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A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors
Charlotte Lemech 1 . Natasha Woodward2 . Nancy Chan3 . Joanne Mortimer4 . Louie Naumovski5 . Silpa Nuthalapati5 . Bo Tong5 . Fang Jiang 5 . Peter Ansell5 . Christine K. Ratajczak5 · Jasgit Sachdev6,7
Received: 5 March 2020 / Accepted: 28 May 2020 C Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, phar- macokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7-109.35 µg/kg. Patients enrolled had colorectal cancer (n= 11), breast cancer (n =6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n=2; both at 99.9-ug/kg dose level), neutropenia (n=2; 78.3-µg/kg and 99.9-ug/kg dose levels), and pancytopenia (n= 1; 109.35-ug/kg dose level). The most common treatment- emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients.
Keywords Antibody-drug conjugate · Solid tumor · Prolactin receptor · Phase 1 · Pyrrolobenzodiazepine
☒ Jasgit Sachdev jsachdev@honorhealth.com
1 Scientia Clinical Research, Sydney, NSW, Australia
2 Mater Misericordiae Ltd and Mater Research Institute/University of Queensland, Raymond Terrace, South Brisbane, QLD, Australia
3 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
4 City of Hope National Medical Center, Duarte, CA, USA
5 AbbVie Inc, North Chicago, IL, USA
6 HonorHealth Research Institute, Scottsdale, AZ 85258, USA
7 Translational Genomics Research Institute, Phoenix, AZ 85004, USA
Introduction
The antibody-drug conjugate (ADC) mechanism of action combines the specificity of antibodies and the potency of cy- totoxic payload, with the goal of achieving antitumor activity with better tolerability than payload alone. Currently, 5 ADCs have been approved in oncology indications: 4 for hematolog- ic malignancies and 1 for solid tumors. Many additional ADCs are currently in development [1]. ABBV-176 is an ADC composed of anti-prolactin receptor (PRLR) humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic DNA-crosslinking pyrrolobenzodiazepine (PBD) dimer (SGD-1882) via a maleimidocaproyl-valine-alanine linker.
While the PRLR and its peptide hormone ligand, prolactin, have been recognized for their role in mammary gland devel- opment and lactation, epidemiologic and preclinical data also suggest a role for PRLR in the pathogenesis of cancer [2, 3]. Data from 2 large epidemiologic studies showed that high than normal levels of circulating prolactin in both postmeno- pausal and younger women are associated with increased breast cancer risk [4, 5].
Most breast tumors express PRLR, and increased PRLR expression has been noted in malignant vs. normal human breast tissue [6, 7]. PRLR has also been reported to be fre- quently expressed at high levels in other tumor types, includ- ing adrenocortical carcinoma, hepatocellular carcinoma, and colorectal cancer [8-10]. Additionally, PRLR has previously been noted to be expressed at varying levels in several normal tissues, including the kidney, liver, brain, lung, and adrenal glands [8, 11].
PRLR antagonists have been shown to inhibit in vitro pro- liferation of breast cancer cells and in vivo tumor growth in rodent cancer models [12-14]. However, LFA102, an anti- PRLR neutralizing antibody, failed to demonstrate antitumor activity in an early clinical study [15].
The properties of PRLR nevertheless suggested it as a po- tential target for an ADC in the treatment of cancers likely to express PRLR. In addition to its high level of expression in some cancers, PRLR is a suitable ADC target due to its rapid internalization upon binding with its ligand [16]. Here we report the findings of a first-in-human phase 1 study that eval- uated the safety, pharmacokinetics, and antitumor activity of ABBV-176 in patients with advanced solid tumors.
Materials and methods
Study design and treatment
This was a phase 1, open-label, dose-escalation study (NCT03145909) to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and pharmaco- kinetic profile of ABBV-176 administered intravenously ev- ery 21 days to patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 until progression per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or unacceptable toxicity. Results from the dose-escalation cohort are reported.
In the dose-escalation cohort, patients were administered ABBV-176 according to an exposure-adjusted continual reas- sessment method (EACRM) [17]. The EACRM incorporates information from all prior events (such as the previous doses and tolerability) and drug exposure into a statistical dose- response model guiding the selection of the subsequent doses. The initial dose was 2.7 ug/kg. After 1 patient at the initial dose completed the dose-limiting toxicity (DLT) assessment
period without a DLT, a statistical model was fitted using all available cumulative DLT and exposure data to generate an updated estimate of the MTD. The next patient was enrolled at this newly estimated MTD. Subsequently, for each newly en- rolling patient, the assigned dose was assumed to be the MTD as estimated from current results. Dose increment was capped at a 100% increase, or at a 50% increase if a grade ≥2 drug- related toxicity had been observed. The 50% cap was removed if ≥2 patients at the higher dose level completed the DLT observation period without experiencing a grade ≥2 toxicity of the same Medical Dictionary for Regulatory Activities (MedDRA) system organ class. Enrollment was to continue until there was sufficient evidence for final MTD estimation or futility, whichever occurred first. Futility was defined as (1) observed DLT rate > 33% at the initial dose, with a minimum of 3 patients assigned to that dose; or (2) estimated MTD less than the initial dose with a minimum of 3 patients evaluated. The MTD was defined as the highest dose for which the prob- ability of a DLT was ≤33% at the end of the DLT assessment period. Sufficient evidence of tolerability was considered achieved when the estimated MTD was the same as the 3 previous MTD estimates, and the recommended MTD (or the MTD plus adjacent doses close to the MTD) were studied in 3 to 6 patients. The DLT assessment period commenced on the first cycle of ABBV-176 dosing (from first dose until next dose).
