REVIEW ARTICLE

Paweł Rogala, Piotr Rutkowski

Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute — Oncology Centre, Warsaw

Olaratumab (LARTRUVO®) as a new therapeutic option in the treatment of patients with advanced soft tissue sarcomas

ABSTRACT

Olaratumab is a newly approved human monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-α). In a relatively small, randomised phase 2 trial the drug given in combination with doxorubicin produced an overall survival improvement in patients with unresectable and/or metastatic soft tissue sarcomas. Further studies are necessary to establish the role of this agent in the treatment of advanced sarcomas. In this paper the current clinical data on olaratumab are presented.

Key words: olaratumab, doxorubicin, soft tissue sarcoma

Oncol Clin Pract 2017; 13, 1: –8

Introduction

Olaratumab is a human-derived monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-α). In a randomised phase 2 clinical trial the use of olaratumab in combination with doxorubicin resulted in improved overall survival of patients diagnosed with advanced/metastatic soft tissue sarcomas (STS). Based on the results of this study, in October 2016 olaratumab was registered by the Food and Drug Administration (FDA), and afterwards in 2017 by the European Medicines Agency (EMA), in combination with doxorubicin, for the treatment of patients with advanced STS. It was a fast-track registration based on the results of a phase 2 study [1]. Currently a multicentre phase 3 study (ANNOUNCE) is ongoing with the aim to ultimately establish the efficacy of this drug.

Mechanism of action

Olaratumab is a human-derived monoclonal IgG1 antibody against platelet-derived growth factor alpha (PDGFR-α) — it prevents linking of the receptor with its ligand (PDGF) and thus does not allow the activation of the next signal pathway [2]. PDGFR-α is a receptor with tyrosine kinase activity occurring on mesenchymal cells [3]. This receptor was also detected on tumour cells [4], including sarcoma cells [5]. The signal transmitted to the tumour cell via this receptor causes cell proliferation and facilitates metastasis. Olaratumab antineoplastic activity depends on binding to PDGFR-α on tumour cells and on tumour-associated fibroblasts [6].

In the murine xenograft model, the PDGFR-α blockade with olaratumab in human prostate cancer cells PC3-ML resulted in delayed development of bone metastases and reduction in existing bone lesions [7]. The anti-PDGFR-α antibody also had anti-tumour activity in the lung cancer model without the PDGFR-α mutation, suggesting the important role of inhibiting this protein in the tumour stroma [8].

Selective blockade of PDGFR-α may also be associated with the avoidance of side effects associated with multiple kinase inhibitors, such as PDGFR-β blockade-dependent fluid retention [9, 10] or C-KIT-dependent myelosuppression [11].

Pharmacokinetics

Olaratumab is administered intravenously. The volume of distribution at steady state is 7.7 litres. The steady state after intravenous administration at a dose of 15 mg/kg on days 1 and 8 of a 21-day cycle was achieved in cycle 3. Average clearance is 0.56 l/day. The estimated half-life is approximately 11 days (between 6 and 24 days). In patients with mild or moderate renal impairment (creatinine clearance calculated as Cockcroft-Gault pattern in the range of 30–89 ml/min) and mild or moderate hepatic impairment (bilirubin elevated to 3 × GGN), no clinically significant disturbances were observed in olaratumab pharmacokinetics. The pharmacokinetic parameters of this drug are not known in patients with severe renal impairment (creatinine clearance calculated using the Cockcroft-Gault pattern below 29 ml/min) and for patients with severe liver injury (bilirubin level above 3 × GGN). Age, sex, race, and weight were not observed to affect the pharmacokinetics of olaratumab. There is no known interaction of olaratumab with other drugs [12].

Dosage

Olaratumab is administered on days 1 and 8 of the 21-day cycle at a dose of 15 mg/kg for 60 minutes in combination with doxorubicin (suggested dose of 75 mg/m2) on day 1 every 21 days for up to eight cycles. In this dosing regimen doxorubicin is usually administered up to eight courses. Olaratumab is given until progression of the disease or appearance of unacceptable toxicity.

Due to infusion-related reactions observed in clinical studies, intravenous premedication with antihistamines (e.g. clemastine and diphenhydramine) and dexamethasone during the first cycle is indicated before administration of olaratumab.

