Published OnlineFirst July 25, 2011; DOI: 10.1158/1078-0432.CCR-11-0859
`
`Cancer Therapy: Clinical
`
`Clinical
`Cancer
`Research
`
`Randomized Phase II Trial of Custirsen (OGX-011) in Combination
`with Docetaxel or Mitoxantrone as Second-line Therapy in
`Patients with Metastatic Castrate-Resistant Prostate Cancer
`Progressing after First-line Docetaxel: CUOG Trial P-06c
`
`Fred Saad1, Sebastien Hotte3, Scott North4, Bernie Eigl5, Kim Chi6, Piotr Czaykowski8, Lori Wood9,
`Michael Pollak2, Scott Berry10, Jean-Baptiste Lattouf1, Som D. Mukherjee3, Martin Gleave7, and Eric Winquist11,
`for the Canadian Uro-Oncology Group
`
`Abstract
`
`Purpose: Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance
`when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-
`resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy.
`Patients and Methods: Men were randomized to receive either docetaxel þ prednisone þ custirsen
`(DPC) or mitoxantrone þ prednisone þ custirsen (MPC).
`Results: Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients
`treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain
`progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13
`(23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90%
`or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients,
`respectively.
`Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median
`TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were
`observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients,
`respectively.
`Low serum CLU levels during treatment showed superior survival for patients based on modeling with
`proportional hazard regression with a time-dependent covariate and different landmarks.
`Conclusions: Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive
`mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting
`correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of
`custirsen with taxane therapy is ongoing. Clin Cancer Res; 17(17); 5765–73. Ó2011 AACR.
`
`Introduction
`
`Docetaxel is standard first-line chemotherapy for men
`with metastatic
`castration-resistant
`prostate
`cancer
`
`Authors' Affiliations: 1CRCUM-Universite de Montreal; 2Jewish General
`Hospital, Montreal, Quebec; 3Juravinski Cancer Centre, Hamilton, Ontario;
`4Cross Cancer Institute, Edmonton, Alberta; 5Tom Baker Cancer Centre,
`Calgary, Alberta; 6British Columbia Cancer Agency; 7Vancouver Prostate
`Centre, Vancouver, British Columbia; 8Cancer Care Manitoba, Winnipeg,
`Manitoba; 9Queen Elizabeth II Health Sciences Centre, Halifax, Nova
`Scotia; 10Odette Cancer Centre, Toronto, Ontario; and 11London Health
`Sciences Centre, London, Ontario, Canada
`Corresponding Author: Fred Saad, CRCUM-Universite de Montreal,
`1560 Sherbrooke East, Montreal, Quebec, Canada H2L4M1. Phone:
`514-890-8000 (ext. 27466); Fax: 514-412-7620; E-mail:
`fred.saad.chum@ssss.gouv.qc.ca
`
`doi: 10.1158/1078-0432.CCR-11-0859
`Ó2011 American Association for Cancer Research.
`
`(mCRPC; 1, 2). With progression, survival is less than
`1 year (3–6). Second-line treatment with mitoxantrone
`and retreatment with docetaxel are commonly used despite
`limited data on safety and efficacy. A pressing need exists
`for novel therapeutics that target the molecular basis of
`treatment resistance in mCRPC.
`Experimental and clinical studies have associated ele-
`vated clusterin (CLU) levels with development of treatment
`resistance in prostate, lung, breast, ovarian, and other
`cancers (7–12). CLU is a stress induced, cytoprotective
`chaperone (8–13) upregulated to inhibit cell death that
`confers broad-spectrum resistance by inhibiting protein
`aggregation and proteotoxic stress, cytochrome C release,
`and Bax and caspase activation (13–18). CLU is an attrac-
`tive candidate for inhibition at the mRNA level.
`Custirsen, a second-generation antisense oligonucleo-
`tide (ASO), has high affinity for CLU RNA, with increased
`potency, and a prolonged tissue half-life compared with
`
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`Published OnlineFirst July 25, 2011; DOI: 10.1158/1078-0432.CCR-11-0859
`
`Saad et al.
