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This first-in-human phase I/IIA study was designed to evaluate the safety and pharmacokinetics (PKs) of AGS-PSCA a fully human monoclonal antibody directed to prostate stem cell antigen (PSCA) in progressive castration-resistant prostate cancer.
Twenty-nine patients were administered infusions of AGS-PSCA (1–40 mg/kg) every 3 weeks for 12 weeks; 18 final patients received a 40-mg/kg loading dose followed by 20-mg/kg repeat doses. Primary end points were safety and PK. Immunogenicity, antitumor activity and circulating tumor cells were also evaluated.
No drug-related serious adverse events were noted. Dose escalation stopped before reaching the maximum tolerated dose as target concentrations were achieved. Drug levels accumulated linearly with dose and the mean terminal half-life was 2–3 weeks across dose levels. The 40-mg/kg loading dose followed by repeated 20-mg/kg doses yielded serum drug concentrations above the projected minimum therapeutic threshold after two to three doses without excessive drug accumulation or toxicity. Significant antitumor effects were not seen.
A 40-mg/kg loading dose followed by 20-mg/kg infusions every 3 weeks is the recommended phase II dose of AGS-PSCA. PSCA is a promising drug target and studies in prostate and other relevant solid tumors are planned.
Four approved therapies prolong survival in patients with metastatic castration-resistant prostate cancer (CRPC), conferring an incremental survival benefit of 25%–35% relative to best supportive care or palliative chemotherapy [1–4]. Such treatments are generally well tolerated, but those with a cytotoxic mechanism can have side-effects that can impair quality of life and can even contribute to mortality . For patients with CRPC and other treatment-resistant solid tumors, drugs targeting molecules uniquely expressed on the cancer cell have the potential to significantly alter the natural history of the disease with minimal side-effects.
Fundamental to this approach is a molecule that is primarily present on the cancer cell, minimally expressed by normal tissue and insignificantly shed into the circulation and expressed in metastatic sites. Prostate stem cell antigen (PSCA), a 123-amino acid glycosyl phosphatidylinositol-anchored cell-surface antigen, is upregulated in prostate, bladder, renal cell and pancreatic cancers. For prostate cancer, PSCA is found, whether at a messenger RNA or protein level, in the majority of primary cancers and bone metastases . PSCA expression been found to be present in ~90% of primary prostate cancers, and expression increases with tumor grade, extent of disease and exposure to androgen deprivation [5–8]. In metastatic disease, PSCA has been found in 100% of bone metastases in one report of a small number of available specimens . In a larger group of patients with bone metastases, 41/47 (87%) osseous metastatic sites manifest PSCA protein expression .
In preclinical models, anti-PSCA antibodies have been shown to inhibit established orthotopic tumor growth and inhibit metastases, resulting in prolonged survival in tumor-bearing mice . AGS-PSCA (Agensys, Santa Monica, CA) is a fully human immunoglobulin G1κ monoclonal antibody, using XenoMouse® technology, in which the murine heavy- and light-chain loci have been inactivated and a majority of the human heavy- and kappa light-chain immunoglobulin have been inserted. AGS-PSCA has been shown to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) above background levels in PSCA-positive pancreatic cancer cell lines (HPAC, PAN0203) but not in PSCA-negative cell lines (MIAPACA-2 and BxPC3) [11, 12]. It inhibits growth of both castration-resistant and castration-sensitive prostate cancer xenografts and completely inhibits in vivo growth of PSCA-expressing PC3 cells . It appeared to have a mean terminal elimination half-life of 5–7 days after a single dose, 8–15 days on repetitive dosing in primates and did not result in any clear treatment-related toxicity. Based on allometric scaling from mouse in vivo efficacy studies, 200 μg/ml was selected as the serum concentration necessary to achieve significant antitumor effects.
In human pathology studies, AGS-PSCA binds to ocular, ureteral, gastric and prostate tissue. This first-in-human trial designed to establish the safety profile and pharmacokinetic (PK) properties of AGS-PSCA is the first study ever to target PSCA clinically.
