Abstract
Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25–7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.
Introduction
Tumor angiogenesis, a multifaceted process associated with increased aggressiveness of disease, is based on outcomes from the interaction between endothelial and tumor cells, and various cellular signaling pathways. Tumor angiogenesis has been highlighted as one of the integral hallmarks of cancer (1). Two of the most relevant pathways that have a central role in tumor angiogenesis are the VEGF–VEGF receptor and the delta-like ligand 4 (DLL4)–Notch signaling pathways (2–4).
Clinical benefits have been demonstrated with anti-VEGF therapies (5–8); however, intrinsic and acquired resistance to such therapies occurs and highlights the need for more effective treatments capable of targeting both VEGF-dependent and -independent pathways crucial for tumor growth.
DLL4 is a cell-surface ligand that activates the Notch-1 receptor pathway involved in cell proliferation and cell-fate determination (9, 10), and was discovered as another pivotal signaling node in regulating tumor angiogenesis (11, 12). Of note, both DLL4 and VEGF activity are critically required for proper vascular function (13, 14). Several studies reported that DLL4 is upregulated on tumor vasculature relative to the endothelium of adjacent normal tissues (15–17), and endothelial expression levels were found to be inversely correlated with survival of some patients with cancer treated with anti-VEGF therapy (18, 19). This indicates a critical role in tumor angiogenesis that is VEGF independent. Blockade of DLL4 was shown to inhibit tumor growth across multiple tumor types, including those tumors that are resistant to VEGF inhibition (11, 12). Collectively, these observations indicate that targeting both the DLL4 and the VEGF pathways may improve outcomes of current anticancer therapies.
Dilpacimab, formerly called ABT-165, is a novel immunoglobulin G (IgG)–like DLL4/VEGF bispecific molecule that uses a proprietary dual-variable domain-Ig platform (20). In preclinical studies, dilpacimab potently inhibited both DLL4 and VEGF pathways, resulting in significantly greater tumor growth inhibition relative to blocking either axis alone (21). Importantly, in combination with chemotherapy agents in preclinical xenograft models, dilpacimab induced greater antitumor response and outperformed anti-VEGF treatment (21).
The present study describes the safety/tolerability, pharmacokinetic (PK) profile, and preliminary efficacy results of dilpacimab in patients with advanced solid tumors. Pharmacodynamic (PD) and predictive biomarkers for association with safety and efficacy are also discussed.
Patients and Methods
Patient eligibility
Patients (≥18 years of age) with advanced solid tumors not amenable to surgical resection or other approved therapeutic options with demonstrated clinical benefit were enrolled and treated. Patients were required to have Eastern Cooperative Oncology Group (ECOG) performance status from 0 to 2; measurable disease per RECIST version 1.1 or evaluable disease by assessment of peripheral blood tumor antigen markers; adequate bone marrow function (absolute neutrophil count ≥1,000 cells/mm3, platelets ≥100,000/mm3, hemoglobin ≥9.0 g/dL), renal function [serum creatinine ≤1.5× upper limit of normal (ULN) or creatinine clearance ≥50 mL/min], hepatic function (bilirubin ≤1.5× ULN, and aspartate aminotransferase and alanine aminotransferase ≤2.5× ULN or ≤5× ULN for patients with liver metastases), and coagulation function (activated partial thromboplastin time ≤1.5× ULN within 7 days prior to cycle 1 day 1). Exclusion criteria included: prior anticancer therapy (eg, chemotherapy, immunotherapy, radiotherapy, biologic therapy, or any investigational therapy) within 21 days or anticancer herbal therapy within 7 days prior to study-drug administration; clinically significant condition(s) that might put the patient at higher risk for (or history of intolerability to prior) antiangiogenic therapy; uncontrolled metastases to the central nervous system; unresolved clinically significant toxicities from prior anticancer therapies; prior history of clinically-significant pulmonary hypertension and cardiovascular disease.
The trial was registered with ClinicalTrials.gov (trial registration ID: NCT01946074) and was approved by institutional review boards (IRB) prior to initiation. The study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the 1964 Declaration of Helsinki, with written informed consent obtained from all patients before study enrollment.
Study design
This phase I open-label, multicenter, dose-escalation, and safety-expansion study evaluated dilpacimab dosed every 14 days in 28-day cycles (Supplementary Fig. S1). Arms that enrolled dilpacimab plus other agents (chemotherapy and immune checkpoint inhibitor) will be reported elsewhere after data analysis. The primary objectives of this study were to evaluate the safety/tolerability and PK profile of dilpacimab monotherapy and to determine the recommended phase II dose (RP2D). The secondary objective was to assess the preliminary antitumor activity of dilpacimab. An exploratory objective was to evaluate PD and predictive biomarkers for associations with efficacy.
