Annals of Oncology Advance Access published online on September 28, 2007
Annals of Oncology, doi:10.1093/annonc/mdm463
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© 2007 European Society for Medical Oncology
A phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory mantle cell lymphoma
1 Hematology, Hopital C. Huriez Centre Hospitalier Universitaire, Lille, France
2 Hematology, Peter Maccallum Cancer Center, East Melbourne, and University of Melbourne, Australia
3 Hematology, University Medical Center Groningen, University of Groningen, The Netherlands
4 Clinical Hematology and Medical Oncology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
5 Onkologie, Hamatologie, Immunologie, Klinikum Kassel gmbh, Kassel
6 Onkologie, Hematology, Klin Immunologie & Rheumatologie, Universitatskliniken Des Saarlandes, Homburg/Saar, Germany
7 Centre Henri Becquerel, Rouen Cedex, France
8 Hematology, University Medical Centre Nijmegen, Nijmegen
9 Hematology, Erasmus Medisch Centrum, Rotterdam, The Netherlands
10 Hematology, Chru De Nantes Hotel-Dieu, Nantes Cedex
11 Hematology, and Cell Therapy, Chru De Tours Hopital Bretonneau, Tours Cedex, France
12 Med Klinic M.S.Hematologie/Oncologie, Universitatsklinikum Charite Med, Berlin, Germany
13 Hematology and BMT, The Alfred Hospital, Melbourne, Australia
14 Clinical Hematology, Hopital Henri Mondor, Creteil Cedex, France
15 Klinikum Grosshadern der Ludwig-Maximilians-Universitat, Munchen, Germany
* Correspondence to: Dr F. Morschhauser, Lille University Hospital, Rue Michel Polonovski, 59037 Lille, France. Tel: +33-3-20-44-42-90; Fax: +33-3-20-44-47-08; E-mail: f-morschhauser{at}chru-lille.fr
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Abstract |
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Background: Protein kinase C beta (PKCß), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKCß/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis.
Patients and methods: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily.
Results: Sixty patients, median age 66 years (range 45–85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3–5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for 
3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months.
Conclusion: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.
enzastaurin, mantle cell lymphoma, PKCbeta inhibitor
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introduction |
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Mantle cell lymphoma (MCL) represents
4%–6% of all non-Hodgkin's lymphomas (NHL) [1, 2]. Patients usually present with advanced disease, have one of the worst 5-year survival rates (11%) of the major NHL subtypes, and have median overall survival times of 3–4 years [3–5]. MCL is often initially responsive to a variety of chemotherapy regimens, especially more aggressive treatments, with up to 97% response rates, but the responses are frequently of a short duration [5]. Moreover, no therapy currently available is curative [6, 7], and the favorable response rates seen with newer therapies such as rituximab [8] have not translated into an improved long-term outcome [9, 10]. These challenges underscore the need for additional, innovative, molecularly targeted approaches in the treatment of MCL [11]. Protein kinase C beta (PKCß) is the major PKC isoform involved in B-cell receptor signaling [12]. PKCß enhances B-cell proliferation and survival [13, 14] and is also implicated in TGFß/NFkB signal transduction [15–17]. PKCß is an important modulator of the angiogenic activity of vascular endothelial growth factor (VEGF) [18], which may enhance tumor angiogenesis in lymphoid malignancies. Elevated baseline levels of VEGF and increased vascularity are associated with poor prognosis in NHL patients, including those with MCL and diffuse large B-cell lymphoma (DLBCL) [19, 20]. PKCß was found to be overexpressed in fatal, treatment-refractory DLBCL in both gene expression profiling [21] and immunohistochemistry [22] experiments and was found to be associated with shortened survival [22]. Independent immunohistochemical (IHC) studies have shown that PKCß is expressed in 90% of all MCL samples [23]. These data indicate that PKCß is a rational target in MCL since inhibition of PKCß may impact both the microvasculature and tumor cell growth.
