Ovarian cancer remains the most fatal of the gynecologic malignancies.1 Although more than 70% of women treated with a combination of aggressive debulking surgery and platinum/taxane-based chemotherapy are placed into remission, most will go on to develop recurrence and die of drug-resistant disease. It has been shown that women with platinum-free intervals over 6 to 12 months after their first exposure to platinum-based chemotherapy (platinum sensitive) are likely to achieve a significant benefit from re-treatment with platinum combinations such as when carboplatin is combined with paclitaxel, gemcitabine, or pegylated liposomal doxorubicin.2–4 Unfortunately, the same has not been shown in women with a platinum-free interval between 0 and 6 months (platinum resistant). For example, a Gynecologic Oncology Group (GOG) study evaluating cisplatin and gemcitabine in this group of women showed a 16% response rate with an overall survival of 14.9 + months.5 These data exemplify the urgent need to find novel therapy for recurrent ovarian cancer.
Histones constitute a major protein in chromatin and assist in DNA packaging and assembly of nucleosomes and are important regulators of gene expression.6 The histone tail domain is a target of enzymatic modification, including phosphorylation and acetylation, which are associated with transcriptional activities, and deacetylation, which results in transcriptional repression. Acetylation and deacetylation is controlled by histone acetyltransferases and histone deacetylases (HDAC). Epigenetic modulation, for example, changes in acetylation levels of histone and nonhistone proteins can potentially interfere with resistance mechanisms of standard chemotherapy agents like carboplatin and enhance activity of such agents.6
Belinostat (Bel, PXD101) is a low–molecular weight class I and class II HDAC inhibitor of the hydroxamate class, which alters acetylation levels of histone and nonhistone proteins, rendering it a potentially important player in the epigenetic regulation of gene expression.7 Histone deacetylase inhibitors induce the expression of many genes, some of which are involved in cell cycle arrest and tumor suppression. Combined with carboplatin, belinostat showed enhanced growth inhibitory activity over monotherapy in both platinum-sensitive and platinum-resistant ovarian specimens grown in 3-dimensional organoid culture and in the mouse A2780 tumor xenograft model.7 Furthermore, synergy was noted in the cisplatin-resistant ovarian cell line A2780/cp70 when belinostat was combined with cisplatin.7
The combination of belinostat with carboplatin and paclitaxel (BelCaP) was evaluated in a phase 1 study for patients with solid tumors.8 No dose-limiting toxicities were observed during dose escalation. Evaluation showed that belinostat in combination with paclitaxel and carboplatin showed similar pharmacokinetic characteristics to that observed with belinostat monotherapy. In addition, belinostat did not alter excretion of paclitaxel or carboplatin. This study showed that treatment with all 3 agents was feasible and the recommended phase 2 dose was set at belinostat, 1000 mg/m2, on days 1 to 5, with carboplatin AUC 5 and paclitaxel, 175 mg/m2, on day 3, given every 3 weeks. In phase 1, 23 patients were treated with a median of 4 cycles (range, 1–32), including 10 patients completing 6 or more cycles. Two of 20 patients had a partial response, and an additional 11 patients had stable disease for 2 to 28+ cycles. The median treatment duration was 116 days (range, 43–592 days).
After completion of the phase 1 study, further investigation was planned to explore this combination in 2 independent phase 2 expansions: one in patients with recurrent ovarian carcinoma and the other in patients with recurrent urothelial (transitional cell) carcinoma of the bladder. Here, we report the exploratory phase 2 results of BelCaP in recurrent ovarian cancer.
MATERIALS AND METHODS
Patient’s eligibility was defined by the following criteria: (1) the signing of an institutional review board–approved consent form; (2) documented epithelial ovarian, primary peritoneal, fallopian tube, or mixed mullerian tumor of ovarian origin; (3) Eastern Cooperative Group (ECOG) performance status of 2 or less; (4) life expectancy of at least 3 months; (5) age 18 years or older; (6) acceptable liver, renal, and bone marrow functions defined as follows: bilirubin 1.5 times or less the upper limit of normal (ULN); serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), and alkaline phosphatase 3 times or less the ULN (if liver metastases are present, then ≤5 × ULN is allowed); measured EDTA renal clearance 45 mL/min or greater (EU sites) or calculated creatinine clearance 45 mL/min or greater using the Jeliffe formula (US sites); leukocytes greater than 2.5 × 109/L, neutrophils greater than 1.0 × 109/L, platelets greater than 100 × 109/L; hemoglobin greater than 9.0 g/dL; acceptable coagulation status: PT-INR/PTT 1.5 × ULN or less or in the therapeutic range if on anticoagulation therapy; negative pregnancy test for women of childbearing potential, with the use of effective contraceptive methods during the study required; serum potassium within reference range; and at least one unidimensional measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria.