In preclinical in vivo studies, olaratumab was administered in doses of up to 75 mg/kg per week with no observable adverse effects [13].

Clinical trials

Phase I study — olaratumab used in patients with advanced solid tumours. NCT00768391 [14]

In this clinical study, olaratumab was administered to humans for the first time. This multicentre and no-blinded study included patients with advanced or recurrent solid tumours and lymphomas. The study was conducted from December 2006 to March 2009. The primary objectives of the study were to assess safety profile, maximum tolerated dose, and recommended dose for phase 2 trial. Secondary endpoints of the trial included pharmacokinetics and pre-assessment of antitumor activity.

Olaratumab was administered intravenously once a week (cohorts 1–3) or once every 2 weeks (cohorts 4–5). Patients who achieved clinical benefit (complete response, partial response, or stable disease) after 6 weeks (cohort 1–3) or 8 weeks (cohort 4–5) were able to receive additional infusions at the same dose and schedule as above until progression or toxicity. Treatment efficacy was evaluated according to RECIST 1.0 criteria.

The dosage in individual cohorts has been established on the basis of preclinical data. Significant inhibition of tumour growth in the U118 glioma model was observed when olaratumab was administered at 20 and 60 mg/kg. The minimum observed drug concentration (c min) associated with tumour growth inhibition at a dose of 20 mg/kg bw was estimated at 258 μg/ml. Significant tumour growth inhibition was observed with olaratumab at doses of 6, 20, and 60 mg/kg twice a week in studies using SKLMS-1 smooth muscle cell sarcoma. Effective minimum concentration ranged between 155 and 210 μg/ml. Based on the results of these studies, it was found that in order to reach the level of antitumor activity, the concentration of olaratumab should be in the range of 155–258 μg/ml.

Nineteen patients were included in the study (Table 1) — 13 were treated in cohorts 1 to 3 (given weekly), whereas 6 received the study drug in cohorts 4 and 5 (given every 2 weeks). Various doses were used: 4, 8, and 16 mg/kg weekly, and 15 and 20 mg/kg every 2 weeks.

Table 1. Characteristics of patients in phase I study with olaratumab (n = 19)

Age (years)
Average	68.7
Range	46.8–85.7
Sex (n)
Men	17
Women	2
Race (n)
White	18
Black	1
ECOG (n)
0	11
1	7
2	1
Tumour type (n)
Prostate cancer	11
Neuroendocrine tumours
Large intestine	2
Bronchus	1
Head and neck	1
Pancreas	1
Bladder cancer	1
Lung cancer	1
Endometrial cancer	1
Previous treatment [n]
Chemotherapy	16
Hormonotherapy	10
Immunotherapy	1
Other	2

Among all patients, the average number of drug doses was 9 (range 1–54), and the mean duration of treatment was 12.1 weeks (range 1–57.9). The main reason for discontinuation of treatment was radiological progression of the disease (13 patients); other reasons — general status deterioration (3 patients) and side effects (2 patients). The maximum tolerated dose of olaratumab was not reached.

The most common treatment-related side effects during the study were fatigue and reactions to intravenous infusion (grade 1 and 2) that occurred in 2 patients. There were only 2 grade 3 adverse events — increase in alkaline phosphatase level (1 patient with bronchial carcinoid and liver metastases). The intensity of other side effects was classified as grade 1 or 2. In general, the drug was well tolerated by patients. There was no increased incidence of oedema or fluid retention; the absence of these side effects is associated with the selective blocking of PDGFR-α.

The half-life of the first dose was in the range of 3.08–7.79 days, and after several doses ranged from 3.69 to 11.3 days. Minimal observed drug concentrations (c min) after dosing in cohorts receiving a 16 mg/kg weekly dose and 20 mg/kg biannual were above 155 μg/m, which in xenograft models was considered to be effective.

Efficacy

No objective response was observed in this study. In 12 (63.2%) patients stable disease was the best response with an average duration of 3.9 months. In 4 patients, stabilisation lasted longer than 6 months (8.5–13.1 months).

