• Antiangiogenic;
  • Antimitotic;
  • Cancer;
  • Treatment


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information


ABT-751 is a novel orally available antimitotic agent that targets microtubule polymerization. This mechanism may suggest potential activity in canine lymphoma.


Determine a maximum tolerated dose for ABT-751, and assess long-term tolerability and activity in canine lymphoma.


Thirty dogs with newly diagnosed (n = 19) or relapsed (n = 11) non-Hodgkin's lymphoma.


Dogs (n = 11) were enrolled in a rapid dose escalation study to define the maximum tolerated dose. Upon definition of a maximally tolerated dose, a cohort expansion of 19 dogs allowed verification of long-term tolerability and assessment of activity. Study endpoints in the cohort expansion included chronic tolerability, response rate, response duration, and time to progression. Additional endpoints included serum pharmacokinetics, lymph node drug concentrations, and changes in circulating endothelial cells.


The maximum tolerated dose of ABT-751 was 350 mg/m2PO q24h. Dose-limiting toxicities included vomiting and diarrhea, which resolved with a schedule adjustment to 350 mg/m2PO q48h. ABT-751 was consistently detected in lymphoma tissue samples from dogs treated at or above the maximum tolerated dose. In the cohort expansion, objective responses were seen in 3/15 (20%) dogs with a response duration ranging from 21 to 111 days. Decreases in circulating endothelial cells were seen in 10 dogs at day 7 (2 responding dogs and 8 nonresponding dogs).


ABT-751 was well tolerated at 350 mg/m2PO q24h for 7 days and then q48h thereafter. Activity of ABT-751 suggested a rationale for additional studies of ABT-751 as part of a combination chemotherapy protocol for lymphoma or other canine cancers.


maximum tolerated dose


dose-limiting toxicity


World Health Organization


non-Hodgkins lymphoma


circulating endothelial cells


area under the curve


maximum concentration


every other day

ABT-751 is a novel orally available antimitotic agent that binds to the colchicine site on beta tubulin and inhibits polymerization of microtubules.[1] ABT-751 functions as a potent antimitotic agent by inhibiting the proliferation of a broad spectrum of human cancer cell lines at nanomolar to low micromolar concentrations in vitro (molecular weight, 371.4).[1, 2] Antimitotic agents fall into 3 classes: vinca alkaloids (eg, vincristine, vinblastine, vinorelbine), taxanes (eg, paclitaxel, docetaxel), and colchicine-site binders (eg, ABT-751).[3] Both vinca alkaloids and colchicine-site binders are potent inhibitors of microtubule polymerization and block cell proliferation at metaphase during mitosis. These classes have distinct binding sites on the beta-tubulin subunit.[1] The taxanes stabilize microtubules and block their depolymerization.[4] Unlike other microtubule toxins, ABT-751 is not a substrate for multidrug resistance (MDR).[1] In vitro studies with ABT-751 have indicated a mechanism of action linked to cell cycle inhibition.[1, 2] As predicted by the mechanism of action, in vivo activity of ABT-751 has been confirmed in several xenograft and syngeneic model systems, including breast, gastric, lung, and colon cancer.[2, 5, 6]

Based on pharmacokinetic exposures predicted to be active against cancer, a reasonable therapeutic index was anticipated in human studies. The clinical development of ABT-751 has included evaluation in patients with hematologic malignancies, pediatric solid tumors, castration-resistant prostate cancer, and nonsmall cell lung cancer.[7-11] In a phase I study of ABT-751 in human patients with refractory hematologic malignancies, 2 treatment regimens were assessed. The first involved the administration of ABT-751 PO for 7 consecutive days every 21 days. The second included treatment for 21 consecutive days every 4 weeks. Both schedules were well tolerated, with the most common dose-limiting toxicity being gastrointestinal.[6] At a dosage of 175 mg/m2 PO once a day for 21 days on a 28-day cycle, notable clinical responses have been seen in previously treated patients with acute leukemia.[7]

