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© 2003 American Society for Clinical Oncology Phase II Trial of Carboxyamidotriazole in Patients With Relapsed Epithelial Ovarian CancerFrom the Medical Oncology Clinical Research Unit, Medical Ovarian Cancer Clinic and Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD. Address reprint requests to Elise C. Kohn, MD, 10 Center Dr, MSC 1500, Bethesda, MD 20892-1500; e-mail: kohne{at}mail.nih.gov.
Purpose: Carboxyamidotriazole (CAI) is a cytostatic inhibitor of nonvoltage-operated calcium channels and calcium channel–mediated signaling pathways. It inhibits angiogenesis, tumor growth, invasion, and metastasis. We hypothesized that CAI would promote disease stabilization lasting  6 months in patients with relapsed ovarian cancer.
Patients and Methods: Patients with epithelial ovarian cancer, good end-organ function, measurable disease, and three or fewer prior regimens were eligible. Oral CAI was given daily using a pharmacokinetic-dosing approach to maintain plasma concentrations between 2 and 4 µg/mL. Radiographic imaging to assess response was performed every 8 weeks. Positive outcome included stabilization or improvement of disease lasting
Results: Thirty-six patients were assessable for primary end point analysis, and 38 were assessable for toxicity. Forty-four percent of patients had three prior regimens, more than 50% had four or more disease sites, and 48% had liver metastases. Thirty-three patients reached the targeted concentration range during the first cycle. Eleven patients (31%) attained the Conclusion: CAI is a potential agent for additional study in the stabilization of relapsed ovarian cancer. Given a limited toxicity profile, it may have utility as a maintenance therapeutic agent for this disease.
OVARIAN CANCER is the leading cause of death from gynecologic malignancies in the United States, with 14,300 expected deaths in 2003.1 Despite aggressive cytoreduction and platinum-based chemotherapy, 50% of advanced-stage patients will relapse and die within 5 years. Patients who are refractory to front-line therapy or who develop recurrence within the first 6 months have the worst prognosis.2–4 We reviewed phase II/III studies of treatment for relapsed or persistent ovarian cancer published between 1988 and 1997 (n = 140) including a variety of cytotoxic chemotherapeutic agents such as paclitaxel, topotecan, gemcitabine, and etoposide.5 A response frequency of 0% to 89% was observed, with 42% of patients achieving disease stabilization. The mean progression-free survival (PFS) time was 3.5 months (n = 98 reporting; 95% CI, 3.1 to 4.2 months). A statistically significant but not clinically meaningful improvement of 6 days per year in overall survival and PFS occurred over the 20-year period (P < .01). The limited benefit of cytotoxics, combined with their multisystem toxicity profiles, suggests that new therapeutic paradigms are needed. Cytostatic treatments have more limited toxicity profiles and some have resulted in time to progression equivalent to cytotoxic therapy.4,6–8 CAI, a synthetic carboxyamidotriazole, was the first oral signal-transduction inhibitor tested.9–12 It inhibits proliferation, invasion and metastasis, and neovascularization both in vitro and in vivo.13–22 It inhibits transmembrane calcium influx in nonexcitable cells, such as endothelial cells and carcinoma cells.15,18,21–23 Calcium homeostasis and calcium-regulated cellular events are important in the generation and maintenance of a malignant phenotype, including angiogenesis.15,16,19,24–30 This is supported by CAI’s inhibition of endothelial-cell basic fibroblast growth factor signaling, matrix metalloproteinase (MMP)-2 production, proliferation, and motility.17 The pro-angiogenic cytokines, vascular endothelial growth factor (VEGF) and interleukin (IL)-8, both elicit a calcium response and require cytosolic calcium for their expression.24,26,27,30–33 CAI reduces production of VEGF and IL-8 from tumor and endothelial cells and may be a marker of activity of the local microenvironment.24,26,34–36 Phase I evaluation of CAI in three different oral formulations demonstrated disease stabilization, as defined by lack of disease progression in existing or new sites lasting at least 2 months, in over 40% of patients (median, 3 months).9–12 Disease stabilization lasting 5 to 7 months was observed in patients with ovarian and breast cancer, cholangiocarcinoma, and melanoma, with shorter periods of stabilization in colorectal, lung, and pancreatic cancers. The most common side effects were mild nausea and vomiting (24% in gelatin capsule and liquid formulations); dose-limiting toxicity was cerebellar ataxia with the gelatin capsule formulation and rapidly reversible cerebellar ataxia and confusion with micronized CAI.9–11 A target serum concentration of 2 to 4 µg/mL (4 to 10 µmol/L) and a starting dose of 250 mg/m2 each morning were recommended for phase II studies.10 The aim of the current study was to demonstrate the ability of CAI to promote disease stabilization lasting 6 months or longer in patients with relapsed ovarian cancer.