Stable disease lasting more than 4 months was found in 2 patients with prostate cancer and 3 patients with neuroendocrine tumours. It is worth noting the duration of stabilisation in patients with prostate cancer with bone metastases. The study used the RECIST criteria to measure the response to treatment — these criteria do not adequately reflect the clinical condition of patients with prostate cancer [15]. PDGFR-α may be overexpressed in prostate cancer (particularly in advanced disease with bone metastases) [16]. In this study, 7 out of 11 prostate cancer patients (64%) achieved stable disease.

PDGFR-α overexpression in neuroendocrine tumours is associated with a shorter survival time [17]. In the study, 3 of 5 patients (60%) with neuroendocrine neoplasms achieved stable disease lasting from 8.5 to 13.1 months.

A phase I study — olaratumab used in Japanese patients with advanced solid tumours, I5B-IE-JGDF [18]

This was single-centre study of 16 patients treated in 3 cohorts. In the first cohort, patients received olaratumab 10 mg/kg on days 1 and 8, every 3 weeks; the second cohort was given a dose of 20 mg/kg every 2 weeks; and the third group was given 15 mg/kg on days 1 and 8, every 3 weeks. The primary objective of the study was to determine the safety profile and pharmacokinetics of the drug.

No dose-limiting toxicity was observed, so no maximum tolerated dose was determined. The most common side effects associated with olaratumab were proteinuria (25%) and elevated AST (12.5%). One patient from the second cohort developed 2 olaratumab-related grade 3 adverse events: elevated levels of aspartate aminotransferase (AST) and tumour bleeding. In addition, side effects associated with olaratumab were reported in grade 1 and 2. The drug was well tolerated by patients.

Of 16 patients, 7 were diagnosed with colorectal cancer, 2 with gastric cancer, 4 with gastrointestinal stromal tumours (GIST), 2 with head and neck cancer, and 1 with STS (leiomyosarcoma).

Seven patients (43.8%) achieved stabilisation as the best response to treatment. The 2 longest disease stabilisations were observed in a patient with laryngeal cancer (4.2 months) and in a patient with STS (5.6 months).

Based on the study of blood concentrations of olaratumab, recommended dosing regimens for further studies are 15 mg/kg on days 1 and 8 every 3 weeks and 20 mg/kg every 2 weeks.

Phase II study — olaratumab used in patients previously treated for metastatic gastrointestinal stromal tumours (GIST) [19]

Patients in this study were divided into 2 cohorts depending on the presence of the gene mutation for PDGFR-α. Both groups received olaratumab 20 mg/kg every 14 days for disease progression or unacceptable toxicity. The aim of the study was to evaluate the 12-week response, progression-free survival (PFS), overall survival (OS), and safety.

All patients had received prior imatinib and sunitinib, and some other tyrosine kinase inhibitors (dasatinib, nilotinib, sorafenib). Thirty patients were included in the study, of which 21 received at least 1 dose of olaratumab. The first cohort included 7 patients with PDGFR-α gene (D842V) mutation. The second cohort included 14 patients without mutation.

Analysis of treatment effectiveness was performed in 20 patients — no objective response was observed. Stabilisation of the disease was reported in 3 patients in cohort 1 (50%) and 2 in the second cohort (14.3%). Progression of the disease was observed in 3 patients from the first cohort (50%) and 12 patients from the second cohort (85.7%). Stabilisation of the disease lasted more than 12 weeks in 5 patients (3 from the first cohort and 2 from the second). The median (PFS) was 32.1 (5–35.9) weeks in the first cohort and 6.1 (5.7–6.3) in the second cohort. The median OS was not achieved for the first cohort (6-month OS was 71.4%), and in the second cohort it was 24.9 weeks (14.4–49.1).

The most common side effects associated with olaratumab were: fatigue (38.1%), nausea (19%), and peripheral oedema (14.3%). Two adverse events (suncope and hypertension) had grade 3 intensity.

Although no objective response was noted, the researchers point out the relatively long PFS (as compared to historical data) in patients with PDGFR-α mutations.

Registration study Phase Ib and II — olaratumab used in combination with doxorubicin versus doxorubicin for the treatment of advanced soft tissue sarcomas [20]

In preclinical studies, olaratumab activity was observed when used alone or in combination with doxorubicin in sarcoma xenograft models. This observation and the important role of PDGF and PDGFR in tumour stromal biology were the theoretical basis for the olaratumab study of patients with STS [6, 21].