All patients provided their informed consent. All study procedures were conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and Good Clinical Practice guidelines. The protocol received institution- al review board approval.
Patients
Patients eligible for the dose escalation were 18 years and older with histologically confirmed, locally advanced or met- astatic solid tumor types associated with PRLR expression, including breast cancer, colorectal cancer, and adrenocortical carcinoma. Patients had progressed on prior treatment, were not amenable to treatment with curative intent, and had no other therapy options known to provide clinical benefit, or were ineligible for such therapies. Patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function. Patients were required to consent to provide archived tumor tissue or fresh tumor biopsy for biomarker analyses.
Patients were not eligible if they received anticancer thera- py including chemotherapy, immunotherapy, radiotherapy, biologic therapy, or any investigational therapy within 21 days prior to the first dose of ABBV-176; received radiation ther- apy for tumor lesion symptom palliation or small-molecule targeted anticancer agents within 14 days of the first dose of
ABBV-176; had prior exposure to any PBD-containing agent; or had uncontrolled metastases to the central nervous system.
Safety and tolerability
Safety evaluations were performed throughout the study. Adverse events (AEs) were coded using MedDRA version 21.0 and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Treatment-emergent AEs were defined as any AEs with an onset date on or after the first dose of study drug and ≤ 30 days after the last dose of study drug. Any AEs with an onset date outside this period were considered non-treatment emergent. Treatment-related AEs were those considered by the investigator as having a reasonable possibility of being related to ABBV-176.
DLTs were defined as any grade ≥3 AE except as follows: AEs that the investigator determined were due to underlying illness or disease progression; grade 3 nausea, vomiting, or diarrhea adequately managed with best supportive care; grade 3 neutropenia without fever or clinically significant symptoms and not resulting in treatment delay >7 days; grade 3 throm- bocytopenia without clinically significant symptoms, not re- quiring supportive care, and not resulting in treatment delay >7 days; grade 3 or 4 lymphopenia without clinically signifi- cant symptoms; grade 3 or 4 leukopenia without clinically significant symptoms and not resulting in treatment delay of
7 days; grade 3 anemia not requiring transfusion and not resulting in treatment delay >7 days.
Exploratory efficacy
Efficacy endpoints were exploratory and included assessment of objective response using RECIST version 1.1 criteria. Tumor assessments were performed within 28 days of cycle 1 day 1, then every 6 weeks (± 1 week) for 30 weeks, then every 9 weeks (± 2 weeks) and at the end-of-treatment visit.
Pharmacokinetics
Blood samples for pharmacokinetic assessments were collect- ed predose, and postdose on days 1 (2 h and 4 h), 2, 3, 8, and 15 of cycle 1; predose and postdose on days 1 (2 h and 4 h), 2, 3, 5, 8, and 15 of cycle 3; predose on day 1 of cycles 2, 4, and 6; predose on day 1 of every 4 cycles after cycle 6; and at an end-of-treatment visit. Pharmacokinetic assessments included conjugated antibody (ABBV-176) and total antibody, uncon- jugated PBD, antidrug antibodies (ADA), and neutralizing ADA. Noncompartmental methods were used to estimate the pharmacokinetic parameters. Pharmacokinetic parameters es- timated included: the maximum observed concentration (Cmax), the time to maximum concentration (Tmax), and the area under the plasma concentration-time curve (AUC). The
dose-normalized Cmax and AUC parameters were calculated by dividing the respective pharmacokinetic parameters by the dose administered.
Biomarker analysis
PRLR chromagenic in situ hybridization (CISH)
Five-micron-thick sections of formalin-fixed paraffin-embed- ded (FFPE) tissue were processed for CISH using the RNAscope® 2.5 LS PRLR probe kit-automated assay from Advanced Cell Diagnostics (ACD, Newark, CA, USA) on Leica Biosystems’ BOND RX System (Buffalo Grove, IL, USA). The PRLR single-plex assay was performed following the manufacturer’s instructions. Briefly, the FFPE tissue slides were rehydrated using xylene, graded alcohol, and double- distilled water (DDH2O), then immersed in a preheated epi- tope retrieval solution (95 ℃) followed by incubation of PRLR probe, visualization of brown chromagen, and back- ground staining by hematoxylin. A positive-control probe of human housekeeping gene peptidylpropyl isomerase B was used to assess samples’ RNA integrity. A negative-control probe of mouse dapB was used to assess background staining.