Based on the mechanism of action for ABT-751, its oral bioavailability,[3] established therapeutic index, and evidence of activity in lymphoid cancers[7] we conducted a prospective, single-arm study in dogs with non-Hodgkin's lymphoma (NHL) that first sought to define a maximally tolerated dose (MTD) of ABT-751, and then evaluated potential activity and tolerability of long-term dosing.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

All dogs that entered the study were client owned. Dogs were evaluated at one of the following veterinary hospitals: The Oncology Service LLC at Friendship Hospital for Animals, Washington, DC; Gulf Coast Veterinary Specialists, Houston and San Antonio, TX; Arizona Veterinary Specialists, Gilbert, AZ; New England Veterinary Oncology Group, Waltham, MA; Regional Veterinary Referral Center, Springfield, VA; Southwest Veterinary Oncology, Tucson and Gilbert, AZ; Southpaws Veterinary Referral Center, Fairfax, VA; Veterinary Specialty Hospital, San Diego, CA; with centralized trial oversight by Animal Clinical Investigation, LLC (

ABT-751 Formulation

[N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl] 4 methoxybenzenesulfonamide] was formulated in capsules, containing microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate. Capsule strengths of 25 and 100 mg were prepared for dosing purposes.

Dose Escalation Study with ABT-751

Dogs with NHL with peripheral nodal involvement of any clinical stage were eligible. Dogs with concurrent medical conditions, unfavorable performance scores, or those that had already received prior treatment for lymphoma did not qualify for entry into this initial phase of the study. Current treatment with chemotherapy, radiation, or prednisone was not allowed. Before initiation of treatment, animals underwent a physical examination and clinical staging, which included CBC, serum biochemistry, urinalysis, and thoracic and abdominal radiographs. After staging, 3 target lymph nodes were measured and recorded.

The initial cohort of dogs was entered in a rapid dose escalation study design. One dog was entered into each dose cohort until development of any adverse effects was noted. After development of a dose-limiting adverse event, 2 additional dogs were entered to that cohort. Conventional 3+3 rules then were used to guide further dose escalation.[12] Dogs were monitored for adverse effects, with post hoc description by means of the Veterinary Co-operative Oncology Group (VCOG) Common Toxicity Criteria for dogs, where dose-limiting toxicities (DLT) were defined as any grade 3 or grade 4 toxicity.[13] In total, 11 dogs were enrolled in the dose-finding arm of this study.

A summary of diagnostics and procedures performed during the dose escalation phase of the study is presented in Table S1. After day 42, dogs were evaluated once every 21 days. At the time of disease progression, a physical examination, CBC, serum biochemistry, and urinalysis were performed, as well as completion of a quality of life questionnaire.

Table 1. Dose-dependent adverse effects in dogs receiving escalating doses of ABT-751.
DoseVomiting GradeDiarrhea GradeNeutropenia
50 mg/m2000
100 mg/m2000
200 mg/m2000
300 mg/m2320
350 mg/m22,2,1,12,2,0,00
400 mg/m21,33,20

Cohort Expansion at Maximally Tolerated Dose

Dogs were eligible for inclusion if they had measurable, histologically diagnosed NHL of any stage. These patients were newly diagnosed or relapsed cases. Patients were ineligible if they had received recent chemotherapy (within 14 days of study entry) or radiation treatment (within 21 days of study entry). Dogs receiving prednisone for >21 days without clinical improvement were deemed eligible for entry into the study.

