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Clinical Cancer Research Vol. 12, 4882-4887, August 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Clinical

A Phase 1 Study of ABT-751, an Orally Bioavailable Tubulin Inhibitor, Administered Daily for 7 Days Every 21 Days in Pediatric Patients with Solid Tumors

Elizabeth Fox1, John M. Maris2, Brigitte C. Widemann1, Kysa Meek4, Anne Goodwin1, Wendy Goodspeed1, Marie Kromplewski2, Molly E. Fouts3, Diane Medina4, Steve Y. Cho1, Susan L. Cohn3, Andrew Krivoshik4, Anne E. Hagey4, Peter C. Adamson2 and Frank M. Balis1

Authors' Affiliations: 1 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; 2 Children's Hospital of Philadelphia and the University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; 3 Children's Memorial Medical Center, Chicago, Illinois; and 4 Abbott Laboratories, Abbott Park, Illinois

Requests for reprints: Elizabeth Fox, Pediatric Oncology Branch, National Cancer Institute, Room 1-5750, Building 10-CRC, 10 Center Drive, Bethesda, MD 20892. Phone: 301-402-6641; Fax: 301-480-8871; E-mail: foxb{at}mail.nih.gov.


   Abstract
Top
 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: To determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days, repeated every 21 days.

Experimental Design: Patients who were ≤18 years of age, with relapsed or refractory solid tumors, and who were able to swallow capsules were eligible. The starting dose was 100 mg/m2/d (n = 3) and was escalated to 130 mg/m2/d (n = 6), 165 mg/m2/d (n = 6), 200 mg/m2/d (n = 6), and 250 mg/m2/d (n = 2) in cohorts of three to six patients. The maximum tolerated dose was determined from dose-limiting toxicities occurring during the first treatment cycle.

Results: Twenty-four children (median age, 13 years; range, 4-18 years) were enrolled; 23 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 8), sarcomas (n = 8), primary brain tumors (n = 2), Wilms' tumor (n = 2), and other solid tumors (n = 3). Dose-limiting toxicities (grade 3 sensory and motor neuropathy, grade 3 hypertension, and grade 3 fatigue) were observed in patients enrolled at the 250 mg/m2/d dose level. The maximum tolerated dose of ABT-751 administered daily for 7 days every 21 days was 200 mg/m2/d. Non-dose-limiting toxicities at the maximum tolerated dose included anemia, fatigue, peripheral sensory neuropathy, abdominal pain, nausea, constipation, anorexia, fever, and weight loss. Myelosuppression was minimal at the maximum tolerated dose. The median number of cycles administered is 2 (range, 1-50). No significant ABT-751-related cumulative toxicities were observed.

Conclusion: ABT-751 is well tolerated in children. The recommended dose for phase 2 trials in solid tumors is 200 mg/m2/d administered orally, daily for 7 days every 21 days. This dose is >40% higher than the maximum tolerated dose in adults receiving the same dosing schedule.

ABT-751 (Abbott Laboratories, Abbott Park, IL) is an orally bioavailable sulfonamide that binds to the colchicine binding site on ß-tubulin and inhibits polymerization of microtubules (1, 2). ABT-751 had a broad spectrum of antitumor activity in a panel of 30 tumor cell lines in vitro and in xenograft models of human tumors in vivo, including gastric, colorectal, lung, and breast cancer models. ABT-751 is not a substrate for P-glycoprotein and is active against HC-15, a human colon carcinoma model that is resistant to the tubulin inhibitors, paclitaxel and vincristine, due to overexpression of P-glycoprotein (3). By oligonucleotide microarray analysis, ABT-751 exposure down-regulated {alpha}-tubulin transcripts in HC116 human colon carcinoma cells (4, 5). Similar to other agents that bind the colchicine binding site of tubulin, ABT-751 has shown antivascular effects in animal models (6).

