Drug Evaluation
`
`Future Oncology
`
`Keywords
`
`n antisense oligonucleotide
`n cancer n chaperone protein
`n clusterin n custirsen
`n prostate cancer
`
`Custirsen (OGX-011): a second-
`generation antisense inhibitor of
`clusterin in development for the
`treatment of prostate cancer
`
`Robert Zielinski1 & Kim N Chi*2
`1Bristish Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, V5Z 4E6, Canada
`2University of British Columbia, Vancouver, Canada
`*Author for correspondence: Tel.: +1 604 877 6000 ext. 2746 n Fax: +1 604 877 0585 n kchi@bccancer.bc.ca
`
`Clusterin is a stress-induced cytoprotective chaperone that confers broad-
`spectrum treatment resistance and is overexpressed across a number of cancers.
`custirsen (OGX-011) is a promising novel second-generation antisense inhibitor
`of clusterin in clinical development. This article describes the mechanism of
`action and safety profile of OGX-011 and details the Phase I and II results in human
`solid organ malignancies. Two Phase III registration trials are currently under
`recruitment evaluating OGX-011 in combination with chemotherapy in patients
`with metastatic castration-resistant prostate cancer. These studies not only have
`the potential to significantly alter the standard of care in prostate cancer, but
`would also endorse a new class of targets and targeted therapy approach for
`cancer.
`
`Custirsen (OGX-011, OncoGenex Pharma-
`ceuticals Inc., WA, USA and Teva Pharma-
`ceuticals Ltd, Petach Tikva, Israel) is a novel
`antisense oligonucleotide compound that tar-
`gets expression of the clusterin gene. This arti-
`cle describes clusterin’s structure, function and
`influential role in the development of treatment-
`resistant cancers. The rationale for employing
`antisense technology, and in particular OGX-
`011, to target gene overexpression is discussed.
`Finally, detailed efficacy and tolerability data
`are presented that establish the safety of OGX-
`011 in combination with chemotherapy and
`the potential role of OGX-011 in overcoming
`t reatment resistance in many malignancies.
`Clusterin is a secretable cytoprotective protein
`that is upregulated in response to cellular stress,
`which includes standard cancer treatments such
`as hormone-, radiation- and chemo-therapy, and
`is implicated in treatment resistance. Clusterin is
`expressed in many malignancies including pros-
`tate, breast, ovarian, non-small-cell lung, colon,
`renal, urothelial and pancreatic cancers, and
`anaplastic large-cell lymphoma and melanoma
`[1–7]. Since clusterin binds to a wide variety of cli-
`ent proteins involved in a diverse array of biologi-
`cal processes and regulated by HSF-1 it is viewed
`as a heat shock-like protein that chaperones and
`stabilizes proteins at times of cellular stress to
`promote cell survival. As clusterin isoforms are
`also secreted extracellularly, some investigators
`suggest that clusterin may be the first identified
`secreted mammalian chaperone [8].
`
`OGX-011 is a phosphorothioate antisense oli-
`gonucleotide (ASO) inhibitor of clusterin expres-
`sion that incorporates second-generation chemis-
`try in the form of a 2´-methoxyethyl (2´-MOE)
`modifications to increase tissue half-life, enhance
`potency and decrease nonsequence-specific tox-
`icity of the molecule. The clusterin gene was
`screened with a series of ASO sequences, and
`the most potent at inhibiting expression was the
`OGX-011 sequence targeting the translation ini-
`tiation site. Preclinical studies have demonstrated
`the potency of OGX-011 at inhibiting clusterin
`expression in vitro and in vivo, resulting in the
`therapeutic enhancement of s tandard anticancer
`treatments including hormone-, r adiation- and
`chemo-therapy [9].
`Phase I and II clinical trials with OGX-011 have
`demonstrated biologically active dosing and suc-
`cessful delivery of the drug to malignant tissues
`with inhibition of clusterin expression in both
`tissue and serum. A randomized Phase II study
`of OGX-011 in combination with docetaxel
`in patients with metastatic castration-resistant
`prostate cancer (CRPC) demonstrated a survival
`advantage for patients receiving the combination
`[10]. This led to the current registration pathway
`for OGX-011 in combination with standard
`therapies in patients with metastatic CRPC.
