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Journal of Clinical Pharmacology, 2005; 45:453-460
© 2005 the American College of Clinical Pharmacology

PHARMACOKINETICS AND PHARMACODYNAMICS

Safety, Tolerability, and Pharmacokinetics of a Capsule Formulation of DRF-1042, a Novel Camptothecin Analog, in Refractory Cancer Patients in a Bridging Phase I Study

Arani Chatterjee, MBBS, MPhil, Raghunadharao Digumarti, MD, DM, Kasiram Katneni, MPharm, Vijay V. Upreti, MPharm, Rao N. V. S. Mamidi, PhD, Ramesh Mullangi, PhD, Anjna Surath, MBBS, DCH, Maddali L. Srinivas, MD, DM, Srihari Uppalapati, BHMS, Sangeeta Jiwatani, MBBS and Nuggehally R. Srinivas, PhD, FCP

From Dr. Reddy's Laboratories Ltd, Hyderabad, India (A. Chatterjee, K. Katneni, V. Upreti, Dr Mamidi, Dr Mullangi, Dr N. R. Srinivas) and Nizam's Institute of Medical Sciences, Hyderabad, India (Dr Digumarti, A. Surath, Dr M. L. Srinivas, S. Uppalapati, S. Jiwatani).

Address for reprints: Nuggehally R. Srinivas, PhD, FCP, Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad—500 049, India.


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m2. Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 µM•h, suspension = 5.33 µM•h; total: capsule = 393 µM•h, suspension = 176 µM•h) and day 12 (lactone: capsule = 22.1 µM•h, suspension = 6.1 µM•h; total: capsule = 1302 µM•h, suspension = 309 µM•h). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 µM•h, total = 605 µM•h) relative to fasted conditions (lactone = 8.53 µM•h, total = 393 µM•h) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m2.

Key Words: DRF-1042 • camptothecin • pharmacokinetics • toxicity • cancer • topoisomerase I inhibitors

Inhibitors of the enzyme topoisomerase I are cytotoxic for tumor cells because of their ability to cause DNA damage.1 Camptothecin (CPT), an alkaloid first isolated from the Chinese tree Camptotheca acuminata,2 is a topoisomerase I inhibitor.3-8

DRF-1042 [5(RS)-(2-hydroxyethoxy)-20(S)-CPT] (Figure 1), a semisynthetic derivative of CPT, is the first anticancer agent to enter phase I clinical development in India. DRF-1042 was found to have a promising pre-clinical profile. A phase I clinical study of DRF-1042—in which the drug was given as a suspension orally for 5 consecutive days every week for 2 weeks, repeated every 3 weeks, to patients with refractory solid tumors—has demonstrated that myelosuppression and diarrhea are the dose-limiting toxicities (DLTs) and that the maximum tolerated dose (MTD) is 120 mg/m2. In that study, 2 complete responses occurred in 1 patient each with renal cell carcinoma and osteosarcoma. In addition, 2 partial responses were documented in 1 patient each with osteosarcoma and breast carcinoma. Four patients also had disease stabilization.9,10



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  		Figure 1. Chemical structure of DRF-1042.

 

This report summarizes the results of a bridging phase I trial and pharmacokinetic (PK) study of DRF-1042 given orally as a capsule for 5 consecutive days for 2 weeks, repeated every 3 weeks, in adult patients with refractory cancer.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Purpose
The principal objectives of this study were to (1) characterize the incidence and severity of toxicities associated with the solid-dosage formulation of DRF-1042, (2) obtain the PK profile of the solid-dosage formulation of DRF-1042 and a possible food effect, (3) seek preliminary evidence for antitumor activity, and (4) recommend a dose for phase II trials.

Patients
Between May and October 2002, patients admitted to the Nizam's Institute of Medical Sciences (NIMS; Hyderabad, India) and meeting the following criteria were entered in this trial: (1) histologically or cytologically confirmed diagnosis of a malignant solid tumor refractory to conventional treatment or for which no established therapy exists; (2) aged 18 to 75 years; (3) Eastern Cooperative Oncology Group (ECOG) performance status ≤2; (4) measurable or assessable disease; (5) estimated life expectancy ≥12 weeks; (6) adequate bone marrow function: white blood cell (WBC) count ≥4 x 109/L, platelet count ≥100 x 109/L, and hemoglobin ≥10 g/dL; (7) adequate liver function: bilirubin within normal limits and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase ≤2 times normal (unless due to bone metastases); (8) adequate renal function: creatinine ≤1.5 times normal; and (9) recovery from toxicity of previous treatments. Patients were ineligible if they (1) had active infection, (2) were pregnant or lactating, (3) had central nervous system tumors, (4) had major surgery within 2 weeks or radiotherapy or chemotherapy within 4 weeks before entry (6 weeks for mitomycin or nitrosoureas), and (5) had radiotherapy to >10% of bone marrow. The NIMS investigational review board approved the study protocol. Informed consent was obtained from each subject.

