Cancer 7i-eatment Reviews (1985) 12 (Supplement A), 35-41

Phase I study and pharmacokinetics of intraperitoneal carboplatin

J. Gordon McVie, * Wim ten Bokkel Huinink,* Ria Dubbelman,* Hilary Franklin,* Wim van der Vijgh* and Ina Klein?

* The Netherlands Cancer Institute, Antoni van Leeuwenhoek-Huis, Plesmanlaan 121, Amsterdam, and t Department of Oncology, Free University, Amsterdam, The Netherlands

In the early stages of this phase I study the tolerance of carboplatin intraperitoneally was good. Pharmacokinetic profiles suggest a possible therapeutic advantage for giving the drug intraperi- toneally for the treatment of tumour nodules situated in the peritoneum. The extent of penetration of carboplatin through tumour nodules has not yet been assessed but tumour nodules are being processed for nuclear activation analysis

Introduction

The advent of cisplatin containing regimes for treatment of ovarian cancer has led to dramatic remissions in bulky tumours. Pathologically complete remissions in 30% of patients are consistently being reported. A significant percentage of patients (between 20 and 30%) have at second look laparotomy, only microscopical residual disease or so called ‘minimal residual disease’, which is variously described as less than 1 or 2 cm tumour nodules scattered throughout the peritoneal and organ surfaces within the abdomen (1). Persistence with intravenous combination chemotherapy has rarely led to late complete remissions in minimal residual disease patients even after total doses of approximately 600 mg/m* cisplatin (2). High dose cisplatin regimes delivering 200 mg/m* per cycle have however produced clinical remissions in the 30% range, but at the cost of severe neurotoxicity, ototoxicity and visual disturbance (3). Radiation is a third possibility, and although long-term survivors have been reported there are few studies in which laparotomy proven complete remission rates are given.

Intraperitoneal cisplatin has been assessed in this clinical situation with consistent complete remission rates around 30% (4). The experience of the Netherlands Cancer Institute is 12 complete remissions, laparotomy proven, of 37 evaluable patients (5).

Address for reprint requests: J. G. McVie, Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.

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0 1985 Academic Press Inc. (London) Limited

36 J. GORDON McVIE ET AL

Administration of cisplatin via the intraperitoneal route gives less toxicity than the intravenous route due to lower plasma levels of both protein bound and ultrafiltered drug. Toxicity however is not negligible, consisting of myelosuppression, nephrotoxicity and neurotoxicity. The introduction of concomitant intravenous sodium thiosulphate, a so called rescue agent, has reduced the incidence of myelosuppression and renal toxicity in two large series but neurotoxicity has remained unaltered in the Amsterdam study, and was the dose limiting toxicity (4, 5).

Carboplatin is a new analogue of cisplatin with a low neuro- and nephrotoxic potential. It has been evaluated in ovarian cancer in phase II studies and found to have activity in the same range as cisplatin (6). The mechanism of action of carboplatin is not clear. It has a larger molecular weight than cisplatin so might be cleared more slowly from the peritoneal space. Furthermore, it is cleared faster from the plasma and this is a second reason for testing the drug intraperitoneally.

As with all phase I studies our objective was primarily to identify the maximum tolerated dose for intraperitoneal carboplatin. Further, we were interested in determining the nature of the side effects and the dose limiting toxicity and to detect possible efficacy. The opportunity was taken of sampling peripheral blood and ascites at varying time intervals after administration of the drug to determine the pharmacokinetic profile. Previous studies of intraperitoneal cisplatin had also raised the possibility of measuring penetration of that drug through peritoneal tumour nodules after local administration into the peritoneum with the use of proton induced X-ray emission (7). App ro p riate tumour samples from the carboplatin study were planned in order to ask the same question of the derivative.

