Investigational New Drugs 8: $73-$78, 1990. 9 1990 Kluwer Academic Publishers. Printed in the Netherlands.
Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer Theera Umsawasdi 1, Tyrone B. Felder 2., Diane Jeffries 1 and Robert A. Newman 2
1Sections of Head and Neck and Thoracic Medical Oncology, and the 2Section of Pharmacology, Department of Medical Oncology, The University of Texas M.D. Anderson Cancer Center (Present address: * College of Pharmacy, Texas Southern University College of Pharmacy and Health Sciences, Houston, Texas 77004, USA)
Key words: non-small cell lung cancer, chemotherapy of lung cancer, 4-demethoxydaunorubicin, idarubicin, 4-DMDR, treatment of advanced lung cancer
Summary Fifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 m g / m 2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations o f 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3 - 7 3 + weeks). Toxicities were tolerable. Neutropenia ( < 1,000 mm 3) occurred in only 16~ of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon. Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml). Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.
Introduction The prognosis of extensive non-small cell lung cancer is poor, with a response rate between 30~ and 6007o and a median survival of about 8 months in patients treated with various chemotherapeutic regimens [1,2]. Therefore, there is an urgent need to search for other active new drugs. Idarubicin (4-demethoxydaunorubicin, 4-DMDR) is a new daunorubicin analogue that has been shown to have antitumor efficacy in various human malignancies [3-6]. This drug can be given effectively by the oral
route without the vesicant effect which may occur when given intravenously [5,6]. In a study of 11 patients with E-NSCLC who had received no prior chemotherapy, one patient responded when 4-DMDR was given orally at the dose of 4 0 - 4 5 m g / m 2 [7]. Our previous study showed that 1 of 7 patients who had no previous chemotherapy had stable disease in lungs and bone for 56 weeks with minimal toxicity (Umsawasdi T, unpublished data). We found that at the oral dose of 10 mg/m2/day x 5 days, 4-DMDR caused minimal myelosuppression in most patients, but nausea and vomiting were common.
$74 Since there was a suggestion of activity in our pilot study of idarubicin in patients with E-NSCLC who had received no prior chemotherapy and only nausea and vomiting were significant toxicities, we therefore conducted a more comprehensive phase II study to evaluate the therapeutic efficacy and toxicity in patients with E-NSCLC who had received neither chemotherapy nor radiotherapy. Routine antiemetic drugs were used in order to suppress nausea and vomiting. A study of the pharmacokinetics of the parent compound was attempted to aid in evaluation of the bioavailability of this drug.
Table 1. Toxicity criteria
Toxicity
Grade I
Grade II
Nausea and vomiting Malaise
Slight nausea, no vomiting Mild, tolerable without treatment Mild, tolerable without treatment Semisolid movements
Nausea-occasional vomiting Tolerable with treatment Tolerable with treatment Watery and frequent movements (3-4 or less per day) Complete loss Patchy mucositis; brisk enanthema
Anorexia Diarrhea
Alopecia Stomatitis
Partial loss Faint pinkish enanthema
Patients and methods The eligibility criteria included histologic p r o o f of E-NSCLC; no prior chemotherapy or radiotherapy; age >_ 15 years; a life expectancy of ___ 12 weeks with a Z u b r o d ' s performance status score of >_ 2; adequate bone marrow, liver and renal function; and informed written consent. Patients should have had no cardiac failure or arrhythmias requiring treatment or a prior history of myocardial infarction. 4-DMDR (Idarubicin) was supplied by Adria Laboratories. It was administered orally on an empty stomach at the dose of 10 m g / m 2 / d a y • 5 days. This dose was chosen because of the concern of myelosuppression in the previous study [7]. The 4-DMDR doses in subsequent courses were administered according to the degree of myelosuppression, with the range of total dose per course ranging f r o m 37.5 to 75 m g / m L Because the drug came in 5, 10, and 25 mg capsules which could not be broken down, the dose was adjusted to the lower nearest number of mg divisible by 5 (e.g., calculated dose = 18 mg, the dose to be given = 15 mg). The courses were repeated every 3 weeks if possible. Antiemetic drugs included lorazepam (2 mg) given orally 2 hours before each dose of chemotherapy, followed by metoclopramide (10 mg) one half hour later and again 6 hours after the 4-DMDR dose. This antiemetic regimen was a modified antiemetic program from a previous reported study [8] with a substitution of dexamethasone with metoclopramide at a less intensity of treatment with oral administration.