PRLR CISH quantification using Halo algorithm
The microscope images for each sample were analyzed after whole tissue slide scanning (Aperio ImageScope, Buffalo, NY, USA). The Halo ISH single-plex algorithm (ISH v2.2, cell-based ISH probe copies counting) was determined by Indica Labs (Albuquerque, NM, USA), which quantified PRLR ISH signal numbers on a per-cell basis within defined tumor areas of whole tissue slides. The ISH scoring was based on all tumor areas of whole tissue slides, and the ISH copy (signal dot) counts were put in 5 bins for final H-score calcu- lation: 0, 1+ (1-3 dots per cell), 2+ (4-9 dots per cell), 3+ (10- 14 dots per cell), and 4+ (≥15 dots per cell). The final H-score was obtained by the formula: (1 x 1%+) + (2 x 2%+) + (3 x 3%+) + (4 × 4%+), giving a range of 0-400.
PRLR immunohistochemistry (IHC) and manual scores
The assay was executed by Flagship Biosciences (Westminster, CO, USA) using the antibody clone 1A2B1 (Invitrogen, Carlsbad, CA) and the Leica BOND autostainer system. Briefly, the FFPE slides were rehydrated using xylene, graded alcohol, and DDH2O, then antigen retrieval was performed using Tris-EDTA pH 9 for 20 min at 90 ℃, followed by a protein-free blocking solution for 5 min. Subsequently the slides were incubated with PRLR immunoglobulin G2b antibody, 2.5 µg/mL, for 60 min followed by Leica Refine Detection kit (brown). The slides were rinsed with washing buffer between steps. The evaluation of PRLR expression was performed by 2
pathologists using a general guideline for manual IHC scores: 0, no staining; 1+, faint stain in more than 10% of the tumor cells; 2+, weak to moderate staining in more than 10% of the tumor cells; 3+, strong staining in more than 10% of the tumor cells. H- score was obtained by the formula: (3 x 3%+) + (2 x 2%+ )+ %1+ stained tumor cells, giving a range of 0-300.
Results
Patient characteristics and treatment exposure
A total of 19 patients were enrolled at 5 sites in the United States and Australia, and all received doses of ABBV-176 from 2.7 µg/kg to 109.35 µg/kg. On the basis of qualitative evaluation of AEs observed with increasing dose, data are presented for 3 retrospectively assigned dosage groups (2.7 to <12.15 µg/kg, 12.15 to <72.9 ug/kg, and≥72.9 ug/kg. Patients received a median of 2 cycles of ABBV-176 (range, 1-5 cycles). Patient demographics and baseline characteristics are reported in Table 1. Tumor types of the enrolled patients were adrenocortical (n =2), breast (n = 6), and colorectal (n = 11).
DLTs
There were no DLTs during the first-cycle observation period in patients treated at doses from 2.7-72.9 ug/kg. After a DLT
(pancytopenia) was observed in a patient treated at 109.35 µg/kg, the dose was decreased to 99.9 µg/kg, and then to 78.3 µg/kg, and finally to 50.0 µg/kg. In total, 4 patients receiving ABBV-176 at ≥72.9 ug/kg had DLTs. Two of the 4 patients experienced multiple DLTs. Each of the 4 patients had at least 1 DLT that was hematologic in nature (1 patient experienced febrile neutropenia, 1 patient thrombocytopenia, 1 patient pancytopenia, and 1 patient anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia). All DLTs are listed in Table 2. Although MTD was not formally determined, the safety profile after the first and subsequent doses (see below) suggested that determining the MTD for the 21-day DLT window might not be relevant for dosing ABBV-176 beyond the first dose, due to cumulative toxicity.