`
`Translational Relevance
`
`Many strategies used to induce the apoptosis of cancer
`cells also induce stress responses that activate survival
`pathways and promote emergence of a treatment resis-
`tant phenotype. Clusterin (CLU) is a stress-activated
`cytoprotective chaperone upregulated by a variety of
`anticancer therapies that confers treatment resistance
`when overexpressed. Preclinical studies have shown that
`targeted knockdown of CLU enhances the effects of
`cytotoxic drugs, including docetaxel, in docetaxel-refrac-
`tory cells. This clinical trial provides evidence that
`combining custirsen with chemotherapy is feasible in
`patients with progressive metastatic castration-resistant
`prostate cancer following first-line docetaxel therapy
`and, as pain relief was higher than expected, provided
`some proof-of-principle of enhanced docetaxel activity.
`Moreover, it reaffirms that custirsen treatment signifi-
`cantly decreases levels of its target protein, CLU, and for
`the first time identifies correlations between serum CLU
`and survival that support further evaluation of serum
`CLU as a predictive biomarker. Two phase III trials
`evaluating custirsen plus docetaxel are currently
`ongoing.
`
`first-generation ASOs. Custirsen potently suppresses CLU
`levels both in vitro and in vivo (19, 20). In preclinical CRPC
`prostate cancer models, treatment with custirsen increased
`tumor cell death and improved chemosensitivity to multi-
`ple drugs, including docetaxel and mitoxantrone (19, 21–
`25). A phase I study used a novel neoadjuvant designed to
`identify the optimal biologic dose for custirsen in prostate
`cancer tissue (26). CLU levels decreased in a dose-depen-
`dent manner, with 92% knockdown of CLU protein and
`mRNA at the 640-mg dose; the mean apoptotic indices
`increased 3-fold.
`The primary objective of the current study was to eval-
`uate the safety of treating patients with mCRPC who
`progressed after first-line docetaxel chemotherapy with
`custirsen and prednisone in combination with either doc-
`etaxel þ prednisone þ custirsen (DPC) or mitoxantrone þ
`prednisone þ custirsen (MPC). The DPC arm of the study
`was motivated by preclinical data that custirsen resensitizes
`docetaxel-refractory prostate cancer cells to docetaxel (25).
`
`Patients and Methods
`
`Study design
`This was an open label, noncomparative, randomized
`study at 10 Canadian sites to evaluate the safety and efficacy
`of 2 second-line treatments for mCRPC. The primary end-
`point was safety. Exploratory endpoints analyzed included
`measures of efficacy [pain response and time to pain
`progression (TTPP); prostate-specific
`antigen (PSA)
`response; measurable disease response; progression-free
`survival (PFS); and overall survival (OS)] and the relation-
`ship between serum CLU levels and survival.
`
`Eligibility criteria
`Patients had a histologic diagnosis of adenocarcinoma of
`the prostate, metastatic disease by imaging, and 2 or more
`cycles of first-line docetaxel-based chemotherapy, with
`disease progression documented within 6 months of dis-
`continuing treatment. Patients had a Karnofsky perfor-
`mance status (PS) of 60% or more, had adequate organ
`function, and had recovered from prior therapy-related
`toxicity to grade 2 or less. Documentation and mainte-
`nance of a castrate serum testosterone level was required.
`Exclusion criteria included other active malignancies, con-
`gestive heart failure, and central nervous system metastases.
`No change in current bisphosphonate usage was permitted.
`All patients provided written informed consent, and the
`study was approved by local Research Ethics Boards.
`
`Treatment plan
`Custirsen, 640 mg, (supplied by OncoGenex Technolo-
`gies Inc.) was administered i.v. 3 times during a 9-day
`loading-dose period followed by once-weekly administra-
`tion. Premedication included ibuprofen or acetamino-
`phen. Either docetaxel, 75 mg/m2 i.v. for 60 minutes, or
`mitoxantrone, 12 mg/m2 i.v. for 30 minutes, was adminis-
`tered on day 1 of each 21-day cycle. Patients were
`premedicated with corticosteroids and received 5 mg of
`prednisone orally twice daily unless they were intolerant of
`steroids. Study treatment was continued until completion
`of 9 cycles; disease or prostate-cancer pain progression;
`need for radiation therapy; deterioration of PS; unaccep-
`table toxicity; or more than a 3-week delay in treatment.