Enzastaurin HCl is an acyclic bisindolylmaleimide that was initially developed as an ATP-competitive, selective inhibitor of PKCß [24, 25]. The compound also inhibits signaling through the PI3Kinase/AKT pathway [25], a key regulator of apoptosis [26, 27], also reported to be deregulated in many cases of lymphoid malignancies, including MCL [28, 29]. In vitro preclinical assays show 95% plasma protein binding and an IC90 of 70 nM for PKCß (Upstate kinase profilerTM data) and other PKC isoforms. Based on these data, a plasma concentration of 1400 nM is predicted to be adequate to inhibit most PKC isoforms. In preclinical studies, enzastaurin induced apoptosis and inhibited the proliferation of several cancer cell lines including DLBCL [27, 30] and has demonstrated antiangiogenic, antiproliferative, and proapoptotic effects in xenograft studies and the rat corneal micropocket assay [27, 31]. Based on plasma exposures and safety data from a phase I study, 525 mg of daily, oral enzastaurin was the recommended dose [32]. At this dose, in multiple phase I studies, enzastaurin was generally well tolerated in patients with advanced cancers, both as a single agent and in combination with cytotoxic therapy [32–34]. In a phase II trial in patients with advanced relapsed/refractory DLBCL, enzastaurin showed a favorable toxicity profile and several patients achieved prolonged disease stabilization, including 4 of 55 patients who continued treatment for 2–4 years [35].
Because of the need for novel, effective agents in the treatment of MCL, the role of PKCß and the PI3Kinase/AKT pathway in MCL, and the preclinical and clinical data obtained with enzastaurin, a phase II trial of enzastaurin in MCL was initiated. The primary objective of this study was to estimate the rate of freedom from progression for at least three cycles. Secondary objectives included the evaluation of objective response rate, progression-free survival (PFS) time, overall survival time, safety, immunohistochemistry, and pharmacokinetics.
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eligibility criteria
Adult patients (age
18 years) with a pathologically confirmed diagnosis of MCL who had relapsed/refractory disease were eligible. Patients could not have received more than four prior treatment regimens. Rituximab, used alone, was not considered a separate prior regimen. Other entry criteria included evaluable (blood and bone marrow disease only) or bidimensionally measurable disease; an estimated life expectancy of at least 12 weeks; a performance status of zero to two on the Eastern Cooperative Oncology Group (ECOG) scale; and adequate organ function including total bilirubin 
1.5 x upper limit of normal (ULN), alanine transaminase and aspartate transaminase 2.5 x ULN, and serum creatinine 2.0 x ULN. Patients were excluded if they had known central nervous system or leptomeningeal involvement; human immunodeficiency virus-associated lymphoma; a serious concomitant disorder (such as an active bacterial, fungal, or viral infection); an absolute neutrophil count 0.5 x 109/l and platelets 50 x 109/l; uncorrected potassium <3.4 mmol/l; clinically significant cardiac abnormalities, including myocardial infarction that occurred < 6 months before inclusion, symptomatic angina pectoris, or cardiac failure not controlled by medication; or an inability to swallow tablets. The protocol was approved by the Institutional Review Board of each participating institution. Written informed consent was obtained from each patient before study enrollment. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable laws and regulations.
study design and treatment plan
In this phase II, multicenter, open-label, single-arm study, we planned to enroll up to 60 patients using a two-stage design. Twenty patients were entered in the first stage of the study. If at least three patients were progression free after three cycles, accrual was planned to continue until a total of 60 patients were enrolled. If at least 11 of the 60 enrolled patients were progression free after three cycles, it would be concluded that the regimen is worthy of further study. Patients received 500 mg (100- and 200-mg tablets, equivalent to 525 mg capsules) oral enzastaurin once daily, in the morning, during each 28-day cycle of therapy for a planned treatment duration of up to six treatment cycles. Treatment continued until unacceptable toxicity or progressive disease occurred. No other chemotherapy, immunotherapy, experimental medications, or radiation therapy was permitted while patients were onstudy.