Safety
All 19 patients experienced ≥1 treatment-emergent AE. The most commonly reported treatment-emergent AEs related to ABBV-176 were thrombocytopenia (42%), neutropenia, in- creased aspartate aminotransferase, nausea, fatigue, pleural effusion (21% each), anemia, diarrhea, peripheral edema, hy- poalbuminemia, and pericardial effusion (16% each) (Table 3). Treatment-emergent AEs related to ABBV-176 oc- curred in 50% (3/6) of patients at ABBV-176 doses of 2.7 to <12.15 µg/kg, 71% (5/7) of patients at≥12.15 to<72.9 µg/kg, and 100% (6/6) of patients at ≥72.9 ug/kg. The most frequent grade ≥3 related treatment-emergent AEs were neutropenia,
| Characteristic | ABBV-176 dose group, n (%) | |||
|---|---|---|---|---|
| 2.7 µg/kg to < 12 µg/kg* n=6 | 12 µg/kg to < 72.9 µg/kg n =7 | ≥72.9 µg/kg n =6 | Total N= 19 | |
| Sex | ||||
| Female | 5 (83.3) | 2 (28.6) | 4 (66.7) | 11 (57.9) |
| Male | 1 (16.7) | 5 (71.4) | 2 (33.3) | 8 (42.1) |
| Age | ||||
| Median (range) | 61 (54-71) | 62 (52-78) | 51.5 (28-60) | 56 (28-78) |
| Race | ||||
| White | 4 (66.7) | 6 (85.7) | 4 (80.0) | 14 (77.8) |
| Black | 0 | 1 (14.3) | 0 | 1 (5.6) |
| Asian | 2 (33.3) | 0 | 1 (20.0) | 3 (16.7) |
| Type of cancer | ||||
| Breast | 3 (50.0) | 1 (14.3) | 2 (33.3) | 6 (31.6) |
| Colorectal | 3 (50.0) | 5 (71.4) | 3 (50.0) | 11 (57.9) |
| ACC | 0 | 1 (14.3) | 1 (16.7) | 2 (10.5) |
*ABBV-176 2.7 µg/kg to <12 µg/kg category includes patients dosed at ABBV-176 2.7 µg/kg, 4.05 µg/kg Q3W, and 6.075 µg/kg; ABBV-176≥ 12 ug/kg to <72.9 ug/kg category includes patients dosed at 12.15 µg/kg, 24.3 µg/kg, 36.45 µg/kg, and 50.0 µg/kg; ABBV-176>72.9 ug/kg category includes patients dosed at ABBV-176 72.9 µg/kg, 78.3 µg/kg, 99.9 µg/kg, and 109.35 µg/kg
ACC, adrenocortical carcinoma; Q3W, every 3 weeks
| Dose level | DLT |
|---|---|
| 78.3 µg/kg | 1 patient |
| · G3 enteritis | |
| · G3 febrile neutropenia | |
| 99.9 µg/kg | 1 patient |
| · G4 thrombocytopenia | |
| 1 patient | |
| · G3 anemia | |
| · G3 blood bilirubin increased | |
| · G3 cholecystitis | |
| · G3 pulmonary edema | |
| · G3 pyrexia | |
| · G3 melena | |
| · G3 vulvitis | |
| · G3 supraventricular tachycardia · G3/4 lymphopenia | |
| · G3/4 thrombocytopenia | |
| · G3/4 leukopenia | |
| · G3/4 neutropenia | |
| . G4 respiratory failure | |
| · G4 pleural effusion · G3/4/5 hepatic failure | |
| 109.35 µg/kg | 1 patient · G4 pancytopenia |
DLT, dose-limiting toxicity; G, grade
thrombocytopenia, and anemia (each 11%). All patients discontinued study drug; the most common reasons for dis- continuation were AEs related to disease progression (n= 9; 47%) and progressive disease (n = 6; 32%). Three (16%) pa- tients discontinued for AEs not related to disease progression, and 1 (5%) patient due to physician’s decision.
Edema and effusions were common in patients receiving ABBV-176, and these events were more frequent in patients receiving higher doses. Four patients (21%) had treatment- emergent AEs of pleural effusion considered related to ABBV-176; 3 of these patients received ABBV-176 doses ≥72.9 µg/kg. Three patients had drug-related treatment-emer- gent AEs of peripheral edema, of whom 2 received ABBV- 176 at ≥72.9 ug/kg. There was 1 patient with a drug-related treatment-emergent AE of pulmonary edema, who also was dosed at ≥72.9 µg/kg.
One patient who received 3 doses of ABBV-176 at 72.9 µg/kg developed a grade 2 pericardial effusion consid- ered related to ABBV-176 after the third dose. The patient subsequently experienced grade 3 generalized edema 31 days after the last dose and grade 4 cardiac tamponade 158 days after the last dose, before having a grade 5 event of cardiac tamponade 161 days after the last dose of ABBV-176. Each of these events was considered related to ABBV-176. The late onset suggested a possible relationship of edema/effusions to the cumulative dose of ABBV-176. Time to first fluid retention-related event for each patient dosed is illustrated in
Fig. 1. Several patients receiving ABBV-176 at doses >12.15 µg/kg had their first onset of effusion/edema after multiple doses of study drug. Edema/effusion events occur- ring in patients receiving ABBV-176 at doses of 2.7 to <12.15 µg/kg generally had a faster onset, but these events were less likely to be considered related to study drug by the investigator.