Dilpacimab was administered via a 60-minute intravenous infusion on days 1 and 15 in 28-day cycles at escalating dose levels ranging between 1.25 and 7.5 mg/kg to determine the maximum tolerated dose (MTD). A minimum of 6 (up to 9) patients were enrolled at each dose level (Supplementary Fig. S1) and MTD was defined as the highest dose level at which fewer than 2 of 6 (<33%) patients experience a dose-limiting toxicity (DLT). Patients with clinical benefit[), or stable disease) could continue dilpacimab at investigator's discretion until progressive disease or unacceptable toxicity.
Dose escalation
The initial dose-escalation enrolled patients at 2.5 (n = 9; 1 patient with a DLT of headache), 5 (n = 6), and 7.5 (n = 3) mg/kg. Due to hypertension not easily controlled by antihypertensives that occurred outside the 28-day DLT window in patients treated at 5 and 7.5 mg/kg, a second dose-escalation enrolled at least 6 patients per cohort at dose levels of 1.25 (n = 8), 2.5 [n = 9; 1 patient with DLT hypertension, 1 patient with DLTs (grade 3 elevated aspartate amino transferase and alanine aminotransferase)], 3.75 (n = 9), and 5 mg/kg (n = 2) so that safety observations could be made outside of the DLT window on patients who were able to continue therapy.
Dose expansion
The dose expansion was intended to enroll up to 24 patients, with expansion at or below the MTD to be performed to evaluate the safety, tolerability, and PK of dilpacimab. The dose expansion was terminated after 9 patients were enrolled, due to sponsor's decision to terminate further monotherapy development.
Safety
Treatment-emergent adverse events (AE) were assessed in the safety population (included all patients who received any study drug) from the time of study drug administration until 60 days following discontinuation of study drug and graded per the NCI Common Terminology Criteria for Adverse Events version (CTCAE) 4.03. Treatment-related AEs (TRAE) were those considered by investigator or sponsor to be related to dilpacimab.
Blood pressure and cardiac monitoring
The initial dose escalation did not have strict guidance for dosing based on blood pressure and after several patients had blood pressure that was difficult to control, a second dose escalation was started with stricter blood pressure monitoring and dosing criteria. In the second dose escalation (and expansion) enrolled patients recorded daily at-home blood pressure readings starting after dosing on cycle 1, day 1 and lasting through the end of cycle 1. Enrolled patients could receive up to 4 antihypertensive medications at any one time, and reduced monitoring was allowed if hypertension was well controlled at the start of cycle 2. Additionally, blood pressure was measured in triplicate at every study visit. If either an in-clinic or at-home reading showed systolic ≥140, diastolic ≥90 mm Hg, or if a patient required the addition of a fifth antihypertensive agent, study drug was withheld. If systolic was ≥180 or diastolic ≥110 mm Hg, patient was discontinued from study drug. Cardiac evaluations [including electrocardiogram (ECG) and echocardiogram] were performed every 2 cycles prior to dosing of dilpacimab, or upon the occurrence of any cardiac symptoms (including B-type natriuretic peptide greater than twice the institutional normal range, measured at the start of each cycle). Additionally, triplicate ECGs were collected before and within 30 minutes after dosing on cycle 1, day 1 and cycle 2, day 15, as well as within 45 days of the final study visit.
Pharmacokinetics
The PK population included all patients who received at least one dose of dilpacimab and from whom adequate drug concentration measurements were obtainable during the study. Blood samples for dilpacimab PK analyses were collected on day 1 (preinfusion and 30 minutes postinfusion), day 3 or 4, day 8, and day 15 (preinfusion and 30 minutes postinfusion) in cycle 1. In addition, blood samples were collected preinfusion and 30 minutes postinfusion on days 1 and 15 in cycle 2 and day 1 of each cycle thereafter, and at final visit. Serum concentrations of dilpacimab were determined using a validated method. PK parameters, including area under the serum concentration-time curve, maximum observed serum concentration (Cmax), time to Cmax (Tmax), and terminal phase elimination half-life (T1/2), were estimated using noncompartmental analysis [Phoenix WinNonlin 8.0 (QC 17320)].
Efficacy and biomarker assessments
The efficacy population included all patients who received at least one dose of dilpacimab. All efficacy analyses were exploratory in nature, and their end-points included objective response rate (ORR; CR or PR) and progression-free survival (PFS). Baseline radiographic tumor assessment (CT or MRI) was performed within 28 days prior to day 1 of cycle 1 and repeated every 2 cycles (56 days; assessments could occur up to 7 days prior to end of cycle). ORR included confirmed CR and PR and was assessed by RECIST version 1.1. PFS was defined as the time from first dose date of dilpacimab to either disease progression or death, whichever occurred first. If a patient was still responding, the patient's data were censored at the date of the last tumor assessment. If a patient received a new line of anticancer therapy, data were censored at the date of the last tumor assessment prior to initiating the new therapy.
Plasma, whole blood, serum, and tumor tissue (archival or fresh biopsy) samples were collected and stored at −70° C or below until quantitative biomarker assessment. Serum and plasma biomarker samples were collected predose on days 1 and 15 of cycle 1; day 1 of cycles 2 and 3; and at the final visit. Plasma was also collected 2 hours postdose on day 1 of cycle 1. Tumor tissue had to be confirmed available prior to enrollment.
