Dose-Escalation and Pharmacokinetic Study Following a Single Dose of Oxaliplatin in Cancer-Bearing Dogs
ABSTRACT
Oxaliplatin is more potent than cisplatin, lacks cross-resistance to other platinum agents, and has a favorable toxicity profile. This study’s objective was to define the maximally tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin in cancer-bearing dogs. This was a prospective, single-patient-cohort, dose-escalation study of oxaliplatin in client-owned dogs with confirmed, spontaneous malignancy. A single infusion was administered; the starting dose was 50 mg/m 2 , with 10 mg/m 2 escalation-increments if no DLT was documented, up to a maximum dose of 140 mg/m 2 . Plasma total platinum was measured at multiple timepoints and patients were monitored weekly. Ten dogs were enrolled in single-patient-cohort treatment levels up to the maximum level of 140 mg/m 2 . There were no DLTs, and the maximally tolerated dose was not determined. The area under the curve 0–7 days for 100–140 mg/m 2 ranged from 77,850 to 82,860 ng/mL × hr; the area under the curve 0–4 hr for 50–140 mg/m 2 was linear with dose (r 2 = 0.639, P = .0055). The data suggest a single infusion of oxaliplatin is well tolerated in cancer-bearing dogs up to 140 mg/m 2 . There was good correlation between exposure and dose, while achieving plasma levels similar to therapeutic levels documented in humans.
Introduction
Oxaliplatina is a third-generation cisplatin analogue with a 1,2-diaminocyclohexane carrier ligand and oxalate as the leaving group.1 Similar to cisplatin, oxaliplatin reacts with the N7 position of guanine and adenine residues to form intra- and interstrand deoxyribonucleic acid (DNA) crosslinks, and the majority of the adducts are bifunctional, guanine–guanine, and guanine–adenine intrastrand lesions.1 Despite similar or increased cytotoxicity of oxaliplatin compared with cisplatin, oxaliplatin DNA adducts are fewer, bulkier, slower to form, and more hydrophobic, making oxaliplatin more potent than cisplatin.2,3
Oxaliplatin has demonstrated activity in cancer cells that are resistant to other platinum agents, and a key component appears to be the recognition of platinum-DNA adducts by the mismatch repair (MMR) proteins.2 The cytotoxicity of carboplatin and cisplatin are dependent upon a functional MMR pathway to detect DNA damage; the platinum complexes interfere with activity and prevent the repair. Inability to complete the repair of DNA damage results in apoptosis.2 Inherited defects or epigenetic silencing of MMR in ovarian, endometrial, gastric, and colorectal carcinomas result in a lack of recognition of the DNA damage; thus, no repair attempt is thwarted by the platinum-containing DNA adducts and the resulting apoptosis is avoided, conferring resistance to cisplatin and carboplatin.4 The size and conformation of 1,2-diaminocyclohexane distorts the DNA differently than cisplatin or carboplatin, and the proteins in the MMR complex do not recognize oxaliplatin adducts; therefore, the cytotoxicity of oxaliplatin is MMR independent, and the loss of this repair pathway does not lead to resistance.2–4
Clinically, oxaliplatin has demonstrated efficacy against human cancers with acquired or inherent platinum resistance, including cisplatin-refractory ovarian carcinoma as well as pancreatic, gastric, gastroesophageal, hepatocellular, breast, and non–small cell lung carcinomas.3 Whereas traditional platinum agents were ineffective in colorectal carcinoma, oxaliplatin demonstrated single-agent activity as first-line therapy, as well as in patients refractory to the standard of care of 5-fluorouracil.5
Oxaliplatin also lacks the renal and auditory toxicity profiles of cisplatin and is not routinely associated with clinically significant myelosuppression.6 However, more than half of human patients receiving oxaliplatin will experience gastrointestinal side effects, and the most common and dose-limiting toxicity (DLT) is a cold-induced sensory neuropathy, with both an acute form and a chronic form that occurs with increased risk following cumulative dosing.6–9 This toxicity may be related to the chelation of calcium by oxalate, impacting neuronal voltage-gated sodium channels.7 Although there are conflicting studies in human medicine, clinical recommendations include the administration of 1 g each of calcium gluconate (Ca++) and magnesium sulfate (Mg++) as a 15 min IV infusion prior to and following oxaliplatin.10–12 In preclinical toxicity studies of oxaliplatin in healthy beagles, neurotoxicity was not documented. However, leukopenia, salivation, vomiting, and diarrhea were noted at single-dose 2 hr infusions and daily × 5 dosing when the total dose exceeded 100 mg/m2, and at lower doses administered over shorter infusion times (45 mg/m2 over 20 min). The highest nonseverely toxic dose was determined to be 150 mg/m2, at which ventricular fibrillation and sudden death were seen following a single-dose, 2 hr infusion. Single dosing or daily dosing of total doses of 200 mg/m2 and greater were universally lethal.13