Physical examination, CBC, differential, platelet counts, SMA-12, serum electrolytes, chest roentgenogram, and E K G were done prior to each treatment course. Multiple gated cardiac scans were done before initiation of the first treatment and every three treatment courses or sooner as clinically indicated. Other radiologic or radioisotopic studies were repeated every 2 - 3 courses as necessary to determine the response. Standard criteria of response were used. The toxicity criteria are shown in Table 1. The criteria were graded as N C O G toxicity criteria per requirement f r o m Adria Laboratories with supplement criteria f r o m our institution. No grade III and IV toxicities were shown in the table because none of these patients had either grade III or IV toxicities.
Clinical pharmacokinetic studies Nine patients were studied. Blood (10 ml) was drawn at 15, 30, 45 minutes and 1, 2, 3, 4, 6, and 8 hours after the doses on days 1 and 5. Plasma was obtained by centrifugation and then frozen at - 2 0 ~ until analysis. Calibration curves were made as follows. Pooled, drug-free h u m a n plasma (1-ml aliquots) was spiked with 20/A of appropriate stock solutions of 4-DMDR to yield a final drug concentration range of 1 to 20 ng/ml. Daunorubicin (25 n g / m l in plasma) was used as the internal standard. Sodium
$75 hydroxide (50 ~1 of a 0.005 M solution) was added, and the tubes were briefly vortexed. Ethyl acetate (6 ml) was added, and the plasma was extracted for 30 minutes. The tubes were then centrifuged, and the ethyl acetate phase was aspirated and transferred to another glass tube. The organic phase was evaporated to dryness at 50~ under a stream of nitrogen. The residue was reconstituted in 200 ~1 of water and 5 0 - 1 0 0 ~1 injected onto the column for H P L C analysis. 4-DMDR was quantitated using a fluorescence set at an excitation wavelength of 245 nm with a 550 nm emission cutoff filter (A.B.I. Analytical, Kratos Division). The analytical column used was a uBOND A P A K Phenyl column (3.9 m m x 15 cm, Waters Associates, Milford, MA). The mobile phase consisted of citrate buffer (0.1 M, p H 4.5)-methanolacetonitrile (2:1:1) at a flow rate of 1 ml/min.
Results Fifteen patients were entered into the study. One of them was not eligible because of his prior history of myocardial infarction but was evaluated for both response and toxicity. Patient characteristics are shown in Table 2. Patients received a median of two courses of therapy (range 1-12) with the cumulative dose range from 50 to 712.5 m g / m 2. Five patients received only 1 course of treatment but had rapid progression of their diseases. Two of them had significant neutropenia ( < 1000/cumin) but others had mild toxicities. One patient with a diagnosis of adenocarcinoma achieved a partial response with a duration of 14 weeks. Two patients had minor responses with a duration of 14 and 24 weeks. Stable disease occurred in three patients for 21, 22, and 27 weeks. The remaining patients had progressive disease. Median survival from onset of therapy for all patients was 33 weeks (range 3 - 7 3 + weeks).
Toxicity All patients tolerated the treatment well, and hematologic toxicities were tolerable (Table 3). Neu-
Table 2.
Patient characteristics
Total No. of Pts. Median age (range) Sex: Male/female Histology: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Bronchoalveolar cell carcinoma Adenosquamous carcinoma Tumor sites:Lung Skin/subcutaneous tissue Bone Adrenal Liver Lymph nodes Others
15 58 (35-63 Yrs) 10/5 9 2 2 1 1 15 5 4 3 2 2 3
tropenia ( < 1,000/mm 3) and thrombocytopenia ( < 100,000/mm 3) occurred in 16~ (9/57) and 11 ~ (6/57) of all treatment courses respectively. One patient developed a treatable pneumonia during a neutropenic period. Three patients had correctable arrhythmia (two with atrial fibrillation and one with accelerated junctional rhythm). Two of these patients received additional 4-DMDR treatment under close observation but without further problems. One did not receive further 4-DMDR therapy. No evidence of decreased ejection fraction determined by multigated cardiac scan was observed. Other toxicities are shown in Table 4.