baseline and treatment assessments
Disease status was assessed by physical examination at baseline and before every cycle for palpable or visible lesions and at baseline and after every third cycle for measurable disease using radiological imaging (computed tomography scan of chest, neck, thorax, abdomen, and pelvis). Unilateral bone marrow aspirate and/or biopsy (for patients with a history of bone marrow involvement) and cytology of peripheral blood lymphocytes (for patients with blood involvement) were carried out at baseline and after every third cycle. ECOG performance status and B symptoms (fever >38°C, weight loss >10% of body weight in the preceding 6 months, and night sweats) were assessed at baseline and before every cycle. Serum chemistry and hematology laboratory tests were carried out at baseline and before each cycle. Electrocardiogram was carried out at baseline and in cycles 1 and 2. Prognostic risk factors were classified at baseline using the International Prognostic Index (IPI). Poststudy follow-up included evaluation of performance status, tumor measurements and imaging studies, and poststudy drug treatment.
Response for patients with measurable disease was recorded using standardized response criteria for NHLs [36]. Objective response was defined as complete response (CR) or partial response (PR). Freedom from progression was defined as CR, PR, or stable disease (SD) for 3 cycles. SD was defined as less than partial response, with no findings consistent with progressive disease and no appearance of new lesions. The rate of freedom from progression was computed as the number of patients documented to be progression free after three cycles of enzastaurin divided by the number of treated patients. PFS time was defined as the time from the date of enrollment to the first date of documented disease progression or death due to any cause, whichever occurred first. Overall survival time was defined as the time from the date of enrollment to the date of death due to any cause. CRs or PRs were confirmed with scans carried out at least 4 weeks after the initial response. All enrolled patients were assessed before each cycle for treatment-related toxicity using Common Toxicity Criteria, version 2.0 [37].
pharmacokinetic analysis
Plasma samples for pharmacokinetic evaluation were collected between 1–4 and 4–8 h postdose on day 1 of cycle 1; predose, 2–4 and 6–8 h postdose on day 1 of cycle 2; and predose and 2–8 h postdose on day 1 of cycle 3. Samples were assayed for enzastaurin and its metabolites using high-performance liquid chromatography–tandem mass spectrometry. A population pharmacokinetic approach was used to analyze the sparse plasma concentration versus time data in individual patients. Data from all patients were combined and analyzed using nonlinear mixed effect modeling.
IHC analysis of PKCß expression
Tumor samples at baseline were obtained from patients for IHC staining of PKCß expression. Immunohistochemistry was carried out at Ventana Medical Systems, Inc. (Tucson, AZ), using a mouse monoclonal antibody, specific to the PKCß2 isoform (Sigma, catalog #P2584, clone PK-B26) and a mouse immunoglobulin (VMSI, Catalog No. 760-2014) as negative control [38]. Staining intensity was measured on a semiquantitative scale of 0 (or negative) to 3 (high intensity). The final score combined the components of staining intensity and the percentage of positive cells and was defined as [1 x (percentage of cells staining at 1)] + [2 x (percentage of cells staining at 2)] + [3 x (percentage of cells staining at 3)].
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patient characteristics
Sixty patients were enrolled from March 2004 to August 2005. Table 1 shows the baseline patient characteristics. Thirty-nine (65%) patients were diagnosed with MCL at least 3 years before study enrollment. Central pathology review carried out for confirmation of MCL revealed that one patient had a diagnosis of chronic lymphocytic leukemia. This patient was not included in the survival analyses. Additional pathology data available from 23 patient samples showed that 20 patients had classical morphology and two had the blastic variant. Four patient samples exhibited a high proliferation rate with Ki67
40%.