Cisplatin, carboplatin and satraplatin are the only platinum-containing cytotoxic agents with a known dose and toxicity profile for treatment of cancer in pet dogs.14–16 Currently, only carboplatin and cisplatin are available for clinical use, and although studies have demonstrated a survival benefit, treatment is associated with clinically significant toxicities.17–22 Oxaliplatin has not been evaluated in dogs with spontaneous tumors. The lack of cross-resistance, mechanism of cytotoxicity that is MMR independent, and a potentially favorable toxicity profile make oxaliplatin an attractive drug for treatment of canine malignancies.
Accelerated titration design (ATD) of phase 1 clinical studies provides enhanced efficiency with acceptable safety, and it is commonly employed in human phase 1 studies to decrease the number of patients treated at subtherapeutic doses and to achieve the DLT with the minimum patient number.23,24 Phase 1 studies of oxaliplatin in humans reported minimal biochemical or hematological toxicity up to doses of 200 mg/m2, with similar findings noted in healthy beagles in preclinical studies at doses below 150 mg/m2, justifying the use of ATD of a phase 1 clinical trial of oxaliplatin in cancer-bearing pet dogs.6,8,13,25
The purpose of this study was to determine the maximally tolerated dose (MTD) and the DLT of oxaliplatin in canine patients with spontaneous solid tumors. Pharmacokinetic (PK) data were collected to correlate plasma concentration of drug with any identified toxicities detected.
Materials and Methods
Trial Design
This was a prospective, open-label, accelerated titration phase 1 study investigating the MTD and DLT after a single IV infusion of oxaliplatin. All patients were enrolled and treated at a single institution. Patients were assigned to a dose level sequentially in single-patient cohorts until a DLT was observed. The starting and maximum dose of oxaliplatin was determined based on preclinical studies in healthy beagles.9,13 The starting dose was set at the dose with no reported side effects (50 mg/m2). The maximum dose was set at 140 mg/m2, one level below the dose at which sudden death due to cardiac arrhythmia was reported and what was determined in preclinical studies to be the canine highest nonseverely toxic dose (150 mg/m2).13 Dose escalation was designed to occur in 10 mg/m2 increments and dose de-escalation at 5 mg/m2 steps. There was no intrapatient dose escalation and no assessment of multiple dosing in this study. Participation in the study was concluded on day 21. Patients could be withdrawn from the study prior to day 21 for disease progression, other signs of ill health, or for trial noncompliance at the discretion of the investigator, the owner, or both. Response assessment was not an objective of this study. The clinical protocol was approved by the institution’s Animal Care and Use Committee and the Veterinary Teaching Hospital Board.
Patient Eligibility
Client-owned dogs who were presented to the Virginia-Maryland College of Veterinary Medicine Veterinary Teaching Hospital were recruited for enrollment. Inclusion criteria included cytological or histological diagnosis of treatment-naïve, refractory, relapsed, or recurrent solid malignancy; minimum body weight of 10 kg; hematologic and biochemical parameters deemed adequate for the safe administration of chemotherapy; minimum life expectancy of 6 wk; and Veterinary Comparative Oncology Group Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 performance status of 0 (fully active, able to perform at predisease level) or 1 (activity less than predisease level but able to function as an acceptable pet). Dogs were excluded if the creatinine exceeded 1.5 times the upper reference limit, the alanine aminotransferase or aspartate aminotransferase exceeded 2 times the upper reference limit, the albumin was <2.0 mg/dL, or there were grade 3 or higher VCOG cytopenias on complete blood count (CBC). Based on preclinical data in healthy beagles, patients were excluded if there was a pre-existing, clinically significant cardiac arrhythmia.9,13 Prior therapy was acceptable, with a 3 wk washout period for chemotherapy or kinase inhibitor therapy, and/or 4 wk washout for radiation therapy. Concurrent corticosteroid or nonsteroidal anti-inflammatory therapy was permitted. For all dogs enrolled in the study, standard treatment options were presented to their owners. Dogs were enrolled only if they met all of the inclusion criteria and none of the exclusion criteria, and written owner informed consent was obtained.