Methods

Patients suffering from histologically proven ovarian cancer FIG0 stage III or IV usually were pretreated with cisplatin before entering this phase I study. Patients who were suffering from adenocarcinomas of other origins than ovary, but whose tumour had only metastasized transperitoneally and who were resistant to conventional therapy were also admitted to the study. Patients whose performance status was 4, WHO scale, > 75 years, or life expectancy less than 3 months were excluded from the study. Patients were required to have a creatinine clearance > 40 ml/min, white blood count > 3000 x log/1 and platelet counts > 100 x log/l. The starting dose was 200 mg/m’ carboplatin given in 2 1 of dialysis fluid for a dwell time of 4 hours via a Tenckhoff catheter. Therapy was usually started 1 week after insertion of the Tenckhoff catheter, sometimes coupled to a ‘port a cath’ reservoir. On the day before treatment distribution offluid throughout the peritoneal space was checked by a CT scan of the abdomen after infusion of 2 1 of dialysis fluid. Carboplatin treatment was planned to be repeated every 4 weeks according to recovery from toxicity. Escalation doses were 100 mg/m’ until WHO toxicity 3 was enountered and thereafter steps of 50 mg/m2 were planned. Three patients were treated at each dosage step with 1 week between patients and 3 weeks between dosage steps.

Analysis of platinum in plasma, ultrafiltrate, peritoneal fluid and urine was carried out by flameless atomic absorption spectrometry. Blood samples were centrifuged immediately after withdrawal from the patient. Plasma and ascites samples were ultrafiltered by centrifugal ultrafiltration using the AMICON MPS-1 system with YMT filters. Ultrafiltrates were obtained after centrifugation for 8 minutes at 2000 g. All samples were stored at -25°C until analysis. Just prior to analysis and after thawing, samples were

PHASE 1 STUDY AND PHARMACOKINETICS OF INTRAPERITONEAL CARBOPLATIN 37

diluted 1 : 1 (V/V) for pl asma, 9: 1 for ip fluid, urine and ultrafiltrate with a solution containing 0.4 M HCl and 0.15 M NaCl for plasma, or 2 M HCl in 0.6 M NaCl for the other samples. Standards prepared in the appropriate matrix containing 5, 10 and 15 pmol/l carboplatin were treated as the samples. A Perkin Elmer model 5000 atomic absorption spectrometer equipped with a MGA-500 graphite furnace and an AS40 autosampler were used. A four stage heating programme was used consisting of drying at 110°C for 65 set, ashing at 1400°C for 55 set, atomizing at 2650°C for 3 set using maximum power and conditioning at 2550°C for 5 sec. The inert gas was nitrogen. Initial pharmacokinetic parameters were worked out using a standard fit procedure.

Results

At time of presentation 9 patients had entered on study, at 2 dose levels. The reasons for admission to the protocol are given in Table 1. All patients had been previously treated with cisplatin and the number of courses given at 2 dose levels are shown in Table 2. As yet there have been no catheter-related problems but mild myelosuppression has been noted. The median nadir of platelets is 100 x 109/1 with a lowest platelet count of 60. The time of nadir for platelets was around day 24 with recovery around day 31. The cycles given at 300 mg/m2 are still too few to deserve much comment but there seems to be little difference from 200 mg/m2. At the first dose level one patient has developed white count suppression to 2.4 x 109/1 which was seen at day 32 and lasted until day 50, leading to the patient going off study. No further leukopenia has been noted. One patient at 300 “g/m2 has also dipped to 2.4 x 109/1 at day 12 and had recovered by day 36.

As shown in Table 3 patients complained of nausea, but no diarrhoea was seen in contrast to our experience with cisplatin. Three patients who had pre-existing neuropathy from cisplatin complained of increased symptoms after one course of carboplatin. In two of these this could not be objectively verified but in one, clear deterioration of EMG was confirmed. These patients were seen by a neurologist before each course oftherapy. The last patient with a clear objective neuropathy went off treatment.

Table 1. Patient selection

No. of patients

Progression on cisplatin regime 3 Neuropathy from cisplatin 3 Nephropathy from cisplatin 0 .Minimal residual disease 3

Table 2. Number of patients entered

Number of patients (previous cisplatin) Number of courses Number of courses with toxicity

200 mg/m’ 300 mg/m*

7 (lwh) 4 (lw4 13 7

5 TE

TE = Too early.

J. GORDON McVIE ET AL.

Table 3. Non-haematological toxicity

No. of patients (WHO)

LOCd

Catheter related Drug related

Systemic Nausea Diarrhoea Nephropathy Objective neuropathy” Subjective neuropathya

0 0

5 (3) 0 0 1 (3) 2 (1)

‘Deterioration of existing neuropathy.