Clinical pharmacokinetic studies The assay for 4-DMDR was linear from 3 to 20 ng/ml, with 3 n g / m l the lower limit of detection. No interfering peaks were present in the chromatograms obtained using drug-free plasma. Plasma 4-DMDR levels of patients that received the drug were apparently below the limit of detection. This was true even after the fifth dose. In addition, the occurrence of myelosuppression in several patients could not be associated with higher or detectable plasma 4-DMDR concentrations.
$76 Table 3. Hematologic toxicities Median lowest counts x lOVmm 3
Dose
mg/m2/ course
No. of courses
Absolute granulocytes (range)
Platelets (range)
37.5 50 60-62.5 70-75
2 28 16 11
2.3 3.2 2.2 1.8
181 323 182 185
(1.6-3.1) (0.1-11.9) (0.5-3.9) (0-3.3)
(137-226) (96-738) (94-406) (62-371)
Table 4. Other toxicities No. of courses with toxicities Dose
mg/mV course 37.5
No. of courses 2
50
28
60-62.5
16
70-75
11
Grade
Nausea/ vomiting
Malaise
Anorexia
Diarrhea
Alopecia
Stomatitis
1 2 1 2 1 2 1 2
0 0 10 12 5 8 3 6
0 0 6 2 8 0 6 2
0 0 4 0 8 0 5 0
1 0 4 2 1 3 0 0
0 0 3 0 1 0 2 0
0 0 1 0 2 0 1 2
Discussion In this study, 4-DMDR was found to have only limited activity in E-NSCLC patients who had received neither prior chemotherapy nor radiotherapy. This evaluation confirmed the limited activity of this drug in previously untreated E-NSCLC [7]. The latter study used 4-DMDR as a single dose from 40 to 50 m g / m 2 and found that one of 11 patients had an " i m p r o v e d " major response lasting 5.2 months [7]. The dose schedule used in the present study indicates that the drug has tolerable toxicity. Nausea and vomiting occurred even with routine antiemetic drug administration but were tolerable. These results are in agreement with other studies [4, 6, 9 - 1 3 ] that showed nausea and vomiting were c o m m o n and that a more aggressive use of antiemetic drugs should be considered. Mucositis was u n c o m m o n in our study, and none occurred in three previously
reported studies using 4-DMDR doses between 10 and 50 m g / m 2 [7, 10, 12]. Mucositis occurred in 8-17~ of patients who received higher doses (50-60 m g / m 2) [4, 13]. Alopecia was mild in our study but varied in other studies [4,6,7, 11, 12]. Although several studies [4,6,7,12,13] had shown significant myelosuppression from this drug, we and other investigators [11] did not find it to be a limiting toxicity at doses between 45 and 50 m g / m 2. The discrepancy could be due to a healthier patient population (i.e., previously untreated in these two studies), whereas most other studies were of previously treated patients. It is possible that our dose schedule, with the dose divided over a 5-day period, could influence the degree of toxicity; the other study found significant myelotoxicity even in previously untreated patients when 4-DMDR was given as a single dose [7]. Cardiotoxicity in humans so far has been uncommon. No clinical evidence of congestive heart fail-
$77 ure or reduction of left ventricular ejection fraction (LVEF) occurred in the present study. Other investigators [4, 6, 7, 9 - 1 3 ] did not observe congestive heart failure in their patients with the highest cumulative 4-DMDR dose of 800 m g / m 2. No diminution in resting LVEF, determined by either radionuclide left ventriculograms or echocardiogram, was found [4,7, 10, 12]. Lionetto et al. [9] observed a greater than 10% decrease in LVEF (11% and 19%) in two patients who received 135 and 450 m g / m 2 of 4-DMDR respectively, but with final values of LVEF > 50% and without clinical signs of cardiotoxicity. Correctable cardiac arrhythmias occurred in 20% of our patients. The cause-and-effect relationship with 4-DMDR is uncertain, since two patients continued to receive more 4-DMDR without recurrence of cardiac arrhythmias. Bonfante et al. [4] reported a 66% incidence of E K G abnormalities in their patients who received oral 4-DMDR treatment. However, only 37.5% of the abnormalities were arrhythmias (atrial premature beats, 22~ ventricular premature beats, 12.5%; sinus arrhythmias 3%). Other E K G abnormalities could be due to nonspecific changes. No E K G abnormalities were found in other studies [6, 11,13]. Cardiac toxicities of this drug need to be investigated further in a larger number of patients for a longer duration of follow-up time. At this dose schedule (10 m g / m 2 P O / d a y x 5 days), we did not observe a detectable plasma level of 4-DMDR. Berman e t al. [12] detected a level of 4-DMDR in plasma of about 20 n g / m l in a patient who took a single dose of 50 m g / m ~ of 4-DMDR orally but the level decreased to 2 n g / m l after 48 hours. In other studies, after a single oral dose of 4 0 - 6 0 m g / m 2 or 50 m g / m 2 in three divided doses of oral 4-DMDR over 24 hours, the mean peak plasma levels were between 6.3 and 13.2 n g / m l [11, 13]. The mean plasma 4-DMDR half-lives were short (3.2 + 0.4, and 8.75 hours) in two studies [11, 13]. Our dose schedule, which divided the drug to be given over a 5-day period, could result in an undetectable plasma level. A modification of the assay technique such as that suggested by Smith [14], which reports the limit of sensitivity of a modified assay to be 0.25 ng/ml, m a y be required to determine the pharmacokinetics of 4-DMDR more accurately in future studies.