Adverse Events
Adverse events (AEs) were graded according to the VCOG-CTCAE v.1.1.26
An AE was defined as any expected or unexpected toxicity. A serious AE (SAE) was defined as any expected or unexpected grade 4 or 5 toxicity. All AEs were defined as unrelated, unlikely, possible, probable, or definitely related to administration of oxaliplatin. For most AEs, grade 3 or higher toxicity was considered a DLT. However, afebrile, asymptomatic grade 3 neutropenia or thrombocytopenia were not considered a DLT, whereas febrile grade 3 neutropenia or grade 4 myelosuppression of any kind constituted a DLT. Observation of a DLT would result in trial conversion to a classic open-label 3 + 3 cohort design.27 In the event of an unforeseen SAE, patient recruitment would be suspended. Dose de-escalation and conversion to a classic 3 + 3 phase 1 study design would occur, or the trial would be terminated and the investigators would conclude that oxaliplatin therapy is not suited for use in dogs with cancer if an SAE had a probable or definite relationship with the investigational agent. If the SAE was determined to be possible, not likely, or unrelated with the investigative agent, dose escalation would resume and additional monitoring or safety measures may be instituted at the discretion of the primary investigator for the remainder of the trial.
Administration of Calcium Gluconate and Magnesium Sulfate
Coadministration of IV Ca++ and Mg++ before and after oxaliplatin is the standard of care for human patients to ameliorate neurotoxicity without affecting PKs or efficacy.10 The doses of Ca++ and Mg++ are not known for canine patients lacking deficiency in these minerals. The canine dose of Ca++ as treatment for hypocalcemia is 75–500 mg IV slowly and the dose of Mg++ as treatment of deficiency is 0.2–0.3 mEq/kg (123.1 mg = 1 mEq).28 Side effects of Ca++ or Mg++ can include cardiotoxicity. The design of our study was that canine patients would receive treatment paralleling standard recommendations for humans but starting at a low dose of Ca++ and Mg++ and escalating in cohorts of three.11 The starting dose was 250 mg of each drug, or 25% of the dose administered to human patients, and below the maximum canine treatment dosages. Dose escalation was set at 100 mg increments, with a maximum of 500 mg.
Treatment Schedule: Day 0
Within 7 days of screening and enrollment, patients were presented to the clinic for treatment with oxaliplatin. Hematology, serum biochemistry, and urinalysis were performed, and plasma was collected for PK analysis prior to treatment. Maropitantb (1 mg/kg) was administered subcutaneously at least 30 min prior to treatment, per standard of care in the Virginia-Maryland College of Veterinary Medicine Veterinary Teaching Hospital and based on preclinical canine data reporting gastrointestinal toxicities (salivation, vomiting).13 Ca++ (10% solution) and Mg++ (500 mg/mL) were each administered IV over 15 min prior to, and upon completion of, oxaliplatin infusion. Oxaliplatin was diluted in 5% dextrosec and administered according to manufacturer recommendations, IV over 2 min. Because of concern for cardiotoxicity secondary either to oxaliplatin or to calcium and magnesium administration, patients received treatment in the intensive care unit under continuous electrocardiogram (ECG) monitoring. Plasma collection timepoints on day 0 in our study were the end of infusion (EOI) and at 2 hr and 4 hr after infusion in order to encompass the anticipated peak plasma concentration. Dogs were discharged the same day with an additional 4 days of oral maropitant (2 mg/kg, q 24 hr) to be administered at owner discretion. Patients at the 130 mg/m2 and 140 mg/m2 dose levels were also discharged with a Holter monitor worn for the first 24 hr. Owners were provided with a diary to record any changes in thirst, urination, appetite, stool, behavior, or other clinical variables at home on a daily basis.