Two additional patients experienced AEs leading to death. One patient who received 1 dose of ABBV-176 at 50 µg/kg experienced a grade 5 non-treatment-emergent AE of respira- tory failure 40 days after the last dose that was not considered to be related to study treatment. One patient experienced a grade 5 treatment-emergent AE of hepatic failure 30 days after the last dose that was considered to be related to ABBV-176. This patient received 1 dose of ABBV-176 at 99.9 ug/kg and subsequently experienced multiple DLTs, including cholecys- titis and increased blood bilirubin prior to hepatic failure. Notably, cholecystitis (grade 2) was reported in another pa- tient who received 1 dose of ABBV-176 at 24.3 ug/kg; how- ever, this event was not considered related to ABBV-176 by the investigator.
Pharmacokinetics
Following the first ABBV-176 dose, median time to Cmax was 1.1 and 1.2 h for ABBV-176 and total antibody, respectively. Terminal elimination half-life was short, at <24 h (range, 6.5- 33 h) at doses >12.15 µg/kg (Table 4). Total antibody expo- sures (AUC) were similar to ABBV-176 exposures (Fig. 2). With increasing dose, the increase in Cmax was approximately dose proportional, but the increase in AUC was greater than dose proportional for both ABBV-176 and total antibody (Fig. 2). Unconjugated PBD was below the limit of quantitation of the assay at all doses. One patient had a positive titer for ADA above the 10-unit threshold predose as well as postdose.
PRLR expression and exploratory efficacy
PRLR expression level varied among patients with testing completed (Table 5). Objective responses were not observed in any patients.
Discussion
ADCs have been developed with the goal of limiting the tox- icity of the cytotoxic payload by targeting the drug directly to cancer cells. However, tolerability remains an issue for many ADCs in development. ADCs have generally demonstrated toxicity profiles that recapitulate those of their cytotoxin.
ABBV-176 has a safety profile that reflects those of PBD and of other ADCs with a PBD payload. As was observed with ABBV-176, cytopenias (most notably
Table 3 Treatment-emergent adverse events considered related to ABBV-176 occurring in >1 patient
Event, n (%)
ABBV-176 dose, n (%)
| 2.7 to < 12 µg/kg* n = 6 | 12 to < 72.9 µg/kg* n =7 | ≥72.9 µg/kg* n = 6 | Total N=19 | |||||
|---|---|---|---|---|---|---|---|---|
| All grades | Grade ≥3 | All grades | Grade ≥3 | All grades | Grade ≥3 | All grades | Grade ≥3 | |
| Any AE | 3 (50) | 0 | 5 (71) | 2 (29) | 6 (100) | 4 (67) | 14 (73) | 6 (32) |
| Thrombocytopenia | 0 | 0 | 3 (43) | 0 | 6 (100) | 2 (33) | 8 (42) | 2 (11) |
| Aspartate aminotransferase increased | 0 | 0 | 0 | 0 | 4 (67) | 0 | 4 (21) | 0 |
| Fatigue | 1 (17) | 0 | 1 (14) | 0 | 2 (33) | 0 | 4 (21) | 0 |
| Nausea | 0 | 0 | 1 (14) | 0 | 3 (50) | 0 | 4 (21) | 0 |
| Neutropenia | 0 | 0 | 1 (14) | 0 | 3 (50) | 2 (33) | 4 (21) | 2 (11) |
| Pleural effusion | 0 | 0 | 1 (14) | 0 | 3 (50) | 1 (17) | 4 (21) | 1 (5) |
| Anemia | 0 | 0 | 0 | 0 | 3 (50) | 2 (33) | 3 (16) | 2 (11) |
| Diarrhea | 0 | 0 | 0 | 0 | 3 (50) | 1 (17) | 3 (16) | 1 (5) |
| Hypoalbuminemia | 1 (17) | 0 | 1 (14) | 1 (14) | 1 (17) | 0 | 3 (16) | 1 (5) |
| Peripheral edema | 0 | 0 | 1 (14) | 0 | 2 (33) | 0 | 3 (16) | 0 |
| Pericardial effusion | 0 | 0 | 1 (14) | 0 | 2 (33) | 0 | 3 (16) | 0 |
| Blood bilirubin increased | 0 | 0 | 0 | 0 | 2 (33) | 1 (17) | 2 (11) | 1 (5) |
| Blood creatinine increased | 1 (17) | 0 | 0 | 0 | 1 (17) | 0 | 2 (11) | 0 |