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study drug administration
All 60 enrolled patients received at least one dose of enzastaurin. There were five dose omissions due to adverse events not related to enzastaurin. Two patients discontinued enzastaurin due to possibly drug-related adverse events (diarrhea and syncope).
clinical toxic effects
All 60 enrolled patients were evaluated for safety. The most common toxic effects observed were fatigue (in five patients, grade 2) and diarrhea (in three patients with grade 1 and one patient with grade 3). Other drug-related toxic effects observed in more than one patient were myalgia, sweating, chromaturia (orange–red color of urine due to the color of the drug tablet), and anorexia (all grade 1). Grade 2 toxic effects were fatigue (in two patients) and thrombocytopenia (in one patient). Grade 3 toxic effects reported were anemia, diarrhea, dyspnea, syncope, hypotension, and vomiting (in one patient each). No enzastaurin-related grade 4 toxicity or death occurred.
efficacy
Of the 60 study patients, 22 [37%, 95% confidence interval (CI) 25% to 49%] were free from progression (FFP) for 3 cycles (2.8 months). Six of the 22 patients were FFP for >6 months, which was similar to the time to new treatment after the previous conventional chemotherapy regimen (Table 2). Two patients were FFP for >23 months. The median PFS time was 2 months (95% CI 1.45–2.66 months) (Figure 1). The median PFS time for the 22 patients who were FFP for 3 cycles was 4.3 months (95% CI 3.29–5.55 months). The median overall survival time in this study was 22 months (range 0.9–23+ months). A comparison of the baseline characteristics of the patients who were FFP for 3 cycles and patients who did not meet the primary end point revealed that the latter group of patients had elevated lactate dehydrogenase (LDH) levels (42% versus 14%) and lesions 5 cm (53% versus 32%) (Table 3).
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No CRs or PRs were observed in this study. One patient, who had relapsed after prior therapy with high-dose cytosine arabinoside, achieved a minor response (a 25%–50% reduction in lesion size).
pharmacokinetics
Pharmacokinetic data were available on 56 patients. In these patients, the average steady-state concentration (Cav,ss) was 627 nmol/l (74.4% coefficient of variation [CV]) for enzastaurin (Table 4). There were no differences in steady-state enzastaurin exposures between patients who met the primary end point (FFP for 3 cycles), all patients, and patients who were FFP for >6 months (Table 4).
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immunohistochemistry
Samples were available from 18 patients for PKCß immunohistochemistry: 14 (78%) samples had a score
100 and a staining intensity 2 (high intensity indicating overexpression) and four samples had a score <100 and a staining intensity 1 (data not shown). Of the 14 patients who had PKCß overexpression, seven patients met the primary end point (FFP for 3 cycles) and seven did not (Table 3). |
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Here we report the results from the first study of the PKCß inhibitor enzastaurin in patients with MCL. Twenty-two of 60 (37%) patients enrolled achieved the primary end point of freedom from progression for
3 cycles. Although overall response rate remains the usual primary end point to evaluate anticancer drugs, other parameters such as freedom from progression are increasingly being used to evaluate new targeted therapeutic agents. These agents, with their novel mechanism of action, have a predominantly inhibitory effect on tumor growth, unlike traditional cytotoxic agents, which cause tumor shrinkage [39]. Given the characteristics of enzastaurin and its typical profile in the class of targeted therapeutics, freedom from progression for 3 cycles was considered a pertinent efficacy end point in this population of patients with relapsed/refractory MCL, whose prognosis is generally poor. In this study, patients had a median age of 66 years, and most patients had high intermediate to high IPI scores at relapse. Patients had relapsed after multiple prior therapies including rituximab and/or high-dose chemotherapy + autologous purged stem-cell transplantation. A few patients might have had indolent disease, but all patients had progressed after prior therapy and required new treatment. The median PFS of 2 months clearly indicates that patients enrolled in this study were candidates for new therapy. Although there was no objective response to enzastaurin, 22 patients had freedom from progression for 3 cycles, six patients were FFP for >6 months and two of these six patients continue to be FFP for >2 years. These data indicate that oral enzastaurin monotherapy has clinical activity in a subgroup of patients with relapsed MCL. These results obtained with enzastaurin monotherapy in patients with MCL are comparable with those in 55 patients with DLBCL, four of whom were FFP for 24–48+ months [35] and are consistent with enzastaurin's activity as a tumor growth inhibitory agent that lacks direct tumor cytotoxicity. Of the patients who were FFP for >6 months, two patients had Ki67 40% and two patients were 80 years of age. Enzastaurin was well tolerated in this study. No grade 4 toxic effects were reported. The majority of patients did not experience any adverse event. There were only six grade 3 toxic effects, each of which occurred in only one patient. Anemia (in one patient) was the only grade 3 hematological toxicity reported. No significant hepatobiliary, cardiac, or severe bone marrow toxicity was observed. The safety profile of enzastaurin indicates that it can be used in a maintenance setting, even in elderly patients who typically have severe toxic effects following aggressive chemotherapy. Interestingly, in addition to the low toxicity, the duration of freedom from progression after enzastaurin in the six patients who were FFP for >6 months was comparable to the time between the last previous conventional chemotherapy regimen and initiation of enzastaurin.