Biomarker analysis
Blood sample collections for plasma VEGF/DLL4 measurements
Venous blood was drawn in EDTA tubes at day 1 (baseline), and 2 hours and 3 or 4 days post-dilpacimab dosing in cycle 1. Additional samples were also collected immediately before dosing on cycle 1 day 15, and then at the start of each new cycle. Plasma was extracted within 30 minutes of blood draw, aliquoted, and kept frozen until the analysis.
Circulating soluble DLL4
An electrochemilluminescent assay by Meso Scale Discovery (MSD) technology (Meso Scale Discovery; catalog no. 1506- D4/CF) was used to determine the concentration of soluble DLL4 in human plasma. Two DLL4 antibodies (E9–2B and h38H12.11, produced by AbbVie) that do not compete with dilpacimab for DLL4 binding were ruthenylated and biotinylated, respectively, and mixed with study samples. The homogeneous solutions were then pipetted into streptavidin-coated MSD plates. Following an incubation and wash step, assay plates were read on an MSD instrument.
Circulating VEGF
VEGF plasma levels were measured by Quantikine (R&D Systems, catalog no. DVE00) assay. In an additional step, dilpacimab was removed from post–dilpacimab-dosed samples using Protein A Spin Columns (Thermo Scientific; catalog no. 89952 or 89948), to decrease interferences in detecting free VEGF. The intensity of color was measured at 450 and 570 nmol/L using SpectraMax by Molecular Devices (catalog no. ABS).
Statistical analyses
Data were summarized by dose level and for all patients pooled in the dose-escalation and -expansion phase. Categorical data were summarized by frequency counts and percentages, and continuous data were summarized by descriptive statistics. All safety summaries were descriptive, and no statistical inference was performed on the safety data. The two-sided 95% confidence intervals (CI) for the ORR, as well as complete response and PR rates, were provided using the Clopper–Pearson exact method. PFS was estimated using the Kaplan–Meier method; median time and associated two-sided 95% CIs, and the 25th and 75th percentiles of the time were provided.
Results
Patient demographics and baseline characteristics
As of August 2, 2018, 55 patients with solid tumors were enrolled in 2 sequential dose-escalation cohorts (46 patients) and a dose-expansion cohort (9 patients). Key patient demographics and clinical characteristics are summarized in Table 1. The median age was 60 years (range, 40–75) and the most common primary tumor was ovarian (n = 17; 30.9%). The sponsor chose to enrich for ovarian tumors, since VEGF inhibitors have monotherapy activity in ovarian cancer. Prior systemic therapies received by patients with ovarian cancer are listed in Supplementary Tables S1 and S2.
Table 1.
Baseline demographics and clinical characteristics.
| Dilpacimab | |
|---|---|
| Characteristics | N = 55 |
| Median age, years (range) | 60 (40–75) |
| Sex, n (%) | |
| Male | 15 (27.3) |
| Female | 40 (72.7) |
| Median number of prior therapies (range) | 4 (1–10) |
| Primary tumor, n (%) | |
| Ovarian | 17 (30.9) |
| Breast | 6 (10.9) |
| Colon | 4 (7.3) |
| Renal | 4 (7.3) |
| Esophageal | 3 (5.5) |
| Other typesa | 21 (38.2) |
aTumor types with <5% were combined.
Safety profile
In the initial dose-escalation using a 3 + 3 design, the first patient treated with 2.5 mg/kg dilpacimab had a DLT of grade 3 headache, and although no other DLTs were observed in that or subsequent cohorts, patients receiving multiple doses at 5 and 7.5 mg/kg showed evidence of hypertension that was not easily controlled with antihypertensive agents, beyond the 28-day DLT window. Therefore, the initial dose-escalation was suspended, and after evaluation of the safety data, dose escalation was resumed starting at 1.25 mg/kg with revised treatment criteria requiring systolic blood pressure less than 140 mm Hg and diastolic blood pressure less than 90 mm Hg prior to any treatment with dilpacimab. The RP2D for dilpacimab monotherapy was determined to be 3.75 mg/kg (a total of 15 patients were treated at this dose level: 9 in dose escalation and 6 in dose expansion), on the basis of the safety and lack of tolerability of higher doses due to hypertension that occurred outside the DLT window. Further details of the dose-escalations are provided in the Patients and Methods section.
Treatment-emergent AEs regardless of attribution were reported in all patients (N = 55; 100%). Any-grade and grade ≥3 treatment-emergent AEs are summarized in Table 2. The most common treatment-emergent AEs (>40%) of any grade reported with dilpacimab monotherapy were hypertension (63.6%), fatigue (49.1%), headache (43.6%), and nausea (41.8%). Any-grade TRAEs were reported in 48 (87.3%) patients (Table 2). Most common TRAEs (>20%) of any grade were hypertension (n = 33; 60.0%), headache (n = 17; 30.9%), and fatigue (n = 12; 21.8%). The most common grade ≥3 TRAE was hypertension (n = 21; 38.2%). Less frequent TRAEs of special interest were gastrointestinal perforation (GIP; n = 2; 3.6%) and pulmonary hypertension (any grade) detected by echocardiogram (n = 8; 14.5%); 1 patient died as a result of GIP.