`Patients did not discontinue study therapy for PSA progres-
`sion. Patients were followed every 2 months for survival.
`Growth factor administration and blood transfusions were
`at the discretion of the investigator. Bone and CT scans
`were obtained at baseline, every 3 cycles, and with symp-
`toms of disease progression. Responses were confirmed 3
`or more weeks after the initial scan. Blood tests and pain
`assessment data were collected prior to the first loading
`dose, on day 1 of each cycle until progression, and at an
`end-of-treatment visit.
`
`Dose modifications
`Adverse events (AE) were graded according to the Com-
`mon Terminology Criteria for Adverse Events v3.0. Dose
`modifications were made on day 1 of each cycle. Patients
`were removed from therapy for recurrence of toxicity
`despite 2 dose-reductions or grade 4 life-threatening AEs.
`Docetaxel or mitoxantrone was held until recovery for a
`neutrophil count less than 1.5  109 cells/L or platelet
`count less than 100  109/L. The dose of either drug was
`reduced at the next cycle for grade 3/4 hematologic toxicity
`lasting more than 7 days; febrile neutropenia or infection
`with neutropenia; and grade 4 thrombocytopenia or gross
`bleeding associated with a platelet count less than 50 
`109/L. Both drugs were held until recovery and subse-
`quently dose-reduced or discontinued depending on the
`level of
`increase in aspartate aminotransferase (AST)
`and/or bilirubin. Docetaxel or mitoxantrone was held
`
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`and subsequently dose-modified for grade 4 non–life-
`threatening and any other grade 3 or prolonged grade 2
`toxicity related to study treatment and considered to be
`clinically significant. Patients receiving mitoxantrone were
`removed from therapy for symptomatic congestive heart
`failure. Custirsen was dose-modified for hyponatremia.
`
`Efficacy analyses
`Pain was assessed on an 11-point numeric rating worse
`pain scale (WPS; 27). Analgesics were coded according to
`the World Health Organization analgesic ladder, which
`classifies analgesics into 3 levels: level 1: mild (nonopioids);
`level 2: moderate (codeine-class opioids); and level 3:
`strong (morphine-class opioids) (28). Patients with a base-
`line WPS of 2 or more and/or receiving opioids were
`considered evaluable for pain response. Pain response
`was defined as 2-point or more reduction in the WPS from
`baseline without an increase in the analgesic level, or a
`reduction in the analgesic level from 3 to 2 or less or from 2
`to 1 or less, without an increase in the WPS, both main-
`tained for 3 or more weeks. TTPP for all patients was defined
`as the time from start of study treatment to a 2-point or more
`increase from the average of all previous WPS scores; an
`increase in analgesic level from 0 or 1 to 2 or 3, or from level
`2 to 3, both maintained for 3 or more weeks; or requirement
`for radiation therapy.
`PSA response was defined as a decrease in PSA values of
`50% or more relative to baseline on 2 or more consecutive
`measurements 4 to 6 weeks apart. Disease progression was
`defined as 1 or more of the following: measurable progres-
`sion by Response Evaluation Criteria in Solid Tumors
`(RECIST), pain progression, and deterioration of PS, the
`latter two due to prostate cancer progression. OS was
`defined as the time from the start of study treatment to
`the date of death. OS time was censored at the date of the
`last follow-up for subjects who were still alive. PFS was
`defined as the time from the start of study treatment to the
`first documentation of disease progression or the date of
`death. Patients who failed to return for assessments or
`received new anticancer therapy were censored at the time
`of the last disease assessment.
`
`Serum clusterin analysis
`Serum CLU samples were collected at baseline and on
`day 1 of each cycle. Samples were analyzed at Mayo Clinical
`Trial Services utilizing the BioVendor Clusterin ELISA kit, a
`solid-phase ELISA in microplate format designed for
`the quantitative measurement of human CLU in serum,
`plasma, and cerebrospinal fluid.