This multicenter, first-in-human, open-label, phase I/IIA dose-escalation study was approved by local institutional review boards. All participating patients signed informed consent and were enrolled sequentially into six planned dose cohorts (1, 3, 5, 10, 20 and 40 mg/kg) according to a classic 3 + 3 dose-escalation schema. Further dose escalation was not planned as the selected doses were hypothesized to achieve the 200-μg/ml target concentration. To explore whether steady state drug concentrations could be achieved more rapidly and to perform early efficacy evaluations, a seventh cohort utilizing a 40-mg/kg loading dose followed by repetitively dosed 20 mg/kg every 3 weeks was added. Primary end points were safety and PK. Secondary end points included immunogenicity, antitumor activity and changes in circulating tumor cells (CTC). The trial was conducted under the auspices of the Department of Defense/Prostate Cancer Foundation Prostate Cancer Clinical Trials Consortium (PCCTC).
Patients with progressive CRPC with or without metastases were eligible. Progression was defined by either the appearance of new lesions on bone scintigraphy, by soft tissue imaging or by three consecutive rising prostate-specific antigen (PSA) values. Patients were required to progress through anti-androgen withdrawal if they previously responded to an anti-androgen. They were required to have an Eastern Cooperative Oncology Group score of 0 or 1, normal coagulation profile and adequate hematologic, hepatic and renal function. Subjects in cohort 7 had to progress biochemically or by scans during or after one prior taxane regimen. Patients with untreated central nervous system metastases, history of other primary tumor excepting nonmelanoma skin cancer, angina or class III or IV heart failure were excluded, as were those with grade 2 or more neuropathy or conjunctivity or conjunctival keratitis.
AGS-PCSA was administered by i.v. infusion over 60 min (doses ≤20 mg/kg) or 120 min (doses >20 mg/kg) every 3 weeks for four intended doses. Patients with stable disease were eligible to receive extended treatment at the dose and schedule of their assigned cohort until intolerability to AGS-PSCA or disease progression. Castrating hormonal therapy was continued in all patients. If a subject had a dose-limiting toxicity (DLT) at any time during the study, AGS-PSCA treatment was discontinued in that subject.
Adverse events (AE) were measured by National Cancer Institute—Common Terminology Criteria of Adverse Events (CT–CAE) version 3.0. A DLT was defined as any grade 3 or worse treatment-related AE, excluding grade 3 infusion-related reactions. Safety assessments were carried out weekly in the first month and then every 3 weeks thereafter, excepting cohort 7 in which assessments were assessed every 3 weeks. Visual acuity and dilated slit-lamp exams were carried out at baseline, week 6 and week 14 for cohorts 1–6 and at baseline, week 14 and study termination for cohort 7.
PK assessments were carried out pre-infusion, upon infusion completion and 2, 4, 6 h to 8, 24, 48 and 72 h after the first and third infusions in cohorts 1–6. Additional samples were taken pre-infusion at weeks 4, 10 and 14 and on nontreatment days during weeks 2 and 3. For cohort 7, PK assessments were taken pre-infusion every 3 weeks beginning at week 1 while the patient received treatment. PK analysis included the observed minimum and maximum concentrations (Cmin and Cmax), the area under the serum concentration time curve (AUC) and the mean terminal half-life (T1/2).
Disease assessments were conducted approximately every 13 weeks. Changes in PSA were described by the incidence of a PSA that declined ≥25% from baseline confirmed by a second value or in conjunction with clinical or radiographic evidence of disease progression during that time period. Additional measure of PSA change included the incidence of a ≥50% decline and the change from baseline to post-baseline values. Tumor response was defined per RECIST criteria , which was confirmed ≥28 days later. Subjects without post-baseline data or confirmed response were considered nonresponders.
Immunogenicity was described by the incidence of anti-AGS-PSCA antibody formation. Anti-AGS-PSCA antibody testing was carried out every 3 weeks in the 10-week treatment period and every 6 weeks for subjects who entered extended treatment. An enzyme-linked immunosorbent assay bridging format to detect antibodies to AGS-PSCA in human serum was used, with a biotinylated AGS-PSCA and streptavidin-HRP (horseradish peroxidase) conjugate. A human serum panel of 10 individuals and a positive control at three concentrations, run in duplicate, were included on each plate as negative and positive controls, respectively. The samples were screened at 1 : 2 and 1 : 6 dilutions, in duplicate, to determine the presence or absence of antibody and were evaluated relative to the cut-point optical density (OD) of the plate where the cut-point OD was defined as the mean OD of the 10 normal human serum individuals plus 1.645 times the standard deviation of the same individuals. Samples generating an OD below the cut point were considered negative.