Table 2.
Summary of treatment-emergent AEs occurring in ≥10% of patients or treatment-emergent AEs considered to be related to dilpacimab occurring in ≥5% of patients.
| Related or unrelated to dilpacimab | Related to dilpacimab | |||
|---|---|---|---|---|
| Any grade | Grade ≥3 | Any grade | Grade ≥3 | |
| dilpacimab | dilpacimab | dilpacimab | dilpacimab | |
| Treatment-emergent AEs | (N = 55) | (N = 55) | (N = 55) | (N = 55) |
| Any AE | 55 (100) | 47 (85.5) | 48 (87.3) | 28 (50.9) |
| Hypertension | 35 (63.6) | 22 (40.0) | 33 (60.0) | 21 (38.2) |
| Fatigue | 27 (49.1) | 2 (3.6) | 12 (21.8) | 0 |
| Headache | 24 (43.6) | 1 (1.8) | 17 (30.9) | 1 (1.8) |
| Nausea | 23 (41.8) | 2 (3.6) | 7 (12.7) | 1 (1.8) |
| Abdominal paina | 22 (40.0) | 3 (5.5) | 1 (1.8) | 0 |
| Diarrhea | 20 (36.4) | 2 (3.6) | 10 (18.2) | 0 |
| Decreased appetite | 19 (34.5) | 2 (3.6) | 6 (10.9) | 1 (1.8) |
| Urinary tract infection | 13 (23.6) | 1 (1.8) | 0 | 0 |
| Anemia | 12 (21.8) | 3 (5.5) | 6 (10.9) | 0 |
| Arthralgia | 12 (21.8) | 0 | 0 | 0 |
| Cough | 12 (21.8) | 0 | 0 | 0 |
| Dizziness | 11 (20.0) | 0 | 3 (5.5) | 0 |
| Anxiety | 10 (18.2) | 0 | 0 | 0 |
| Constipation | 10 (18.2) | 0 | 3 (5.5) | 0 |
| Depression | 10 (18.2) | 0 | 0 | 0 |
| Back pain | 9 (16.4) | 1 (1.8) | 0 | 0 |
| Dehydration | 9 (16.4) | 2 (3.6) | 0 | 0 |
| Dyspnea | 9 (16.4) | 0 | 3 (5.5) | 0 |
| Hypokalemia | 9 (16.4) | 6 (10.9) | 0 | 0 |
| Malignant neoplasm progression | 9 (16.4) | 9 (16.4) | 0 | 0 |
| Pulmonary hypertension | 9 (16.4) | 2 (3.6) | 8 (14.5) | 1 (1.8) |
| Vomiting | 9 (16.4) | 2 (3.6) | 0 | 0 |
| Insomnia | 8 (14.5) | 0 | 0 | 0 |
| Myalgia | 8 (14.5) | 0 | 3 (5.5) | 0 |
| Decreased weight | 8 (14.5) | 0 | 0 | 0 |
| Hypomagnesemia | 7 (12.7) | 0 | 0 | 0 |
| Peripheral edema | 7 (12.7) | 0 | 3 (5.5) | 0 |
| Upper respiratory tract infection | 7 (12.7) | 1 (1.8) | 0 | 0 |
| Pain in extremity | 6 (10.9) | 0 | 0 | 0 |
| Proteinuria | 6 (10.9) | 0 | 6 (10.9) | 0 |
| Muscular weakness | 5 (9.1) | 0 | 3 (5.5) | 0 |
| Stomatitis | 5 (9.1) | 0 | 3 (5.5) | 0 |
| Confusional state | 4 (7.3) | 1 (1.8) | 3 (5.5) | 1 (1.8) |
| Dry mouth | 4 (7.3) | 1 (1.8) | 3 (5.5) | 0 |
| Epistaxis | 4 (7.3) | 0 | 3 (5.5) | 0 |
| Increased blood ALP | 4 (7.3) | 1 (1.8) | 3 (5.5) | 0 |
| Aphasia | 3 (5.5) | 0 | 3 (5.5) | 0 |
Abbreviation: ALP, alkaline phosphatase.
aIncludes upper abdominal pain.
All patients discontinued study drug except 1 patient with pancreatic adenocarcinoma. Reasons for treatment discontinuation included AEs (n = 9), clinical PD (n = 8), radiographic PD (n = 20), sponsor discontinued dosing (n = 2), patient withdrew consent (n = 2), and other reasons (n = 4).
Pharmacokinetics
PK parameters for dilpacimab are presented in Table 3. The T1/2 for dilpacimab ranged from 5.0 to 7.2 days in the dose range tested (1.25–7.5 mg/kg). The exposure (Cmax and AUC) of dilpacimab appeared to be dose proportional between 1.25- and 5-mg/kg dose groups, and slightly greater than dose proportional at 7.5 mg/kg. Body weight did not appear to be a significant covariate for dilpacimab exposure.