`
`Statistical considerations
`The planned sample size was 20 patients per arm. With
`20 patients, an AE with 10% probability of occurrence is
`highly likely to be observed at least once with 88% prob-
`ability. Patients were centrally randomized to eliminate
`subjectivity in arm selection. The primary analysis set
`included patients who initiated both custirsen and che-
`motherapy. The primary endpoint was safety, reported as
`
`Custirsen plus Docetaxel or Mitoxantrone in Metastatic CRPC
`
`the percentage of patients experiencing any serious or grade
`3 or more AE. Feasibility, reported as the median number of
`treatment cycles administered within treatment arms, was
`also of interest. Assessments for PSA response and TTPP
`were preplanned.
`To evaluate the effect of custirsen on CLU, minimum
`CLU levels during treatment were compared with baseline
`levels using a 2-sided paired t test. In addition, exploratory
`analyses to assess the relationship between survival and
`serum CLU levels were done using a proportional hazard
`regression procedure. A CLU response was defined as 3
`successive CLU levels during therapy less than or equal to
`median baseline CLU for the population. Patients with less
`than 3 CLU levels during therapy were defined as non-
`responders. The starting survival model included the base-
`line CLU level (as above or below the baseline median), the
`chemotherapy arm, a time-dependent variable indicating
`the start of response, and all interactions (3-way or below).
`The model reported is the most parsimonious hierarchical
`step-down model using a 0.1 criterion for exclusion of
`terms. Only patients with baseline and assessments
`through the day 50 landmark (cycle 3 day 1) were
`included in the analyses to reduce the bias related to
`censoring due to early deaths (29). Other patient selection
`criteria, including no landmark and a day 30 landmark
`(cycle 2 day 1), were evaluated to assess robustness of the
`conclusions.
`To assess the consistency of the results, in addition to the
`hazard regression analysis, Kaplan–Meier estimates for 3
`classifications of patients were plotted based on median
`baseline CLU ( median vs. > median); median minimum
`CLU ( median vs. > median) for the population during
`treatment; and a threshold minimum CLU level of 45
`mg/mL or less ( 45 vs. >45 mg/mL) during treatment.
`Although several threshold minimum CLU levels were
`evaluated, 45 mg/mL was chosen as a value between the
`median baseline CLU level of 54 mg/mL and the median
`minimum CLU level of the population during treatment of
`34 mg/mL. Survival by the above described classifications
`was compared using a median estimate and log-rank test.
`
`Results
`
`Patient characteristics and demographics at study
`entry
`Between July 2006 and April 2007, 45 patients were
`randomized (21 to the DPC arm and 24 to the MPC
`arm). Three patients (1 in the DPC arm and 2 in the
`MPC arm) did not initiate both components of the study
`(custirsen and chemotherapy) and, therefore, were not
`included in the primary analysis set. Baseline characteristics
`of the 20 remaining patients in the DPC arm and 22 in the
`MPC arm are presented in Table 1. For the entire popula-
`tion, the median age was 66 (range, 48–81) years and
`median PSA was 130 (range, 5–3570) ng/mL. Forty-three
`percent were on opioids for pain. The median time from
`the end of first-line therapy to study treatment was 4.2
`(range, 0.6–11) months.
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`Saad et al.
`
`Table 1. Demographics at study baseline
`
`Docetaxel/
`prednisone/custirsen
`(n ¼ 20)
`
`Mitoxantrone/
`prednisone/custirsen
`(n ¼ 22)
`
`Total
`population
`(N ¼ 42)
`
`Median age, y, range
`Median PSA, ng/mL, range
`PSA 20 ng/mL (%)
`Median hemoglobin, g/dL, range
`Median LDH, U/L, range
`Karnofsky score (% of patients)
`
`Receiving bisphosphonates (%)
`Radiotherapy since progression (%)
`Worst pain score 2 at study entry (%)
`On opioids at study entry (%)
`Sites of disease (% of patients)
`Bone
`Node
`Visceral
`Measurable disease (% of patients)
`Median time (mo) from end of first-line
`docetaxel therapy to study treatment (range)
`
`Abbreviation: LDH, lactic dehydrogenase.