`For prostate cancer in 2012, standard treat-
`ments for the metastatic CRPC patient include
`chemotherapeutics (docetaxel [11], mitoxantrone
`[12] and cabazitaxel [13]), bone-targeting agents
`(zoledronic acid [14] and denosumab [15]),
`
`10.2217/FON.12.129 © 2012 Future Medicine Ltd
`
`Future Oncol. (2012) 8(10), 1239–1251
`
`ISSN 1479-6694
`
`1239
`
`part of
`
`For reprint orders, please contact: reprints@futuremedicine.com
`
`AVENTIS EXHIBIT 2046
`Mylan v. Aventis, IPR2016-00712
`
`

`
`immuno therapy (sipuleucel-T [16]) and a potent
`inhibitor of androgen biosynthesis (abiraterone
`acetate [17]). A novel, next-generation androgen
`receptor inhibitor, MDV3100 (enzalutamide)
`[18], and the infusional radioisotope radium-223
`[19], have also demonstrated improved over-
`all survival in patients after docetaxel or in
`docetaxel-ineligible patients (in the case of
`radium-223). Both agents remain investigational
`and are expected to enter the CRPC market in
`2012–2013. Despite these therapeutic advance-
`ments, treatment for metastatic CRPC remains
`palliative with a median overall survival of
`approximately 18 months [11]. Due to the role of
`clusterin in cell survival across multiple mecha-
`nisms and broad-spectrum treatment resistance,
`inhibition of clusterin with OGX-011 has the
`potential to improve outcomes across all these
`therapeutic modalities.
`
`Overview of the market
`Prostate cancer is the most frequently diagnosed
`cancer other than skin cancer and the second-
`leading cause of death from cancer in men in
`North America [20]. In 2011, prostate can-
`cer was diagnosed in 240,000 men and led to
`nearly 33,000 deaths in the USA. Worldwide,
`approximately 910,000 cases of prostate can-
`cer were recorded in 2008, accounting for
`approximately 14% of all new cancer cases in
`men [101]. CRPC is the lethal phenotype of the
`disease that may emerge after standard andro-
`gen ablation therapy for advanced disease. The
`term CRPC is commonly used when a patient’s
`cancer progresses despite castrate levels of testos-
`terone (<50 ng/ml). The therapeutic landscape
`has recently become enriched with multiple
`
`new agents that are either US FDA approved or
`recently reported in Phase III trials with positive
`results in terms of overall survival, progression-
`free survival (PFS) and symptomatic outcomes.
`Docetaxel was the first chemotherapeutic agent
`to demonstrate a survival advantage in CRPC
`[11], whereas mitoxantrone was only approved for
`palliation of symptoms in a similar patient group
`[12]. More recently cabazitaxel, a third-generation
`taxane, gained FDA approval by establishing a
`2.4-month survival advantage in patients pro-
`gressing after docetaxel [13]. Sipuleucel-T, the
`first FDA-approved vaccine-based therapy for
`any malignancy, established a 4.1-month sur-
`vival advantage in patients with asymptomatic
`or minimally symptomatic metastatic CRPC [16].
`New agents that target persistent androgen recep-
`tor signaling in CRPC through either inhibition
`of extragonadal steroidogenesis or direct inhi-
`bition of the androgen receptor have also been
`developed. Abiraterone acetate is currently the
`first approved drug in this class after establishing
`a 3.8-month median overall survival advantage
`in the postdocetaxel setting [17]. MDV3100 is a
`novel oral anti-androgen that directly inhibits
`the androgen receptor, which has also shown
`a survival advantage in the same patient group
`[18]. Lastly, the bone-targeting agents zoledronic
`acid and denosumab are also employed in the
`CRPC treatment model after demonstrating
`reduction in skeletal-related events and postpon-
`ing development of bone metastases [14,15]. Table 1
`summarizes both the currently approved agents
`and promising agents with unpublished positive
`Phase III results.
`The current approach to managing metastatic
`CRPC is under major transformation as the
`
`Table 1. Agents that are currently US FDA approved or with positive Phase III study
`data in castration-resistant prostate cancer.
`
`Agent
`
`Enzalutamide
`(MDV3100)
`
`Sipuleucel-T
`
`Mode of action
`
`Benefit
`
`Anti-androgen
`
`4.8-month median OS
`
`Immunotherapy
`
`4.1-month median OS
`
`Abiraterone acetate
`
`Anti-androgen
`
`3.9-month median OS
`
`Alpharadin
`
`Docetaxel
`
`Cabazitaxel
`
`Mitoxantrone
`
`Denosumab
`
`Radiopharmaceutical
`
`2.8-month medial OS
`
`Chemotherapeutic
`
`2.4-month median OS
`
`Chemotherapeutic
`
`2.4-month median OS
`
`Chemotherapeutic
`
`Pain palliation
`
`RANK ligand inhibitor
`
`4.2-month bone metastasis-free survival
`
`Inhibitor of osteoblasts Delayed time to SRE†
`Zoledronic acid
`†Pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone (including the use of
`radioisotopes) or a change of antineoplastic therapy to treat bone pain.