More than 450 adults with cancer have been enrolled in clinical trials of ABT-751 and a variety of oral dosing schedules have been studied. Based on pharmacokinetics and tolerability, the daily for 7 days and daily for 21 days schedules have entered phase 2 clinical trials in adults. Reversible peripheral neuropathy, ileus, partial small bowel obstruction, asthenia, increased bilirubin, and hyponatremia were serious ABT-751-related toxicities in adults. Other ABT-751-related adverse events included constipation, anorexia, nausea, pain, abdominal pain, myalgias, diarrhea, and dehydration. No significant myelosuppression or renal toxicity has been reported (7–10). In adults with solid tumors, the maximum tolerated dose of ABT-751 administered orally daily for 7 days every 21 days was 250 mg ({approx}140 mg/m2/d based on body surface area of 1.8 m2). Dose-limiting toxicities were reversible peripheral neuropathy and ileus (9).

We conducted pediatric phase 1 trial of ABT-751 to determine the toxicity profile, dose-limiting toxicities, and maximum tolerated dose of ABT-751 administered orally once daily for 7 days with cycles repeated every 21 days.


   Patients and Methods
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 Abstract
 Patients and Methods
Results
 Discussion
 References
 
Eligibility. Pediatric patients ≤18 years of age with a histologically confirmed solid tumor refractory to standard treatment were eligible for this study. Patients must have recovered from the toxic effects of prior therapy and have a Karnofsky (children >10 years) or Lansky (children ≤10 years) performance score of >50. Patients had to be able to swallow capsules. Patients must have had their last dose of chemotherapy with any standard or investigational agent at least 30 days before study entry, their last dose of limited field radiation therapy at least 4 weeks before study entry, and be off colony stimulating factors for at least 72 hours before study entry. Patients with brain tumors receiving corticosteroids for the control of tumor-associated edema had to be on a stable or decreasing dose for at least 1 week before study enrollment. Patients were required to have an absolute neutrophil count ≥1,500/µL, hemoglobin >8 g/dL, and platelet count ≥100,000/µL; normal left ventricular ejection fraction as measured by echocardiogram; bilirubin ≤1.5 x upper limit of normal; alanine aminotransferase and aspartate aminotransferase ≤2.5 x the upper limit of normal; and an age-adjusted normal serum creatinine or a creatinine clearance ≥60 mL/min/1.73 m2.

Patients currently receiving other investigational chemotherapeutic agents were excluded, as were patients with a history of myeloablative therapy requiring bone marrow or stem cell transplantation within the previous 4 months, pregnant or breast-feeding females, and patients with clinically significant unrelated systemic illness that would compromise the patient's ability to tolerate this therapy or interfere with the study procedures or results. Patients with a history of allergy to sulfa medications were also excluded. Patients with preexisting grade ≥2 sensory or motor neuropathy or with central nervous system tumors with motor or sensory neuropathies that might obscure assessment of ABT-751-related neuropathy were excluded.

This trial was approved by the Institutional Review Board of each participating institution. All patients or their legal guardians signed a document of informed consent indicating their understanding of the investigational nature and the risks of this study.

Treatment regimen and dose escalation. ABT-751 was supplied as 25- and 100-mg capsules by Abbott Laboratories. The drug was administered orally after breakfast daily for 7 days. The starting dose was 100 mg/m2/d. The dose escalation scheme is shown in Table 1 . In phase 1 studies in adults, a fixed dose was administered at each dose level; therefore, a maximum daily dose was established for each dose level in this trial. A dosing nomogram was used to round each dose to the nearest 25 mg. Unless contraindicated, all patients received docusate sodium daily while on study. Treatment cycles were repeated every 21 days once the patient had recovered to grade ≤1 from the ABT-751-related toxicities on the previous cycle.


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  		Table 1. ABT-751 dose escalation scheme and patient enrollment by dose level

 
Cohorts of three to six patients were treated at each ABT-751 dose level. When a minimum of three patients who were evaluable for toxicity completed one cycle of therapy at a dose level without evidence of dose-limiting toxicity, subsequent patients were enrolled at the next higher dose level. No intrapatient dose escalation was permitted.