Table 3.
Pharmacokinetic parameters of dilpacimab for N = 55 available samples.
| 1.25 mg/kg | 2.5 mg/kg | 3.75 mg/kg | 5 mg/kg | 7.5 mg/kg | |
|---|---|---|---|---|---|
| Pharmacokinetic parameters (units) | (N = 9)a | (N = 20)b | (N = 15)c | (N = 8)d | (N = 3)e |
| T max, he,f | 1.5 (1.5, 1.5) | 1.5 (1.5, 1.5) | 1.5 (1.5, 49) | 1.5 (1.5, 49) | 1.5 (1.5, 49) |
| Median (min, max) | |||||
| C max, μg/mL | 27.6 (34) | 60.0 (20) | 108 (34) | 125 (32) | 207 (19) |
| Geometric mean (%CV) | |||||
| AUC336h, μg/day/mL | 139 (47) | 309 (29) | 659 (24) | 796 (28) | 1,421 (23) |
| Geometric mean (%CV) | |||||
| AUCinf, μg/day/mL | 192 (40) | 416 (38) | 946 (26) | 943 (30) | 1,666 (1,567, 1,765)e |
| Geometric mean (%CV) | |||||
| T 1/2, day | 5.0 | 5.2 | 7.4 | 5.4 | 7.2 (7.9, 6.4)e |
| Harmonic mean | |||||
| CL (mL/h/kg) | 0.27 (55) | 0.25 (52) | 0.17 (28) | 0.22 (28) | 0.19 (0.20, 0.18) |
| (6.5 mL/d/kg) | (6.0 mL/d/kg) | (4.0 mL/d/kg) | (5.3 mL/d/kg) | (4.5 mL/d/kg)e |
Abbreviations: AUC336h, area under the serum concentration-time curve from time zero to 336 hours; AUCinf, area under the serum concentration-time curve from time zero to infinity; CL, clearance.
a N = 8 for T1/2, AUCinf, and CL.
b N = 16 for T1/2, AUCinf, and CL.
c N = 11 for T1/2, AUCinf, and CL.
d N = 5 for T1/2, AUCinf, and CL.
e N = 2, presented as a mean (individual values).
fTime relative to start of the infusion, presented as median (min, max).
Preliminary efficacy
The best percentage change from baseline in tumor size is shown in Fig. 1A. ORRs for all treated patients with available data are presented in Table 4. The ORR was 10.9% (6 of 55); 6 patients achieved PR; median PFS was 3.7 months (95% CI, 2.7–3.9). The remaining patients either had stable disease (n = 29), PD (n = 13), or were not evaluable (n = 7). As expected for an antiangiogenic agent, the antitumor activity was concentrated in patients with ovarian cancer, with 25.0% (4 of 16) achieving PR (Table 4 and Fig. 1B). Change in tumor target lesions sum of longest diameter over time for patients with ovarian cancer treated with dilpacimab at all dose levels is shown in Fig. 1C. The median time on treatment for patients with ovarian cancer was 10.1 weeks (range, 0.1–96.3); 2 patients with PR were on treatment for more than 50 weeks (55.1 and 96.3). One patient with pancreatic adenocarcinoma continues on study, with sustained PR for appproximately 5 years. The original dosing regimen was dilpacimab 3.75 mg/kg every 14 days; the patient is currently receiving dilpacimab 2.5 mg/kg every 28 days. Dose and schedule were modified due to treatment-emergent pulmonary hypertension which resolved.
Figure 1.
A, Best percentage change in tumor lesion for dilpacimab at all dose levels (n = 47). B, Patients with ovarian cancer treated with dilpacimab at all dose levels (n = 16). C, Change in tumor lesion over time for patients with ovarian cancer treated with dilpacimab at all dose levels (n = 16). aPatients without prior bevacizumab treatment.
Table 4.
Best response for evaluable patient population.
| Dilpacimab | |
|---|---|
| Best response per investigator, n (%) | (N = 55)a |
| PR | 6 (10.9) |
| Ovarian (n = 16) | 4 (25.0) |
| Stable diseaseb | 29 (52.7) |
| Progressive disease | 13 (23.6) |
a7 patients were not evaluable for efficacy, including one patient with ovarian cancer.
bFirst scan performed within 7 days prior to the end of cycle 2.
Correlative biomarkers
To evaluate target binding, circulating levels of free VEGF and total serum (s)DLL4 levels were measured in the dose-escalation cohort. The baseline levels of VEGF (N = 53 available samples) varied from 15 to 867 pg/mL (Fig. 2A). Within 2 hours of dilpacimab dosing, a significant decrease was observed in free VEGF levels, suggesting saturation of VEGF by dilpacimab. The decrease in VEGF levels compared with predose was statistically significant for all dose levels and time points tested (P <0.001) but was not dose dependent. A dose-dependent desaturation of VEGF binding by dilpacimab was also observed.
Figure 2.