`
`68 (48–80)
`154 (5–3570)
`90
`12.3 (9.0–13.7)
`231 (157–596)
`70%–80%: (35)
`90%–100%: (65)
`40
`50
`40
`45
`
`100
`65
`20
`65
`4.9 (0.9–7)
`
`61 (49–81)
`116 (20–2776)
`100
`12.6 (8.5–14.3)
`291 (142–1088)
`70%–80%: (41)
`90%–100%: (59)
`36
`45
`55
`41
`
`96
`50
`27
`50
`3.9 (0.6–11)
`
`66 (48–81)
`130 (5–3570)
`95
`12.3 (8.5–14.3)
`270 (142–1088)
`70%–80%: (38)
`90%–100%: (62)
`38
`48
`48
`43
`
`98
`57
`24
`57
`4.2 (0.6–11)
`
`First-line docetaxel therapy prior to study entry
`Patients had received a median of 10 (range, 2–22) of
`docetaxel. Twenty-two of 42 patients (52%) progressed
`while on first-line therapy. More patients on the MPC
`arm progressed while on first-line therapy (64%) than
`patients on the DPC arm (40%). The median time from
`the end of first-line therapy to progression for the remaining
`patients was 3.0 (1.1–6.4) months. Three patients received
`1 to 2 "chemotherapy holidays" during first-line therapy.
`
`Thirty of 35 patients (86%) with available PSA data had
`30% or more declines in PSA. Disease progression following
`first-line therapy was based on radiographic evidence in half
`the patients. Table 2 summarizes first-line therapy.
`
`Protocol therapy received
`A median of 8 (range, 1–9) cycles of DPC and 6 (range,
`1–9) of MPC were administered. Treatment with DPC was
`discontinued early in 10 patients: 6 for disease progression,
`
`Table 2. First-line docetaxel therapy received prior to study entry
`
`Docetaxel/prednisone/
`custirsen (n ¼ 20)
`
`Mitoxantrone/prednisone/
`custirsen (n ¼ 22)
`
`Total population
`(N ¼ 42)
`
`10 cycles (2–22)
`
`Median number of treatment cycles
`administered (range)
`30% decline in PSA at any time (%)a
`88
`Patients relapsing while receiving first-line therapy (%) 40
`Median time from end of first-line
`2.5 (1.1–5.1)
`therapy to disease progression for
`patients progressing after first-line
`therapy, mo (range)
`Basis of progression (%):b
`Bone scan
`CT scan
`PSA only
`
`20
`20
`60
`
`10 cycles (2–22)
`
`10 cycles (2–22)
`
`84
`64
`4.3 (1.8–6.4)
`
`86
`52
`3.0 (1.1–6.4)
`
`27
`27
`45
`
`24
`24
`52
`
`aPSA data available on 35 of 42 patients.
`bPatients could have progressed by more than one method.
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`Custirsen plus Docetaxel or Mitoxantrone in Metastatic CRPC
`
`9.9–23.3) for DPC, with 4 patients alive at 39 to 44
`months, and 11.5 months (95% CI, 6.1–15.2) for MPC,
`with one alive at 43 months. The 2-year survival rate was
`25% (95% CI, 9.1–44.9) for DPC and 14% (95% CI, 3.4–
`30.9) for MPC. Median PFS was 7.2 months (95% CI, 4.4–
`9.3) for DPC and 3.4 months (95% CI, 1.6–5.2) for MPC.
`Kaplan–Meier estimates for median OS from the start of
`first-line therapy was 30.2 months (95% CI, 19.9–36.4) for
`patients receiving DPC and 23.5 months (95% CI, 13.8–
`32.0) for those receiving MPC.
`Eight patients on the DPC arm and 14 on the MPC arm
`progressed while receiving first-line therapy. The median
`survival of this group, irrespective of arm, was 9.9 months.
`For the remaining patients who progressed after disconti-
`nuing first-line therapy (median of 3.0 months), the OS
`was 17.9 months (21.4 and 12.8 months for the DCP and
`the MCP arms, respectively).
