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Annals of Oncology Advance Access originally published online on May 25, 2006
Annals of Oncology 2006 17(8):1313-1319; doi:10.1093/annonc/mdl097
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© 2006 European Society for Medical Oncology

A phase I study of intravenous TZT-1027 administered on day 1 and day 8 of a three-weekly cycle in combination with carboplatin given on day 1 alone in patients with advanced solid tumours

A. Greystoke1, S. Blagden1, A. L. Thomas3, E. Scott3, G. Attard1, R. Molife1, L. Vidal1, S. Pacey1, D. Sarkar1, A. Jenner2, J. S. De-Bono1 and W. Steward3,*

1 Drug Development Unit, Royal Marsden Hospital, Sutton; 2 Daiichi Pharmaceuticals UK Ltd, London, 3 Leicester Royal Infirmary, Leicester, UK

* Correspondence to: Prof. W. Steward, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, UK. E-mail: wps1{at}leicester.ac.uk


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: TZT-1027 is a tubulin-binding drug and synthetic derivative of dolastatin-10 with cytotoxic and antivascular activity in vitro and in vivo. Studies have demonstrated anti-tumour activity in several tumour types.

Methods: Patients were treated with escalating doses of TZT-1027 and carboplatin at doses from 1.6 to 2.0 mg/m2 and AUC 4 and 5 respectively. For pharmacokinetic analysis, plasma sampling was done during the first course using a high-performance liquid chromatographic assay.

Results: 14 patients received a total of 55 cycles at three dose levels. Dose limiting toxicities (DLTs) were first observed with 1.6mg/m2 TZT-1027 and carboplatin AUC 5; 1 patient had grade 4 neutropenia and a delay in day 8 treatment occurred in two patients (gr 2 fatigue, gr 3 diarrhoea). At TZT-1027 2 mg/m2 and carboplatin AUC 5, one patient experienced grade 3 paralytic ileus. The most frequent toxicities were neutropenia, anaemia, fatigue, constipation, infection and vomiting. Peripheral neuropathy was reported in 36% of patients. One patient (pancreatic adenocarcinoma) achieved a partial response lasting 181 days. Pharmacokinetic analysis did not demonstrate any interaction between TZT-1027 and carboplatin.

Conclusions: The recommended phase II dose is TZT-1027 1.6mg/m2 and carboplatin AUC 5. No evidence of a PK interaction between these agents was observed.

Key words: carboplatin, dolastatin 10 analogue, phase I, solid tumours, TZT-1027


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
The dolostatins are a new class of tubulin binding cytotoxics originally derived from the marine mollusc Dolabella auricularia [1Go]. TZT-1027 (soblidotin), a semi-synthetic derivative of dolostatin-10, binds to tubulin, inhibiting polymerisation of microtubules in dividing cells [2Go]. The result is G2/M cell cycle arrest and apoptosis [3Go]. The binding site of TZT-1027 overlaps that of the vinca alkaloids, but it appears that the two agents interact with tubulin in different ways [4Go, 5Go]. TZT-1027 also appears to have an anti-vascular effect not seen with docetaxel [6Go]. In mouse xenograft models the administration of TZT-1027 led within 3 h to congestive thrombi formation in the tumour vasculature with subsequent blood vessel collapse and necrosis [7Go].

Three phase I studies of single-agent TZT-1027 investigating different schedules have been reported. Yamamoto et al. administered TZT-1027 weekly for 3 weeks only at doses ranging from 0.3 mg/m2 to 2.1 mg/m2 in 40 patients. A patient with thymoma achieved a partial response (PR) lasting 183 days. Dose-limiting neutropenia was demonstrated at 2.1 mg/m2 [8Go]. In the second study 21 patients received TZT-1027 every 3 weeks with a recommended dose of 2.7 mg/m2 [9Go]. Seven patients demonstrated stable disease and the main toxicities noted were neutropenia, fatigue and reversible peripheral neuropathy. In the final study 17 patients were treated on days 1 and 8 of a 3-weekly cycle [10Go]. A patient with liposarcoma demonstrated a PR of longer than 54 weeks and the main toxicities observed were neutropenia and pain in the infusion arm. A dose of 2.4 mg/m2 was recommended for single-agent phase II assessment.

These studies showed TZT-1027 to be a well tolerated and active cytotoxic. The day 1 and 8 schedule was considered most promising for further development. The present study is the first to combine TZT-1027 with carboplatin. Although carboplatin and TZT-1027 appear to have similar toxicity profiles, their distinct mechanisms of action suggest that the combination has potential for a broad range of activity.