This study consisted of 2 parts: phase 1b and phase 2. The study was conducted in 16 centres in the United States. Phase 1b was planned to assess safety of the combination of olaratumab and doxorubicin. This part of the study was open — patients received doxorubicin 75 mg/m2 on day 1 (up to 8 cycles) and olaratumab 15 mg/kg on days 1 and 8, every 21 days.. Olaratumab was allowed to be continued until disease progression or unacceptable toxicity. In this part of the study 15 patients were treated.

The primary objective of the phase 2 study was median PFS; secondary goals were OS, objective response rate, safety, and pharmacokinetics.

For both phases, patients with either locally advanced or metastatic STS previously untreated with anthracyclines or PDGFR or PDGFR drugs, and ECOG 0–2 performance (Eastern Cooperative Oncology Group) were allowed.

Phase 2 patients were randomised 1:1 to olaratumab and doxorubicin (regimen as in phase 1b) or doxorubicin alone (75 mg/kg on day 1 every 21 days, for 8 cycles). The study in both parts was open label. Evaluation of response to treatment was conducted every 6 weeks according to RECIST 1.1. A total of 133 patients were included — 66 of them were randomly assigned to the combination therapy group and 67 to the monotherapy group (Table 2). Almost all patients (129) received at least 1 dose of scheduled treatment.

Table 2. Characteristics of patients in phase I/II study

	Olaratumab + doxorubicin	Doxorubicin
Age
Median	58.5	58
Range	22–85	29–86
Sex
Men	26 (39%)	33 (49%)
Women	40 (61%)	34 (51%)
Race
White	55 (83%)	60 (90%)
Black	6 (9%)	5 (8%)
Asian	2 (3%)	2 (3%)
Other	3 (5%)	0
ECOG
0–1	62 (94%)	63 (94%)
2	4 (6%)	4 (6%)
Histological subtype
Leiomyosarcoma	24 (36%)	27 (40%)
Pleomorphic sarcoma	10 (15%)	14 (21%)
Liposarcoma	8 (12%)	15 (22%)
Angiosarcoma	4 (6%)	3 (5%)
Other	20 (32%)	8 (12%)
PDGFR status
Positive	58 (88%)	59 (88%)
Negative	8 (12%)	8 (12%)

Median PFS in patients treated with olaratumab and doxorubicin was 6.6 months (95% CI 4.1–8.3), while PFS in patients treated with doxorubicin was 4.1 months (95% CI 2.8–5.4). The difference in favour of the combination reached the prerequisite level of statistical significance (this level was p = 0.1999) — HR 0.672, CI 95% 0.442–1.021, p = 0.0615. Blinded independent retrospective radiological analysis showed similar HR (0.67, 95% CI 0.4–1.12, p = 1208). Median PFS for the combination was 8.2 months (95% CI 5.5–9.8), while for monotherapy it was 4.4 months (95% CI 3.1–7.4).

The proportion of objective responses was 18.2% (95% CI 9.8–29.6%) for olaratumab with doxorubicin and 11.9% (95% CI 5.3–22.2) for doxorubicin monotherapy (p = 0.3421). In independent analysis, the percentage of objective responses was also 18.2% (95% CI 9.8–29.6%) for olaratumab and doxorubicin, while for doxorubicin alone it was 7.5% (95% CI 2.5–16.6).

The median OS was 26.5 months (95% CI 20.9–31.7) for combination and 14.7 months (95% CI 9.2–17.1) for monotherapy — there was almost 12 months difference in favour of olaratumab (HR 0.46, 95% CI 0.3–0.71, p = 0.0003). In the analysis of stratification subgroups (including leiomyosarcoma vs. other histologies, no prior systemic treatment vs. previous systemic treatment, ECOG 0 vs. 1) all patients benefited from olaratumab treatment. Two post hoc analyses of OS were performed. In one case, patients who had less than 8 cycles of treatment due to side effects and clinical progression were excluded. Median OS for combination therapy (61 patients) was 26.8 months, while for monotherapy (49 patients) it was 16.1 months (HR 0.55, p = 0.012). In the second analysis, patients who completed less than 4 cycles of treatment were excluded. Median OS for olaratumab and doxorubicin (49 patients) was 31.7 months, and for doxorubicin (38 patients) alone it was 17.1 months (HR 0.47, p = 0.005).