Patient Monitoring and Assessment of Toxicity: Days 7, 14, and 21
Dogs were assessed at 7, 14, and 21 days following oxaliplatin administration. Clinical and laboratory evaluation included owner diary documentation, physical examination including neurological exam, body weight, CBC, serum biochemistry, urinalysis, ECG recordings, and plasma collection for PK analysis. ECG recordings were 6-lead, performed in right lateral recumbency. There is no accepted standard evaluation method for assessment for sensory neuropathy in dogs. Evaluation for sensory neuropathy in participants was based on subjective findings on physical exam, owner diary report, and directed questions of behaviors at intake, such as willingness to step on cold surfaces, drink cold water, or chewing or licking at feet, which might be indicative of cold-induced paresthesia experienced by human patients. Imaging and additional diagnostics were performed as needed based on clinician discretion. ECG recordings were obtained on day 0 prior to treatment, and on days 7, 14, and 21. The recordings were evaluated by the clinician of record at the time of recheck for evidence of major abnormalities. If normal sinus rhythm was recorded, patients were documented to have no cardiotoxicity. If any cardiac rhythm other than sinus rhythm or sinus arrhythmia was recorded, consultation with a cardiologist was sought. All ECG recordings were re-evaluated at the conclusion of the study by a single cardiologist (J.A.). A dog was considered evaluable for assessment of toxicity if all planned clinical and laboratory evaluation data were collected and available for analysis.
Pharmacokinetic Plasma Analysis
Blood samples were collected in sodium heparin tubes prior to infusion, at the EOI, and at 2 hr, 4 hr, 7 days, 14 days, and 21 days after treatment. Plasma was analyzed from the day 0 time points for peak plasma concentration and evaluation of exposure versus dose. The plasma obtained at days 7, 14, and 21 was collected to evaluate drug concentration relative to a documented DLT. In the higher-dose cohorts, the PK timepoints in this study were selected based on preclinical data of reporting maximum drug in plasma at the EOI, and an elimination half-life of 10–100 hr.13 For sample collection, blood was collected in sodium heparin tubes. Samples were centrifuged in a clinical centrifuge at 3,000 rpm for 15 min. The plasma was removed and stored at –80°C in 1.0 mL aliquots until batch analysis. Plasma platinum quantification of total platinum analysis was performed by a commercial laboratoryd. Time points for assessment of maximum plasma concentration of platinum and evaluation of dose–exposure relationship for all dogs were pretreatment, EOI, and 2 hr and 4 hr after infusion. Time points for calculation of mean plasma exposure were pretreatment, EOI, and 2 hr, 4 hr, and 7 days after treatment for dose cohorts of 100–140 mg/m2. The higher-dose cohorts were selected to reflect the clinically applicable dose range for which mean plasma exposure would be relevant.
The specific methods performed by the commercial laboratory were not shared with the authors. The plasma samples were shipped overnight on dry ice for analysis at Midwest Laboratoriesd. Sample analysis was conducted via inductively coupled plasma mass spectrometry, which followed an acid digestion/preparation of the sample to destroy and solubilize the sample, creating a stream of elemental ions. The ions were then separated by a mass spectrometer into their individual elements. The mass spectrometer measured the masses of the elements present and quantified the levels present. These results were correlated to known levels of standards and calculated back to original concentration in the sample analyzed.
Statistical Analysis
Descriptive statistical analysis was performed using Microsoft Excel 2016e. Pharmacokinetic analysis was performed by noncompartmental analysis using Phoenix WIN NONLIN softwaref. The assumptions of linear regression were met. Correlations between plasma platinum concentrations and dose were analyzed by Pearson correlation using GraphPad Prism version 8.2.1 for macOSg.
Results
Study Population
Twelve dogs were screened for eligibility between September 2015 and April 2016. The number of evaluable dogs is summarized in Figure 1. Patient demographics, tumor type, prior treatment(s), and cohort assignments are described in Table 1. Patients were diagnosed with treatment-refractory disease (n = 4), evidence of gross metastatic disease (n = 5), and/or malignancies for which there is no known effective therapy (n = 6). The most common breed was mixed-breed dog (n = 2), and the remaining eight dogs represented eight individual breeds. The median age was 8.5 yr (2.7–11.8), and the median weight was 28.5 kg (10.9–51.4).