DRF-1042 Formulation
DRF-1042 was manufactured at Dr. Reddy's Laboratories (Hyderabad, India) as a capsule prepared in 2 dose strengths: 20 mg and 40 mg.

Dosage and Administration
All patients were hospitalized for the duration of the treatment. The starting dose (81 mg/m2) corresponded to 1 dose level lower than the MTD in humans.9,10 DRF-1042 was administered orally in the morning on an empty stomach to the first 3 patients for 5 consecutive days for 2 weeks every 3 weeks. This 3-week period constituted 1 cycle or course of treatment. The drug was administered in the same schedule to the next 3 patients in the morning, 1 hour after a standardized breakfast (on day 1) that consisted of the following components:Go


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Cycles could be repeated in the absence of irreversible DLT. For any grade 4 hematologic or ≥ grade 3 gastrointestinal (except emesis) toxicity, drug administration was withheld until complete recovery. Patients could continue treatment if they did not develop progressive disease (PD) or unacceptable toxicity. Patients with reversible DLT could continue treatment at the next lower dose level. Once a dose was reduced, the patient received that reduced dose for the entire remaining treatment course. Patients were taken off protocol in case of PD.

Pretreatment and Follow-up Studies
History and physical examination, including performance status, routine laboratory measurements, chest x-rays, and resting 12-lead electrocardiograms, were obtained at baseline and before each subsequent course. Routine laboratory studies included a complete blood count (CBC), including WBC differential; sodium, potassium, chloride, calcium, phosphorus, magnesium, bilirubin, total protein, serum albumin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, amylase, blood urea nitrogen, serum creatinine, uric acid, cholesterol, and glucose levels; prothrombin time; partial thromboplastin time; and urinalysis. During the study, CBC and serum chemistries were measured 2 to 3 times a week. Patients with measurable disease had appropriate diagnostic imaging studies at baseline, as well as every 2 cycles thereafter, to assess tumor response.

Toxicity and Response Evaluation
Toxicities were graded according to NCI-CTC (version 2). Patients with measurable disease at enrollment were considered evaluable for response. Response was assessed according to World Health Organization (WHO) criteria11 if a minimum of 2 cycles had been administered.

Criteria for DLT
DLT was defined as (1) grade 4 neutropenia or ≥ grade 3 thrombocytopenia for >5 days, (2) ≥ grade 3 nonhematological toxicity (except mucositis for <3 days, alopecia, fatigue, pain, or nausea), and (3) delay of >1 week in the initiation of a subsequent course due to un-resolved toxicity related to DRF-1042.

Analytic Methods
For PK analysis, whole blood samples were collected before administration of DRF-1042 and 0.25, 0.5, 1, 2, 3, 5, 8, 12, and 24 hours thereafter on days 1 and 12. Concentrations of DRF-1042 for both lactone and total forms were determined by using a previously validated HPLC method.12 Briefly, sample preparation involved deproteinization with acidified methanol, resulting in almost 100% recovery of DRF-1042. Detection was monitored with the fluorescence set at excitation and emission wavelengths of 370 and 430 nm, respectively. The mobile phase was isocratic and consisted of acetonitrile/water (20:80) with 1% v/v triethanolamine. The pH of the mixture was adjusted to 5.5 with acetic acid. The flow rate was maintained at 1 mL/min. Standard curves, ranging between 4 and 2000 ng/mL, produced r2 values > 0.999. Quality control (QC) samples, run along with the study samples for every standard curve, confirmed the accuracy and precision of analytical determination, therefore supporting the validity of the PK disposition data of both forms of DRF-1042. Stability of DRF-1042 in the injection solvent was detected periodically by injecting processed lower, medium, and upper QC samples for 22 hours after the initial injection. The peak areas of the analyte obtained in the initial cycle were used as a reference to determine the stability at subsequent points. Stability of DRF-1042 in the biomatrix was determined up to 24 hours at ambient temperature (25 ± 3°C) at low, medium, and upper concentrations. Freezer stability of DRF-1042 in human plasma was assessed by analyzing the QC samples stored at -20°C for 1 month. Stability of DRF-1042 stocks stored at -20°C was determined up to 1 month by injecting appropriate dilutions of the stock in acidified methanol on days 1, 15, and 30 and comparing the peak areas with fresh stocks prepared on the day of analysis. The stability of DRF-1042 in human plasma following quick repeated freeze-thaw cycles was assessed using QC samples spiked with DRF-1042. Samples were considered stable if assay values were within acceptable limits of accuracy (±15% deviation from the nominal values) and precision (15% relative standard deviation [RSD]).