Before treatment, 3 target lymph nodes were measured and recorded, a lymph node biopsy was performed, and whole blood and plasma were collected for secondary bio-endpoints. To define the chronic tolerability of ABT-751 and begin to define activity in dogs with lymphoma, a cohort of 19 dogs was treated with ABT-751 at the defined maximally tolerated dose of 350 mg/m2 orally PO q24h for 7 days and then q48h for 21 days. If an objective response or dose-limiting toxicity was not noted after 28 days on treatment, investigators were permitted to restart a q24h regimen for 7 days, otherwise, dogs continued on an EOD schedule until study discontinuation. Study discontinuation was defined as progressive disease or an adverse event that was a dose-limiting toxicity. Dogs stayed on treatment at the investigator's discretion. A summary of diagnostics and procedures performed in the cohort expansion is provided in Table S2. Owners were instructed to contact the investigator within 24 hours of any adverse event. Adverse events were attributed to the study drug, disease, study participation, or other cause. Each patient in which adverse effects were noted had a physical examination after speaking with the owner. Serum was collected for ABT-751 pharmacokinetics on days 0, 7, and 28 for the first 4 dogs enrolled in the study. Sample collections included day 0: 0, 0.5, 1, 4, 6, 24 hours post-ABT-751 treatment; day 7: 0, 0.5, 1, 4, 6 hours post-ABT-751 treatment; day 28: single predose sample. Lymph node biopsies were collected to assess tissue drug concentrations on day 0, 7 and 21, with day 7 and day 21 lymph node biopsies collected between 18–30 hours after the most recent dose of ABT-751. Whole blood for CEC analysis was collected on days 0, 7, 28, and conducted as previously reported in the dog.[14] A 5-color flow cytometric assay was developed for CEC enumeration with CD146-FITC, CD34-PE and CD45-APC, and nuclear stain. CEC phenotypic analysis used CD106-PE (activation) or Annexin V-PE (apoptosis) or CD133-PE (endothelial progenitor cells; EPCs). Immunocytochemistry was used to validate the identity of the sorted population. Optimal conditions of sample collection and storage were assessed.

Response Was Defined as Follows

Complete response was defined as the disappearance of all clinical evidence of measurable lesions. Partial response was considered to be a decrease of 50% or more in the sum of the products of measurements for measurable lesions. Stable disease was defined as no response to treatment, or a response less than a partial response without the appearance of new lesions or worsening of clinical signs. Progressive disease was considered to be an unequivocal increase of 50% or more in the size of any measurable lesion or the appearance of any new lesions. Relapse was defined as appearance of new lesions or reappearance of old lesions in dogs that had a complete response; in dogs that only had a partial response, relapse was defined as at least a 50% increase in the sum of the products of measurements of representative lesions, compared to measurements obtained at the time of maximum response.

By means of a Min–Max study design in the cohort expansion, it was determined that 18 dogs per cohort would be sufficient to determine if ABT-751 was not active in dogs with lymphoma. Two dogs were eligible for entry at the same time, and therefore both were entered leading to a total of 19 dogs in the cohort expansion.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

Dose Escalation Cohort

Eleven dogs (6 males, 5 females; including a variety of breeds) were enrolled in the dose escalation phase of the study. Patients were enrolled from May 11, 2004 until November 9, 2004. Five of 11 dogs had WHO stage IIIa lymphoma. The remaining 6 dogs had WHO stage IVa lymphoma. Dogs were treated with ABT-751 daily, and the administration regimen and schedule for ABT-751 cohorts was as follows:

Dog #1: 50 mg/m2 PO q24h

Dog #2: 100 mg/m2 PO q24h

Dog #3: 200 mg/m2 PO q24h

Dog #45: 300 mg/m2 PO q24h

Dog #811: 350 mg/m2 PO q24h

Dog #67: 400 mg/m2 PO q24h

Table 1 provides a summary of adverse events noted. Three of 11 (27.3%) dogs had dose-limiting toxicities that included vomiting, diarrhea, anorexia, or some combination of these. No dose-limiting toxicities were seen in dogs that received <300 mg/m2. Toxicity grades for vomiting, diarrhea, and neutropenia are shown in Table 1. One dog, treated with 300 mg/m2, developed transient grade 3 vomiting and grade 2 diarrhea. Signs resolved when metoclopramide (0.3 mg/kg PO q8h) was initiated, and a dose delay or reduction was not necessary. One of the dogs treated with 350 mg/m2 developed grade 2 vomiting and diarrhea that required a 7-day dose delay and treatment with metoclopramide (0.3 mg/kg PO q8h) and metronidazole (15 mg/kg PO q12h). One dog treated at 400 mg/m2 (for 14 days) had resolution of grade 1 vomiting and grade 3 diarrhea after study drug discontinuation and the initiation of metoclopramide and metronidazole at the previously stated dosages. A second dog treated with 400 mg/m2 (for 7 days) with grade 3 vomiting developed subsequent aspiration pneumonia and died. The development of dose-limiting toxicities in 2/2 dogs at 400 mg/m2 resulted in de-escalation of dose cohorts to 350 mg/m2. A total of 4 dogs were treated at this dosage (1 dog during upward escalation and 3 dogs at final de-escalation). The absence of dose-limiting toxicities in this cohort allowed the maximum tolerated short-term daily dosage to be defined as 350 mg/m2. Non–dose-limiting toxicities were gastrointestinal and typically were seen after 7 days of treatment. These signs resolved with drug discontinuation, antiemetics, and antidiarrheals within 7 days. Schedule modification to every other day resulted in control of these chronic signs. No signs of cardiotoxicity, neurotoxicity or biochemical changes were observed during treatment with ABT-751. The first dog entered into the study started at a dosage of 50 mg/m2 and was permitted to undergo individual dose escalation to 100 and 300 mg/m2. Assessment of tolerability was limited to this dog's entry at 50 mg/m2 because of the concern that subsequent doses could be confounded by cumulative dosing. No dose-limiting toxicities were noted in this dog even at 300 mg/m2. In the dose escalation phase of the study, objective responses were seen in 3/11 (27%) dogs. Objective responses were seen in 3 of 5 (60%) of the dogs receiving a dosage of 350 mg/m2 by day 7 whereas no dogs (0/7) had objective response when receiving <350 mg/m2. Treatment time ranged from 786 days with a median of 21 days.

Cohort Expansion at Maximally Tolerated Dose

Cohort expansion at the defined MTD was undertaken to assess chronic tolerability and activity of ABT-751 in dogs with NHL. The development of mild (ie, grade 2 or less) but persistent gastrointestinal toxicities seen after 7 days of treatment at the MTD or above resulted in attenuation of the treatment regimen to 350 mg/m2 daily for 7 days, then every other day thereafter. A total 19 dogs were enrolled in this expanded cohort with the attenuated schedule, including 10 males and 9 females (median age, 8.25 years). One dog was WHO stage II, 11 were stage III, 6 were stage IV, and 1 stage V. Three dogs were substage b. Eleven dogs enrolled in this study were relapsed lymphoma cases and had received prior chemotherapy with the study mandated wash-out period. Patients were enrolled from February 1, 2005 to March 31, 2005.

Based on the expectation that chronic ABT-751 administration would be necessary for optimal clinical use in dogs, dose-limiting toxicities were defined as grade 2 or higher in the expanded cohort. Table S3 summarizes toxicities that occurred during the cohort expansion. Gastrointestinal side effects were noted in 10 (52%) dogs. Dose-limiting toxicities were noted in 4/19 (21.1%) dogs and consisted of vomiting and diarrhea. Three of the 4 dogs with dose-limiting toxicities had clinical signs controlled with supportive medications (metoclopramide and metronidazole). All these dogs were able to continue on the study despite development of adverse events with supportive medications. No hematologic or biochemical changes were appreciated for dogs receiving ABT-751. A single dog developed central nervous system signs after 2 days on ABT-751 treatment that were subsequently attributed to disease progression.