Eligibility This study was approved by the Institutional Review Board of the National Cancer Institute (NCI; Bethesda, MD). Eligible patients had persistent or recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancers, an Eastern Cooperative Oncology Group performance status of 0 to 2, a life expectancy of 4 months, three or fewer prior treatment regimens, and good end-organ function (hemoglobin > 9 g/dL, absolute granulocyte count 1,000/µL, and platelet count 100,000/mL, hepatic transaminases within 3x the upper limit of normal, and normal total bilirubin). Measurable disease by physical examination, noninvasive radiographic imaging, or surgical evaluation was required. No chemotherapy or radiation therapy were allowed within 4 weeks (6 weeks for carboplatin or mitomycin), and clinical toxicities recovered to grade 1 or better before study entry. Patients had to be more than 18 years of age and able to give informed consent. Patients with brain metastases, cardiac dysrhythmias requiring treatment, infection, a history of acute visual loss, prior invasive cancer, or concomitant use of medications with a potential interaction with CAI were ineligible (antiretroviral therapy and agents that interact with cytochrome P450 IIIA4, listed by appendix in the protocol). All eligible patients referred for the study who elected to participate were entered. Patients with rapidly progressing disease with potential for an imminent medical catastrophe (eg, bowel obstruction) were counseled to consider cytotoxic chemotherapy.
Pretreatment Evaluation
Drug Administration and Pharmacokinetic Analysis Blood samples were collected into heparin tubes at day 1 before treatment and at 2, 8, 14, 24, 72, 120, and 168 hours after the first dose and at each clinic visit. On day 14 and subsequent reassessments for dose modifications, samples were collected before CAI dose and at 3, 6, and 8 hours after dose. Plasma was collected, aliquoted, and stored at -80°C until analysis. The CAI concentration was determined using a high-performance liquid chromatography assay with a lower limit of quantitation of 0.02 µg/mL.38 The pharmacokinetic data were analyzed using ADAPT II version 4 (Biomedical Stimulation Resource, University of Southern California, Los Angeles, CA) using the maximum a posteriori Bayesian estimator.39 A one-compartment open linear model was fit to the data. Pharmacokinetic parameters and variances reported in previously published phase I and II studies of CAI were used as Bayesian prior estimates: apparent volume of distribution 390.5 ± 335.3 L, absorption rate constant 0.210 ± 0.154 h-1, and elimination rate constant 0.0281 ± 0.0527 h-1.9,10,37,38,40 The maximum observed plasma concentration for CAI was reported from direct observation of the data.
Dose Modification
Evaluation During Therapy
Statistical Analysis
Clinicolaboratory Correlates
Patients Thirty-nine patients were enrolled onto the study (Table 1  ). Two patients are not assessable for response or the 6-month outcome evaluation, one for withdrawal for nystagmus (grade 1) during cycle 1 and the other for small bowel obstruction on day 3 of treatment; this latter patient is not assessable for toxicity. One patient is not yet assessable for primary outcome analysis (stable disease at 3+ months) but is included in the PFS analysis. All patients had recurrent ovarian cancer at the initiation of CAI treatment, and 44% had received the maximum allowable three prior treatment regimens. More than 50% of the patients had four or more sites of disease at enrollment where multiple lesions within a site were counted only once, including 48% with parenchymal liver metastases. The majority of patients had papillary serous histology (82%) and grade 3 disease (72%). Twenty-nine patients (74%) had platinum-sensitive disease according to the criteria of Markman et al.2
Pharmacokinetic-Directed Dose Administration Prior pharmacokinetic analysis from phase I studies revealed variable intra- and interpatient bioavailability with the micronized formulation.9–12,37,40 Thus, a pharmacokinetic-directed dosing approach was used. The initial pharmacokinetic assessment obtained at the starting dose of 250 mg/m2/d was used to direct dose modifications to target a plasma concentration of 2 to 4 µg/mL. Eleven patients (31%) required a dose increase, and five required a decrease (14%; Tables 2 and 3), with 33 of 39 patients reaching the targeted concentration range. The observed pharmacokinetic parameters do not differ from those previously described (Table 4).9–12,37,40 Two patients had low CAI concentrations despite dose adjustments (maximum observed plasma concentration: 0.59 and 0.78 µg/mL). Both patients had progressive disease at 2 months.