The primary aim of this study was to determine the maximally tolerated dose (MTD) of TZT-1027 and carboplatin when given on a 21-day cycle, in minimally pretreated patients with advanced solid tumours. Secondary objectives were to assess the toxicity and pharmacokinetic profile of the combination and obtain preliminary evidence of anti-tumour activity.


   patients and methods
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 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
patient selection
Patients with histologically confirmed locally advanced or metastatic solid tumours refractory to conventional therapy were eligible provided they met the following criteria: age ≥ 18, Eastern Co-operative Oncology Group (ECOG) performance status (PS) 0–2; expected survival of ≥ 12 weeks; adequate haematopoietic (absolute neutrophil [ANC] count ≥1.5 x 109L, platelet count ≥100 x 109l), hepatic (bilirubin ≤1.5xupper limit of normal [ULN], aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN [or ≤5 x ULN when liver metastases are present]), and renal (serum creatinine ≤1.5 x ULN, estimated or measured creatinine clearance ≥ 40 ml/min [11Go]) function; fully recovered and 4 weeks from major surgery, radiotherapy or chemotherapy (6 weeks from mitomycin-C and nitrosurea chemotherapy); and a negative pregnancy test for females of childbearing potential. All patients provided written informed consent.

Patients were excluded if they had: known hypersensitivity to carboplatin; concurrent serious infection; leptomeningeal or brain metastases unless previously treated, off anti-epileptics and steroids and stable for 4 weeks; or concomitant severe underlying medical disease including left ventricular ejection fraction (LVEF) of <40%.

concomitant medications
Treatment with bisphosphonates, LHRH therapy and erythropoietin were allowed. GCSF or GM-CSF was allowed from cycle 3 only if dose reduction did not prevent haematological toxicity.

study procedures
The trial protocol, investigators' brochure and patient information sheet and consent form were approved by a Research Ethics Committee. The study was performed according to the Declaration of Helsinki and ICH GCP guidelines. The study was fully monitored and audited.

pre-treatment and study procedures
Baseline assessments (within 14 days of starting therapy) included: full medical history, physical examination (PE) including PS, height, weight and vital signs; full blood count (FBC), serum biochemistry including creatinine, bilirubin, alkaline phosphatase, AST, ALT, albumin and electrolytes, urinalysis, and pregnancy test where appropriate. Procedures carried out within 28 days of start of therapy included: written informed consent (prior to any study procedure), electrocardiogram (ECG), chest X-ray, cardiac evaluation via multi-acquisition gated (MUGA) or echocardiogram, and tumour assessment by computed tomography or magnetic resonance imaging. Assessments prior to each cycle included a record of adverse events, concomitant medications and physical findings. On days 1 and 8 of each course, vital signs and urinalysis were performed. FBC was performed weekly, except if ANC <0.5 x 109/l, when FBC was performed twice weekly until recovery. Biochemistry was measured weekly for course 1 and 2 only; thereafter, testing was on days 1 and 8 only. An ECG was performed immediately prior to and 3 h after the first TZT-1027 infusion only. Cardiac function was evaluated after course 2 and repeated only if LVEF fell below 40%, or if clinically indicated.

Disease was assessed according to the RECIST criteria every two cycles until discontinuation from the study [12Go]. Radiological responses were confirmed by repeat imaging within 28 days. End of study assessments included PE, FBC, serum chemistry, urinalysis and tumour evaluation. Ongoing adverse events were monitored until resolution. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria Version 3.0 [13Go]. Patients were withdrawn from the study in the case of progressive disease (PD), unacceptable toxicity, withdrawal of consent or pregnancy.

drug administration
TZT-1027 was supplied by Daiichi Pharmaceutical Co., Ltd. (Tokyo, Japan) as a clear colourless aqueous solution in glass vials that were stored in darkness at room temperature (15–25°C). The required dose of TZT-1027 was diluted in 250–500 ml of either 0.9% saline or 5% dextrose, stored at 5° ± 3°C or room temperature and used within 24 h. Carboplatin was supplied as a liquid for injection, stored in darkness and at room temperature and prepared as per the product datasheet. The dose was calculated according to the Calvert formula using a measured or calculated creatinine clearance [11Go, 14Go].