`OS: Overall survival; SRE: Skeletal-related event.
`
`Ref.
`[18]
`
`[16]
`
`[17]
`
`[19]
`
`[11]
`
`[13]
`
`[12]
`
`[15]
`
`[14]
`
`1240
`
`Future Oncol. (2012) 8(10)
`
`future science group
`
`Drug Evaluation Zielinski & Chi
`
`

`
`optimal sequencing of these new agents contin-
`ues to evolve. Yet perhaps the greater challenge is
`how best to manage the emergence of universal
`treatment resistance. Targeting the fundamental
`effectors of treatment resistance is an appealing
`approach; inhibition of heat-shock and cellular
`chaperone proteins fit into this category.
`
`The target: clusterin
`Clusterin is a single-copy gene, organized into
`nine exons (eight introns) and a 5´-untranslated
`region, located on chromosome 8p21–p12 and
`extending more than 16 kb [21,22]. It is highly
`conserved across species and constitutively
`expressed in almost all mammalian tissues. In
`humans, the clusterin gene codes for two secre-
`tory isoforms (sCLU-1 and sCLU-2), originat-
`ing from transcriptional start sites in exons 1
`and 2, respectively; only sCLU-2 is expressed
`in subprimates. Secreted clusterin (sCLU) is an
`endoplasmic reticulum-targeted, 449-amino
`acid polypeptide that represents the predomi-
`nant translation product of the human gene.
`Although sCLU is cytoprotective and anti-apop-
`totic, a pro-apoptotic activity ~55-kDa nuclear
`(nCLU) splice variant lacking exon 2 and the
`endoplasmic reticulum signal peptide has been
`described [23,24]. Analysis of the promoter has
`revealed numerous transcription factor-binding
`sites and also a conserved clusterin element, rec-
`ognized by HSF-1/HSF-2 heterocomplexes [25].
`Clusterin is transcriptionally activated by HSF-1
`in response to cellular stress [26,27].
`In malignancy, clusterin has largely been
`defined as an inhibitor of apoptosis [28–31]. Its
`anti-apoptotic actions have been described as
`functioning through a variety of mechanisms
`including inhibition of activated Bax [32] and
`enhanced survival signaling through upregu-
`lation of PI3k/Akt pathway signaling [33].
`Clusterin has also been implicated in tumo-
`rigenesis through loss of the tumor suppres-
`sor gene Nkx3.1 [34], and its overexpression in
`response to hormonal ablation, chemotherapy
`and radiotherapy contributes to treatment
`resistance [6,29,35]. This clusterin-induced treat-
`ment-resistant phenotype has been much stud-
`ied in prostate cancer and docetaxel-resistant
`prostate tumor cells have been resensitized to
`docetaxel following exposure to OGX-011
`[36,37]. However, drug resistance induced by
`clusterin has been observed within other tumor
`types and with chemotherapy agents includ-
`ing doxorubicin, camptothecin, cisplatin,
`5-fluorouracil, gemcitabine, dacarbazine and
`etoposide [2,32,38–42].
`
`Introduction to the compound
`OGX-011 is a novel second-generation 2´-MOE-
`modified phosphorothioate ASO complementary
`to clusterin mRNA. OGX-011 is a potent inhibi-
`tor of clusterin expression in vitro, in vivo and in
`humans in clinical trials. As a single agent and
`in combination with chemotherapy, OGX-011
`has been well-tolerated in Phase I trials and with
`promising activity in Phase II clinical trials.
`Registration Phase III trials are underway with
`OGX-011 in combination with chemotherapy in
`patients with metastatic CRPC.
`
`Chemistry
`ASO therapy is one strategy to specifically target
`functionally relevant genes. ASOs are chemically
`modified stretches of single-strand DNA com-
`plementary to mRNA regions of a target gene
`that inhibit translation by forming RNA/DNA
`duplexes, thereby reducing mRNA and pro-
`tein levels of the target gene [43]. OGX-011 is
`a 21-nucleoside ASO complementary to the
`clusterin exon 2 mRNA AUG translation ini-
`tiation site, with one CpG motif. The custirsen
`sequence was identified as the most potent to
`inhibit clusterin expression after the gene was
`‘walked’ with a series of antisense sequences.