Outcome A positive outcome for the study was defined as stable or improved disease lasting 6 months or longer. All patients except one had measurable disease on-study, and tumor was evaluated according to criteria as described. The one patient with disease measurable by laparoscopy at study entry had progression by noninvasive imaging at 4 months. Eleven (31%) of 36 assessable patients attained a positive disease outcome (Table 5 ). One patient with stable disease had platinum-resistant disease; the other patients with a positive outcome had platinum-sensitive disease. There was no correlation between the number of prior regimens and outcome. Patients with measurable disease reduction had a benefit lasting 8 months (partial response), and 8, 12+, and 13 months (minor responses). The partial response occurred in a patient who was receiving CAI at first relapse, and the minor responses occurred in patients with one (n = 2) and a patient with three (n = 3) prior regimens. All four patients had greater than three sites of parenchymal disease at enrollment. The median potential follow-up time was 34.2 months, and the median time to progression was 3.6 months (range, 1.6 to 13.3 months; Fig 1). Four of 37 assessable patients had their follow-up censored for progression (two were off-study before progression, and two were without evidence of progression at 3+ and 12+ months). Two patients elected to discontinue drug; one patient did not wish to continue traveling to NCI, whereas the other patient, who had stable disease, elected to discontinue treatment because of side effects (grade 1 nausea and anorexia, grade 2 fatigue).
Adverse Events Treatment with CAI was tolerated by all patients (Table 6 ). Adverse events were mostly grade 1 and 2, with fatigue, nausea, depression, headache, and constipation being the most common toxicities. Thirteen patients (38%) used antiemetics. One patient withdrew with grade 1 end-gaze nystagmus that occurred during cycle 1. This patient had an esotropia with a normal baseline retinal exam. She developed rotary nystagmus with upwards gaze and superior lateral bilateral field cuts on cycle 1, day 20. Neurologic examination revealed mild dysmetria, and ophthalmologic examination was normal. A head magnetic resonance imaging scan revealed a 3-mm left frontal lobe lesion not thought to be contributory. The clinical attribution was grade 2 vestibular dizziness with grade 1 nystagmus. CAI was held until symptoms resolved and was restarted at a 50% dose reduction on day 23. Nystagmus did not recur; however, the patient developed recurrent dizziness and elected to discontinue therapy. Her CAI plasma concentration did not exceed 4 µg/mL. There were five grade 3 adverse events (13%), fatigue in two patients (5%), vomiting in one patient (2%), neutropenic fever without documented infection in one patient (2%), and transient neutropenia that resolved while on CAI in one patient (2%). The patient with neutropenic fever had a 50% reduction in dose. Another patient had grade 2 fatigue and depression with a CAI concentration above 4 µg/mL. These side effects did not recur after dose modification, and the patient had stable disease lasting 10 months. There were no grade 4 adverse events or treatment-related fatalities. Adverse events occurring during the first cycle were explored further. Table 7 shows that these events generally resolved within the first cycle in a tachyphylactic fashion but may have recurred as ongoing events later during drug administration.
Clinicolaboratory Correlates Serial samples were analyzed for VEGF, IL-8, and MMP-2 concentrations. Fig 2 shows results from seven randomly selected patients. No correlation was observed between plasma concentrations of the putative surrogates and clinical behavior for the cohort as a whole. There were individual patients for whom a parallel trend was seen between clinical outcome and VEGF and IL-8 concentrations. A recommendation for the use of these markers as potential surrogates for CAI activity cannot be made. Serum CA125 level concentrations were measured at each visit but not used to evaluate clinical outcome. Preliminary data using cultured ovarian cancer cells suggest that CAI may have a role in inducing CA125 secretion into the culture medium (Kohn and Kulpa Oliver, unpublished observations). A trend was seen in which patients with prolonged stabilization of disease had a slower overall rate of rise or a plateau in CA125 concentration, followed by a subsequent increase at the time of progression (Fig 3).
