Phase I study of rubitecan and gemcitabine in patients with advanced malignancies

P. M. Fracasso+, J. S. Rader, R. Govindan, T. J. Herzog, M. A. Arquette, A. Denes, D. G. Mutch, J. Picus, B. R. Tan, C. L. Fears, S. A. Goodner and S. L. Sun

Alvin J. Siteman Cancer Center, Departments of Medicine and Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO; and SuperGen, Inc., Dublin, CA, USA

Received 23 May 2002; revised 10 July 2002; accepted 9 August 2002


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

Rubitecan (9-nitrocamptothecin, 9-NC, OrathecinTM) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies.

Patients and methods:

Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m2/day administered orally on days 1–5 and 8–12 in combination with gemcitabine 1000 mg/m2 administered intravenously on days 1 and 8 of a 21-day cycle.

Results:

The MTD was defined as rubitecan 1 mg/m2 administered orally days 1–5 and 8–12, and gemcitabine 1000 mg/m2 administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients.

Conclusions:

The recommended phase II dose is rubitecan 1 mg/m2 given orally on days 1–5 and 8–12 in combination with gemcitabine 1000 mg/m2 as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.

Key words: gemcitabine, Gemzar®, 9-nitrocamptothecin, OrathecinTM, phase I, rubitecan


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rubitecan [9-nitrocamptothecin, 9-nitro-20(S)-camptothecin, 9-NC, RFS 2000, OrathecinTM] is a semi-synthetic analog of camptothecin and is a derivative of the Asian tree, Camptotheca acuminata. Similar to other camptothecins, such as irinotecan and topotecan, rubitecan is a direct, highly potent inhibitor of DNA topoisomerase I and causes DNA strand breaks [1]. It has broad in vitro and in vivo activity [29].

A phase I trial of rubitecan given orally for five consecutive days every week for 4 weeks determined the maximum tolerated dose (MTD) to be 1.5 mg/m2/day [10]. The dose-limiting toxicity (DLT) was myelosuppression, including grade 4 anemia, neutropenia and thrombocytopenia. Nausea, vomiting, diarrhea, weight loss and chemical cystitis were also observed. Pharmacokinetic data showed that oral absorption of rubitecan was prompt, with peak plasma levels of total drug occurring ~4 h after ingestion. Of the 28 evaluable patients, five responses were observed including a complete response in a patient with pancreatic carcinoma, partial responses in a patient with breast carcinoma and two patients with ovarian carcinoma, and a hematological remission in a patient with acute myelogenous leukemia.

A phase II study of rubitecan administered at 1.5 mg/m2/day for five consecutive days every week was performed in 107 patients with advanced pancreatic cancer [11]. Primary toxicities were myelosuppression and interstitial cystitis, although nausea, vomiting and diarrhea were noted. Only 60 patients received the minimum 8 weeks of treatment necessary to be considered evaluable for response. Response was defined as improvement in all lesions on computed tomography (CT) scan, a decrease in the level of CA 19-9, improvement in quality of life and survival. The response rate was 31.7% in the evaluable patients. Median survival for all patients was 6.5 months and for evaluable patients was 8.7 months. In addition, a phase II study of rubitecan administered at 1.5 mg/m2/day for four consecutive days every week was performed in 35 heavily pre-treated patients with ovarian, tubal or peritoneal carcinoma [12]. Toxicities included myelosuppression with neutropenic sepsis, nausea, vomiting, diarrhea, weight loss and cystitis. Only 29 patients received the minimum of 6 weeks of treatment necessary to be considered evaluable for response. Of the 29 evaluable patients, a 7% response rate was observed and 34% of patients had stable disease.

Gemcitabine (2', 2'-difluorodeoxycytidine, Gemzar®), a fluorine substituted cytarabine analog, is an anti-metabolite that is activated by deoxycytidine kinase to gemcitabine triphosphate, which competes with deoxycitidine triphosphate for incorporation into DNA [13]. Once incorporated into DNA, it causes a premature chain termination one base pair after the insertion. Gemcitabine also interferes with DNA repair and induces apoptosis. It has a broad range of antitumor activity against solid tumors and leukemias in vitro and in vivo [13]. Standard doses of gemcitabine have ranged from 800 to 1250 mg/m2, usually given as a weekly infusion for 3 weeks out of a 4-week cycle [13]. The most common toxicities include myelosuppression, elevated liver function tests, nausea, vomiting, mild proteinuria, skin rash, pruritus and flu-like symptoms [13]. Gemcitabine is active against pancreatic, non-small-cell lung, bladder, ovarian and breast carcinomas [1320].