More than 65% of patients in each of the 2 groups received subsequent line of treatment after disease progression (Table 3 and 4), but the frequency of did not differ significantly. Subsequent treatment had no effect on the benefit of olaratumab.

Table 3. Subsequent lines of treatment in the study of the combination of olaratumab with doxorubicin

	Olaratumab + doxorubicin (n = 66)	Doxorubicin* (n = 67)
Any further line of treatment	44 (67%)	33 (49%)
1	18 (27%)	16 (24%)
2	12 (18%)	10 (15%)
3	9 (14%)	2 (3%)
4	1 (2%)	1 (2%)
> 4	4 (6%)	4 (6%)

*Olaratumab monotherapy after progression to doxorubicin was not counted as another line of treatment

Table 4. Treatment systems in subsequent lines

Scheme	Olaratumab + doxorubicin (n = 66)	Doxorubicin (n = 67)
Doxorubicin	1 (1.5%)	6 (9%)
Gemcitabine/docetaxel	14 (21.2%)	8 (11.9%)
Gemcitabine	15 (22.7%)	11 (16.4%)
Pazopanib	15 (22.7%)	10 (14.9%)
Docetaxel	14 (21.2%)	8 (11.9%)
Dacarbazine	12 (18.2%)	8 (11.9%)
Trabectedin	11 (16.7%)	3 (4.5%)
Treatment in clinical trial	8 (12.1%)	2 (3%)
Ifosfamide	8 (12.1%)	8 (11.9%)
Eribulin	3 (4.5%)	2 (3%)

Patients in the monotherapy group were given olaratumab after progression; 30 (46%) of 65 patients received olaratumab as the next line of treatment. Subjects in this group were given a median of 4 infusions of olaratumab (range 1–81).

The mean peak plasma concentration of olaratumab was 284 μg/mL and 293 μg/mL after the first and second dose. The half-life, assessed in the third cycle, was 14.4 days. In the olaratumab group, the mean number of doses of doxorubicin was 7, with an average cumulative dose of 487.6 mg/m2. In the doxorubicin group, the average drug was 4 administrations, with a cumulative average of 299.6 mg/m2. The average intake of olaratumab was 16.5 mg/m2 (range 1–83).

Thirty-one out of 64 patients in the olaratumab and doxorubicin group completed 8 cycles of treatment, while in the doxorubicin group 8 cycles were administered to 17 of 64 patients. In both groups the most common reason for study discontinuation was progression of the disease. The most common adverse event leading to the discontinuation of doxorubicin was the reduction in ejection fraction (3%) in 64 patients treated with combination and in 4 (6%) of 64 patients treated with monotherapy. For olaratumab, side effects was associated with infusion-related reactions, and drug administration was stopped in 2 (3%) of 64 patients.

The most common treatment-related adverse events in the olaratumab and doxorubicin group included nausea, fatigue, neutropaenia, and mucositis. In the doxorubicin group they were fatigue, nausea, hair loss, and neutropaenia. Selected side effects are listed in Table 5.

Table 5. The most common adverse events reported in patients receiving olaratumab in combination with doxorubicin compared with doxorubicin in the treatment of soft tissue sarcoma during phase 1b/2 study

Adverse events	Olaratumab + doxorubicin (n = 64)			Doxorubicin (n = 65)
	All grades	Grade 3	Grade 4	All grades	Grade 3	Grade 4
Treatment-related adverse events	63 (98%)	18 (28%)	25 (39%)	63 (97%)	19 (29%)	17 (26%)
Nausea	47 (73%)	1 (2%)	0	34 (52%)	2 (3%)	0
Fatigue	44 (69%)	6 (9%)	0	45 (69%)	2 (3%)	0
Neutropaenia	37 (58%)	12 (19%)	22 (34%)	23 (35%)	5 (8%)	16 (25%)
Inflammation of mucous membranes	34 (53%)	2 (3%)	0	23 (35%)	3 (5%)	0
Hair loss	33 (52%)	0	0	26 (40%)	0	0
Vomiting	29 (45%)	0	0	12 (18%)	0	0
Anaemia	26 (41%)	8 (13%)	0	24 (37%)	6 (9%)	0
Neutropaenic fever	8 (13%)	7 (11%)	1 (2%)	9 (14%)	9 (14%)	0
Reactions related to infusion	8 (13%)	0	2 (3%)	0	0	0
Peripheral oedema	10 (16%)	0	0	7 (11%)	0	0
Reduction of ejection fraction	5 (8%)	1 (2%)	0	4 (6%)	0	0