Our study shows the limited efficacy of 4-DMDR given at the dose of 10 m g / m 2 / d a y • 5 days in previously untreated E-NSCLC patients. However, because the toxicities are mild and the drug has a short half-life, it is possible that increasing the dose of 4-DMDR given in a 5-day schedule could increase therapeutic efficacy. The discrepancies of the results of bioavailability of this agent administered orally indicates that further studies are needed. Evaluation of the activity of this drug in this disease with intravenous route to ensure a proper dose of 4-DMDR is needed.
Acknowledgements This study was partially supported by grant from Adria Laboratories, Columbus, Ohio 43216. We thank Paul Y. Holoye, M.D., Alan M. Kramer, M.D., Isaiah W. Dimery, M.D., Bonnie S. Glisson, M.D., Jin Soo Lee, M.D., David T. Cart, M.D., and William K. Murphy, M.D. for their collaboration, James A. Neidhart, M.D., and Waun Ki Hong, M.D. for their valuable comments and suggestions, and Pamela Ansley and Cynthia Argo for their secretarial assistance. This study was presented in part at the annual meeting of the American Association for Cancer Research, New Orleans, May 25, 1988.
References 1. Klasterky J, Sculier JP: Chemotherapy of non-small lung cancer. Semin Oncol 12 (Suppl 6): 38-48, 1985 2. Ruckdeschel JC: Chemotherapy of disseminated non-small cell lung cancer. In: Bitran JD, Golomb HM, Little AG, Weichselbaum RR (eds) Lung Cancer. A Comprehensive Treatise. Grune & Stratton, Inc., Orlando, 1988, pp 233-241 3. Tan CTC, Hancock C, Steinherz P, Bacha DM, Steinherz L, Luks E, Winick N, MeyersP, Mondora A, Dantis E, Niedzwiecki D, Stevens Y: Phase I and clinical pharmacological study of 4-demethoxydaunorubicin (Idarubicin) in children with advanced cancer. Cancer Res 47: 2990-2995, 1987 4. Bonfante V, Ferrari L, Villani F, Bonadonna G: Phase I study of 4-demethoxydaunorubicin. Invest New Drugs 1: 161-168, 1983 5. Falkson G, Coccia-Portugal MA, Vorobiof DA, Terblanche APS, Dreyer R: Oral idarubicin in combination with cytosine arabinoside in previously untreated patients with acute non-lymphocytic leukemia. Am J Clin Oncol 9: 311-314, 1986
$78 6. Smith DB, Howell A: A phase II study of oral weekly 4-demethoxydaunorubicin in advanced breast cancer. Eur J Cancer Clin Oncol 23: 391-394, 1987 7. Kris MG, Gralla RJ, Kelsen DP, Casper ES, Burke MT, Fiore J J, Cibas IR, Heelan RT: Phase II trial of oral 4-demethoxydaunorubicin in patients with non-small cell lung cancer. Am J Clin Oncol 8: 337-379, 1985 8. Gagen M, Gochnour D, Young D, Gaginella T, Neidhart J: A randomized trial of metoclopramide and a combination of dexamethasone and lorazepam for prevention of chemotherapy-induced vomiting. J Clin Oncol 2: 696-701, 1984 9. Lionetto R, Pronzato P, Conte PF, Sertoli MR, Amoroso D, Rosso R: Idarubicin in advanced breast cancer: A phase I1 study. Cancer Treat Rep 70: 1439-1440, 1986 10. Chachoua A, Green M, Laubenstein L, Wernz J, Muggia FM: Phase II study of oral idarubicin in patients with AIDSassociated Kaposi's sarcoma. Cancer Treat Rep 71: 775-776, 1987 11. Milroy R, Cummings J, Kaye SB, Banham SW: Phase II
clinical and pharmacological study of oral 4-demethoxydaunorubicin in advanced non-pretreated small cell lung cancer. Cancer Chemother Pharmacol 20: 75-77, 1987 12. Berman E, Wittes RE, Leyland-Jones B, Casper ES, Gralla R J, Howard J, Williams L, Baratz R, Young CW: Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer. Cancer Res 43: 6096-6101, 1983 13. Kaplan S, Sessa C, Williams Y, Pacciarini MA, Tamassia V, Cavalli F: Phase I trial of 4-demethoxydaunorubicin (idarubicin) with single oral dose. Invest New Drugs 2: 281-286, 1984 14. Smith DB, Margison JM, Lucas SB, Wilkinson PM, Howell A: Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin. Cancer Chemother Pharmacol 19: 138-142, 1987