Citation: Journal of the American Animal Hospital Association 56, 4; 10.5326/JAAHA-MS-7007
Dosing and Pharmacokinetics
Ten doses of oxaliplatin were administered to the enrolled patients, one at each dose level (Table 1). Twenty doses of Ca++ and 20 doses of Mg++ were administered: six doses at 250, 350, and 450 mg each and two doses at 500 mg.
Individual dog PK from EOI to 4 hr after infusion is depicted in Figure 2A, and total plasma platinum concentration at EOI relative to dose is depicted in Figure 2B. There was no statistically significant relationship between increasing dose and EOI (Cmax; r2 = 0.294, P = .1054).
Citation: Journal of the American Animal Hospital Association 56, 4; 10.5326/JAAHA-MS-7007
When averaged over time, the platinum concentration in the plasma up to 4 hr after infusion increased with increasing dose for all dose levels, showing a linear relationship between dose and exposure (Figure 3; r2 = 0.6387, P = .005).
Citation: Journal of the American Animal Hospital Association 56, 4; 10.5326/JAAHA-MS-7007
The mean plasma exposure (±SD) over 7 days in patients receiving 100–140 mg/m2 was 81.2 ± 2.26 µg/mL × hr.
Adverse Events
There were no grade 3 or 4 AEs. No deaths were attributed as “probable, likely, or definitely related” to oxaliplatin administration. A DLT and MTD for a single dose of oxaliplatin in solid tumor–bearing dogs were not identified up to the preset maximum dose level of 140 mg/m2.
There were two patient deaths during the study. The dog in the 70 mg/m2 cohort was euthanized following the day 14 assessment as a result of progressive local disease (urinary obstruction). This dog had been diagnosed with urothelial cell carcinoma of the urethra. This event was deemed unlikely to be related to administration of oxaliplatin. The dog in the 120 mg/m2 cohort died within 12 hr after infusion. Postmortem cytologic diagnosis was malignant neoplasia, suspected carcinoma or anaplastic sarcoma. Enrollment evaluation included three-view thoracic radiographs, abdominal radiographs, abdominal ultrasound, CBC, serum biochemistry, urinalysis, and cytologies of the hepatic lymph node and liver. Gross necropsy findings were consistent with acute hemorrhage, possibly secondary to disseminated intravascular coagulation. A large pancreatic mass and multiple hemorrhagic masses diffusely affected the liver and omentum, and there were several markedly enlarged hepatic lymph nodes. Histologically, the postmortem diagnosis was pancreatic carcinoma metastatic to the liver and lymph nodes as well as hemorrhage. There were no gross or histological cardiac abnormalities. This event was deemed a grade 5 hemorrhage, and the relation to oxaliplatin was determined to be “possibly related.” Per trial protocol, trial enrollment resumed, and further dose levels were monitored for the first 24 hr after infusion with a Holter monitor. No further hemorrhage or sudden death events occurred for the remainder of the study.
All AEs observed during the course of the study are outlined in Table 2. There were 20 events determined to be probably or definitely related to oxaliplatin treatment: 9 events were assigned grade 2, and the remaining events were grade 1. Lethargy was the most common AE (n = 6), followed by anorexia (n = 4), nausea/vomiting (n = 3), and anemia (n = 3). Constitutional and gastrointestinal events were the only clinically significant AEs, all of which occurred within the first week and were transient and self-limiting. There were no cardiac AEs with probable or definite relation to oxaliplatin treatment noted during oxaliplatin infusion, at days 7, 14, or 21, or during the 24 hr Holter recordings for cohorts 130 and 140 mg/m2. One dog had second-degree atrioventricular block during infusion (80 mg/m2 cohort), and this was considered to be a grade 1 AE, unlikely related. This dog also had occasional premature supraventricular atrial complexes on days 14 and 21, which were also considered grade 1 AEs with unlikely relation to oxaliplatin. Another dog had a solitary premature ventricular complex on day 7, which was considered a grade 1 AE and unlikely related to oxaliplatin. There were no neurological AEs documented on physical exam or patient history. There was no clinically significant myelosuppression or metabolic toxicities.