We postulate that the combination of rubitecan and gemcitabine may be synergistic. Preclinical data of another camptothecin, irinotecan, in combination with gemcitabine have demonstrated concentration-dependent synergy against human breast and small-cell lung cancer cell lines [21]. A mechanism for this synergy has been proposed. Gemcitabine triphosphate, the active metabolite of gemcitabine, may be inserted into the DNA strand breaks caused by rubitecan during religation. This has the potential to convert readily repairable DNA damage into irreparable damage causing cell death [21]. Furthermore, preclinical and clinical data indicate that the rate of intracellular gemcitabine triphosphate accumulation in peripheral blood mononuclear cells is saturated when gemcitabine is given at a constant infusion rate of 10 mg/m2/min, during which steady-state gemcitabine levels of 15–20 µmol/l are achieved in plasma [2224]. Therefore, we performed a dose-escalation phase I trial of rubitecan combined with gemcitabine either administered as a constant infusion or as a fixed infusion given on an every 21-day schedule. This trial was designed to evaluate the safety and to determine the MTD and DLT of this combination. The effects of drug scheduling on tolerability and toxicity were also evaluated.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient selection
Eligibility criteria included presence of a pathologically confirmed malignancy refractory to standard treatment or for which no standard treatment exists, evaluable disease (by tumor markers, physical exam or radiology), age >=18 years, life expectancy of >=2 months, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. Required laboratory parameters were hemoglobin >=9 g/dl, neutrophil count >=1500/mm3, platelet count >=100 000/mm3, creatinine <=2 mg/dl, bilirubin <=1.5 times the institutional upper limit of normal (ULN), and AST and ALT <=2 times the institutional ULN. Patients with prior exposure to rubitecan or gemcitabine were excluded. No treatment with chemotherapy, radiation therapy or immunotherapy was allowed 3 weeks prior to enrollment. Other exclusion criteria included pregnancy or breast feeding and active or uncontrolled central nervous system metastases. All patients provided written informed consent.

Treatment plan
Within 14 days prior to treatment initiation, all patients underwent a history, physical exam (PE), PS, laboratory studies [complete blood count (CBC), chemistries, urinalysis and tumor markers], and imaging assessment. A toxicity assessment and CBC were checked weekly and a PE, PS assessment and medication assessment were recorded every 3 weeks. In addition, tumor measurements either by physical examination, imaging studies and/or tumor markers were performed every 6 weeks. Adverse events were reported and recorded when they occurred.

Rubitecan was provided by SuperGen, Inc. (OrathecinTM; Dublin, CA, USA). Gemcitabine hydrochloride (Gemzar®; Eli Lilly and Company, Indianapolis, IN, USA) was obtained commercially. Rubitecan was administered orally at the designated dose, rounded to the nearest 0.25 mg, on days 1–5 and 8–12 every 21 days. Patients were instructed to take rubitecan in the morning on an empty stomach with orange juice, cola or any acidic pH beverage. In addition, patients were advised to increase their oral hydration by at least 3 l per day during the rubitecan treatment to reduce the possible occurrence of cystitis. Gemcitabine was administered intravenously at 1000 mg/m2 either as a continuous infusion of 10 mg/m2/min or as a fixed infusion rate over 30 min, days 1 and 8 every 21 days. A cycle was defined as treatment with both agents on a 21-day schedule.

Dose escalation and dose modifications
Three to six patients were enrolled at each dose level. Toxicities were graded according to the NCI Common Toxicity Criteria, version 2.0. If no DLTs were observed for the first three patients at a given dose level during the first cycle, escalation proceeded to the next dose level. After the first DLT, up to three more patients were enrolled at that same dose level. Escalation continued only if DLT was limited to one of six patients. Escalation halted if DLTs occurred in two or more patients. DLTs were defined as: (i) grade 4 neutropenia >7 days or any episode of febrile neutropenia; (ii) any grade 3 or 4 thrombocytopenia; (iii) a >=14 day delay in the start of the subsequent cycle due to any toxicity; or (iv) grade 3 or 4 non-hematological toxicity (with the exception of nausea and vomiting). This definition represents an amendment due to severe toxicities and death of patients on cohort 5. Prior to this time, a DLT did not include grade 3 thrombocytopenia, and a >=21-day delay in the start of the subsequent cycle due to any toxicity was used. There was no amendment in the definition of MTD. The MTD was defined as one dose level below that in which DLTs were observed in two or more patients from the dose cohort of two to six patients. Six patients were accrued at the defined MTD to fully evaluate any toxicity encountered at this level. There was no intra-patient dose escalation.