Carboplatin was administered on day 1 and TZT-1027 on day 1 and 8 of a 21-day cycle. Carboplatin was infused over 30 min followed 30 min later by TZT-1027 over 1 h; TZT-1027 was administered over 1 h on day 8. Both drugs were administered intravenously (IV) into a peripheral vein using a programmed peristaltic pump. The anti-emetic regime comprised of granisetron 1mg and dexamethasone 8 mg given IV prior to carboplatin, with dexamethasone 4 mg orally tds for 2 days and metoclopromide 10 mg tds for 3 days post therapy.

dose escalation procedure, definition of dose-limiting toxicity and maximum tolerated dose
The starting dose of TZT-1027 was set at two-thirds the recommended single agent dose, i.e. 1.6 mg/m2, in combination with carboplatin dosed at AUC 4 [10Go]. The planned dose escalation schedule is shown in Table 1. Each dose level was administered to a cohort of three patients. In the absence of a DLT, dose escalation continued in successive cohorts of three patients when three patients had completed one cycle. DLT was defined as any of the following occurring in the first cycle: febrile (>38.5°C) grade 4 neutropenia; grade 4 neutropenia lasting >5 days; platelets <25 x 109/l; grade 4 vomiting with maximal anti-emetic therapy; grade 3 diarrhoea in the absence of anti-diarrhoeal use; other grade 3 or 4 non-haematological toxicities; and the inability to receive day 8 treatment or to start a second course of treatment despite 1 week delay due to treatment-related toxicity.


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  		Table 1. Dose escalation schedule

 
If one of three patients experienced a DLT, an additional three patients were treated at the same dose level. If no further DLTs were observed dose escalation proceeded. However, if a further DLT (two out of six patients) was observed, the MTD was exceeded and at least six patients were treated at the preceding dose level to further characterise toxicity.

Once DLT was first observed, all patients subsequently recruited were minimally pre-treated (MP). Such patients should have received <6 cycles of an alkylating agent, ≤6 course of carboplatin, <2 courses of mitomycin-C or a nitrosurea as part of a single regimen and not received prior bone marrow transplantation or radiotherapy to >25% of the bone marrow.

dose modification
Day 8 treatment was withheld if ANC <1.0 x 109/l or platelets <100 x 109/l, or if all non-haematological toxicities (excluding alopecia) had not recovered to either grade 1 or baseline. Treatment could be delayed by a maximum of 2 weeks (day 36) to allow recovery; otherwise the patient was taken off study. Recovery was defined as ANC ≥ 1.5 x 109/l, platelets ≥ 100 x 109/l and return to baseline, or grade 1 of all non-haematolgical toxicities (excluding alopecia). If a patient experienced DLT, the doses for subsequent courses were decreased by 1 dose level. If DLT recurred further reduction was not permitted and the patient was taken off study. No dose re-escalations or intra-course dose reductions were permitted.

pharmacokinetic sampling and assay
Pharmacokinetic sampling was carried out on day 1 and day 8 of the first cycle. On day 1, 5 ml of whole blood were taken just prior to the start of and at the end of the carboplatin infusion. On days 1 and 8, 10 ml of whole blood were taken immediately prior to the TZT-1027 infusion, at 30 and 60 min during the infusion, and 30 min, 1, 2, 4, 6 and 24 h after the end of the TZT-1027 infusion. Two 6 ml blood samples were drawn on days 1 and 8 to quantify {alpha}-1-acid glycoprotein ({alpha}1-AGP). Samples were spun at 3000 r.p.m. for 15 min and the plasma stored at –80°C until analysis. This was performed with a previously validated assay using High Performance Liquid Chromatographic Mass Spectrometry at MDSPS, Montreal, Canada.

The following PK parameters were evaluated from the plasma samples by non-compartmental analyses: time of maximum concentration (Tmax), half-life (T1/2), maximum concentration (Cmax), area under the curve (AUC), volume of distribution (Vss), and clearance (Cl). The linearity of the TZT-1027 and carboplatin plasma kinetics in relation to dose and the relationship between toxicity and the PK parameters Cmax, AUC0-t, AUC0-{alpha} and clearance were assessed. The correlation between plasma {alpha}1-AGP concentrations and TZT-1027 clearance was analysed.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
general
Fourteen patients (nine male and five female) were treated, with a median age of 59 (range 34–76) years. A wide range of tumour types was treated and all 14 patients had received prior treatment (13 had received prior chemotherapy) as outlined in Table 2. No DLT was seen in the three patients who received treatment with TZT-1027 1.6 mg/m2 and carboplatin AUC 4. In the next cohort (TZT-1027 1.6 mg/m2 and carboplatin AUC 5) a patient, previously treated with three lines of chemotherapy, failed to receive his cycle 2 treatment due to prolonged grade 3 neutropenia. Therefore the cohort was expanded to six patients, and only MP patients were subsequently enrolled.