`OGX-011 is a second-generation phospho-
`rothioate and incorporates the 2´-O-2´-MOE
`modification with four 2´-MOE-modified nucl-
`eosides at the 3´ side, four 2´-MOE-modified
`nucleosides at the 5´ side and 13 2´-deoxyribo-
`nucleosides in between (referred to as a 4-13-4
`MOE gapmer).
`Phosphorothioate ASOs are water-soluble, sta-
`ble agents resistant to nuclease digestion through
`substitution of a nonbridging phosphoryl oxy-
`gen of DNA with sulfur [44]. In clinical trials, a
`major technical limitation with the first genera-
`tion of phosphorothioate ASOs was the require-
`ment for continuous or frequent intravenous
`infusions owing to the short tissue half-life of
`these agents. The approach to overcome this has
`been by a 2’-MOE modification to the 2´-posi-
`tion of the carbohydrate moiety. This forms
`ASO–RNA duplexes with a significantly higher
`affinity relative to unmodified phosphorothioate
`ASOs. This increased affinity has been shown to
`result in improved antisense potency in vitro and
`in vivo. In addition, 2´-MOE second-generation
`ASOs display significantly improved resistance
`against nuclease-mediated metabolism resulting
`in an improved tissue half-life in vivo, which
`produces a longer duration of action and allows
`for an intermittent dosing regimen [45]. Finally,
`these second-generation phosphorothioate
`
`1241
`
`future science group
`
`www.futuremedicine.com
`
`Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin Drug Evaluation
`
`

`
`ASOs have the potential for an improved safety
`profile relative to u nmodified phosphorothioate
`ASOs [46].
`
`Pharmacokinetics
`The disposition and metabolism of OGX-011
`was measured in mice and monkeys. Consistent
`with pharmacokinetic (PK) studies with other
`ASOs, plasma was rapidly cleared of OGX-011
`in both species [47]. Plasma concentrations of
`OGX-011 generally peaked at the end of the
`60-min intravenous infusion period and then
`decreased in an apparent biexponential fash-
`ion that included two distinct half-lives. Mean
`concentrations increased with dose in all tissues
`examined, except for brain where no measur-
`able drug could be detected. Approximately
`90% of the compound was found in the par-
`ent form in all tissues at all time points. PK
`parameters were similar at the beginning and
`end of the treatment period in both species,
`suggesting no plasma accumulation or changes
`in plasma kinetics after multiple dosing in
`either species.
`In humans, plasma PK parameters for
`OGX-011 have followed predictions from pre-
`clinical studies. The first-in-man Phase I trial
`[48] was uniquely designed to permit a dose-
`dependent analysis of OGX-011 levels in the
`plasma and prostatic tissue. The mean plasma
`distribution half-life was 3.3 h at the 640-mg
`dose. Average peak concentrations and area
`under the curve were dose dependent and dis-
`played proportional and predictable increases in
`a linear fashion. This study also demonstrated
`concentrations in prostate cancer cells of full-
`length OGX-011 at levels sufficient for inhibi-
`tion of clusterin expression. Furthermore, the
`prostate tissue concentrations were proven to
`be dose dependent: 320 mg delivered 223 nM
`tissue concentration and 640 mg delivered
`644 nM into the prostate tissue. PK plasma
`parameters for humans are detailed in Table 2.
`As ASOs are degraded by both serum and intra-
`cellular nucleases [45] and only 7% of the drug is
`excreted unchanged in the urine, tissue distribu-
`tion of OGX-011 dominates plasma clearance.
`
`Pharmacodynamics
`OGX-011 is a potent inhibitor of clusterin
`expression in in vitro and in vivo laboratory mod-
`els [45]. Furthermore, because of the targeting to
`exon 2 of clusterin RNA there is a specificity for
`OGX-011 to inhibit only the expression of the
`anti-apoptotic secreted form of clusterin, with
`no effect on the pro-apoptotic nuclear form [49].
`In vitro activity of ASOs and documented
`overexpression of tissue clusterin has been
`demonstrated in multiple chemotherapy resist-
`ant tumor cell lines [35,50]. In prostate cancer, a
`docetaxel-resistant human prostate cancer cell
`line (PC-3dR) had significantly higher secreted
`clusterin levels compared with controls [37].