Serum Pharmacokinetics and Lymphoma Tissue ABT-751 Concentrations

ABT-751 pharmacokinetic analysis was performed during dose escalation studies after the 1st dose and 1st week of ABT-751 treatment. A direct relationship between administered dose and blood exposure of ABT-751 was found (Fig 1). The mean AUC and Cmax for ABT-751 at the MTD of 350 mg/m2 was 5.55 ± 2.44μg-hr/mL and 0.9 ± 0.4 μg/mL, respectively, after the 1st dose of ABT-751. No significant differences in serum pharmacokinetics were seen between the 1st dose and 1st week of dosing analyses (P = .81 – AUC; P = .73 – Cmax). ABT-751 drug concentrations in lymphoma tissues were proportional to the administered dose, but drug levels within dose cohorts were highly variable. ABT-751 drug concentrations were detectable in lymphoma tissues from 4/6 dogs treated at or above the defined MTD. The mean ABT-751 concentration among these dogs was 1.48 μg/g.


Figure 1. Oral administration of ABT-751 to dogs with lymphoma results in serum exposures that are proportional to the administered dose. Serum pharmacokinetic analysis was conducted following the first dose of ABT-751.

Download figure to PowerPoint

The intent-to-treat population in the expanded cohort included all 19 dogs entered in the study. The treatment-received population included dogs that received ABT-751 for >7 days. Fifteen dogs were included in the treatment-received population. Three of the 4 dogs not included in the treatment-received population experienced disease progression before day 7 and were withdrawn. One dog was withdrawn because of the owner's decision related to grade I adverse gastrointestinal effects attributed to ABT-751 that consisted of diarrhea and lethargy. Within the treatment-received population, 3 of 15 (20%) dogs had partial responses, with a response duration ranging from 21 to 111 days.

Circulating Endothelial Cells (CEC)

Whole blood was collected at day 0, 7, and 28. Whole blood was collected for CEC analysis at the time of response, relapse or progressive disease. Of the 19 dogs in the intent-to-treat group, 16 dogs had day 0 and 7 CEC's evaluated (Supplemental Table S4, online only). Ten dogs in this group had a reduction in CEC count at day 7 with the median percentage of reduction of –68.95%. Of the 3 dogs with objective responses to ABT-751, 2 dogs had a decrease in CEC counts at day 7. Ten dogs enrolled had CEC concentrations evaluated at day 0, 7, and 28. Three of the 10 dogs had a decrease in CEC concentrations from day 7 to day 28. Two of 3 dogs with an objective response had a decrease in CEC concentrations at day 28.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information

The MTD for ABT-751 in dogs with lymphoma was determined to be 350 mg/m2 given daily for 7 days. Dose-limiting toxicities identified during the acute (7-day) dose escalation phase were primarily gastrointestinal. During cohort expansion at the MTD, less severe but persistent grade 2 gastrointestinal toxicities were modulated by every other day dosing at the MTD after day 7. Activity was demonstrated at this dosing schedule, with an objective response rate of 20%. The oral bioavailability, unique mechanism of action, chronic tolerability, and single agent activity of ABT-751 suggest a rationale for its use as part of a combination chemotherapy protocol in dogs with NHL. Evaluation in other canine tumors also should be considered in light of experience in humans.[5, 7-11]

The emetogenic profile for ABT-751 may be the result of its effect on the gastrointestinal tract or attributable to stimulation of the central nervous system chemo-receptor trigger zone. In studies in humans, DLT has been gastrointestinal (eg, ileus, constipation, nausea, anorexia, vomiting, diarrhea) in adults,[7] and neurological, gastrointestinal, and cardiovascular (hypertension) in children.[8, 9] Toxicities were not seen in dogs treated with <300 mg/m2. Myelosuppression, neurotoxicity, and cardiotoxicity were not identified in any of the dogs treated.