Toxicity monitoring. Monitoring for treatment-related toxicity included weekly physical examination and serum chemistries as well as twice-weekly complete blood counts. Clinical and laboratory adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 2.5 Given that dose-limiting peripheral neuropathy was observed in adults receiving ABT-751, monitoring for neurotoxicity in pediatric patients on this trial included a standardized complete neurologic exam before each cycle and development of pediatric-specific grading scales for sensory and motor neuropathy (Table 2 ).


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  		Table 2. Grading for sensory and motor neuropathy

 
As part of the standardized neurologic exam, the Purdue Pegboard test (model 3020, Lafayette Instruments, Lafayette, IN)6 and WEST-hand esthesiometry (Connecticut Bioinstruments, Inc., Danbury, CT)7 were used to objectively monitor for neuropathy in the upper extremities. The Purdue Pegboard test was used to assess movements of fingers, hands, and arms by testing the patient's ability to place pins in holes on the pegboard. This test has been validated in a group of 150 children with learning problems, in a group of 46 reading disabled children, and in 1,334 normal school children (ages 5-16 years; ref. 11). The WEST-hand esthesiometer was developed to objectively quantify levels of sensation of applied force to defined areas of the hand. It uses five monofilaments with soft tips, calibrated for applied force. Each patient served as his/her own control, and we compared baseline score results to those obtained after completion of cycle 1 after repeated courses of treatment (if administered) and at the time of the off-study evaluation. Wilcoxon signed rank sum test was used to compare baseline measurements to scores obtained after cycle 1, the worst score at any point during therapy, and off-study scores. P < 0.05 was considered statistically significant.

Definition of dose-limiting toxicity and maximum tolerated dose. Hematologic and nonhematologic dose-limiting toxicities were defined differently. Hematologic dose-limiting toxicity was grade 4 neutropenia (<500/µL) or grade ≥3 thrombocytopenia (<50,000/µL) occurring while receiving drug (days 1-7) or grade 4 neutropenia (<500/µL) of ≥5-day duration or grade 4 thrombocytopenia (<10,000/µL) on ≥2 days of a treatment cycle occurring after completion of the 7 days of drug administration. A platelet transfusion for a platelet count that was <20,000/µL but >10,000/µL was considered to be grade 4 thrombocytopenia. Failure to recover a neutrophil count to ≥1,500/µL or a platelet count to ≥75,000/µL by day 28 of the treatment cycle was also hematologic dose-limiting toxicity. Nonhematologic dose-limiting toxicity was any grade 3 or 4 nonhematologic toxicity related to ABT-751 or failure to recover to grade ≤1 toxicity or to baseline toxicity level (if higher than grade 1) by day 28 of the treatment cycle. Exceptions were grade 3 elevations in alanine aminotransferase or aspartate aminotransferase that recovered to grade ≤1 by day 28 of the treatment cycle and grade 3 nausea or vomiting that was successfully controlled with antiemetics.

The maximum tolerated dose was determined from dose-limiting toxicity occurring during the first treatment cycle. The maximum tolerated dose was the dose level immediately below the dose level at which ≥2 patients in a cohort (dose level) of two to six patients experienced a dose-limiting toxicity. Three patients <12 years old and three patients ≥12 years old were enrolled at the maximum tolerated dose.