`Clusterin protein expression was significantly
`decreased upon exposure to OGX-011 compared
`with a control oligonucleotide. Chemotherapy
`resensitization was demonstrated by combin-
`ing the docetaxel-resistant PC-3dR cells with
`OGX-011 resulting in a fall of the IC50 of
`docetaxel from >1000 nM to 125 nM.
`Downregulation of sCLU was established in
`multiple in vivo mice models (lung [35], bladder
`[50] and prostate [37,45]). In prostate cancer, treat-
`ment with OGX-011 decreased sCLU expression
`in both PC-3 and PC-3dR xenografts. Western
`blot analysis of protein harvested from tumors
`obtained from mice at the end of the study indi-
`cated that OGX-011 decreased sCLU expression
`levels to 32 and 27% of the sham ASO-treated
`controls in PC-3 and PC-3dR tumors, respec-
`tively. Resembling the in vitro data, baseline
`sCLU expression were 2.25-fold higher in the
`PC-3dR tumors compared with the wild-type
`PC-3 tumors (p < 0.001).
`Antitumor effect was also confirmed across
`several mouse models. In the prostate cancer mice
`xenografts, OGX-011 treatment significantly
`enhanced the antitumor effects of paclitaxel
`compared with the sham ASO control, reduc-
`ing the mean PC-3 tumor volume to 33% of
`controls at week 9 (p < 0.01). More importantly,
`OGX-011 was also able to significantly enhance
`cytotoxicity of paclitaxel in PC-3dR xenografts,
`decreasing mean tumor volume by 76% com-
`pared with the MOE gapmer mismatch control
`
`Table 2. Plasma and tissue pharmacokinetic data for OGX-011.
`
`Dose
`
`AUC
`(μg/h/ml)
`
`Plasma
`Clearance
`(ml/h/kg)
`
`Cmax
`(μg/ml)
`
`Half-life
`(h)
`
`Tissue
`Mean prostate tissue
`concentration (μg/g)
`
`69.85
`640 mg† 290.15
`†Recommended dose in humans.
`AUC: Area under the curve.
`
`32.9
`
`7.63
`
`4.82
`
`1242
`
`Future Oncol. (2012) 8(10)
`
`future science group
`
`Drug Evaluation Zielinski & Chi
`
`

`
`Historical controls
`
`
`
`Ptrend = 0.008
`
`600
`
`500
`
`400
`
`300
`
`200
`
`100
`
`Relative % clusterin mRNA
`
`
`
`
`
`
`
`0
`OGX-011 dose (mg) =
`
`NT <2M NHT 40/80
`
`
`160
`
`n =
`
`8
`
`10
`
`4
`
`3
`
`320
`
`6
`
`480
`
`6
`
`640
`
`
`
` 6
`
`Ptrend < 0.001
`
`Historical controls
`
`3.00
`
`2.50
`
`2.00
`
`1.50
`
`1.00
`
`0.50
`
`Overall IHC score
`
`
`
`
`
`0.00
`OGX-011 dose (mg) =
`n =
`
`NT <2M NHT 40/80
`10
`15
`4
`
`160
`3
`
`320
`6
`
`480
`6
`
`640
`6
`
`Figure 1. OGX-011 inhibits clusterin expression in human prostate tissue.
`(A) Box-plot of clusterin mRNA expression in prostate cancer cells of men with
`prostate cancer who were treated with OGX-011 prior to prostatectomy and in
`historical control subjects. (B) Box-plot of the overall score of
`immunohistochemistry staining. Three slides per patient and ten fields per slide
`were evaluated for staining intensity from 0 to 3 (representing negative to strong
`staining, respectively) and graded independently by two pathologists.
`<2M NHT: Less than 2 months of neoadjuvant hormone therapy historical controls;
`IHC: Immunohistochemistry; NT: No treatment.
`Reproduced with permission from [48] © JNCI Oxford University Press.
`
`and is due for completion in December 2013 with
`a planned enrollment of 1000 men and a pri-
`mary outcome of overall survival. The trial has
`been designed for 90% power to detect a hazard
`ratio of 0.75 assuming an 18-month expected
`overall survival in the control arm. A second
`Phase III trial in patients with metastatic CRPC
`previously treated with docetaxel, SATURN
`[103], aimed to assess pain response as a primary
`end point with OGX-011 in combination with
`docetaxel–prednisone retreatment versus pla-
`cebo and docetaxel–prednisone. The study was
`
`at week 9 (p < 0.01). Collectively, these results
`show that sCLU knockdown using OGX-011
`not only sensitizes PC-3 tumors to chemotherapy
`in vivo, but also reverses resistance and enhances
`chemosensitivity in PC-3dR xenografts.