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  		Table 2. Patient characteristics

 
In the expanded cohort two further patients experienced DLT. One patient experienced prolonged (7 days) grade 4 neutropenia. This patient did not receive the day 8 treatment due to grade 2 fatigue. The other patient failed to receive day 8 treatment in cycle 1 due to grade 3 diarrhoea. The etiology of this diarrhoea was unclear as the patient was on long-term antibiotics and did not receive maximum anti-diarrhoeal treatment. This cohort was therefore expanded to nine patients (six MP patients) in order to determine whether the MTD in MP patients had been exceeded at this dose level. No further DLT was seen and so a further cohort was recruited for treatment with 2.0 mg/m2 TZT-1027 and carboplatin AUC 4.

Only two patients were treated in this cohort, one of whom experienced DLT. A patient previously treated with two lines of systemic therapy, including a cisplatin-containing regimen, did not receive day 8 therapy due to grade 3 paralytic ileus. Concurrently one of the patients in the previous cohort developed protracted grade 4 neutropenia during cycle 2, and despite dose reduction he developed grade 4 neuropathy during cycle 4. There was concern about the appearance of cumulative toxicity both haematological and neurological in nature, therefore it was decided that the MTD had been reached at carboplatin AUC 5 and TZT-1027 1.6 mg/m2.

Table 3 shows the number of courses and patients treated at each dose level. The median number of cycles per patient was three (range 1 to 11). Day 8 treatment was omitted due to toxicity in five patients (36%). Dose delay between courses occurred in 79% (11) of patients, with dose reductions in 43% (6) of patients. The delays in dose administration were similar between dose levels with a mean delay in starting a cycle of therapy of 5, 3 and 7 days in the three cohorts respectively. The commonest reason for dose delay and reductions was hematological toxicity in nine and four patients respectively.


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  		Table 3. Drug administration and dose levels of carboplatin and TZT-1027 studied

 
non-haematological toxicity
All patients were evaluable for safety. The frequencies of the most common non-haematological toxicities are outlined in Table 4. Overall, in all cycles, the most frequent toxicities were fatigue in 57% (21% grade 3), constipation in 50% (7% grade 3), infection in 50% (7% grade 3), vomiting in 50% (7 % grade 3) and nausea in 43% (7% grade 3).


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  		Table 4. Total episodes of non-haematological toxicity observed in all cycles and in the first cycle administered by dose level (T, dose TZT-1027 mg/m2; C, carboplatin AUC)

 
Neuropathy was reported in 36% of patients with a median duration of onset 3.5 days after treatment and median duration of 24 days. During a fourth treatment cycle a patient presented with bilateral foot drop, global areflexia and sensory neuropathy bilaterally to his knees (grade 4). The neuropathy improved to grade 1 within 28 days. Other episodes of neuropathy were sensory in nature mostly affecting the distal extremities. A patient with facial parasthesia at baseline secondary to his disease noted an increase in severity whilst one patient developed parasthesia over his torso on treatment.

Two patients experienced grade 3 dizziness and one patient developed grade 3 elevated transaminases and {gamma}-glutaryl transferase during cycle 2. Other toxicities were mild (grade 1–2) and included mucositis (36%), elevated ALP (21%), and altered taste and anorexia —both in 14% of patients.

haematological toxicity
The haematological toxicities are summarised in Table 5. The most common toxicity was neutropenia with a median onset 15 days after treatment and a median duration of 7 days. Two neutropenic events were dose limiting; however, there were only three patients who developed febrile neutropenia. Seventy-one percent of patients experienced anemia (35% grade 3), whilst 43% and 36% developed leucopenia and thrombocytopenia respectively.


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  		Table 5. Episodes of hematological toxicity observed in all cycles and in the first cycle administered by dose level

 
pharmacokinetics
Complete plasma sampling was acquired at day 1 for all 14 patients and on day 8 for 11 patients. Peak plasma concentrations of TZT-1027 and carboplatin were reached within 1 hour of administration. The mean clearance (l/r.r.) of TZT-1027 was 8.1 ± 3.7 in patients treated in the 1.6 mg/m2 cohort and 5.4 ± 0.5 in the 2.0 mg/m2 cohort. The mean plasma half-life after day 1 administration in the 1.6 mg/m2 cohort was 5.9 ± 3.3 hours. The pharmacokinetic parameters are shown in Table 6. The plasma concentration-time profiles of TZT-1027 were similar for all patients studied and are shown in Figure 1. There is a poly-exponential decline similar to that reported with single agent TZT-1027 administered using the same schedule [10Go]. The plasma concentration-time profiles for total and free carboplatin (Figure 2) were in keeping with previously reported linear kinetics and confirmed there were no significant pharmacokinetic interactions between the TZT-1027 and carboplatin [15Go].