Dose modification for toxicity. Patients who experienced an ABT-751-related dose-limiting toxicity were offered a dose reduction to the next lower dose level for their subsequent course of treatment, if in the judgment of the treating physician, they had benefited from the prior treatment cycle of ABT-751. Patients who experienced dose-limiting toxicity after a dose reduction could have a second dose reduction to the next lower dose level, but if dose-limiting toxicity occurred after the second dose reduction, the patient was removed from the study.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Patients. Twenty-four children with recurrent or refractory solid tumors were enrolled at the three participating institutions between May 2002 and July 2004. The patient characteristics are shown in Table 3 . One patient, a 15-year-old with malignant peripheral nerve sheath tumor, enrolled on dose level 1, was not evaluable for toxicity because consent was withdrawn on day 3 of ABT-751 administration due to an unrelated infection without neutropenia. Neuroblastoma (n = 8) and sarcoma (n = 8) were the most common diagnoses. The patients were heavily pretreated with a median number of prior chemotherapy regimens of 4 (range, 1-6). The median number of cycles of ABT-751 administered was 2 (range, 1-50). Two patients with neuroblastoma continue on study after receiving 27 and 41 cycles of ABT-751, as of July 1, 2005. The number of patients entered at each dose level is shown in Table 1.


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  		Table 3. Patient characteristics

 
Doses were rounded to the nearest 25 mg based on a dosing nomogram in the protocol, and patients with a body surface area >1.6 m2 received a capped maximum daily dose. The median deviation between the protocol prescribed dose level (mg/m2) and the actual dose per square meter administered was –2.1%. Four patients' actual doses per square meter deviated by >10% from the protocol prescribed dose level, including one patient (body surface area, 0.90 m2; dose, 100 mg/d) at the 100 mg/m2/d dose level, whose actual dose was 111 mg/m2/d (+11% deviation), and three patients (body surface areas of 1.99, 1.70, and 1.98 m2), one each at the 130, 165, and 200 mg/m2/d dose levels, whose actual doses were capped resulting in deviations of –22.7%, –10.9%, and –24.2%. None of these patients experienced dose-limiting toxicity.

Toxicity. ABT-751 administered orally, daily for 7 days every 21 days was well tolerated. ABT-751-related toxicities observed during cycle 1 are listed in Table 4 . As can be seen from the table, most toxicities were more frequent or severe at higher dose levels. During cycle 1, no dose-limiting toxicities were observed in children (n = 3) treated at the first dose level (100 mg/m2/d). One of six children treated at the 130 mg/m2/d dose level experienced grade 3 hyponatremia and bilateral wrist drop, which did not resolve to grade ≤1 by day 28 of cycle 1 (persistent grade 2 motor neuropathy). At dose level 3 (165 mg/m2/d), one of six patients developed grade 3 constipation. None of the first three patients enrolled at dose level 4 (200 mg/m2/d) experienced dose-limiting toxicity, and the dose of ABT-751 was escalated to 250 mg/m2/d.


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  		Table 4. ABT-751-related toxicity during cycle 1 by dose level and Common Toxicity Criteria (v.2) grade

 
Both patients enrolled at dose level 5 (250 mg/m2/d) experienced dose-limiting toxicity as well as multiple non-dose-limiting toxicities. The actual dose administered to both patients was 375 mg/d. One patient, a 14-year-old with neuroblastoma, experienced grade 3 shoulder pain (sensory neuropathy) with winged scapula (motor neuropathy) and transient grade 3 hypertension. Non-dose-limiting toxicities experienced by this patient included neutropenia (grade 3), thrombocytopenia (grade 3), and cardiac toxicity (grade 2, asymptomatic decrease in left ventricular shortening fraction, and grade 1 tachycardia), weight loss (grade 2), fever (grade 2), and insomnia (grade 2). The second patient at this dose level, a 16-year-old with recurrent Ewing's sarcoma, experienced dose-limiting fatigue (grade 3). Non-dose-limiting toxicities experienced by this patient included grade 2 bradycardia, nausea, anorexia, dizziness/lightheadedness, headache, constipation, arthralgias, myalgias, insomnia, and grade 1 sensory neuropathy (pain), hypotension, weight loss, and alopecia. This patient received a reduced dose of 200 mg/m2/d (actual dose, 300 mg/d) on cycle 2 and did not experience grade 3 or 4 toxicity but did experience a similar spectrum of grade 2 toxicities, which resulted in this dose also being intolerable.