| Constipation | 0 | 0 | 0 | 0 | 2 (33) | 0 | 2 (11) | 0 |
| Decreased appetite | 0 | 0 | 0 | 0 | 2 (33) | 0 | 2 (11) | 0 |
| Dyspnea | 1 (17) | 0 | 0 | 0 | 1 (17) | 0 | 2 (11) | 0 |
| ECG prolongation | 2 (33) | 0 | 0 | 0 | 0 | 0 | 2 (11) | 0 |
| Eructation | 0 | 0 | 1 (14) | 0 | 3 (50) | 0 | 2 (11) | 0 |
| Hypomagnesemia | 0 | 0 | 0 | 0 | 2 (33) | 0 | 2 (11) | 0 |
| Oral candidiasis | 0 | 0 | 0 | 0 | 2 (33) | 0 | 2 (11) | 0 |
| Vomiting | 0 | 0 | 1 (14) | 0 | 1 (17) | 0 | 2 (11) | 0 |
*ABBV-176 2.7 µg/kg to <12 µg/kg dose group includes patients dosed at ABBV-176 2.7 µg/kg, 4.05 µg/kg, and 6.075 µg/kg; ABBV-176 ≥ 12 µg/kg to <72.9 µg/kg group includes patients dosed at 12.15 µg/kg, 24.3 µg/kg, 36.45 µg/kg, and 50.0 µg/kg; ABBV-176≥ 72.9 µg/kg dose group includes patients dosed at ABBV-176 72.9 µg/kg, 78.3 µg/kg, 99.9 µg/kg, and 109.35 µg/kg
AE, adverse event; ECG, electrocardiogram
1
+
109.35 µg/kg
2
+
99.9 µg/kg
3
+
99.9 µg/kg
ABBV-176 dose level
4
+
≥72.9 µg/kg
78.3 µg/kg
12 to <72 µg/kg
5
+
145.8 ug/kg
<12.5 µg/kg
6
+
+
+
218.7 µg/kg
7
+
+
100 μg/kg
8
+
50 μg/kg
9
+
+
Patients
72.9 µg/kg
10
+
+
72.9 µg/kg
11
+
24.3 µg/kg
12
+
+
+
+
+
121.5 µg/kg
13
+
+
+
+
48.6 μg/kg
14
+
6.075 µg/kg
15
+
+
12.15 µg/kg
16
+
+
+
+
16.2 µg/kg
17
+
+
+
V
5.4 µg/kg
18
+
5.4 µg/kg
19
+
+
5.4 µg/kg
0
21
42
63
84
105
126
147
Days from C1D1
| ABBV-176 dose, n | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Pharmacokinetic parameters (units) | 2.7 µg/kg (n = 3) | 4.05 µg/kg (n=1) | 6.075 ug/kg (n=2)ª | 12.15 µg/kg (n=1) | 24.3 µg/kg (n=2)º | 36.45 µg/kg (n=2)º | 50.0 µg/kg (n=2)° | 72.9 ug/kg (n=2)' | 78.3 µg/kg (n=1) | 99.9 µg/kg (n=2)' | 109 µg/kg (n=1) |
| Cmax, ng/ml | 47.7 (50.4, 37) | 78.8 | 104, 166 | 356 | 428, 437 | 1140, 997 | 0.85, 0.89 | 1600, 1260 | 1560 | 1560, 2280 | 2530 |
| Tmaxª, h | 0.3 (0.2, 0.5) | 0.4 | 0.4, 2.0 | 2.0 | 0.6, 0.3 | 4.0, 4.0 | 2.0, 2.0 | 2.0, 1.1 | 4.0 | 1.1,1.2 | 2.0 |
| AUCt, µg.h/mL | 0.335 (0.38, 63) | 0.81 | 1.16, 1.98 | 6.34 | 9.20, 5.18 | 27.7, 24.8 | 16.7, 36.0 | 93.3, 64.0 | 89.6 | 38.0, 123 | 58.8 |
| AUC., µg.h/mL | 0.32 (0.79)d | 0.90 | 1.31ª | 6.67 | 9.99, 5.2 | – | 17.8, 36.1 | 93.3, 64.0 | 89.6 | 38.0, 123 | 58.8 |
| T1/2 , h | 6.5, 10.3ª | 7.56 | 8.17ª | 12.3 | 14.1, 6.51 | – | 12.7, 19.9 | 26.2, 19.9 | 33.0 | 16.2, 29.5 | 19.0 |
| CL, mL/h/kgº | 8.39, 3.41ª | 4.44 | 4.60€ | 1.81 | 2.43, 4.68 | – | 2.81, 1.39 | 0.78, 1.14 | 0.85 | 2.32, 0.80 | 1.54 |
| Vz, ML/kg | 79.1, 50.6ª | 48.4 | 54.2ª | 32.2 | 49.5, 43.9 | – | 51.5, 39.9 | 29.3, 32.7 | 40.6 | 54.2, 34.1 | 42.2 |
| Cmax/D, (ug/mL)/(mg/kg) | 17.7 (18.7, | 19.7 | 17.3, 27.7 | 29.4 | 17.6, 18 | 31.3, 27.4 | 17.1, 17.8 | 21.9, 17.3 | 19.5 | 15.6, 22.8 | 23.1 |
| 37) | |||||||||||
| AUC/D, µg·h/mL)/(mg/kg) | 124 (141, 63) | 202 | 193, 330 | 524 | 378, 213 | 762, 680 | 333, 719 | 1280, 878 | 1140 | 380, 1230 | 537 |
| AUC./D, | 119, 293ª | 225 | 218e | 551 | 411, 214 | – | 356, 721 | 1290, 879 | 1170 | 431, 1250 | 649 |
| (µg·h/mL)/(mg/kg) | |||||||||||
AUC., area under the plasma concentration-time curve from time zero to infinity; AUCt, area under the concentration-time curve from time zero to time t; CL, clearance; Cmax, maximum observed concentration; D, dose; h, hour; Q3W, every 3 weeks; T1/2, terminal elimination half-life; Tmax, time to maximum concentration; Vz, volume of distribution during the terminal phase ª Median (range)
b Harmonic mean ± pseudo-standard deviation
” CL is calculated as dose/AUC ..