`
`PSA response
`A PSA response, defined as a confirmed decrease in PSA
`of 50% or more relative to baseline, was documented in 8
`of 20 (40%) patients on the DPC arm and 4 of 22 (18%) on
`the MPC arm.
`As illustrated in the waterfall plot in Fig. 1, of the 20
`patients treated with DPC, 4 (20%), 8 (40%), and 11
`(55%) had a PSA best percent change of 90% or more,
`>50% or more, and >30% or more, respectively. Of the 22
`patients treated with MPC, 6 (27%) and 7 (32%) had a PSA
`best percent change of 50% or more and 30% or more,
`respectively.
`
`Measurable disease response
`Patient evaluability for response was defined as having
`measurable disease and at least one follow-up assessment.
`In the DPC arm, a confirmed partial response occurred in
`3 (15%) of 13 evaluable patients for 4.6, 6.7, and 34.7
`
`Chemotherapy groups:
`
`Mitoxantrone
`
`Decetaxel
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`–20
`
`–40
`
`–60
`
`–80
`
`–100
`
`Maximum PSA change from baseline (%)
`
`Table 3. Number (%) of patients with more than
`5% grade 3/4 adverse events in either arm
`
`Docetaxel/
`prednisone/
`custirsen
`N ¼ 20
`
`Mitoxantrone/
`prednisone/
`custirsen
`N ¼ 22
`
`Lymphopenia
`Fatigue
`Asthenia
`Neutropenia
`Leukopenia
`Dyspnoea
`Anemia
`Bone pain
`Hyponatremia
`Insomnia
`Syncope
`Chest pain
`Headache
`Infections
`Febrile neutropenia
`Nausea
`
`6 (30%)
`7 (35%)
`3 (15%)
`2 (10%)
`1 (5%)
`1 (5%)
`
`1 (5%)
`
`2 (10%)
`
`2a (9%)
`
`7 (32%)
`5 (23%)
`4 (18%)
`4 (18%)
`4 (18%)
`4 (18%)
`3 (14%)
`3 (14%)
`3 (14%)
`3 (14%)
`
`2 (9%)
`2 (9%)
`1b (5%)
`2 (9%)
`2 (9%)
`
`aUrinary tract infection and injection site infection.
`bPneumonia and septicemia.
`
`3 for toxicity (fatigue, bronchiolitis, and weakness), and 1
`for withdrawal of consent. Treatment with MPC was dis-
`continued early in 14 patients: 10 for disease progression, 3
`for toxicity (dyspnea, weakness, and increased AST) and 1
`at the investigator’s discretion.
`
`Toxicity
`The most common toxicities felt to be related to either
`custirsen or docetaxel included fatigue (64%), chills (50%),
`nausea (50%), pyrexia (40%), anorexia (38%), diarrhea
`(36%), and vomiting (31%). More than 90% of the AEs
`were grades 1 and 2. In general, toxicities were similar
`between the arms. Thirty percent of patients on the DPC
`arm and 27% on the MPC arm had a documented serious
`AE. Sixty percent of patients on the DPC arm and 73% on
`the MPC arm had a grade 3 or higher AE. Grade 3/4 AEs are
`listed in Table 3. The most common grade 3/4 AEs on either
`arm were fatigue and lymphopenia, the latter of which was
`seen in 31% of all patients. Grade 3/4 neutropenia was low,
`occurring in 10% and 18% of patients treated with DPC
`and MPC, respectively. There was no grade 3/4 neuropathy.
`Two patients on the MPC arm had neutropenic fever, 1
`patient died from pneumonia with septicemia, and 1
`further patient died of heart failure following cycle 8.
`
`Survival and disease progression
`All patients were followed until death or a minimum of
`39 months. No patient was lost to follow-up. Median OS
`from the start of study therapy was 15.8 months (95% CI,
`
`Figure 1. Best percent PSA change from baseline at or after 12 weeks.
`Calculated from lowest PSA value at any time after baseline while on
`treatment by individual patients. One patient in the mitoxantrone group
`had more than 200% increase in PSA. The value was truncated at 100%.