Pharmacokinetic Analysis
The plasma concentration versus time data were subjected to noncompartmental analyses using WinNonlin (Version 3.1, Pharsight Corp, Mountain View, Calif). The peak plasma concentration was denoted as Cmax, and the time of occurrence of Cmax was denoted as tmax. The derived parameters included the following:

AUC0-t: AUC from time 0 to time t, where t denotes the last measurable point;

AUC0-{infty}: AUC extrapolated to infinity using the summation of AUC0-t + Cn/ß, where Cn is the last measurable concentration, and ß is the regression slope of the terminal data points;

t1/2: terminal elimination half-life, calculated as the quotient of 0.693/ß;and

R: accumulation factor, calculated as the quotient of AUC0-t (day 12)/AUC0-t(day 1).

Comparative Pharmacokinetic Data Sets
Capsule versus suspension formulation. The exposure data obtained from all patients (n = 5) taking the capsule formulation at a dose of 81 mg/m2 were compared with previously reported exposure data at a dose of 81 mg/m2 (n = 3) and 120 mg/m2 (n = 6) with the suspension formulation.13

Fed versus fasted (capsule). The PK data obtained from the capsule formulation in fed conditions on day 1 were compared with those obtained in fasted conditions.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Patients
Six assessable patients (4 men, 2 women), with a median age of 50.5 years (range, 22-65), entered the study. The median ECOG performance status was 1 (range, 0-1). Two patients each had breast carcinoma and colorectal cancer, and 1 patient each had tongue carcinoma and osteosarcoma, all with stage IV disease. All patients had previously received chemotherapy; 5 (83%) also had previous surgery, and 4 (67%) had also received radiation.

Drug Administration
Ten assessable cycles of DRF-1042 were administered. The median number of cycles per patient was 1 (range, 1-4).

Mortality
One patient with a history of falls was admitted to the hospital in an unconscious state 5 days after the end of the second cycle at 54 mg/m2. A computed tomography (CT) scan of the brain revealed an infarct involving the midbrain, bilateral thalami, and right cerebellum. She never regained consciousness and expired after 4 days. The cause of death was judged as not being related to the study drug.

Dose-Limiting Toxicity
Dose-limiting hematological and nonhematological toxicities included prolonged severe thrombocytopenia and diarrhea. At the given dose (ie, 81 mg/m2), 2 of 6 patients experienced a dose-limiting event.

Hematological Toxicity
Both severe leukopenia and thrombocytopenia were the principal hematological effects of treatment with DRF-1042 (Tables I and II). Only 1 patient showed grade 3 leukopenia and recovered with granulocyte colony-stimulating factor (G-CSF) support. No episodes of neutropenic fever occurred in this study. Platelet count nadirs occurred between days 12 and 33.


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  		Table I Leukopenia

 

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  		Table II Thrombocytopenia

 

DRF-1042 also affected red blood cells (RBCs). Although grade 3 anemia occurred in 4 (40%) cycles, it was satisfactorily treated with packed RBC transfusions.

Gastrointestinal Toxicity
Gastrointestinal toxicities were the principal nonhematological effect of DRF-1042. These consisted of nausea, vomiting, and various degrees of diarrhea. The frequency and severity of diarrhea are summarized in Table III. Diphenoxylate and a somatostatin analog (Octreotide) were effective in reducing the severity or duration of diarrhea.


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  		Table III Diarrhea

 

Nausea and vomiting were brief and usually noted in the peritreatment period. Although grade 3 nausea and vomiting occurred in 3 (30%) courses, they could be circumvented with parenteral hydration and serotonin inhibitors. Prophylactic antiemetics were not used in this study.