Effect of dilpacimab administration on levels of free VEGF (A) and total sDLL4 (B). C, cycle. D, day.
The baseline levels of sDLL4 (N = 53) varied from 106 to 671 pg/mL (Fig. 2B). The immunoassay measured the total (dilpacimab-bound and -free) sDLL4. The levels of total sDLL4 increased after 3 to 4 days of dosing for all dose cohorts (P <0.01). The increase in sDLL4 levels compared with predose was statistically significant for all dose levels at all time points except 2 hours after first dose. A trend for increased fold-change in sDLL4 levels with dose was also observed.
Discussion
This study represents the first-in-human phase I clinical trial of dilpacimab, a novel IgG-like DLL4/VEGF bispecific molecule. The results demonstrate that dilpacimab is clinically active and has a manageable tolerability and safety profile. The most common TRAEs were hypertension, headache, and fatigue. As expected, dilpacimab displayed anti-VEGF–like toxicity including hypertension, which is one of the most frequently described on-target treatment-related side effects associated with several anti-VEGF–targeted therapies (22) as well as with anti-DLL4 therapy (23). The RP2D of dilpacimab monotherapy was established as 3.75 mg/kg.
Regarding safety, two of 55 (3.6%) patients treated with monotherapy had GIP considered related to dilpacimab. The GIP occurred at the site of a diverticulum (prostate cancer) or diverticulum involved with tumor (ovarian cancer). It is currently unclear if diverticuli or metastatic or primary tumor invading bowel represent increased risk for dilpacimab-associated GIP. Pulmonary hypertension, generally asymptomatic, was detected in dilpacimab-treated patients by echocardiogram, usually after multiple cycles of drug therapy, and managed by dose delays or discontinuation. Although follow-up was not long enough to ensure complete reversal, decrease in pulmonary hypertension after drug cessation was noted, suggesting that the finding was reversible. One patient had a hypertensive emergency after presenting with a minor stroke and retinal vein occlusion. Certain other potential side effects of anti-VEGF therapy such as myocardial infarction, ischemic limbs, nephrotic syndrome, or delayed wound healing were not observed, possibly due to the low number of patients treated.
This phase I study also explored the PK and PD effects of dilpacimab. The exposure of dilpacimab appeared to be dose proportional between the 1.25- and 5-mg/kg dose groups, and slightly greater than dose proportional at 7.5 mg/kg. As expected, dilpacimab treatment resulted in significant decrease in free VEGF within 2 hours of even the lowest dose, suggesting binding of dilpacimab to circulating VEGF. This finding is consistent with prior observations with bevacizumab. We observed a dose-dependent desaturation of VEGF binding by dilpacimab, and increase in VEGF levels was observed predose for the second infusion on cycle 1 day 15. At higher doses, free VEGF was constantly suppressed.
We also observed significant increase in total sDLL4 over time, suggestive of binding of dilpacimab to sDLL4 ligand with stabilization of the complex in circulation. The increase in total sDLL4 was also dose dependent. The pattern of modulation of two ligands, VEGF and sDLL4, after dilpacimab dosing was different. Decrease in free VEGF peaked 3 to 4 days after dosing, then plateaued. The total sDLL4 receptor levels, however, did not plateau, and continued to rise until the loss of exposure after dilpacimab therapy was discontinued.
Dilpacimab has demonstrated robust preclinical efficacy in a wide range of tumor types (21). In our study, dilpacimab monotherapy showed promising clinical antitumor activity, particularly in patients with ovarian cancer, with 4 of 16 patients achieving a PR (25%). Three of the 4 (75%) patients with ovarian cancer with PR had previously received and progressed on bevacizumab in earlier lines of therapy. PRs were also noted in 2 other patients, each of whom had received two prior lines of systemic chemotherapy: 1 patient with cervical cancer and 1 with pancreatic cancer (the latter remaining on study with PR for >60 months).
In the first-in-human, phase I study of the anti-DLL4 mAb enoticumab (REGN421) in patients with advanced solid tumors, modest antitumor activity was demonstrated, with 2 of 44 (5%) evaluable patients achieving PR. One of the 2 patients who achieved PR had ovarian cancer, from a total of 7 evaluable patients with ovarian cancer. In the first-in-human phase Ia study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors, 4 of 66 (6.1%) patients achieved PR; 3 of the 4 patients with PR had ovarian cancer (out of 12 patients with ovarian cancer in total; 25%), comparable with our study. These results suggest the antitumor activity of dilpacimab seen in ovarian cancer may be, at least in part, attributed to the inhibition of DLL4, since some patients were previously treated with bevacizumab. However, no definitive conclusions can be drawn, due to the low number of patients and unknown response rate to bevacizumab rechallenge. Similarly, no conclusive correlation could be drawn between response and angiogenesis gene expression signatures in the ovarian cancer patients due to the small number of patients.