Adverse events related to treatment with doxorubicin (neutropaenia, mucositis, nausea, vomiting) were more common in patients treated with doxorubicin and olaratumab. This did not, however, translate into an increased frequency of neutropaenic fever, hospitalisation, decision to stop treatment or death. Eight (13%) of the 64 patients in the combination group and 12 (18%) of 65 patients in monotherapy group discontinued treatment because of side effects.

Immunohistochemical analysis of PDGFR-α expression showed that in both studied groups 88% of tumours were positive for PDGFR-α. However, it turned out that the test had low specificity for PDGFR-α, also detecting PDGFR-β. Re-analysis of the PDGFR-α-specific assay showed that 33% of patients treated with olaratumab and doxorubicin had PDGFR-α positive tumours, and 34% of patients treated with doxorubicin alone had positive PDGFR-α expression. Expression of PDGFR-α was irrelevant in relation to the OS (p = 0.3209) and PFS (p = 0.5924).

Summary

Adult patients with metastatic and/or unresectable STS still have poor outcomes due to very limited number of available therapies. The registration of olaratumab widens the therapeutic armamentarium in this group of patients, especially since all new drugs registered in recent years did not address the first line of treatment. Table 6 summarises the most important studies in the systemic treatment of STS with new therapies.

Table 6. Summary of major clinical trials of new drugs in advanced soft tissue sarcomas

Type of sarcoma, study phase [reference]	Treatment line	Research arms (experimental vs. control)	Percentage of respondents	Percentage of clinical benefit	Median PFS (months, p value)	Median OS (months, p value)
Soft tissue other than liposarcoma, phase 3, n = 369 [23]	Second or subsequent (after anthracyclines)	Pazopanib 800 mg/m2 vs. placebo	6% vs. 0%	73% vs. 38%	4.6 vs. 1.6 (p < 0.0001)	12.5 vs. 10.7 (p = 0.25)
Liposarcoma and leiomyosarcoma, phase 3, n = 518 [24]	Second or subsequent (after anthracyclines)	Trabectedin 1.5 mg/m2 vs. dacarbazine 1000 mg/m2	10% vs. 7%	61% vs. 42%	4.2 vs. 1.5 (p < 0.001)	12.4 vs. 12.9 (p = 0.37)
Liposarcoma and leiomyosarcoma, phase 3, n = 452 [25]	Third or subsequent (after anthracyclines)	Methylsulfonyl eribulin 1.4 mg/m2 vs. dacarbazine 850–1200 mg/m2	5% vs. 4%	57% vs. 52%	2.6 vs. 2.6 (p = 0.23)	13.5 vs. 11.5 (p = 0.01)
Soft tissue soft tissue, phase 2, n = 133 [20]	First line	Olaratumab 15 mg/kg plus doxorubicin 75 mg/m2 vs. doxorubicin monotherapy 75 mg/m2	18.2% vs. 11.9%	77.3% vs. 62.7%	6.6 vs. 4.1 (p = 0.06)	26.5 vs. 14.7 (p = 0,0003)

OS — overall survival; PFS — progression-free survival

Further studies are needed to confirm the results from the phase II study as well as the search for predictive factors for therapy, individualisation of the histopathological data for sarcoma, and clarification of the improvement of OS without significant effect on PFS. It is also necessary to investigate the mechanism of action of olaratumab in STS (presumably the effect on the microenvironment of the tumour). Recruitment is completed for a randomised, double-blind, phase III ANNOUNCE (NCT02451943) trial comparing doxorubicin alone or combined with olaratumab, in which the endpoint is OS. It is also planned to investigate the combination of olaratumab with gemcitabine and docetaxel.

Address for correspondence:

Prof. dr hab. n. med. Piotr Rutkowski

Klinika Nowotworów Tkanek Miękkich,

Kości i Czerniaków, Centrum Onkologii

— Instytut im. Marii Skłodowskiej-Curie,

Warszawa

e-mail: piotr.rutkowski@coi.pl

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