Most treatment regimens for ABT-751 in humans consist of daily treatments for 7 days repeated in 3 week cycles, or daily treatment for 21 days given every 4 weeks.[3, 7, 8] The majority of dogs had DLT that occurred at or before day 7 of treatment. Although not life-threatening, DLT impacted the quality of life for these dogs and was not acceptable for some pet owners. Because the response rate in dogs with lymphoma was not high, we were concerned that a reduction in daily dose intensity would further limit the opportunity to achieve optimal treatment responses. As such, rather than continuing treatment with dose reduction or with daily dosing (ie, daily for 21 days every 4 weeks), we opted to prioritize the use of ABT-751 at the MTD on an every other day schedule. This schedule attenuation was successful in managing treatment-related adverse effects and provided evidence of ongoing antitumor activity for some responding dogs. Of the 3 dogs with objective responses, all 3 continued to respond with a response duration ranging from 2056 days. Such a schedule may allow the integration of ABT-751 into a combination and ongoing treatment protocol for dogs with lymphoma.

Most canine lymphoma rescue protocols result in a 3050% response rate, but the benefit usually is short lived with a median duration of 1.5–2 months. In our study, there was a 20% (3/15 dogs) response rate with a median response duration of 24 days in the treatment-received population. This activity supports a rationale to include this orally bioavailable antimitotic agent as part of a combination chemotherapy protocol in dogs with lymphoma. Furthermore, the nonspecific mechanism of action and activity of ABT-751 in murine models and clinical trials of humans supports future consideration of ABT-751 for canine tumors other than lymphoma.[2, 7-11]

There was some evidence that exposure to ABT-751 resulted in decreased CECs. A decrease in CEC counts from day 0 to day 7 while receiving ABT-751 was seen in 10/16 dogs. These data may support the proposed vascular targeting mechanisms linked to ABT-751, and based on this proposed mechanism, an expanded study was undertaken combining ABT-751 with an antiangiogenic agent. The results of that study are currently being evaluated. The low response rate seen in this study did not allow robust assessment of CEC changes as a function of clinical response or the development of adverse effects. The highest reductions in CEC counts were seen in 2/3 dogs that had objective responses to ABT-751 treatment.

In summary, these studies demonstrated a tolerable dosage and treatment schedule for ABT-751 in dogs. The pharmacokinetic exposures achieved within this treatment regimen, based on preclinical modeling, predicted therapeutic activity in dogs. Furthermore, drug biodistribution to lymphoma tissue was confirmed. These data provide a rationale for additional studies of ABT-751 as part of a combination chemotherapy protocol for canine lymphoma or in other cancers in dogs.

  1. These studies were carried out at 8 veterinary hospitals across the United States with oversight from Animal Clinical Investigation, LLC and Abbott Laboratories. The dose escalation study was initiated in May 2004 and was completed in November 2004. Accrual to the cohort expansion phase began in February 2005 and was completed 2 months later. This study was funded through a research contract with Abbott Laboratories. Updates on the dose escalation and cohort expansion phases of this study were separately presented at the Veterinary Cancer Society meetings in 2005 and in 2006, respectively.


  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
  • 1
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    Yee K, Hagey A, Verstovsek S, et al. Phase I study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies. Clin Cancer Res 2005;11:66156624.
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    Fox E, Maris J, Widemann B, et al. A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 7 days every 21 days in pediatric patients with solid tumors. Clin Cancer Res 2006;12:48824887.
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    Fox E, Maris J, Widemann B. A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors. Clin Cancer Res 2008;14:11111115.
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    Michels J, Ellard SL, Le L, et al. A phase IB study of ABT-751 in combination with docetaxel in patients with advanced castration-resistant prostate cancer. Ann Oncol 2010;21:30511.
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Supporting Information

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. References
  7. Supporting Information
jvim892-sup-0001-TableS1.docxWord document19KTable S1. Treatment and Clinical Evaluation Plan for the Dose Escalation Cohort.
jvim892-sup-0002-TableS2.docxWord document16KTable S2. Treatment and Clinical Evaluation Plan for the Cohort Expansion Cohort.
jvim892-sup-0003-TableS3.docxWord document18KTable S3. Summary of gastrointestinal toxicities seen dogs receiving ABT-751 during cohort expansion phase.
jvim892-sup-0004-TableS4.docxWord document12KTable S4. CEC summary of dogs treated with single agent ABT-751.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.