Address for offprints: T. Umsawasdi, Department of Medical Oncology, Box 80, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
Phase II study of 4-demethoxydaunorubicin in previously untreated extensive disease non-small cell lung cancer Theera Umsawasdi 1, Tyrone B. Felder 2., Diane Jeffries 1 and Robert A. Newman 2
1Sections of Head and Neck and Thoracic Medical Oncology, and the 2Section of Pharmacology, Department of Medical Oncology, The University of Texas M.D. Anderson Cancer Center (Present address: * College of Pharmacy, Texas Southern University College of Pharmacy and Health Sciences, Houston, Texas 77004, USA)
Key words: non-small cell lung cancer, chemotherapy of lung cancer, 4-demethoxydaunorubicin, idarubicin, 4-DMDR, treatment of advanced lung cancer
Summary Fifteen patients with previously untreated extensive non-small cell lung cancer (E-NSCLC) were treated with oral 4-demethoxydaunorubicin (4-DMDR) at the dose of 10 mg/m2/day x 5 days every 3 weeks with routine administration of antiemetic drugs. They received a median of two courses of treatment with the cumulative dose range from 50-712.5 m g / m 2. One patient achieved partial remission with a duration of 14 weeks. Two patients had minor responses with durations o f 14 and 24 weeks. Stable disease occurred in three patients (21, 22, and 27 weeks). Median survival was 33 weeks (range 3 - 7 3 + weeks). Toxicities were tolerable. Neutropenia ( < 1,000 mm 3) occurred in only 16~ of all treatment courses. Three patients developed correctable arrhythmias (two with atrial fibrillation and one with accelerated junctional rhythm). The cause of arrhythmia was unclear. No clinical evidence of congestive heart failure or decreased cardiac ejection fraction was observed. Nausea and vomiting were common but tolerable. Alopecia and mucositis were uncommon. Clinical pharmacokinetic studies were done in nine patients. However, plasma 4-DMDR levels were below the limit of detection (3 ng/ml). Because 4-DMDR has shown some activity in previously untreated E-NSCLC and the toxicities at this dose schedule are mild, we suggest that further studies of this drug at a higher dose in this schedule are indicated.
Introduction The prognosis of extensive non-small cell lung cancer is poor, with a response rate between 30~ and 6007o and a median survival of about 8 months in patients treated with various chemotherapeutic regimens [1,2]. Therefore, there is an urgent need to search for other active new drugs. Idarubicin (4-demethoxydaunorubicin, 4-DMDR) is a new daunorubicin analogue that has been shown to have antitumor efficacy in various human malignancies [3-6]. This drug can be given effectively by the oral
route without the vesicant effect which may occur when given intravenously [5,6]. In a study of 11 patients with E-NSCLC who had received no prior chemotherapy, one patient responded when 4-DMDR was given orally at the dose of 4 0 - 4 5 m g / m 2 [7]. Our previous study showed that 1 of 7 patients who had no previous chemotherapy had stable disease in lungs and bone for 56 weeks with minimal toxicity (Umsawasdi T, unpublished data). We found that at the oral dose of 10 mg/m2/day x 5 days, 4-DMDR caused minimal myelosuppression in most patients, but nausea and vomiting were common.