Three additional patients were then enrolled at dose level 4, bringing the total number of patients treated at 200 mg/m2/d to six. One patient, a 13-year-old with Wilms' tumor, experienced dose-limiting pain in her scapula (sensory neuropathy, grade 3) and an asymptomatic decrease in left ventricular shortening fraction (grade 2 cardiac toxicity). During cycle 1, non-dose-limiting toxicities attributed to the investigational agent in the six patients receiving ABT-751 200 mg/m2/d daily for 7 days included anemia (n = 2), fatigue (n = 3), peripheral sensory neuropathy (n = 2), abdominal pain (n = 2), stomatitis (n = 1), constipation (n = 1), anorexia (n = 1), fever (n = 1), and weight loss (n = 1). Dose level 4 (200 mg/m2/d) was the maximum tolerated dose and recommended phase 2 dose for ABT-751 on the daily for 7 days schedule in children.

Grade 3 or 4 neutropenia or thrombocytopenia was not observed in patients receiving ≤200 mg/m2/d of ABT-751 and most patients had no substantial change in their blood counts during or after administration of this agent.

Twelve of 23 evaluable patients received >1 cycle of ABT-751, including 2 who received 7 and 27 cycles at the maximum tolerated dose (200 mg/m2/d). No significant ABT-751-related cumulative toxicities have been observed in patients receiving up to 50 cycles of ABT-751 daily for 7 days every 21 days. As of July 1, 2005, a total of 159 cycles of ABT-751 have been administered to children enrolled on this study. ABT-751-related toxicities experienced in the second or subsequent cycles are summarized in Table 5 . One patient receiving ABT-751 (130 mg/m2/d) experienced reversible sensory neuropathy (grade 3) during cycle 3. Other patients experienced mild (grade 1-2) sensory neuropathy, transient elevations in hepatic transaminases, gastrointestinal toxicity, insomnia, or headache. Non-dose-limiting neutropenia (grade 2-3) was observed infrequently. A 10-year-old male with neuroblastoma developed pill aversion during cycle 3. He resumed oral administration of ABT-751 capsules without difficulty during cycle 4.


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  		Table 5. ABT-751-related toxicities in second or subsequent cycles

 
Neurologic toxicity. The Purdue Pegboard and WEST-hand esthesiometer were administered to patients before the start of treatment and at the end of each treatment cycle to objectively assess peripheral neuropathy. Results are presented in Table 6 . There was no statistical difference in the median Purdue Pegboard score or grams of forces detected using the WEST-hand esthesiometer at baseline compared with end of cycle 1, off-study evaluation, or worst score at any evaluation during protocol therapy. The scores were not sensitive to clinical evidence of peripheral sensory neuropathy experienced by patients receiving ABT-751.


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  		Table 6. Sensory and motor function in the upper extremity, measured by the WEST-hand esthesiometer and the Purdue Pegboard test, before, during, and after treatment with ABT-751

 
Response. No complete or partial responses were observed in the 23 patients who were evaluable for response by Response Evaluation Criteria in Solid Tumors. Of eight patients enrolled with neuroblastoma, stable disease (≥5 treatment cycles) was observed in five patients who had evaluable disease by metaiodobenzylguanidine scintigraphy. One patient who received ABT-751 100 mg/m2/d was electively removed from protocol therapy after completing 50 cycles of therapy without evidence of progressive disease or toxicity. Two patients remain on study having received 41 and 27 cycles at the 165 and 200 mg/m2/d dose levels, respectively. One patient received five cycles at 130 mg/m2/d and another patient received seven cycles at 200 mg/m2/d before experiencing tumor progression.