Patients were excluded if they (1) received treatment with investigational agents within the last 4 weeks; had prior anticancer therapy within the last 3 weeks of trial dosing including chemotherapy, radiotherapy, endocrine therapy, or immunotherapy; (2) had a coexisting active infection or any coexisting medical condition likely to interfere with trial procedures; (3) had a history of significant cardiovascular disease (New York Heart Association class III or IV cardiac disease), myocardial infarction within the past 6 months, unstable angina, congestive heart failure requiring therapy, unstable arrhythmia or a need for antiarrhythmic therapy, evidence of ischemia on electrocardiogram, marked baseline prolongation of QT/QTc interval, or required use of concomitant medication that may cause Torsade de Pointes); (4) had an altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies; (5) had a history of a concurrent second malignancy; (6) had a history of hypersensitivity to either platinum or paclitaxel for which desensitization was not an option; (7) had more than 3 prior lines of chemotherapy given for metastatic disease; (8) had a bowel obstruction or impending bowel obstruction; (9) had any existing grade 2 or higher drug-related neurotoxicity due to prior treatment; or had a mixed mullerian tumor of intrauterine origin.
Belinostat, 1000 mg/m2, was administered as a 30-minute intravenous infusion every 24 hours (± 2 hours) for 5 days every 3 weeks. Carboplatin AUC, 5, and paclitaxel, 175 mg/m2, was administered 2 to 3 hours after the infusion of Bel on cycle day 3. All patients were planned to receive at least 2 cycles of therapy.
Patients were required to have measurable disease for participation in this study, and the RECIST 1.0 criteria were used.9 Formal radiological evaluation was performed after every 2 cycles. If a response was noted, a follow-up radiographic assessment was required within 4 weeks (+1 week) after the response was noted.
Tumor markers alone were not used to assess response. However, if markers were initially higher than the upper normal limit, normalization was required for a patient to be considered in complete clinical response.
CA-125 results were judged according to Gynecologic Cancer Inter Group CA-125 response criteria.10 If there was at least a 50% reduction in CA-125 levels from a pretreatment sample, the patient was considered a responder provided the response was confirmed and maintained for at least 28 days. Progression was determined by a doubling of CA-125 from a patient’s nadir value (or the upper limit of normal).
Any patient having received any amount of the study drug was evaluable for safety. Toxicity evaluations were required at baseline and throughout the study, terminating 4 weeks after the last infusion of the study drug, unless the patient started a new anticancer regimen.
The intensity of the adverse event was graded using National Cancer Institute’s Common Toxicity Criteria version 3.0. Patients with an adverse event were followed until return to baseline or grade 1 or less or until the patients started another type of antineoplastic therapy.
This was an exploratory single-arm phase 2 expansion cohort restricted to women with ovarian, primary peritoneal, or fallopian tube carcinomas and used a 2-stage Simon design.11 Eighteen patients were to be enrolled in Simon stage I. If no response was observed, the treatment was to be terminated. If at least 1 objective response was observed, the second stage would accrue an additional 14 patients. If 4 or more responses of a total of 32 patients were observed, the treatment would be deemed to be worthy of further development. Given that the GOG uses a response rate threshold of 15% to define “clinically interesting” in its trials in recurrent ovarian cancer, and given the expected heterogeneity of the patients enrolled on the study (which was not specifically opened to only platinum-resistant or to platinum-sensitive patients), an overall response rate of 20% or higher would be considered clinically significant, whereas an overall response rate (ORR) of less than 5% would not be of clinical interest for further study. As designed, the expansion phase 2 design had a power of 90% with a type 1 error of 10%.