Miscellaneous Toxicities
Grade 2 alopecia occurred in 2 (20%) cycles. Other possible toxicities included transient alterations in hepatic and renal function tests (8 and 1 cycles, respectively).

Pharmacokinetics
Following administration of the capsule, DRF-1042 was rapidly absorbed, and the presence of both lactone and carboxylate forms was evident from the very first sampling time point (0.5 hours). These observations were consistent with previous results from the suspension formulation.9,10,13 The plasma concentration versus time profile for lactone and total forms of the DRF-1042 capsule formulation in both fasted and fed states is provided in Figure 2, and the respective PK parameters are provided in Tables IV and V. Comparative systemic exposure data of the lactone and total forms of DRF-1042 for capsule (81 mg/m2) versus suspension (81 and 120 mg/m2) formulations are provided in Tables VI and VII and Figure 3. DRF-1042 lactone reached peak concentrations within 2.13 to 2.23 hours, whereas it took relatively longer to achieve peak concentrations for the total form, irrespective of first (day 1) or last (day 12) dose. Extrapolation of AUC was not performed in most patients because of the limited number of available data points to accurately estimate terminal elimination. This was more often the case for the lactone form than for the total form. Wherever linear regression was possible with a minimum of 3 points, the parameters were calculated to obtain an apparent value. The t1/2 values on days 1 and 12 were similar for the total form.






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  		Figure 2. DRF-1042 plasma concentration versus time profiles: (A) lactone, day 1; (B) total, day 1; (C) lactone, day 12; and (D) total, day 12.

 

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  		Table IV DRF-1042 (Lactone) Pharmacokinetic Parameters

 

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  		Table V DRF-1042 (Total) Pharmacokinetic Parameters

 

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  		Table VI Range of Systemic Exposure of DRF-1042 From Capsule and Suspension Formulations on Day 1

 

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  		Table VII Range of Systemic Exposure of DRF-1042 From Capsule and Suspension Formulations on Day 12

 



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  		Figure 3. DRF-1042 formulation versus systemic exposure plots: (A) lactone and (B) total.

 

The accumulation factor of both lactone and total forms of DRF-1042 in the fasted (lactone = 1.99 ± 1.3, total = 2.65 ± 0.95) and fed (lactone = 1.06 ± 0.82, total = 1.3 ± 0.93) states indicates that DRF-1042 does not exhibit any induction following multiple doses.

Interpatient variability on day 1, represented by percent coefficient of variation of AUC, was 47.3% and 71.1% for the lactone and total forms, respectively. The variability appeared to be consistent as a function of dosing days and circulating moieties.

Efficacy
Only 1 patient (16%) received more than 2 cycles of DRF-1042. This was a 56-year-old male with colon carcinoma with liver and lung metastases who experienced SD with 4 courses of DRF-1042 at a dose range of 54 to 81 mg/m2. One patient had PD.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGEMENTS
 REFERENCES
 
There has been a shift in the development of topoisomerase I inhibitors, specifically CPTs, from the traditional intravenous to an oral route. In this context, this bridging phase I study evaluated a solid-dosage (capsule) formulation of the novel CPT derivative, DRF-1042, administered orally in a daily x 5 x 2 schedule every 21 days to patients with refractory solid tumors. This was an extension of an open-label phase I study of a suspension formulation of DRF-1042 in patients with refractory solid tumors. The intent was to perform a phase I evaluation without any formulation complexity and arrive at a decision for further clinical development. A solid-dosage form was considered following the determination of the MTD of DRF-1042 in terms of required strengths for further development. In addition, a solid-dosage form was expected to result in better compliance due to the avoidance of the bitter taste associated with the suspension. Finally, a solid-dosage form would enable ease of outpatient treatment during phase II trials. The historic data generated on the suspension, both in terms of safety and pharmacokinetics, were deemed to be adequate to deduce the acceptability of the capsule formulation.

The exposure with capsules at 81 mg/m2 was higher than that with the suspension at the corresponding dose. However, the upper limit of exposure with capsules at 81 mg/m2 did not exceed the highest exposure with the suspension at 120 mg/m2. The increased bioavailability of DRF-1042 following capsule dosing relative to suspension was somewhat unexpected because of the low aqueous solubility of the drug. However, it is possible that DRF-1042, provided in a more solubilized form in the capsule formulation, may be delivered much slower over the entire upper gastrointestinal tract. In addition, the capsule formulation may present the desired particle size to promote enhanced absorption. While designing the bridging study, a dose of 81 mg/m2 instead of 120 mg/m2 was selected to provide a safety window of approximately 50% to counter any unexpected safety concerns arising due to enhanced exposure from capsule. Regardless of the chosen formulation, the PK of DRF-1042 supports once-daily administration.