`The first-in-man study combined OGX-011
`with neoadjuvant hormone ablation for patients
`with localized prostate carcinoma prior to radi-
`cal prostatectomy (RP). Prostate specimens and
`historical controls were then evaluated for clus-
`terin expression. Changes in expression of tis-
`sue clusterin were correlated to the administered
`plasma dose and the dose delivered to the pros-
`tate. OGX-011 produced statistically significant
`dose-dependent suppression of clusterin mRNA
`and protein expression in normal and tumor tis-
`sue. Approximately double the amount of tumor
`cell death (as determined by apoptotic index)
`occurred in the prostate of patients receiving the
`highest dose of OGX-011 (640 mg) compared
`with hormone ablation therapy alone. With this
`novel design and the use of PK and pharmaco-
`dynamic end points, an effective biologic dose of
`640 mg was established for OGX-011 based on
`its ability to suppress clusterin mRNA by >90%
`in prostate cancer tissue (Figure 1) [51].
`In the historical control specimens treated
`with and without neoadjuvant hormone therapy
`(NHT), the mean apoptotic indices were 9.0%
`(95% CI: 5.1–13.0) and 7.0% (95% CI: 4.2–9.9),
`respectively. The apoptotic index from patients
`treated at the lower two dose levels of OGX-011
`was 7.1% (95% CI: 2.4–11.8), but at the 640-mg
`dose level, the mean apoptotic index was 21.2%
`(95% CI: 18.1–24.2). These data provide proof-
`of-principle for the biologic activity of OGX-011
`and reinforce the dose–response effect initially
`demonstrated in preclinical testing.
`
`Clinical efficacy
`To date, two Phase I and five Phase II trials
`have been completed with a total of 313 patients
`enrolled: 213 with prostate cancer and 95 in lung
`and breast cancer. In prostate cancer, OGX-011
`has been evaluated in multiple settings and in
`combination with both hormonal and chemo-
`therapy agents (see Table 3). In advanced lung and
`breast malignancies, OGX-011 has been com-
`bined with chemotherapy agents (platinums,
`gemcitabine and docetaxel). Three Phase III
`trials have been initiated and two are currently
`recruiting patients with CRPC. The SYNERGY
`study is randomizing chemotherapy-naive
`patients with metastatic CRPC to receive stand-
`ard docetaxel and prednisone with or without
`OGX-011 [102]. The study commenced in 2010
`
`1243
`
`future science group
`
`www.futuremedicine.com
`
`Custirsen (OGX-011): a second-generation antisense inhibitor of clusterin Drug Evaluation
`
`

`
`Table 3. List of completed and open clinical trials with OGX-011.
`
`Phase Experimental arm
`
`Comparator arm
`
`Random n
`
`Clinical setting
`
`I
`
`I
`
`II
`
`II
`
`II
`
`II
`
`II
`
`III
`
`III
`
`OGX-011 + LHRH + anti-androgen None
`
`OGX-011 + docetaxel
`
`None
`
`OGX-011 + docetaxel + prednisone Placebo
`
`OGX-011 + docetaxel + prednisone Mitoxantrone
`+ prednisone
`
`OGX-011 + LHRH + anti-androgen None
`
`OGX-011 + platinum†
`+ gemcitabine
`
`OGX-011 + docetaxel
`
`OGX-011 + docetaxel
`
`OGX-011 + docetaxel
`
`Platinum†
`+ gemcitabine
`
`Docetaxel
`
`Docetaxel
`
`Docetaxel
`
`No
`
`No
`
`Yes
`
`Yes
`
`No
`
`No
`
`No
`
`Yes
`
`Yes
`
`25
`
`40
`
`82
`
`42
`
`24
`
`85
`
`15
`
`Neoadjuvant in localized PrCa
`
`Advanced solid organ malignancies
`
`mCRPC
`
`mCRPC
`
`Neoadjuvant in localized, high-risk PrCa
`
`Treatment-naive stage IIIb or IV NSCLC
`
`mBrCa first- or second-line
`chemotherapy
`
`1000‡ mCRPC first-line chemotherapy
`
`300‡ mCRPC second-line chemotherapy
`
`Ref.