Discussion
The data from this phase 1 study suggest that a single dose of oxaliplatin may be well tolerated by cancer-bearing dogs up to doses of 140 mg/m2. The PK analysis demonstrated that there is a linear relationship between exposure and dose, achieving concentrations in the plasma similar to the therapeutic concentrations reported in humans. A DLT was not observed. The most common AE was lethargy. There were no significant hematologic, metabolic, cardiac, or neurological toxicities observed, and no deaths were attributed as probable or likely related to treatment.
The plasma concentration of oxaliplatin at EOI did not show a statistically significant relationship with increasing dose in this study. The primary half-life for intact oxaliplatin in human blood is 14 min.29 There was a statistically significant correlation between dose and exposure when additional time points were evaluated at the higher dose levels, indicating a linear relationship. The total plasma concentrations achieved in our study are similar to those reported in human studies (Table 3). Sampling error at the EOI is the most likely explanation for the lack of statistical significance; the blood sampling for pharmacokinetic analysis was not consistently obtained immediately upon completion of the oxaliplatin infusion and prior to the Ca-Mg infusions. Sampling error or potential lack of stability of oxaliplatin in plasma stored at –80°C may also explain the inconsistent data for the individual dog PK at the first (50 mg/m2) dose level.
Oxaliplatin is highly and rapidly protein bound. The measurement of plasma total platinum in this study does not reflect the free, or active, platinum, which is typically measured in plasma ultrafiltrate. Data for total platinum levels following oxaliplatin administration exist in humans and dogs for the direct comparison of our data regarding achievable concentrations in the plasma.13 PK data in preclinical studies demonstrate that maximum concentration in both plasma and ultrafiltrate is achieved at the EOI and declines biphasically, with an elimination half-life of ∼24 hr.13 Future studies evaluating the PK of oxaliplatin will include measurement of platinum in the ultrafiltrate to reflect the free drug and to correspond with more recent human studies.
It has been reported in human medicine, and supported by a meta-analysis, that patients receiving Ca-Mg infusions before and after oxaliplatin experienced fewer and less severe episodes of sensory neuropathy with no impact on efficacy.11 Subsequent studies in human medicine reported conflicting findings, and a recent systematic review has concluded that there is no beneficial effect for the prevention of oxaliplatin-induced sensory neuropathy.12 However, it remains the standard of care to administer Ca-Mg to human patients receiving oxaliplatin treatment. For the dogs in our study, there were no clinical symptoms consistent with neuropathy reported by owners and no changes in neurological exam findings of the dogs consistent with a sensory neuropathy. It is unknown if there was any benefit of the Ca-Mg infusions in our patients, and neurological toxicity may not be a major concern in dogs receiving oxaliplatin. Additionally, treatment time is prolonged, resulting in an additional 1–2 hr infusion of oxaliplatin. Future veterinary studies including oxaliplatin may consider treatment without Ca-Mg infusions.
Similarly, the coadministration of maropitant may have confounded the toxicity data. However, unlike the coadministration of Ca-Mg infusions for potential for neurotoxicity in canine patients, gastrointestinal toxicity is documented in preclinical studies of oxaliplatin in dogs receiving infusions of 100 mg/m2 and higher. Additionally, it is standard of care to administer antiemetics to human patients receiving treatment with oxaliplatin. Although the degree of benefit experienced by the participants is unknown, ethical considerations of executing a clinical trial in client-owned dogs warranted the additional cost of supportive care measures for a previously identified, preventable toxicity. The data generated by the current study may underrepresent the gastrointestinal toxicity associated with oxaliplatin treatment. However, the findings are relevant for clinical use, and it is expected that further studies evaluating oxaliplatin will include the coadministration of antiemetics.