No patient received further treatment until all grade 3 or 4 toxicities had resolved to grade 1 or 2. Treatment was delayed on a weekly basis for absolute neutrophil count (ANC) <1500/µl and platelet count <100 000/µl. A 25% dose reduction of rubitecan and gemcitabine was administered in subsequent cycles, if during the preceding cycle, the patient’s nadir ANC was <500/µl for 7 days or failed to recover by day 1 of the next cycle, the patient experienced febrile neutropenia, or if the platelet nadir was <50 000/µl. Grade 3–4 non-hematological toxicities (with the exception of alopecia, nausea, vomiting and anorexia) led to a 25% dose reduction of both drugs. Dose modifications were administered for neutropenia and/or thrombocytopenia on day 8. For ANC <=1000/µl or platelets <100 000/µl, treatment was delayed until the ANC was >=1500/µl and platelet count was >=100 000/µl. At the time of retreatment, both rubitecan and gemcitabine were dose reduced by 25%. Both drugs remained 25% dose reduced for subsequent cycles. For an ANC between 1001 and 1499/µl and platelets >=100 000/µl, a 50% dose reduction of both drugs was given on day 8, and for subsequent cycles a 25% reduction of both drugs was administered. Therapy was discontinued for toxicity and/or disease progression.

Response assessment
Response criteria were as follows: a complete response (CR) was defined as a disappearance of all measurable disease or normalization of tumor markers for a minimum of 4 weeks. Partial response (PR) was defined as a >=50% decrease in the sum of the product of the diameters of all measured lesions, with the appearance of no new lesions, for at least 4 weeks. Stable disease (SD) was defined as a <50% decrease and a <25% increase in the sum of the diameter products with no new lesions. Progressive disease (PD) was defined as a >=25% increase in the total area of any bi-dimensionally measurable lesion compared with best response, or the appearance of any new lesion.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Twenty-one patients were enrolled between July 1999 and May 2000. The characteristics of these patients are listed in Table 1, and the dose levels studied are summarized in Table 2. In cohort 1, three patients were treated with rubitecan 0.75 mg/m2 days 1–5 and 8–12, and gemcitabine 1000 mg/m2 at a continuous infusion of 10 mg/m2/min days 1 and 8 every 21 days. Myelosuppression necessitated a dose reduction of rubitecan to 0.6 mg/m2 days 1–5 and 8–12, and gemcitabine to 750 mg/m2 days 1 and 8 in cohort 2. Because of continued myelosuppression on day 8 despite the dose reductions, no further treatment was studied with gemcitabine at the 10 mg/m2/min continuous infusion. Further dose levels were studied with escalating doses of rubitecan and the 30-min fixed infusion rate of gemcitabine. Dose reductions and delays were noted in all cohorts as indicated in Table 2.


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Table 1. Patient characteristics
 

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Table 2. Dose escalation schema
 
Hematological toxicity
Table 3 displays the mean nadir of the ANC, hemoglobin and platelets by cohort. In all cohorts, myelosuppression was noted. In cohort 1, two of the three patients required a dose reduction on day 8 because of grade 3 ANC reduction. Despite a dose reduction in rubitecan and gemcitabine, two of the three patients in cohort 2 required a dose reduction and 1 week delay because of grade 3 ANC reduction on cycle 1, day 8 in one patient and in cycle 2, day 8 in the second patient. As discussed previously, further cohorts continued with escalating doses of rubitecan but with a fixed infusion rate of gemcitabine. Further myelosuppression was noted in these cohorts. Two patients treated on cohort 5 died during the first cycle, one of febrile neutropenia without a documented source of infection and the other of neutropenic sepsis. The first patient with peritoneal carcinoma had been treated with four previous chemotherapy regimens. This patient was admitted to the hospital on day 12 of cycle 1 with nausea, vomiting and diffuse abdominal tenderness. On the second hospital day, the patient was noted to be febrile and neutropenic and was given antibiotics. Despite negative cultures, the patient died on the third day of hospitalization. The second patient with ovarian carcinoma had been treated with seven previous chemotherapy regimens. This patient was hospitalized on day 15 with nausea, vomiting, dehydration and fatigue. The patient was noted to be pancytopenic and on day 18 became febrile. Despite antibiotics, the patient died on day 25. Blood and urine cultures grew Klebsiella pneumoniae. Despite a 25% dose reduction (rubitecan 0.94 mg/m2 and gemcitabine 750 mg/m2) on cycle 2, a third patient with metastatic renal cell carcinoma in this cohort died of neutropenic sepsis. This patient had only received one previous chemotherapy regimen and was hospitalized on day 14 of cycle 2 with diarrhea and abdominal pain. The patient was noted to by pancytopenic and despite aggressive hydration and antibiotics, the patient expired within 24 h. Blood cultures grew out Enterobacter cloacae. In all 21 patients, grade 3/4 neutropenia was observed in seven patients, grade 3/4 thrombocytopenia in four patients and grade 3/4 anemia in one patient during the first cycle of treatment. In 13 patients who were heavily pretreated (three or more prior chemotherapy regimens), seven patients had a grade 3/4 toxicity consisting of neutropenia, thrombocytopenia or anemia during the first cycle of treatment.