`[48]
`
`[51]
`
`[10]
`
`[61]
`
`[52]
`
`[53]
`
`[60]
`
`[102]
`
`– §
`
`Cabazitaxel
`OGX-011 + cabazitaxel
`III
`†Platinum agents in this trial used cisplatin or carboplatin.
`‡Planned enrollment.
`§Trial terminated.
`LHRH: Luteinizing hormone-releasing hormone; mBrCa: Metastatic breast cancer; mCRPC: Metastatic castrate-resistant prostate cancer; NSCLC: Non-small-cell lung
`cancer; PrCa: Prostate cancer.
`
`Yes
`
`630
`
`mCRPC second-line chemotherapy
`
`[104]
`
`opened in March 2010 and planned to enroll 292
`men; however, it was closed prematurely given
`the shifting landscape of new therapies with the
`introduction of abiraterone and cabazitaxel in the
`post-docetaxel indication. With the approval of
`cabazitaxel for CRPC patients previously treated
`with docetaxel, a replacement Phase III trial [104]
`has instead been planned that is combining
`OGX-011 with cabazitaxel versus cabazitaxel
`alone with overall survival as the primary end
`point. Table 3 outlines the clinical trial details that
`are completed or recruiting.
`
`Phase I trial with neoadjuvant OGX-011
`prior to prostatectomy in patients with
`localized prostate cancer
`A uniquely designed first-in-man study adminis-
`tered OGX-011 in escalating doses in combina-
`tion with NHT to men with localized prostate
`carcinoma prior to RP [48]. The design of the trial
`was novel for two reasons; first, it demonstrated a
`dose-dependent relationship between tissue lev-
`els of OGX-011 and its target, prostatic tissue
`clusterin. Secondly, it established a relationship
`between decreased prostatic tissue clusterin (the
`target) and an increased apoptotic index (the
`biological effect). This allowed a biologically
`active dose (640 mg), rather than a dose-limiting
`toxic dose, to be selected as the recommended
`Phase II dose. The Phase II schedule requiredpa-
`tients to receive three loading doses of OGX-011
`(640 mg) prior to chemotherapy followed by
`weekly administration of OGX-011 (640 mg).
`
`Phase I trials with OGX-011 in
`combination with chemotherapy
`The next Phase I trial of OGX-011 examined
`its safety profile in combination with two dif-
`fering schedules of docetaxel [51]. Patients with
`solid organ malignancies were administered
`escalating doses of OGX-011 (40–640 mg) with
`weekly (30 mg/m2) or 3 weekly (75 mg/m2) doc-
`etaxel. Adverse events close to dose limiting were
`observed at 640 mg dosing of OGX-011 with
`docetaxel at 75 mg/m2 and this was declared as
`the recommended dose. These adverse events
`included grade 3–4 fatigue, stomatitis, granu-
`locytopenia, anemia and elevated alkaline
`phosphatase. Antitumor activity was observed
`with two patients (6%) experiencing a partial
`radiological response, 40% of the prostate cancer
`cohort experiencing a prostate-specific antigen
`(PSA) response (defined as post-treatment PSA
`decline of ≥50%) and 11 patients (34%) expe-
`riencing stable disease. Importantly, toxicity of
`the combination was mild or moderate for the
`most part, with toxicities being qualitatively
`and quantitatively in keeping with what would
`be expected with docetaxel alone. Finally, there
`was no apparent effect of OGX-011 on the PK
`behavior of docetaxel.
`
`Phase II trials of OGX-011 in combination
`with NHT
`A two-stage Phase II study combined weekly
`OGX-011 with NHT in previously untreated
`patients with high-risk, localized prostate cancer
`
`1244
`
`Future Oncol. (2012) 8(10)
`
`future science group
`
`Drug Evaluation Zielinski & Chi
`
`

`
`prior to RP [52]. Hormone therapy consisted of
`subcutaneous lutenizing hormone-releasing hor-
`mone agonist every 3 months with either daily
`flutamide or bicalutamide. A total of 12 weeks of
`combined therapy was administered prior to sur-
`gery. The study did not progress from stage 1 as
`it failed to meet its primary end point of at least
`one pathological complete response. However,
`the apoptotic index in prostate tumors was sign-
`ficantly higher in patients given OGX-011 and
`NHT compared with both untreated controls
`and NHT-treated controls.