Further clinical studies are warranted to ascertain whether dilpacimab, through inhibition of both VEGF and DLL4, represents a potential improvement beyond VEGF inhibition alone. A phase II study evaluating the efficacy and tolerability of dilpacimab plus folinic acid, fluorouracil, irinotecan (FOLFIRI) compared with bevacizumab plus FOLFIRI in patients with previously-treated metastatic colorectal cancer (NCT03368859; ref. 24) was discontinued after interim analysis showed lack of improved efficacy beyond bevacizumab.
Disclaimers
AbbVie provided financial support for this study (NCT01946074) and participated in the study design, research, analysis, data collection, interpretation of data, and review and approval of the manuscript. All authors had access to relevant data and participated in the drafting, review, and approval of this manuscript. No honoraria or payments were made for authorship.
Data Sharing Statement
AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols and Clinical Study Reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, or to submit a request, visit the following link: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html.
Authors' Disclosures
M.S. Gordon reports other support from AbbVie, MedImmune, Merck, Bristol Myers Squibb, Amgen, Tesaro, BeiGene, Aeglea, Arcus, Astex, Blueprint, Calithera, Celldex, Corcept, Clovis, Eli Lilly, Endocyte, Five Prime, Genocea, Neon, Plexxikon, Revolution Medicines, Seattle Genetics, Serono, SynDevRx, Tolero, Tracon, and ImaginAb; personal fees and other support from Agenus, Daiichi, Deciphera, and Salarius; and personal fees from Imaging Endpoints outside the submitted work. Z.A. Wainberg reports grants from Abbvie, Genentech, Novartis, Plexxikon, and Ipsen; personal fees from Amgen, Bayer, Astra Zeneca, Daiichi, Five Prime, Merck, Incyte, and BMS; and personal fees from Seagen outside the submitted work. E.P. Hamilton reports grants from OncoMed, Genentech/Roche, Zymeworks, Rgenix, ArQule, Clovis, Silverback Therapeutics, Millenium, Medivation, Acerta Pharma, Sermonix Pharmaceuticals, Aravive, Torque, Black Diamond, Karyopharm, Infinity Pharmaceuticals, Curis, Syndax, Novartis, Boehringer Ingelheim, Immunomedics, FujiFilm, Taiho, Deciphera, Fochon, Molecular Templates, Onconova Therapeutics, Dana Farber Cancer Hospital, Hutchinson, MediPharma, MedImmune, Seagen, Puma Biotechnology, Compugen, TapImmune, Lilly, Pfizer, H3 Biomedicine, Takeda, Merus, Regeneron, Arvinas, StemCentRx, Verastem, eFFECTOR Therapeutics, CytomX, InventisBio, Lycera, Mersana, Radius Health, Abbvie, Nucana, Leap Therapeutics, Zenith Epigenetics, Harpoon, Orinove, AstraZeneca, Tesaro, Macrogenics, EMD Serono, Daiichi Sankyo, Syros, Sutro, GI Therapeutics, Merck, PharmaMar, Olema, Polyphor, Immunogen, Plexxikon, and Amgen; other support from Genentech/Roche, Boehringer Ingelheim, Novartis, Dantari, Lilly, Merck, Puma Biotechnology, Silverback Therapeutics, CytomX, Pfizer, Mersana, Black Diamond, H3 Biomedicine, and Daiichi Sankyo; and other support from AstraZeneca outside the submitted work. G.W. Sledge reports grants from AbbVie during the conduct of the study; other support from Tessa Therapeutics; personal fees from G1 Therapeutics and Pionyr; grants from Pfizer and Genentech; and grants from QED outside the submitted work. H. Yue reports other support from AbbVie during the conduct of the study. M. Blaney reports other support from AbbVie during the conduct of the study and other support from AbbVie outside the submitted work. S. Kasichayanula reports other support from AbbVie Biotherapeutics outside the submitted work. M. Motwani is an Abbvie employee and receives salary. L. Wang reports personal fees from AbbVie Inc., outside the submitted work. L. Naumovski reports other support from AbbVie during the conduct of the study; and other support from AbbVie outside the submitted work; in addition, L. Naumovski has a patent for AbbVie issued to AbbVie; is an employee of AbbVie; and owns stock in the company. J.H. Strickler reports grants, personal fees, and nonfinancial support from Abbvie during the conduct of the study; grants and personal fees from Amgen, AstraZeneca, and Silverback Therapeutics; personal fees from Bayer, Mereo, Natera, Pfizer, Viatris, and Inivata; grants, personal fees, and nonfinancial support from SeaGen; grants from AStar D3, Curegenix, Daiichi Sankyo, Exelixis, Leap Therapeutics, Nektar, and Roche/Genentech; and grants from Sanofi Genzyme outside the submitted work. No disclosures were reported by the other authors.