The pharmacokinetic data are of considerable interest. A representative profile of the disappearance of the drug from ascites is given in Figure 1. Two curves are shown, one for the total platinum concentration and the other for the concentration in ultrafiltrate. An exaggerated fall of the platinum levels was observed at 4 hours after instillation due to removal of the peritoneal fluid. Platinum levels dropped below the detection limit of the analysis at 48 hours after the start ofinstillation. In plasma, however (Fig. 2), ultrafilterable platinum and total platinum could be observed up to 0.5 and 5 days after instillation, respectively. Peak platinum concentrations in either total plasma or ultrafiltrate were not higher than 30 pmol/l after 200 mg/m2 carboplatin (see Table 4). These levels are considerably lower than the peak platinum concentration reached in the peritoneum, reflected in the area under the curves calculated for each patient, and illustrated in Tables 4 and 5. The ratio of the areas under the curve and peak concentrations are expressed in

l Totol concentrotlon

0 End lnfuslon

Hours Doys

Figure 1. Concentrations of platinum (total and ultrafiltered) in ascites following a four hour intraperitoneal exposure to 200 mg/m’ carboplatin.

PHASE 1 STUDY AND PHARMACOKINETICS OF INTRAPERITONEAL CARBOPLATIN 39

l Total ploqo concentrotaon 1 Plosmo ultroflltrote concentrotlon 0 End lnfuslon

Hours Days

Figure 2. Concentrations of platinum (total and ultrafiltered) in plasma following a four hour intraperitoneal exposure to 200 mg/m* carboplatin.

Table 4. Plasma pharmacokinetics

Pat

Dose Max Pt level AUC h,zB(dl-5)

Total Adm Adm-Ret Tot. Pt U.F. Pt Tot. Pt U.F. Pt Tot. Pt

(Wm*) (mg/m2) Wol/l) Wol/l) (pm01 min 1-l) Pays)

M 200 95 10.77 9.37 27984 3734 6.7 C.V. 200 138 30.17 22.36 99489 12271 7.7

Pat = Patient. Adm = Administered. Ret = Recovered. Max Pt = Maximum platinum concentration. U.F. = Ultrafiltrate. AUC = Area under curve.

Table 5. Peritoneal fluid pharmacokinetics

Pat

Dose Init. Pt cone AUC ha(O-1 4 WV l-4 h)

Total Adm Adm-Ret Petit. fluid Tot. Pt. U.F. Pt Tot. Pt U.F. Pt Tot. Pt U.F. Pt

(w/m’) (w/m’) (rmolil) (pm01 min I-‘) (min) (min) (min) (min)

M 200 95 471.7 110756 108596 15.8 15.0 555 440 C.V. 200 138 444.8 77499 61429 14.6 18.7 221 222

Adm = Administered. Ret = Recovered. Init. Pt = Initial platinum AUC = Area under curve. U.F. = Ultrafiltrate. Min = Minutes.

40 J. GORDON McVIE ET AL.

Table 6 to give an indication of the possible therapeutic benefit in terms of increased tumour exposure after giving the drug in this fashion. Accumulated urine excretion of the drug is around 60-65% in the first day (Table 7). There was not much more than an extra 10% collected in the 4 days thereafter.

In one patient venous blood was sampled not only through a Hickman catheter but also through a peripheral vein. The tip ofthe Hickman catheter was in the right atrium and thus measured effectively inferior vena caval concentrations. As can be seen from Table 8, the Hickman concentrations are consistently higher, not only for total platinum but also for ultrafilterable platinum compared to the peripheral arm vein concentrations.

Table 6. Tumour exposure

Patient M C.V.

AUC peritoneum AUC plasma 29 5

Peak peritoneal cont. Peak plasma cont. 50 20

AUC = Area under curve. Cont. = Concentration.

Table 7. Urine pharmacokinetics

Pat

Dose D C.U.E C.U.E

Total Adm (Adm-Ret) Day&l Day O-5 (mg/m’) (w/m*) (%I (%)

M 200 95 62.4 66.7 C.V. 200 138 65.4 74.7

Adm = Administered. Ret = Recovered. C.U.E. = Cumulative urine excretion. D = Dose (administered-recovered).