   Discussion
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 Abstract
 Patients and Methods
 Results
 Discussion
References
 
Tubulin is a target for a number of anticancer drugs, such as the taxanes, Vinca alkaloids, and epothilones, and these drugs have a broad range of antitumor activity. The Vinca alkaloids, which block tubulin polymerization, are frontline therapy for most childhood solid tumors and acute lymphoblastic leukemia. ABT-751, which binds to tubulin at a different site than the other tubulin inhibitors and which also blocks tubulin polymerization, has several pharmacologic advantages. It is orally bioavailable, non-myelosuppressive, and is not a substrate for P-glycoprotein.

ABT-751 was well tolerated in children with solid tumors and had a toxicity profile similar to that of vincristine. The maximum tolerated dose and recommended phase 2 dose on this daily for 7 days schedule is 200 mg/m2/d, which is equivalent to an adult fixed dose of 360 mg. The pediatric maximum tolerated dose is 44% higher than the adult maximum tolerated dose of 250 mg on the same dosing schedule. Although constipation was observed in children, ileus, which was dose-limiting in adults, was not observed in children. Patients on our trial received docusate sodium preventively. Dose-limiting toxicities at 250 mg/m2/d were motor and sensory neuropathy, hypertension, and fatigue. Myelosuppression was minimal in patients receiving ≤200 mg/m2/d. The mechanism for the difference in the maximum tolerated dose for children compared with adults is not known. No plasma pharmacokinetics in adults have been published. Pharmacokinetic evaluation in children on this trial and a second trial evaluating a 21-day schedule in children is ongoing. However, children tolerate higher doses of other tubulin inhibitors such as vincristine (12), paclitaxel (13), and docetaxel (14).

This trial provided some experience with long-term administration of ABT-751 in children with neuroblastoma and prolonged stable disease. There was no evidence of cumulative toxicities in these patients who received up to 50 treatment cycles (up to 350 doses).

Although motor and sensory neuropathy was clinically apparent in patients receiving ABT-751 on our trial, the Purdue Pegboard test and WEST-hand esthesiometry were not useful in quantifying the degree of neuropathy.

We are also investigating a protracted dosing schedule of ABT-751 (daily for 21 days every 28 days) and exploring the tolerability of ABT-751 at the maximum tolerated dose on the daily for 7 days schedule in a cohort of heavily pretreated patients with neuroblastoma with decreased bone marrow function (absolute neutrophil count >250/µL; platelets ≥25,000/µL). This cohort will serve as a pilot for a planned phase 2 study of ABT-751 in this population.


   Footnotes
 
Grant support: Abbott Laboratories (Abbott Park, IL) and the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Presented in part at the American Society of Clinical Oncology Annual Meeting 2004, New Orleans, LA and at the American Society of Clinical Oncology Annual Meeting 2005, Orlando, FL.

5 http://ctep.info.nih.gov. Back

6 http://www.lafayetteinstrument.com/evaldexterity.htm. Back

7 http://www.cbi-pace.com. Back

Received 3/ 6/06; revised 5/ 9/06; accepted 6/ 8/06.


   References
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 Abstract
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 Discussion
 References
 

  1. Yoshimatsu K, Yamaguchi A, Yoshino H, et al. Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin. Cancer Res 1997;57:3208–13.[Abstract/Free Full Text]
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  4. Owa T, Yokoi A, Yamazaki K, et al. Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzene disulfonamide. J Med Chem 2002;45:4913–22.[CrossRef][Medline]
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  7. Hande K, Meek K, Lockhart AC, et al. Pharmacokinetics and safety of ABT-751 a novel microtubulin inhibitor administered daily x 7 days every 3 weeks. Proc Am Soc Clin Oncol 2003;22:#520.
  8. Sprague E, Fleming GF, Cai Y, et al. Phase I study of 21 day continuous dosing of oral antimitotic agent ABT-751 a novel microtubulin inhibitor. Proc Am Soc Clin Oncol 2003;22:#518.
  9. Kobayashi H, Hande K, Berlin J, et al. Phase I results of ABT-751 a novel microtubulin inhibitor administered daily x 7 every 3 weeks [abstract 2079]. Proc Am Soc Clin Oncol 2004;14S:23.
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