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  		Table 6. Pharmacokinetics of TZT-1027 in cycle 1

 

Figure 1
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  		Figure 1. Mean TZT-1027 plasma concentration following TZT-1027 IV administration at dose levels of 1.6 and 2.0 mg/m2 linear plot.

 

Figure 2
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  		Figure 2. Mean plasma concentration over course one of total and free carboplatin IV administration linear plot.

 
response assessment
Of the 13 patients evaluable for efficacy, one patient achieved a partial response (PR), eight stable disease (SD) and four PD. The PR lasting 181 days was seen in a 64-year-old female with pancreatic adenocarcinoma who completed seven cycles of treatment in cohort 1. Of the eight patients achieving SD, two had pancreatic adenocarcinoma, two gastric adenocarcinoma, two NSCLC, one patient oesophageal adenocarcinoma and one peripheral nerve sheath sarcoma. The median duration of disease stability was 70 days (range 31–203).


   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
Here we report the results of a phase I trial using a combination of carboplatin with a novel dolostatin-10 semi-synthetic analogue, TZT-1027. The development of novel tubulin binding drugs has been pursued in order to acquire more active, less toxic agents with improved pharmacokinetic properties and formulation than those currently available. In particular the abrogation of neurotoxicity by these agents remains a priority. Tumors develop resistance to established anti-microtubule agents through a number of different mechanisms including up-regulation of resistant tubulin isoforms and of proteins involved in cellular efflux, such as the MDR pump [16Go, 17Go]. Novel tubulin-binding agents that have differential tubulin binding properties and can bypass these resistance pathways are therefore sought. TZT-1027 is one such agent as its method of inhibiting tubule polymerisation differs from that of the vinca alkaloids [4Go]. Early preclinical assessment showed that TZT-1027 was not only directly cytotoxic to cancer cell lines, but also demonstrated anti-vascular activity and was demonstrated to be pro-apoptotic [3Go].

In this study, we combined TZT-1027 with the cytotoxic agent carboplatin, using a 3-weekly dose-escalation schedule of 1.6 mg/m2 to 2 mg/m2 TZT-1027 on days 1 and 8 alongside carboplatin AUC 4 increased to 5 on day 1 alone. Fourteen patients were treated all with solid tumours refractory to standard therapy. The most frequently observed toxicities were neutropenia, fatigue, constipation and nausea. Nausea was controllable with additional anti-emetics when required. Carboplatin can cause neutropenia and this may account for neutropenia occurring at lower doses of TZT-1027 than in the previous single agent studies.

In pre-clinical toxicology studies no evidence of neurotoxicity was seen with TZT-1027 [6Go, 18Go]. However, in a previous study utilising single-agent TZT-1027 mild neuropathy was seen in five patients (four had received prior platinum therapy) [10Go]. Similarly, Schoffski et al. observed two patients, who had received oxaliplatin treatment, that developed grade 3 neurological symptoms when administered TZT-1027 at doses above the MTD. They suggested that in patients who had received prior neurotoxic therapy, the administration of TZT-1027 could result in neurological side-effects [9Go].

In our study, mild peripheral neuropathy was noted in 28% of patients but two patients developed severe neurological complications. An episode of paralytic ileus was observed after one dose of 2.0 mg/m2 and the patient with grade 4 neuropathy developed symptoms after four cycles of treatment. This suggests that the neuropathy may be dose-related and cumulative; however, the neuropathy was reversible and gradually resolved over 28 days. The patient who experienced grade 4 neuropathy had previously been treated with cisplatin, which could account for the severity of the reaction. In conclusion, carboplatin may increase the risk of neuronal toxicity when combined with TZT-1027. This study demonstrates combination treatment using TZT-1027 and carboplatin can be relatively well tolerated with preliminary evidence of anti-tumor activity.

Received for publication February 22, 2006. Revision received March 29, 2006. Accepted for publication March 30, 2006.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 References
 
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10. de Jonge MJ, van der Gaast A, Planting AS et al. Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors. Clin Cancer Res 2005; 11: 3806–3813.[Abstract/Free Full Text]

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14. Calvert AH, Newell DR, Gumbrell LA et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7: 1748–1756.[Abstract]

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17. Greenberger LM, Lothstein L, Williams SS, Horwitz SB. Distinct P-glycoprotein precursors are overproduced in independently isolated drug-resistant cell lines. Proc Natl Acad Sci USA. 1988; 85: 3762–3776.[Abstract/Free Full Text]

18. Ogawa T, Mimura Y, Isowa K et al. An antimicrotubule agent, TZT-1027, does not induce neuropathologic alterations which are detected after administration of vincristine or paclitaxel in animal models. Toxicol Lett 2001; 121: 97–106.[CrossRef][Web of Science][Medline]


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