Treatment with oxaliplatin was well tolerated in this study. The study was designed to escalate dose up to a maximum of 140 mg/m2. This was based on the finding of sudden cardiac ventricular fibrillation and death in healthy beagles following a single 2 hr infusion of oxaliplatin at 150 mg/m2 in preclinical studies.13 The sudden death of the dog at the 120 mg/m2 dose level was determined to be possibly related to oxaliplatin administration. Gross and histological postmortem findings supported that the dog most likely died as a result of a significant tumor burden of metastatic pancreatic carcinoma. There were no cardiac abnormalities noted grossly or histologically. It is more likely that the cause of death was unrelated to oxaliplatin, but it cannot be completely ruled out whether treatment with oxaliplatin contributed to death. No additional deaths occurred at subsequent dose levels, and there were no arrhythmias or concern for cardiotoxicity upon evaluation of the 24 hr Holter monitoring at these dose levels.
The lack of significant hematologic or metabolic toxicity in the current study parallels findings in the phase 1–2 trials in human patients.6,9 Without concern for overlap in hematologic or metabolic toxicity with most cytotoxic chemotherapeutics, oxaliplatin is an attractive candidate for combination-drug therapy. Oxaliplatin is synergistic with fluorouracil, and this combination is the foundation of treatment of human duodenal and colorectal carcinoma.30
The limitations of this dose-escalation study center on the trial design. An ATD was used based on the tolerability of oxaliplatin in phase 1–2 trials in human patients and in preclinical studies in healthy beagles. Although initial single-patient cohorts allowed for more rapid dose escalation and fewer patients receiving subtherapeutic dosing, it may have resulted in underrepresentation of the toxicity of oxaliplatin. Additionally, each patient was evaluated after a single dose. The DLT of sensory neuropathy in humans is known to be chronic as well as acute, with increasing risk following cumulative dosing. Multidosing of oxaliplatin may reveal toxicity associated with cumulative treatment not observed in this study. The pharmacokinetic sampling at the EOI was inconsistent and likely resulted in lack of statistical significance of the relationship between the plasma concentration at EOI and dose. Consistent and prompt sampling as well as inclusion of additional time points during infusion and following infusion out to five times the terminal half-life would strengthen the understanding of the pharmacokinetic parameters of oxaliplatin in tumor-bearing dogs. Finally, the death of the dog at the 120 mg/m2 dose level was determined to be possibly related to treatment with oxaliplatin, and the approved trial protocol did not mandate cohort expansion at this dose level. An expansion cohort at the highest dose level (140 mg/m2) is indicated to ensure that oxaliplatin can safely be administered to dogs with cancer.
Conclusion
A single infusion of oxaliplatin to tumor-bearing dogs appears to be well tolerated up to doses of 140 mg/m2. There is a linear correlation between exposure and dose, and the total platinum plasma concentration was similar to what has been reported for oxaliplatin in humans. The most common AE was lethargy. There were no significant hematologic, metabolic, cardiac, or neurological toxicities observed, and no deaths were attributed as probable or likely related to treatment. An expansion cohort of dogs with cancer receiving multiple doses of oxaliplatin is indicated to further demonstrate safety of oxaliplatin treatment. Prospective phase 1 combination-drug trials following rational drug selection are needed to determine combination-treatment safety and identify malignancies for phase 2 evaluation of efficacy.
Flow diagram of the progress through the phases of the study for screening, enrollment, treatment, and evaluable data. PD, progressive disease.
Total plasma platinum concentrations. (A) Individual dog total plasma platinum concentration from end of infusion to 4 hr after infusion. (B) The end-of-infusion concentration relative to administered dose. There was no stastically significant relationship between increasing dose and platinum concentration (r2 = 0.294, P = .1054).
Averaged over time (0–4 hr), the platinum concentration in the plasma increased in a linear fashion with increasing dose for all dose levels, showing good correlation between dose and exposure (r 2 = 0.6387, P = .005). AUC, area under the curve; EOI, end of infusion.
Contributor Notes
AE (adverse event); ATD (accelerated titration design); Ca++ (calcium gluconate); CBC (complete blood count); DLT (dose-limiting toxicity); DNA (deoxyribonucleic acid); ECG (electrocardiogram); EOI (end of infusion); Mg++ (magnesium sulfate); MMR (mismatch repair); MTD (maximally tolerated dose); PK (pharmacokinetic); SAE (serious adverse event); VCOG-CTCAE (Veterinary Comparative Oncology Group Common Terminology Criteria for Adverse Events)