`
`Phase II trials of OGX-011 in combination
`with chemotherapy
`A multicenter noncomparative Phase II trial,
`randomized chemotherapy-naive metastatic
`CRPC patients to daily prednisone and doc-
`etaxel every 3 weeks with or without weekly
`OGX-011 (640 mg) [10]. A total of 82 patients
`were enrolled and the primary end point was
`PSA response. The trial was insufficiently
`powered for statistical analysis of observed
`differences; however, the experimental arm
`demonstrated an unadjusted HR of 0.61 (95%
`CI: 0.36–1.02; p = 0.06). The OGX-011 plus
`docetaxel arm obtained median PFS and OS of
`7.3 months (95% CI: 5.3–8.8) and 23.8 months
`(95% CI: 16.2–not reached), respectively while
`the docetaxel-alone arm achieved PFS and OS of
`6.1 (95% CI: 3.7–8.6) and 16.9 months (95%
`CI: 12.8–25.8). A multivariate analysis using
`pre-identified prognostic factors identified per-
`formance status Eastern Cooperative Oncology
`Group of 0 (p < 0.0001), no visceral metasta-
`sis (p = 0.01) and treatment assignment to
`OGX-011 (HR = 0.50, 95% CI: 0.29–0.87; p =
`0.01) associated with an improved overall sur-
`vival. This trial led to the Phase III registration
`path currently underway.
`Another multicenter Phase II lung cancer trial
`used OGX-011 in combination with cisplatin
`(75 mg/m2)/gemcitabine (1250 mg/m2) every 3
`weeks in a treatment-naive cohort of advanced
`non-small-cell lung cancer (NSCLC) patients
`(stage IIIb/IV) for a maximum of six cycles [53].
`The objective response rate was 31% with one
`patient reporting a complete response. A total
`of 95% of patients experienced serum clusterin
`falls compared with baseline. There was a 50%
`reduction in risk of death in patients experienc-
`ing a serum clusterin response, defined as less
`than 38 µg/ml. Finally, overall survival was
`14.1 months, which compares favorably with
`published median survivals of 8–10.8 months
`in similar patients treated with gemcitabine/
`
`platinum doublets [54–58]. The overall survival
`data also compare favorably with the 12.3-month
`OS from newer regimens of platinum doublets in
`combination with bevacizumab [59].
`A multicenter, Phase II breast cancer trial
`used OGX-011 with docetaxel (75 mg/m2)
`every 3 weeks in patients with metastatic and/or
`locally advanced breast cancer as first- or second-
`line chemotherapy [60]. A partial response rate
`of 33% was observed in the experimental arm,
`which was similar to the response rate expected
`of single-agent docetaxel. An additional 60%
`showed stable disease and the median duration
`of response was 4.9 months. Serum clusterin
`decreased by 23–32% from baseline values yet
`no relationship between response rate and serum
`clusterin levels was shown. Although clinical
`activity was demonstrated, the study failed to
`progress to the second stage of accrual due to
`lack of prespecified objective responses.
`The final clinical study sought to address
`the issue of reversing docetaxel resistance or
`improving mitoxantrone efficacy in the second-
`line setting. An open-label, randomized, multi-
`center study evaluated weekly administration
`of OGX-011 in combination with second-line
`chemotherapy in patients with metastatic CRPC
`who were previously treated with a minimum of
`two cycles of a docetaxel-based regimen and pro-
`gressed on or within 6 months of discontinua-
`tion of treatment [61]. Safety and tolerability were
`the primary objectives; however, the secondary
`objective was to assess for reversal of docetaxel
`resistance in this pretreated cohort. A total of
`45 patients were randomized to OGX-011 in
`combination with mitoxantrone 12 mg/m2
`intravenously every 3 weeks with 5 mg pred-
`nisone twice daily or docetaxel retreatment at
`75 mg/m2 every 3 weeks with 5 mg prednisone
`twice daily. An additional 20 patients were ran-
`domized to the docetaxel retreatment following
`preliminary safety and efficacy analysis favoring
`docetaxel. The overall PSA response rate in the
`docetaxel arm was 42%, with 91% experiencing
`a PSA decline of 30% or more. In the mitox-
`antrone arm, the PSA response rate was 27%
`with 59% experiencing a PSA decline of 30%
`or more. The estimated median overall survival
`duration for the OGX-011 plus mitoxantrone
`arm was 11.5 months (95% CI: 6.1–15.2). For
`the OGX-011 plus docetaxel retreatment arm,
`the median overall survival was 15.8 months
`(95% CI: 9.9–23.3) for the 20 randomized
`patients and 12.8 months (95% CI: 9.9–17.0)
`for the combined 45 patients. Serum clusterin
`