CTC samples were collected at weeks 1, 4 and 7 and at the week 14 safety follow-up visit for cohorts 1–6. In cohort 7, samples were taken at weeks 1, 4, 7, 13, 19 and 25, every 6 weeks while on active treatment and at the safety follow-up visit. Samples were processed with AutoPrep System (Immunicon/Veridex LLC, Raritan, NJ) and analyzed via CellSearch, CellProfile and fluorescence in situ hybridization.
As this was the first study of AGS-PSCA in humans, there was no prior estimate of the underlying rate of DLT. Because nonclinical data indicated AGS-PSCA to be well tolerated and a ≤5% underlying DLT rate was assumed, there was a 3% chance that dose escalation would be halted in a given cohort (i.e. observing two or more DLTs in a given cohort). If the toxicology data were not predictive of the tolerability in humans and a 50% underlying DLT rate was assumed, then there was an 83% chance that dose escalation would be halted in a given cohort. In cohort 7, in which 18 subjects were enrolled, the chance of observing two or more PSA responses was ~90% if the underlying response rate was 20% and ~5% if the underlying response rate was 2%. For all dose cohorts (1–7), consented subjects who were enrolled and received one or more doses of AGS-PSCA were included in safety and efficacy analyses.
Forty-seven patients with a median age of 69 years were enrolled on to the study, as shown in Table Table1.1. Forty-three of these patients (91%) had radiographically evident disease, 19 (40%) had bone metastases only, 15 (32%) had bone and soft tissue disease and 9 (19%) had soft tissue disease only. Twelve of the 29 (41.4%) subjects in cohorts 1–6 received prior docetaxel and all subjects in cohort 7 received prior taxane therapy (17 patients received docetaxel and one paclitaxel).
The number of patients treated in each cohort is described in supplemental Table S1 (available at Annals of Oncology online). Additional patients were treated in cohorts 2–6 to clarify PK properties and to allow enrollment of excess patients consented to the study. Thirty-nine subjects (83%) completed the four intended doses. Eight of the remaining subjects (15%) discontinued before the fourth planned treatment either due to disease progression (six patients), transfer of care to hospice (one patient) or other (one patient). Eleven subjects continued treatment beyond four doses in which the median number of AGS-PSCA doses was 8 (range, 5–16). All 11 subjects discontinued extended treatment due to disease progression. Across both phases of the study, the median duration on treatment was 12 weeks (range, 3–48). The median number of treatments for the whole, including the final expansion cohort, was 4 (range, 1–16).
Maximum tolerated dose (MTD) was not reached during the course of the study. Grade 3 or 4 AEs were uncommon and none were related to AGS-PSCA. One patient had grade 3 dehydration and nausea from an intercurrent illness; one patient had grade 3 back pain and fatigue from progressive disease. All instances of grade 3 back pain occurred were felt to be unrelated to study drug. AEs that were considered related to AGS-PSCA were grade 1 or 2, the most common being fatigue, constipation, nausea, anorexia and paresthesia.
Possible infusion reactions were associated with seven infusions among six subjects. Symptoms included grade 1 or 2 rash, pruritus, hypotension, decreased heart rate and hypersensitivity. These occurred in cohorts 1 (one patient), 2 (one patient) and 7 (five patients) without recurrence at future treatments in all but one patient who had persistent rash. For one grade 2 reaction (hypotension), the infusion rate was decreased and for the other (hypersensitivity), the infusion was interrupted and diphenhydramine was given. Detailed safety data are provided in Table Table22.
Patients in cohorts 1–6 received continuous repetitive identical doses (Table (Table3).3). No significant change in T1/2 was observed between the first and repeat infusions. Cmax was reached at the end of the infusion or shortly thereafter followed by biphasic elimination with a mean T1/2 of ~2–3 weeks, across the full range of tested doses. Cmax and AUC values increased linearly and proportionately to dose (Figure (Figure11).
At the 20-mg/kg dose, Cmax was well above the target serum concentration of 200 μg/ml (Table (Table3)3) but trough levels were at target only after 10 weeks (four doses) of treatment (supplemental Table S2, available at Annals of Oncology online). At 40 mg/kg, both peak and trough levels >200 μg/ml were achieved early in the treatment course. However, not only was Cmax considerably elevated at >1000 μg/ml, but trough levels also rose from 269 μg/ml at week 4 to 384 μg/ml at week 10, reflecting drug accumulation. A loading dose of 40 mg/kg with subsequent doses of 20 mg/kg (cohort 7) achieved steady target trough levels by the second or third dose without evidence of significant drug accumulation. Trough serum concentrations at steady state for the every 3-week 20-mg/kg dose and for the 40/20-mg/kg dosing schedule were similar (~200 μg/ml).