Table 8. Hickman vs venous sampling

Hickman Venous Time after start administration Tot Pt U.F. Pt Tot Pt U.F. Pt

(min) (wWC @mol/l) bmol/l) WW)

5 0.36 0.25 ND ND 11 1.30 1.06 0.84 0.65 17 2.03 1.83 1.83 1.52 28 4.12 3.77 35 4.71 4.37 2.43 2.21 47 6.49 5.54 2.94 2.69 76 8.00 7.58 6.75 5.86

Pt = Platinum. U.F. = Ultrafiltrate

PHASE I STUDY AND PHARMACOKINETICS OF INTRAPERITONEAL CARBOPLATIN 41

Discussion

The preliminary results are hardly worthy ofdiscussion at this point. Considerable interest, however, has been aroused by the relative lack of myelotoxicity at 200-300 mg/m’ in patients who without exception have been heavily pretrated with cyclophosphamide, hexamethylmelamine, doxorubicin and cisplatin (3-6 courses). Further, the local tolerance of carboplatin has been acceptable in stark contrast to our experience with drugs such as doxorubicin and methotrexate where peritoneal irritation occurs even at a low dosage. Early pharmacokinetic studies have confirmed a pharmacokinetic advantage for ad- ministering the drug intraperitoneally. Peak plasma levels around lo-30 pmol/l have been achieved. In our experience of carboplatin given at 200 mg/m’ iv. peak plasma levels are about 5 times higher. Satisfactorily high concentrations of carboplatin have been achieved in ascites with a peak around 500 pmol/l and comparing the ratios of the area under the curve for peritoneal carboplatin to plasma carboplatin confirms the increased tumour exposure to the drug. Carboplatin leaks slowly from ascites to plasma and platinum is still measurable in plasma at the lower limit of detection of the assay 5 days after injection. In one patient a clear difference between inferior vena caval carboplatin and the concentra- tions in peripheral vein suggests further extraction of the drug either in lungs or excretion by first pass through the kidneys. The urine excretion pattern mimics that of the intravenously injected drug with the majority of the drug being excreted within the first day after administration. The difference between ultrafilterable platinum and total concentra- tion of platinum is not great, also reminiscent of the intravenous data.

References

1. Bruckner, H. W. (1984) Chemotherapy; the common epithelial ovarian carcinomas. In: Depp, G. ed. Chemotherapy of Gynecological Cancer. New York: A. R. Liss. pp. 151-195.

2. Neyt, J. M., Van der Burg, M. E. L., Vriesendorp, R., Van Lindert, A. C. M., Pinedo, H. M., Ten Bokkel Huinink, W. W. et al. (1984) Randomized trial comparing two combination chemotherapy regimes (HEXA- CAF vs CHAP5) in advanced ovarian carcinoma. Lancet 2: 59+-600.

3. Ozols, R. F., Ostchega, Y., Curt, G., Myers, C. & Young, R. C. (1985) High dose (HD) cisplatin (P) [40 mg/m’ qd x 51 and HD carboplatin (CBDCA) [400 mg/m* qd x 21 in refractory ovarian cancer: active salvage drugs with different toxicities. (Abstract) Pm AX’0 4: 119.

4. Howell, S., Pfeifle, C., Wung, W. et al. (1984) Intraperitoneal cisplatin with systemic thiosulphate protection. Ann. Intern. Med. 100: 19-24.

5. McVie, J. G., Ten Bokkel Huinink, W. W., Aartsen, Ii., Simonetti, G., Dubbelman, R. & Franklin, H. (1985) Intraperitoneal chemotherapy in minimal residual ovarian cancer with cisplatin and i.v. sodium thiosulphate protection. (Abstract) Pm AS’CO 4: 125.

6. Wiltshaw, E., Evans, B. & Harland S. (1985) Ph, ax III randomised trial cisplatin versus JM8 (carboplatin) in 112 ovarian cancer patients, stages III and IV. (Abstract) Pm ASCO 4: 121.

7. McVie, J. G., Dikhoff, T., Van der Heide, J., Dubbelman, R. & Ten Bokkel Huinink, W. W. (1985) Tissue concentration of platinum after intraperitoneal cisplatin administration in patients (PTS). (Abstract) Pm AACR 26: 162.