`
`www.aacrjournals.org
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`Published OnlineFirst July 25, 2011; DOI: 10.1158/1078-0432.CCR-11-0859
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`No landmark
`Nonresponder: n = 12, median = 5.8
`Responder: n = 28, median = 15.1
`Log-rank test P = <0.001
`
`Landmark = 30 d
`Nonresponder: n = 11, median = 6.1
`Responder: n = 28, median = 15.1
`Log-rank test P = <0.001
`
`Landmark = 50 d
`Nonresponder: n = 9, median = 6.5
`Responder: n = 27, median = 15.2
`Log-rank test P = <0.001
`
`8
`
`12 16 20 24 28 32 36
`Time (mo)
`Nonresponder
`
`Responder
`
`40 40
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`0.0
`
`Probability of survival
`
`Probability of survival
`
`Probability of survival
`
`0
`
`4
`
`Figure 2. Survival analysis by landmark. Kaplan–Meier estimates for no
`landmark and 30- and 50-day landmarks classified as to whether a patient
`did or did not have a CLU response during therapy.
`
`Figure 3 shows the Kaplan–Meier estimates for 3 classi-
`fications of patients based on median baseline CLU
`( median vs. > median); median minimum CLU
`( median vs. > median) of the population during treat-
`ment; and a threshold minimum CLU level  45 mg/mL
`( vs. >45 mg/mL) during treatment. Using the median
`baseline CLU level, survival estimates were similar for
`patients above or below the median. However, achieving
`a low serum CLU level during therapy improved survival
`for the other 2 classifications. The median OS for 22
`patients with minimum CLU levels during treatment of
`less than or equal to the median minimum CLU of the
`population was 14.9 months compared with 9.9 month for
`18 patients with CLU above the median (P ¼ 0.03).
`Similarly, the median OS for 33 patients who achieved a
`CLU threshold minimum level of 45 mg/mL or less during
`treatment was 15 months compared with 4.5 months for
`7 patients who did not (P < 0.001).
`
`Saad et al.
`
`months. Nine had stable disease for 1.8 to 12.0 (median,
`5.6) months. In the MPC arm, 5 (71%) of 7 evaluable
`patients had stable disease for 4.5 to 17.2 (median, 6.9)
`months.
`
`TTPP and pain response
`The median TTPP for all patients was 10.0 months in the
`DPC arm and 5.2 in the MPC arm. Twenty-six patients,
`with a median baseline WPS of 3 (range, 0–7), were
`evaluable for pain response. Forty-three percent of evalu-
`able patients were on opioids at baseline. Ten of 13 (77%)
`evaluable patients in the DCP retreatment arm responded,
`with discontinuation of opioids in 6. Six of 13 (46%)
`evaluable patients in the MPC arm responded, with dis-
`continuation of opioids in 3. All responses but one
`occurred within 2 cycles. Overall, the pain response was
`durable (i.e., 3 months) in 14 of the 16 (88%) patients.
`
`Effect of custirsen treatment on serum clusterin levels
`Of the 42 patients, 40 had both baseline and at least 1
`serum CLU value during treatment and are included in
`the serum clusterin analyses. The mean (SD) and median
`CLU levels at baseline for the 40 patients were 55.0
`mg/mL and 54 mg/mL, respectively. Custirsen treatment
`significantly reduced the mean average CLU level during
`treatment by 16.4 mg/mL (26%) compared with baseline
`(P < 0.0001). Thirty-five of 40 evaluable patients (88%)
`had a reduction in CLU during treatment and 31 of 40
`(78%) reached a targeted minimum level of 45 mg/mL or
`less. Twenty-eight (70%) patients were classified as serum
`CLU responders. The median time to CLU response was
`approximately 30 days. The mean and median CLU levels
`at baseline, reduction of mean average CLU levels during
`treatment, and median time to CLU response were similar
`in both arms.
`
`Association of serum clusterin levels and survival
`The classification of baseline serum CLU, chemotherapy
`type, and the interactions were not associated with survival.