Acknowledgments
AbbVie and the authors thank the patients participating in this clinical trial and all study investigators for their contributions. Medical writing support was provided by Mary Smith, PhD, CMPP, of Aptitude Health, Atlanta, GA, funded by AbbVie. This study was funded by AbbVie Inc., Chicago, IL.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Footnotes
Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
Authors' Contributions
M.S. Gordon: Writing–original draft, writing–review and editing. J. Nemunaitis: Writing–original draft, writing–review and editing. M. Barve: Writing–original draft, writing–review and editing. Z.A. Wainberg: Writing–original draft, writing–review and editing. E.P. Hamilton: Writing–original draft, writing–review and editing. R.K. Ramanathan: Writing–original draft, writing–review and editing. G.W. Sledge Jr: Writing–original draft, writing–review and editing. H. Yue: Conceptualization, writing–original draft, writing–review and editing. S.E. Morgan-Lappe: Conceptualization, writing–original draft, writing–review and editing. M. Blaney: Conceptualization, writing–original draft, writing–review and editing. S. Kasichayanula: Conceptualization, writing–original draft, writing–review and editing. M. Motwani: Conceptualization, writing–original draft, writing–review and editing. L. Wang: Conceptualization, writing–original draft, writing–review and editing. L. Naumovski: Conceptualization, writing–original draft, writing–review and editing. J.H. Strickler: Writing–original draft, writing–review and editing.
References
- 1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74. [DOI] [PubMed] [Google Scholar]
- 2. Amini A, Moghaddam SM, Morris DL, Pourgholami MH. The critical role of vascular endothelial growth factor in tumor angiogenesis. Curr Cancer Drug Targets 2012;12:23–43. [DOI] [PubMed] [Google Scholar]
- 3. Liu Z, Fan F, Wang A, Zheng S, Lu Y. Dll4-Notch signaling in regulation of tumor angiogenesis. J Cancer Res Clin Oncol 2014;140:525–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Oon CE, Bridges E, Sheldon H, Sainson RCA, Jubb A, Turley H, et al. Role of Delta-like 4 in Jagged1-induced tumour angiogenesis and tumour growth. Oncotarget 2017;8:40115–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42. [DOI] [PubMed] [Google Scholar]
- 6. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–50. [DOI] [PubMed] [Google Scholar]
- 7. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Barlesi F, Scherpereel A, Rittmeyer A, Pazzola A, Ferrer Tur N, Kim JH, et al. Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 2013;31:3004–11. [DOI] [PubMed] [Google Scholar]
- 9. Gurney A, Hoey T. Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc Cell 2011;3:18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Kuhnert F, Kirshner JR, Thurston G. Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc Cell 2011;3:20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 2006;444:1032–7. [DOI] [PubMed] [Google Scholar]
- 12. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 2006;444:1083–7. [DOI] [PubMed] [Google Scholar]
- 13. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996;380:435–9. [DOI] [PubMed] [Google Scholar]
- 14. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O'Shea KS. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996;380:439–42. [DOI] [PubMed] [Google Scholar]
- 15. Jubb AM, Turley H, Moeller HC, Steers G, Han C, Li JL, et al. Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Br J Cancer 2009;101:1749–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Jubb AM, Soilleux EJ, Turley H, Steers G, Parker A, Low I, et al. Expression of vascular notch ligand delta-like 4 and inflammatory markers in breast cancer. Am J Pathol 2010;176:2019–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Jubb AM, Browning L, Campo L, Turley H, Steers G, Thurston G, et al. Expression of vascular Notch ligands Delta-like 4 and Jagged-1 in glioblastoma. Histopathology 2012;60:740–7. [DOI] [PubMed] [Google Scholar]
- 18. Jubb AM, Miller KD, Rugo HS, Harris AL, Chen D, Reimann JD, et al. Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res 2011;17:372–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Hu W, Lu C, Dong HH, Huang J, Shen DY, Stone RL, et al. Biological roles of the Delta family Notch ligand Dll4 in tumor and endothelial cells in ovarian cancer. Cancer Res 2011;71:6030–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Wu C, Ying H, Grinnell C, Bryant S, Miller R, Clabbers A, et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol 2007;25:1290–7. [DOI] [PubMed] [Google Scholar]
- 21. Li Y, Hickson JA, Ambrosi DJ, Haasch DL, Foster-Duke KD, Eaton LJ, et al. ABT-165, a dual variable domain immunoglobulin (DVD-Ig) targeting DLL4 and VEGF, demonstrates superior efficacy and favorable safety profiles in preclinical models. Mol Cancer Ther 2018;17:1039–50. [DOI] [PubMed] [Google Scholar]
- 22. Keefe D, Bowen J, Gibson R, Tan T, Okera M, Stringer A. Noncardiac vascular toxicities of vascular endothelial growth factor inhibitors in advanced cancer: a review. Oncologist 2011;16:432–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Smith DC, Eisenberg PD, Manikhas G, Chugh R, Gubens MA, Stagg RJ, et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin Cancer Res 2014;20:6295–303. [DOI] [PubMed] [Google Scholar]
- 24. Wainberg ZA, Wang L, Yue H, Motwani M, Kasichayanula S, Blaney ME, et al. ABT-165 plus FOLFIRI vs bevacizumab (bev) plus FOLFIRI in patients (pts) with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine/oxaliplatin and bev. J Clin Oncol 36:15s, 2018. (suppl; abstr TPS3619). [Google Scholar]