A solid-dosage form presents its own complexity. One important aspect needing characterization was with regard to the PK disposition of DRF-1042 when the solid-dosage form was administered after a meal. In the context of an oral cytotoxic agent, preliminary food effect assessment was of paramount importance because of the direct relevance of food effect on oral therapy. For example, a decrease in exposure would compromise efficacy, whereas an increase in exposure could result in safety issues. In the present study, patients who ingested DRF-1042 after food on day 1 exhibited higher systemic exposure relative to those who took the drug in a fasted state. Because the design involved parallel-group comparison for food effect instead of a crossover design, it is difficult to provide a relative change in bioavailability because of food ingestion. In addition, the top strength of capsule available (ie, 40 mg) necessitated multiple dosage units being given to achieve the required dose. This may have been a confounding factor in the assessment of food effect. However, the data generated are sufficient to warrant caution in the dosing of DRF-1042 after food; therefore, until a complete characterization of food effect is made in a crossover manner, it is recommended to administer the capsules on an empty stomach.

The toxicity profile of DRF-1042 in this study was similar to that for the suspension, with myelosuppression, primarily thrombocytopenia, and diarrhea being the DLTs.

In summary, the capsule formulation of DRF-1042 is well tolerated in patients with refractory cancer. Data from this trial show that 81 mg/m2, given for 5 consecutive days each week for 2 weeks, resulted in DLT in 2/6 patients. Thus, the recommended dose for the capsule formulation of DRF-1042 in future trials is 81 mg/m2.


   ACKNOWLEDGEMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
REFERENCES
 
We acknowledge P. Rajendra Kumar and Ishaque Hasan Mumshad, Dr. Reddy's Laboratories, for providing DRF-1042 and giving technical assistance, respectively, and Chandana Pal, study nurse, for patient care.

Source of research support: Dr. Reddy's Laboratories Ltd, Hyderabad, India.

DOI: 10.1177/0091270004270225


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 

1. Liu LF. DNA topoisomerase poisons as antitumor drugs. Ann Rev Biochem. 1989;58: 3511-3375.

2. Wall ME, Wani MC, Cook CE, et al. Plant antitumor agents: the isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibitor from camptotheca acuminata. J Am Chem Soc. 1966;88: 3888-3890.[CrossRef]

3. Hsiang YH, Hertzberg R, Hecht S, et al. Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem. 1985;260: 14873-14878.[Abstract/Free Full Text]

4. Hsiang YH, Liu LF. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 1988;48: 1722-1726.[Abstract/Free Full Text]

5. Hertzberg RP, Caranfa MJ, Holden KG, et al. Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem. 1989;32: 715-717.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

6. Eng WK, Faucette L, Johnson RK, et al. Evidence that the DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol. 1988;34: 755-760.[Abstract]

7. Jaxel C, Kohn KW, Wani MC, et al. Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res. 1989;49: 1465-1469.[Abstract/Free Full Text]

8. D'Arpa P, Liu LF. Topoisomerase-targeting antitumor drugs. Biochim Biophys Acta. 1989;989: 163-177.[Medline] [Order article via Infotrieve]

9. Chatterjee A, Digumarti R, Rao NVSM, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study. J Clin Pharmacol. 2004;44: 723-736.[Abstract/Free Full Text]

10. Chatterjee A, Digumarti R, Rao NVSM, et al. DRF-1042, a novel orally active camptothecin (CPT) analog: safety, pharmacokinetic (PK) and pharmacodynamic evaluation in a phase I dose escalation study. Paper presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Fla, May 18-21, 2002.

11. World Health Organization. The WHO Handbook for Reporting Results for Cancer Treatment. Geneva, Switzerland: World Health Organization; 1979.

12. Upreti VV, Rao NVSM, Katneni K, et al. Quantitative determination of DRF-1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics. Biomed Chromatogr. 2003;17: 385-390.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

13. Srinivas NR, Rao NVSM, Kasiram K, Upreti VV, Chatterjee A, Raghunadharao D. Clinical pharmacokinetics of DRF-1042, a novel orally active camptothecin (CPT) analog. Paper presented at the annual meeting of the American College of Clinical Pharmacology, San Francisco, September 21-23, 2002.
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