PSA values generally rose over the course of treatment. Two patients (one each in cohorts 4 and 7) did achieve a PSA decline of >25%, although only the cohort 4 patient was confirmed. Across all cohorts (N = 47), the median PSA change was +96.8% (range, −47.1 to +4936). No patient demonstrated a >50% decline. A waterfall graph of the post-treatment PSA changes can be found in supplemental Figure S1 (available at Annals of Oncology online). Specifically, in cohort 7 for which response was designed, no radiographic or PSA responses were seen.
No radiographic responses were observed by RECIST.
No subject developed seropositivity to AGS-PSCA.
Samples for CTC enumeration were received from 38 (81%) of the 47 patients treated. Of these patients, 15 (39%) had an unfavorable (five or more cells per 7.5 ml of blood) baseline CTC count, none of which durably converted to a favorable (less than five cells per 7.5 ml of blood) CTC count by the safety follow-up visit . Twenty-three (61%) patients had a favorable baseline CTC count, of whom 14 had follow-up CTC studies. Thirteen (92%) remained in the favorable category, and one converted to an unfavorable count. These data are summarized in supplemental Table S3 (available at Annals of Oncology online).
This study represents the first time that PSCA has been used as a target for the treatment of cancer in humans. This is also the first time that AGS-PSCA has been used in humans. Despite the fact that AGS-PSCA can bind to ocular, ureteral and gastric tissue in human pathology specimens, toxic effects related to these organs were not observed. All grade 3 or higher AEs were considered not related to study treatment and other than occasional minor infusion reactions, we found no significant toxicity; no DLT was demonstrated and the MTD was not established. The phase II dose was determined on the basis PK properties only and not toxicity. No anti-AGS-PSCA antibodies were generated.
The combination of a 40-mg/kg loading dose followed by 20 mg/kg administered every 3 weeks achieved steady state levels that are at or above the target concentration within two to three doses, without apparent drug accumulation. This proposed phase II dose mitigates the limitations of both the 20-mg/kg dose, which results in a lengthy time to achieving steady state peak and trough target concentrations, and the 40-mg/kg dose, which results in drug accumulation as reflected by rapidly increasing peak and trough concentrations.
Although interpreting efficacy is difficult in the setting of a phase I trial given that cohorts are small and doses variable, we observed only limited antitumor activity in this study, even in the expansion cohort in which the 18 patients achieved putatively effective serum drug levels. No patient durably converted from an unfavorable CTC categorization to a favorable one. Even in the expansion cohort, no radiographic responses or confirmed PSA responses were seen, and therefore, the trial failed to meet the predefined efficacy end point.
There are several possible reasons why antitumor effects were not seen in this study. It is possible that the effective serum concentration based on preliminary animal data is too low for efficacy in humans. These animal data are presently being reassessed. Alternatively, it is possible that the target drug levels are accurate and achievable, but that the patients tested in this trial did not express PSCA on their cancers. A downside of this study is that tissue specimens were not analyzed for PSCA expression, and therefore, this question cannot be answered. Finally, it is possible that the naked antibody does not induce ADCC as was shown in preclinical models. In such a case, immune adjuvants may be necessary, as might chemoconjugated or radioconjugated antibodies. More immunogenic anti-PSCA antibodies are being developed, and a screening study to confirm PSCA targeting in humans using CTCs is planned.
This phase I/IIA study demonstrated for the first time the safety of using a monoclonal antibody directed against PSCA. Although antitumor effects using a naked antibody were limited in this trial, the PK profile of AGS-PSCA suggests that targeting PSCA with conjugates and other antibodies warrants further investigation. In addition, PSCA is expressed in bladder, renal cell and pancreas cancers [16, 17] and treating these populations at the recommended AGS-PSCA phase II dose may yield more favorable results.
Agensys; the National Cancer Institute at the National Institutes of Health (CA102544) and 5P30CA006973; the Department of Defense Prostate Cancer Research Program (PC051385) and W81XWH-09-1-0149 and the Prostate Cancer Foundation.
Research support to institution from Agensys: MJM, MAE, RP, SRD, DR, SFS, JF, JC, HIS, MAC; employed by Agensys: MV.