The plasma exposures of enzastaurin in this study were comparable to those obtained with similar doses of enzastaurin in the recently reported phase I trial [32] and in patients with DLBCL. The mean steady-state concentrations for total analytes were >1000 nmol/l, the concentration at which enzastaurin inhibited PKCß and additional PKC isoforms in in vitro kinase screens. This indicates that PKCß inhibition may, at least in part, contribute to enzastaurin activity. Plasma exposures of enzastaurin and total analytes are unlikely to explain the differences observed in the duration of freedom from progression since enzastaurin exposures were not different in the group of patients who achieved long-term freedom from progression (more than six cycles) compared with patients who did not achieve the primary end point of freedom from progression for 3 cycles.
In order to identify patients who are most likely to benefit from enzastaurin treatment, molecular targets and markers predictive of enzastaurin treatment outcome need to be identified. IHC analysis of PKCß expression in a small patient sample indicated that the enzyme was highly expressed in most patients. The fact that we did not observe high PKCß expression in all patients, as was reported in a previous study [25], may be attributed to differences in the antibody used previously [35] and in the quantification of staining intensity. In our study, PKCß overexpression was quantified as a composite of the staining intensity and the number of cells. Due to the small number of tumor samples and the lack of pre-enzastaurin treatment biopsies, it was difficult to draw any conclusions regarding a correlation of PKCß overexpression with either the disease characteristics or survival. Lastly, because PI3K/AKT is also implicated in MCL and since enzastaurin inhibits both PKC and AKT pathways, analysis of downstream proteins, such as phosphorylation of GSK-3ß and S6kinase, in addition to PKC expression, is recommended in future clinical studies to correlate the activation of these enzymes with clinical outcome.
Data obtained from this study indicate that patients with nonbulky disease and normal LDH had SD for the longest duration. Patients who had disease stabilization for >6 months on enzastaurin also had long time to progression on the previous and mainly first-line therapy, which indicates they may belong to the subgroup of indolent MCL [40].
However, all patients had relapsed and were identified as requiring further treatment. Given that the optimal management of relapsed MCL remains quite challenging, with no identified standard of care, it is noteworthy that these patients were FFP on enzastaurin for up to 2 years with minimal toxicity. The favorable toxicity profile and ease of administration further support the use of enzastaurin as maintenance therapy after response to standard treatment and also warrant further evaluation in combination with standard chemotherapy regimens that are the most effective in MCL.
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Eli Lilly and Company
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The authors thank Dr Paula Marlton of Princess Alexandra Hospital, Queensland, Australia, Pauline Huyghe-Lionne of Lille University Hospital, France, and Dr Craig R. Underhill of Border Medical Oncology, Victoria, Australia for clinical trial support and from Eli Lilly and Company, Indianapolis, USA, we thank Dr Donald Thornton for scientific contribution; Philip McNealy, Christelle Darstein, and Yun Ding for statistics; Luna Musib for PK; Eric Powell for immunohistochemistry; Asavari Wagle, Noelle Gasco, and Donna L. Miller for writing, editorial, and technical support. This original report was presented in part at the 48th Annual Meeting of the American Society of Hematology, Orlando, FL, 9–12 December 2006.
Received for publication June 27, 2007. Revision received August 21, 2007. Accepted for publication August 23, 2007.
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