dN =2, presented as individual values
e N = 1, presented as individual value
ABBV-176
Total antibody
· ABBV-176 2.7 µg/kg Q3W (N = 3)
ABBV-176 4.05 µg/kg Q3W (N = 1)
ABBV-176 6.075 µg/kg Q3W (N = 2)
· ABBV-176 12.15 µg/kg Q3W (N = 1)
A ABBV-176 24.3 µg/kg Q3W (N = 2)
· ABBV-176 36.45 µg/kg Q3W (N = 2)
· ABBV-176 72.9 µg/kg Q3W (N = 2)
10000
10000
· ABBV-176 78.3 µg/kg Q3W (N = 1)
ABBV-176 99.9 µg/kg Q3W (N = 2)
ABBV-176 109.35 µg/kg Q3W (N = 1)
ABBV-176 serum concentration, ng/ml
1000
Total antibody serum concentration, ng/ml
1000
100
100
10
10
1
1
0.1
0.1
0
1
2
3
4
5
6
7
42
43
44
45
46
47
48
49
0
1
2
3
4
5
6
7
42
43
44
45
46
47
48
49
Time, day
Time, day
thrombocytopenia), edema/effusions, and hepatic toxicities have been reported for other trials of PBD or PBD- containing ADCs. A clinical study of free PBD dimer in pa- tients with advanced solid tumors reported toxicities of vas- cular leak syndrome (characterized by hypoalbuminemia, pleural effusions, ascites, and peripheral edema) and revers- ible hepatotoxicity [18]. In a phase 1 study of loncastuximab tesirine (CD19-directed ADC with a PBD payload) in patients with relapsed/refractory (R/R) B cell lineage non-Hodgkin lymphoma (NHL), peripheral edema, pleural effusions, cyto- penias, and elevated liver enzymes were among the most com- mon AEs [19, 20]. A phase 1 study of SGN-CD70A (CD70- directed ADC with a PBD payload) in patients with R/R CD70-positive NHL reported cytopenias, most notably thrombocytopenia, and peripheral edema among the most common treatment-related AEs [21]. A phase 1 study of camidanlumab tesirine (CD25-directed ADC with a PBD
payload) in patients with R/R classical Hodgkin lymphoma reported frequent elevations in liver function tests and periph- eral edema/effusions [22]. Rovalpituzumab tesirine, a delta- like ligand 3-directed ADC being investigated in patients with small cell lung cancer, similarly was associated with throm- bocytopenia, serosal effusions, and increased lipase [23]. The safety profile for vadastuximab talirine, a CD33-directed PBD ADC, in patients with acute myeloid leukemia includes fre- quent thrombocytopenia, as well as peripheral edema [24]. Notably, among ADCs with the SGD-1882 PBD payload, the highest reported MTD was 40 µg/kg every 3 weeks [25].
Some edema and effusion events in the reported study had late onset that suggested a possible relationship to the cumu- lative dose of study drug. While the first cycle of dosing is commonly used as the DLT observation period in phase 1 studies, this approach may be insufficient for evaluating the safety profile of PBD-based ADCs. Alternate approaches for
| Tumor type | Gender | Age | CISH H-score (Halo) | IHC H-score (manual) |
|---|---|---|---|---|
| Breast | F | 40 | 167.40 | 160 |
| Colorectal | M | 66 | 26.43 | 50 |
| Colorectal | F | 54 | 17.83 | 20 |
| Breast | F | 55 | 61.07 | 100 |
| Colorectal | F | 71 | 2.86 | 0 |
| Breast | F | 56 | 43.59 | 30 |
| Colorectal | M | 62 | 3.02 | 5 |
| Colorectal | M | 52 | 31.2 | 30 |
| ACC | M | 78 | 5 | 5 |
| Colorectal | M | 49 | 9.07 | 5 |
ACC, adrenocortical carcinoma; CISH, chromagenic in situ hybridization; IHC, immunohistochemistry; PRLR, prolactin receptor
incorporating late toxicities in dose-escalation decisions may be necessary for payloads with delayed-onset toxicity.