`The most parsimonious 50-day landmark proportional
`hazard regression model included only the time-dependent
`serum CLU response indicator and was based on 36
`patients. This model failed to show a between-arm differ-
`ence. A CLU response was defined as 3 successive CLU levels
`during therapy less than or equal to median baseline CLU
`for the population. The estimated death HR (CLU response
`over no response) was 0.3 (95% CI, 0.1–0.6), representing a
`70% reduction in the hazard of death at the start of the
`serum CLU response. The results from the models with no
`landmark (40 patients) and a 30-day landmark (39
`patients) were consistent, with HR estimates of 0.2 and 0.2.
`Figure 2 shows the Kaplan–Meier estimates for no land-
`mark and 30- and 50-day landmarks classified as to
`whether a patient had or did not have a CLU response
`during therapy. Although these 3 graphs do not show the
`temporal relationship to CLU response, they do illustrate a
`consistent relationship between having a CLU response
`and survival for all 3 landmarks.
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`Published OnlineFirst July 25, 2011; DOI: 10.1158/1078-0432.CCR-11-0859
`
`Custirsen plus Docetaxel or Mitoxantrone in Metastatic CRPC
`
`The results of this study indicate that treatment with
`either combination was feasible and safe in the second-line
`setting, with a median of 8 cycles of DCP and 6 of MPC
`delivered. Except for fatigue and lymphopenia, the inci-
`dence of grade 3/4 toxicity was the same or lower than seen
`in the TAX 327 study (1). Grade 3/4 lymphopenia, in part a
`class effect of ASOs, was seen in approximately one third of
`patients, with no clinical sequelae. Grade 3/4 neutropenia
`was documented in 10% of patients on the DPC arm and
`18% on the MPC arm. There was no grade 3/4 neuropathy.
`Although overall AEs, grade 3/4 AEs, and SAEs did not
`differ substantially between arms, 2 patients on the MCP
`arm had febrile neutropenia, 1 died with pneumonia/
`septic shock, and another with cardiomyopathy. This
`may suggest a better safety profile of custirsen in combina-
`tion with docetaxel retreatment.
`Relief of bone pain is important in patients with mCRPC.
`Although studies have assessed pain response in the first-
`line setting (30, 31), information about pain response in
`the second-line setting is limited. In this study, 26 patients
`were evaluable for pain response. Sixteen (62%) experi-
`enced pain relief, with 88% having a durable response of 3
`or more months.
`It is difficult to put the median survival of 15.8 months
`for docetaxel retreatment (21.4 months for patients who
`progressed after discontinuing first-line docetaxel) into
`perspective based on available literature. Although PSA
`responses have been reported (32), reporting of survival
`from the start of second-line therapy is uncommon. In one
`retrospective study, 25 patients were retreated with doce-
`taxel following a PSA response of 30% or more and a
`median treatment interval of 12 months (33). The median
`OS from second-line docetaxel was 9.6 months. In a recent
`letter to the editor, Buonerba and colleagues discussed the
`need for prospective survival studies rechallenging patients
`with docetaxel after response to first-line docetaxel (34).
`Preliminary data were presented on a prospective study that
`enrolled patients who responded and progressed at least
`5 months after discontinuation of first-line docetaxel ther-
`apy. The median survival was 13 months. The size of the
`study was not stated.
`Recently, cabazitaxel was approved by the U.S. Food and
`Drug Administration in combination with prednisone for
`second-line treatment in patients previously treated with a
`docetaxel regimen based on a survival of 15.1 months
`compared with 12.7 months for patients randomized to
`mitoxantrone (HR, 0.72; ref. 35). The pain response rate was
`9%. The reported grade 3 or higher neutropenia rate follow-
`ing cabazitaxel treatment was 82%. Our data with docetaxel
`retreatment plus custirsen are from a similar but smaller
`population and compare favorably with cabazitaxel data.
`Our results are also consistent with a recently published
`randomized phase II study of first-line docetaxel and pre-
`dnisone, with or without custirsen, in patients with mCRPC
`(36). Median survival was longer with the addition of
`custirsen (23.5 vs. 16.9 months), with a HR of 0.49.
`Increased chemotherapy-induced cancer
`cell death
`resulting from custirsen treatment, with lowering of CLU
`
`Median baseline clusterin = 53.5 µg/mL
`Low: n = 20, median = 14.