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Table 3. Hematological toxicities among all treatment cycles
 
Non-hematological toxicity
Table 4 lists the non-hematological toxicities encountered in this dose escalation trial. Nausea, vomiting and diarrhea, felt following rubitecan administration, were the most common toxicities. Fatigue was more prominent in patients who received more than one cycle of treatment. No patients developed chemical cystitis during treatment. Non-hematological grade 3 and 4 toxicities were rare after the first cycle.


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Table 4. Non-hematological toxicities among all treatment cycles
 
Antitumor response
Eighteen patients were evaluable for response. Responses could not be ascertained for three patients, who died prior to assessment. Five patients experienced stabilization of their previously progressive disease, with a mean duration of 19 weeks (range 5–23 weeks). SD occurred in patients with breast carcinoma (one patient), hepatocellular carcinoma (one patient), sarcoma (one patient) and lung carcinoma (two patients).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rubitecan, a camptothecin analog, has activity in phase II trials in pancreatic and ovarian carcinoma [1012]. Gemcitabine has activity in numerous malignancies, including pancreatic and ovarian carcinoma [1320]. Theoretically, this combination may have synergy as documented with another camptothecin, irinotecan, and gemcitabine in breast and small-cell lung cancer cell lines [21]. This phase I trial sought to evaluate the safety profile and MTD of the combination rubitecan and gemcitabine in advanced malignancies.

The first two cohorts in this trial were treated with rubitecan in combination with a prolonged infusion of gemcitabine rather than its usual infusion rate of 30 min. The rationale for infusional gemcitabine resides in preclinical and clinical data, which suggested that the rate of intracellular gemcitabine triphosphate accumulation is maximal when gemcitabine is given at a constant infusion rate of 10 mg/m2/min [2224]. Since cytotoxicity of gemcitabine has been correlated with intracellular levels of gemcitabine triphosphate and with its incorporation into DNA, phase I and II clinical trials have been performed using single-agent gemcitabine in several prolonged infusion schedules [2233]. These trials noted increased myelosuppression with the prolonged infusion schedule. This was confirmed in our trial using the combination of rubitecan and infusional gemcitabine. Significant myelosuppression was observed in the first cohort, rubitecan 0.75 mg/m2 days 1–5 and 8–12 and gemcitabine 1000 mg/m2 days 1 and 8 every 21 days, necessitating dose reductions and delays on day 8 of treatment. In the second cohort, rubitecan was reduced to 0.60 mg/m2 days 1–5 and 8–12 in combination with the same dose of gemcitabine. Despite this dose reduction, continued myelosuppression occurred on day 8 necessitating further dose reductions and delays. As a result, no further treatment with prolonged infusional gemcitabine was performed. Further cohorts were treated with a 30-min fixed infusion rate of this drug. DLTs were observed in cohort 5 (rubitecan 1.25 mg/m2 days 1–5 and 8–12 and gemcitabine 1000 mg/m2 days 1 and 8 every 21 days) after two patients died after developing febrile neutropenia in the first cycle. In cohort 4, there were no DLTs. Importantly, the average number of previous chemotherapy regimens for patients in cohort 4 was 3.1 compared with 4.4 for patients in cohort 5. Stratification of this variable in future studies with this combination may allow for safer administration of this combination. Other toxicities on this study included nausea, vomiting, diarrhea and fatigue. As a result, the phase II recommended starting dose is rubitecan 1 mg/m2 administered orally days 1–5 and 8–12 and gemcitabine 1000 mg/m2 administered as a 30-min intravenous infusion days 1 and 8 every 21 days.

Early phase I and II studies with another camptothecin, irinotecan, in combination with gemcitabine have demonstrated activity in patients with gastric and pancreatic carcinomas and SD in patients with non-small cell lung carcinoma [3438]. In this trial, SD was noted in patients with breast, lung and hepatocellular carcinomas and sarcoma. These results warrant consideration of phase II studies of this combination in breast, lung and pancreatic carcinoma.


    Acknowledgements
 
We thank the nurses and data managers at Siteman Cancer Center for caring for the patients on this trial and Dr Teresa J. Vietti for her editorial assistance. This study was supported by a Clinical Oncology Cancer Development Award CDA-96-27 from the American Cancer Society (to P.M.F.) and by SuperGen, Inc., Dublin, CA, USA.


    Footnotes
 
+ Correspondence to: P. M. Fracasso, Department of Medicine, Washington University School of Medicine, 660 South Euclid Street, St Louis, MO 63110, USA. Tel: +1-314-454-8817; Fax: +1-314-454-5218; E-mail: fracasso{at}im.wustl.edu Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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