Thirty-five patients were enrolled in this trial between January 2007 and November 2007, and demographics are summarized in Table 1. Participants had a median age of 60 years (range, 39–80 years). Thirty-one patients (88%) were white, 3 patients (9%) were African American, and 1 patient (3%) was Hispanic. All patients had an Eastern Cooperative Group performance status of 0 to 1 and were heavily pretreated with a median of 3 prior regimens received (range, 1–4 regimens). All were treated with platinum and taxanes, with 19 patients (54%) having received 2 or more prior platinum-based regimens. The treatment-free interval (from most recent nonprotocol therapy) was 1.8 months (range, 0.3–38.3 months). When characterized by the time to relapse after upfront treatment, 16 patients (46%) had primary platinum-resistant (Pt-R) disease, and 19 patients (54%) had primary platinum-sensitive (Pt-S) disease. Characterized by their last platinum exposure, 22 patients (63%) progressed within 6 months and were Pt-R, whereas 13 patients (37%) progressed 6 months or longer after platinum treatment (Pt-S).
The patients received a median of 6 cycles of treatment (range, 1–23). Three patients had a completed response, and 12 patients had a partial response, for a RECIST 1.0 overall response rate (ORR) of 43% (15/35). Including CA-125 responders (as defined by Gynecologic Cancer Intergroup criteria), the ORR was 54.2% (19/35). Stratified by primary platinum status, the ORR (CA-125 + RECIST) was 44% for those with Pt-R disease and 63% for those with Pt-S disease. If analyzed by the last platinum treatment received, the ORR was 41% and 77%, respectively (Tables 2A–B).
The response data by measurable disease and by CA-125 represented in a waterfall plot characterized by sensitivity to primary and last platinum exposure platinum is in the supplementary attachment (see Supplemental Digital Content 1, http://links.lww.com/IGC/A99).
Eleven patients (31%) discontinued treatment before the completion of 6 cycles. Reasons for early discontinuation were disease progression (5), adverse events (4), and patient request (1). Eight patients (23%) required a dose reduction of belinostat, whereas dose reduction for carboplatin or paclitaxel was required in 7 (20.6%) and 14 (41%), respectively.
Tables 3 and 4 give the hematologic and nonhematologic adverse events experienced by 10% or more of the patients treated. Serious (grade 3/4) toxicity was limited to neutropenia (20%), fatigue (17%), and aspartate aminotransferase or alanine aminotransferase elevation (14% of each), which were managed with dose modifications (delay or reduction). The most frequent drug-related adverse events of any grade were nausea (83%), fatigue (74%), vomiting (63%), diarrhea (37%), alopecia (37%), dysgeusia (31%), thrombocytopenia (31%), anemia (29%), neutropenia (26%), sensory neuropathy (26%), constipation (26%), headache (23%), and dizziness, leukopenia, myalgia, flushing, and transaminitis, all 20%. Two women (9%) experienced a serious drug hypersensitivity reaction on protocol, which reoccurred in one of one of the patients. Of note, these patients were treated according to institutional guidelines. Notably, there were no episodes of febrile neutropenia.
With a median follow-up of 5.4 months (range, 0–29.8 months), median time to progression (TTP) was 5.8 months (95% confidence interval [CI], 5.4–7). When stratified by primary platinum status, the TTP was 6.5 months (95% CI, 2.6–8.2) in the patients with Pt-R disease and 5.6 months (95% CI, 2.9–7.0) in the patients with Pt-S disease. Six-month progression-free survival (PFS6) was 48% (95% CI, 31%–66%). Broken down by primary platinum-status, PFS6 was 57% (95% CI, 31%–83%) in the patients with Pt-R disease and 42% (95% CI, 20%–42%) in the patients with Pt-S disease.
When the data were analyzed according to the platinum status after the last exposure to a platinum salt, the median TTP and PFS6 for the patients with Pt-R disease was 5.7 months (95% CI, 2.9–6.8) and 40% (95% CI, 19%–61%); for the patients with Pt-S disease, it was 7.0 months (95% CI, 2.6–9.7) and 62% (95% CI, 35%–88%) (Tables 2A–B). For the entire group, the median overall survival at the time of database lock (April 2009) was not reached (95% CI, 10.6, NR).
