.
“ABT-165 engages and inhibits both DLL4 and VEGF targets/pathways,” said Michael S. Gordon, MD, president and CEO of Pinnacle Oncology Hematology in Scottsdale, Arizona. “ABT-165 is generally well tolerated at single-agent doses up to 3.75 mg/kg. However, long-term consequences of dual DLL4 and VEGF inhibition need to be evaluated. An ongoing phase Ib study is exploring the combination of ABT-165 and chemotherapy in multiple indications amenable to antiangiogenic therapy.”
ABT-165 is a first-in-class, humanized dual variable domain (DVD) immunoglobulin inhibitor of delta-like ligand-4 (DLL4) and vascular endothelial growth factor (VEGF). DLL4 is a NOTCH pathway ligand involved in angiogenesis and maintenance of tumor-initiating cells (TICs).
Preclinical and clinical studies conducted to date have shown that the agent has specificity for both targets, inhibiting DLL4-mediated activation of the NOTCH-1 pathway and the VEGF receptor pathway. The data have suggested potential suppression of tumor angiogenesis and maintenance of TICs, said Dr. Gordon.
In xenograft tumor models, single-agent ABT-165 outperformed an anti-VEGF monoclonal antibody. ABT-165 plus paclitaxel demonstrated greater activity compared to an anti-VEGF agent plus paclitaxel, and single-agent ABT-165 had activity similar to that of anti-VEGF/paclitaxel combination therapy.
Dr. Gordon reported findings from a phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of ABT-165; determine the recommended phase II dose; and perform a preliminary assessment of antitumor activity. Eligible patients had a malignancy that was unresectable, that had progressed despite standard therapy, or that had no effective therapy.
The 55 patients had a median age of 60 and included 40 women. The patients had received a median of 4 prior regimens. Primary tumors represented in the trial included ovarian (n = 16), breast (6), colon (4), renal (4), and esophagus (3), as well as 22 patients with other tumor types.
The trial had a typical 3 x 3 dose-escalation design, beginning at 2.5 mg/kg q2w and planned escalation to 5 mg/kg and to 7.5 mg/kg. Dose expansion was preplanned for single-agent therapy in ovarian cancer and in phase Ib evaluation of ABT-165 in combination with standard chemotherapy agents.
The maximum tolerated dose (MTD) was defined as DLTs were experienced in 2 of 6 patients treated with a given dose of the drug. One DLT, a headache associated with hypertension, occurred at the starting dose, and another patient continued beyond the DLT period and subsequently developed hypertension and stroke. Another patient had complications of hypertension at the 5 mg/kg dose.
“At that point, we suspended therapy on the protocol for an interval of time to assess management of hypertension,” said Dr. Gordon. “We came back with more stringent and rigid blood pressure management strategies.”
Dose escalation started again at 1.25 mg/kg, and successful escalation occurred through 3.75 mg/kg. After escalation to 5 mg/kg, 2 patients had a “rather typical, perhaps VEGF-related adverse event” in the form of gastrointestinal perforation. One perforation occurred in a patient with ovarian cancer and peritoneal involvement and the other in a man with prostate cancer and diverticular disease.
Investigators decided to enroll additional patients after implementing restrictions on enrollment of patients with peritoneal, bowel, and related conditions. Enrollment continued to the accrual of 55 patients, including 20 treated with a dose of 2.5 mg/kg and 15 at a dose of 3.75 m/kg.
AEs of all grades included hypertension (n = 37), fatigue (26), headache (24), nausea (21), decreased appetite (19), diarrhea (17), urinary tract infection (12), and arthralgia, constipation, and dizziness (11 each). Hypertension accounted for most of the grade 3/4 AEs (16, 29.1%), followed by 3 cases each of anemia, hypokalemia, abdominal pain, and small-intestine obstruction.
AEs of interest consisted of pulmonary hypertension in 6 patients, proteinuria in 5 patients, in addition to the 2 gastrointestinal perforations and the 1 patient who had an ischemic stroke.
Pharmacokinetics studies demonstrated a half-life of about 7 days, and the PK profile was dose related. The studies showed no evidence of antidrug antibodies.
Pharmacodynamics studies conducted after the restart at 1.25 mg/kg showed a rapid drop in soluble free VEGF, consistent with VEGF binding. The studies also showed escalation of DLL4 to the ABT-165 antibody. Analysis of peripheral blood mononuclear cells showed upregulation and downregulation of proteins associated with the NOTCH/wnt pathway, which is consistent with engagement with the protein target.
“This provided evidence, even at this low dose, of binding of the protein targets,” said Dr. Gordon.
In addition to the 5 partial responses documented in response to ABT-165 treatment, several other patients had tumor shrinkage that did not meet criteria for objective response. Additionally, about half of the patients had “persistently stable disease” as best response.
Gordon MS, Nemunaitis JJ, Ramanathan RK, et al. Phase 1, open-label, dose-escalation and expansion study of ABT-165, a dual variable domain immunoglobulin (DVD-Ig) targeting both DLL4 and VEGF, in patients (pts) with advanced solid tumors.J Clin Oncol34, 2016 (suppl, abstr 2507).