Ovarian cancer is a deadly disease for women with relapsed or persistent disease. The choice of second- and later-line agents is often limited by patient intolerance and persistent end-organ toxicity. Thus, patients treated with back-to-back regimens of cytotoxic chemotherapy may have an adverse benefit/risk ratio because of the short average time to progression of 3 to 5 months, coupled with accumulating clinical toxicity. Therefore, there is a need for new approaches that may provide clinical benefit with fewer side effects. This led to the investigation of a novel class of biologic cytostatic agents with a relatively low toxicity profile that may be used to stabilize disease for a respite from chemotherapy or to maintain an optimal therapeutic response or remission. The use of these agents could, therefore, permit recovery from end-organ toxicity and allow patients to maintain or improve general patient function.
CAI is a prototype antisignaling agent. Its molecular target is intracellular calcium homeostasis, which is important in angiogenesis, invasion, and metastasis.15–17,19,21,22,24,26,43 CAI effects are reversible on removal and cytostatic in vitro and in xenograft models.14–17 Given encouraging data from phase I studies, we hypothesized that CAI would stabilize disease for 6 months or longer in patients with relapsed epithelial ovarian cancer. This end point was chosen after analysis of treatment of this cohort indicating that, even with clinical response, the time to progression with cytotoxic chemotherapy is short.5 Disease stabilization in a cohort where progression had been occurring could be beneficial to patients, even if short-lived. A holiday from cytotoxic chemotherapy by prolonging treatment response or stabilizing disease can permit recovery from toxicity. We observed 11 of 36 patients attain a positive outcome as prospectively defined by the trial ( We used a pharmacokinetic dose-monitoring approach to maintain CAI at a targeted plasma concentration of 2 to 4 µg/mL, equivalent to the in vitro and xenograft-active and clinically attainable concentrations of approximately 5 to 10 µmol/L.14,15,17 The lower limit of the range was based on CAI concentrations reported to have in vitro activity, and the upper limit was selected based on phase I clinical toxicity data9,10,14,15,40; although no clear pharmacodynamic relationship for toxicity had been identified.10,11 The mean maintenance dose was 433 mg/d, yielding an average plasma concentration of 2.40 µg/mL. This confirms, by prospective analysis, the daily dose regimen of 400 mg/d (fasting) that was previously proposed.10 The lack of relationship between dose and outcome suggests that modifications can be made based on clinical dose-limiting toxicity (cerebellar ataxia or neuropathy) or persistent adverse effects (mild nausea and fatigue) in the small percentage of patients with symptoms, without the need for pharmacokinetic monitoring. The relatively slow activity of molecular-targeted agents in general and their single-agent cytostatic activity has made it important to attempt to identify reliable, reproducible, and accurate surrogate markers of outcome and biologic activity. Little success has been observed to date for CAI and most other agents. The in vitro and xenograft activity of CAI to regulate production and secretion of VEGF, IL-8, and MMP-2 suggest that these were reasonable candidates to evaluate. No consistent relationship was observed between these potential surrogates and the attainment of a positive outcome; this may represent a lack of utility of these as surrogates of CAI activity or indicate that compensatory homeostatic mechanisms have entered the biochemical picture. There were patients for whom a trend of one or more markers mirrored the clinical picture; however, neither these markers nor CA125 reliably indicated the status of disease as assessed by physical examination and serial computed tomography scans. This negates their use as surrogates of activity of CAI. Newer technologies are available with which to evaluate changes in multiple signaling pathways in blood and tissue.44,45 These allow maximal information assessment from the limited patient sample resources available and may provide more opportunities to dissect potential molecular-target pathway modulation. We have initiated application of these technologies prospectively in current studies. There is a continuing need to identify well-tolerated approaches to ameliorate ovarian cancer and to prolong quality and quantity of life with the fewest adverse effects. Cytostatic agents are a logical direction to take by which one may flatten the progression curve to delay subsequent clinical recurrence or use between chemotherapy regimens to stabilize disease while chemotherapy toxicity resolves. The 31% 6+-month positive outcome combined with the relatively mild toxicity profile and oral route of administration makes CAI a drug that should be consideration as a treatment option for patients with end-organ toxicity and postchemotherapy fatigue that compromises quality of life and limits subsequent chemotherapeutic interventions. The ability to continue therapy without cumulative toxicity in responding or stable patients is attractive both to patients and health care providers. CAI should be considered for further study in this population for disease or response maintenance. Our results suggest that CAI has some activity in ovarian cancer with modest toxicity, warranting further study.
The authors indicated no potential conflicts of interest.
We thank Marianne Noone, Dr Nehal Lakhani, and Dr Lance A. Liotta for their participation and guidance in this trial, Dr James Pluda for helpful comments, and the Clinical Associates of the Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute (Bethesda, MD) for their care and attention to our protocol patients.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