Toxicities observed with ABBV-176 did not appear to be related to the expression profile of PRLR. For example, PRLR expression has been noted in the normal adrenal gland [8]. However, there were no cases of adrenal insufficiency report- ed in the study.
While activity has been reported for other ADCs with a PBD payload that have been explored [19, 21, 23, 24], there were no clinical responses observed with ABBV-176 in pa- tients in this study. The study enrolled patients with tumor types that are likely to have high expression of PRLR, but was not restricted to patients whose tumors were known to have high PRLR expression. As a result, there was a variable level of PRLR expression in the tumors of the 19 treated patients. This variability of expression and the small sample size limited the evaluation of activity.
Although there were limited data to assess activity in this study, the low doses at which toxicity was observed and the possible cumulative toxicity with ABBV-176 suggested that administration of efficacious doses was unlikely to be feasible. Late-onset fluid retention AEs were observed in some patients with cumulative doses of ABBV-176 ≥ 100 µg/kg. On the basis of translational pharmacokinetic/pharmacodynamic analysis using BT-474 breast cancer xenograft and CTG-089 patient- derived xenograft models, the predicted response rate in humans at the dose of 100 µg/kg administered as a cumulative dose over 4 or 6 months either every 3 or every 4 weeks was 10-20% (data on file). Therefore, a cumulative dose higher than 100 µg/kg would be required to show a substantial benefit, on the basis of these simulations. While the minimal human effi- cacious dose of 100 µg/kg was based on only 2 preclinical models and the available clinical data from the current study for assessment of efficacy were limited, the data suggested that the feasible dose was substantially limited by toxicity and a regimen with substantial benefit was unlikely to be tolerable.
A greater-than-proportional increase in AUC with dose was observed with ABBV-176 and the total antibody, sug- gesting target-mediated drug disposition. This dose- dependent change of clearance was also observed with other ADCs [26]. ABBV-176 exhibited a short half-life of <24 h and it was within the large range of 0.7-6.9 days observed with other ADCs carrying different cytotoxins [26]. Total an- tibody exposures were similar to ABBV-176 exposures, sug- gesting that the linker is relatively stable in blood circulation. Steady-state apparent volume of distribution of ABBV-176 ranged from 29.3-79.1 mL/kg, suggesting distribution of ABBV-176 limited to blood volume, as expected. Only 1 of 19 patients (5%) had a positive ADA titer ≥10-unit threshold at predose as well as postdose; this did not impact the phar- macokinetics of ABBV-176.
In this first-in-human trial, the safety profile of ABBV-176 was characterized by hematologic toxicities including
thrombocytopenia, edema/effusions, and hepatic toxicity. Late onset of some events suggested cumulative toxicity of the drug. No objective responses were observed at the doses adminis- tered to 19 patients in the dose-escalation phase. The study was terminated without establishing MTD, as determination of a tolerable dose was confounded by late-onset toxicities.
Acknowledgments AbbVie and the authors thank the patients who par- ticipated in this clinical trial, the study coordinators, and support staff. This study was funded by AbbVie Inc., North Chicago, IL, USA. Medical writing support was provided by Mary L. Smith, PhD, CMPP, Aptitude Health, Atlanta, GA, USA, funded by AbbVie.
Financial support Abb Vie Inc. provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the manuscript.
Author contributions The manuscript was written by the authors, with medical writing assistance funded by the sponsor. All authors approved the final manuscript for submission for publication.
Compliance with ethical standards
Conflict of interest disclosure statements Charlotte Lemech. No relationships to disclose.
Natasha Woodward
Research funding (institutional) from Medivation; advisory board for Roche, Pfizer; travel, accommodations, and expenses from Roche; stock ownership in CSL; editorial writing support from Pfizer.
Nancy Chan No relationships to disclose.
Joanne Mortimer
Consulting or advisory role for Novartis, Pfizer, Puma Biotechnology; honoraria from Novartis.
Louie Naumovski, Silpa Nuthalapati, Bo Tong, Fang Jiang, Peter Ansell, and Christine K. Ratajczak AbbVie employees and may own stock. Jasgit Sachdev
Research funding from Pfizer, Celgene, Genentech; consulting or ad- visory role for Celgene, Puma Biotechnology, TTC Oncology, Pfizer, Novartis, TapImmune, Ipsen, Tempus; travel accommodations, and ex- penses from Celgene; honoraria from Celgene, Ipsen, Puma Biotechnology, Novartis, Pfizer, Tempus.
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 pro- vided 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.
Ethical approval All patients provided their informed consent. All study procedures were conducted in accordance with the ethical standards of the
1964 Declaration of Helsinki and Good Clinical Practice guidelines. The protocol received institutional review board approval.
Informed consent Informed consent was obtained from all individual participants included in the study.
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