Histones play an integral role in the storage of DNA and enable the tight regulation of genetic transcription.12 This mechanism of genetic regulation is felt to play an important role in tumorigenesis and propagation and represents the most prevalent modulator of cancer initiation and metastases.13 The family of histone deacetylators (HDs) constitutes 18 isoenzymes, which structurally can be classified into 4 classes.14 Class I HDAC was found to be expressed in high levels of ovarian carcinoma nuclei in a recent study by Weichert et al,14 with more than 50% of mucinous, serous, or clear cell carcinomas affected. Coupled with preclinical data demonstrating that HDAC inhibitors increase the activity of both platinums and taxanes, these agents are worthy of further study in ovarian carcinoma.
In this study, the addition of belinostat to carboplatin and paclitaxel produced a response rate of 43% among women with previously treated disease, with a time to progression of almost 6 months. The median duration of overall survival was not reached during follow-up. Of the toxicities experienced, there was more grade 1 to grade 3 nausea (83%) and vomiting (63%) experienced with the 3-drug combination than what has been reported with conventional paclitaxel and platinum therapy, although the degree of hematologic toxicity was similar to that reported in the International Collaboration on Ovarian Neoplasms IV Trial (ICON-4), which compared platinum-paclitaxel to conventional platinum-based chemotherapy.2 Interestingly, there was a lack of hematologic toxicity and no episodes of febrile neutropenia reported. This is consistent with the prior experience using belinostat alone and in combination with cytotoxics, which has been hematologically well tolerated.8
The results are encouraging and seem consistent with contemporary phase 2 evaluations that enrolled both patients with Pt-S disease and those with Pt-R disease, which have usually reported a range of response rates between 20% and 67% (Table 5).15–20 Results must, however, be treated as hypothesis generating only owing to a small sample size, a heterogeneous population with regard to prior platinum therapy, and a single-arm design without a comparator arm. Full evaluation of the added benefit of belinostat to carboplatin and paclitaxel is not feasible in the absence of an active comparator arm. In addition, the contribution of prior intervening nonplatinum therapy may have influenced response rates in our patients. Whereas no phase 3 trials have evaluated the concept of restored platinum sensitivity with intervening treatment, retrospective studies differ widely in the estimation of effect of nonplatinum therapy on restoring platinum responsiveness.21–23 As an example, Leitao et al24 also addressed this question with data from Memorial Sloan-Kettering, demonstrating the heterogeneity of women deemed platinum resistant and suggested that those who had responded to prior platinum therapy and those who had received no more than 3 intervening lines of therapy were likely to respond to retreatment despite having met criteria for Pt-R disease.
Belinostat has been evaluated as a single agent in ovarian cancer with little activity seen. In a phase 2 trial conducted by the Princess Margaret Phase II consortium, 32 patients with Pt-R epithelial ovarian cancer (n = 18) or micropapillary low–malignant potential (LMP) tumors were given belinostat, 1000 mg/m2, as a 5-day infusion every 21 days.26 There were no responses recorded among the patients with epithelial ovarian cancer, and PFS was only 2.3 months. In addition, the GOG recently terminated a phase 2 of belinostat and carboplatin in women with Pt-R ovarian cancer after the first stage owing to a lack of responses.27
Although disappointing, it does not negate the potential activity of the triple-drug combination of BelCaP explored in this study. It demonstrates the need for randomized trials in using specifically defined populations of women with ovarian cancer, stratified by platinum sensitivity. The synergy between carboplatin, paclitaxel, and belinostat has been demonstrated previously in an in vitro model system.7 This preclinical data, coupled with the clinical data from the presented BelCaP study, provide sufficient interest to carry forward further studies in ovarian cancer. As such, further trials using BelCaP should be conducted using specifically defined populations of women with ovarian cancer, stratified by platinum sensitivity. In addition, it would be interesting to test this using weekly paclitaxel as a chemotherapy background in women with Pt-R disease.
The study does not allow firm conclusions regarding survival end points, as the study was solely designed to further investigate the activity of this combination specifically in ovarian cancers to determine whether additional development was warranted and did not have survival as a primary end point. Overall results are cautiously encouraging and could represent a potentially novel epigenetic treatment to the standard chemotherapeutic agents that serve as the backbone of adjuvant treatment in ovarian cancer. At this time, belinostat continues in clinical development in ovarian cancer.
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Ovarian cancer; Chemotherapy; Carboplatin; Histone deacetylase inhibitor; Recurrent disease
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