$74 Since there was a suggestion of activity in our pilot study of idarubicin in patients with E-NSCLC who had received no prior chemotherapy and only nausea and vomiting were significant toxicities, we therefore conducted a more comprehensive phase II study to evaluate the therapeutic efficacy and toxicity in patients with E-NSCLC who had received neither chemotherapy nor radiotherapy. Routine antiemetic drugs were used in order to suppress nausea and vomiting. A study of the pharmacokinetics of the parent compound was attempted to aid in evaluation of the bioavailability of this drug.
Table 1. Toxicity criteria
Toxicity
Grade I
Grade II
Nausea and vomiting Malaise
Slight nausea, no vomiting Mild, tolerable without treatment Mild, tolerable without treatment Semisolid movements
Nausea-occasional vomiting Tolerable with treatment Tolerable with treatment Watery and frequent movements (3-4 or less per day) Complete loss Patchy mucositis; brisk enanthema
Anorexia Diarrhea
Alopecia Stomatitis
Partial loss Faint pinkish enanthema
Patients and methods The eligibility criteria included histologic p r o o f of E-NSCLC; no prior chemotherapy or radiotherapy; age >_ 15 years; a life expectancy of ___ 12 weeks with a Z u b r o d ' s performance status score of >_ 2; adequate bone marrow, liver and renal function; and informed written consent. Patients should have had no cardiac failure or arrhythmias requiring treatment or a prior history of myocardial infarction. 4-DMDR (Idarubicin) was supplied by Adria Laboratories. It was administered orally on an empty stomach at the dose of 10 m g / m 2 / d a y • 5 days. This dose was chosen because of the concern of myelosuppression in the previous study [7]. The 4-DMDR doses in subsequent courses were administered according to the degree of myelosuppression, with the range of total dose per course ranging f r o m 37.5 to 75 m g / m L Because the drug came in 5, 10, and 25 mg capsules which could not be broken down, the dose was adjusted to the lower nearest number of mg divisible by 5 (e.g., calculated dose = 18 mg, the dose to be given = 15 mg). The courses were repeated every 3 weeks if possible. Antiemetic drugs included lorazepam (2 mg) given orally 2 hours before each dose of chemotherapy, followed by metoclopramide (10 mg) one half hour later and again 6 hours after the 4-DMDR dose. This antiemetic regimen was a modified antiemetic program from a previous reported study [8] with a substitution of dexamethasone with metoclopramide at a less intensity of treatment with oral administration.
Physical examination, CBC, differential, platelet counts, SMA-12, serum electrolytes, chest roentgenogram, and E K G were done prior to each treatment course. Multiple gated cardiac scans were done before initiation of the first treatment and every three treatment courses or sooner as clinically indicated. Other radiologic or radioisotopic studies were repeated every 2 - 3 courses as necessary to determine the response. Standard criteria of response were used. The toxicity criteria are shown in Table 1. The criteria were graded as N C O G toxicity criteria per requirement f r o m Adria Laboratories with supplement criteria f r o m our institution. No grade III and IV toxicities were shown in the table because none of these patients had either grade III or IV toxicities.
Clinical pharmacokinetic studies Nine patients were studied. Blood (10 ml) was drawn at 15, 30, 45 minutes and 1, 2, 3, 4, 6, and 8 hours after the doses on days 1 and 5. Plasma was obtained by centrifugation and then frozen at - 2 0 ~ until analysis. Calibration curves were made as follows. Pooled, drug-free h u m a n plasma (1-ml aliquots) was spiked with 20/A of appropriate stock solutions of 4-DMDR to yield a final drug concentration range of 1 to 20 ng/ml. Daunorubicin (25 n g / m l in plasma) was used as the internal standard. Sodium
$75 hydroxide (50 ~1 of a 0.005 M solution) was added, and the tubes were briefly vortexed. Ethyl acetate (6 ml) was added, and the plasma was extracted for 30 minutes. The tubes were then centrifuged, and the ethyl acetate phase was aspirated and transferred to another glass tube. The organic phase was evaporated to dryness at 50~ under a stream of nitrogen. The residue was reconstituted in 200 ~1 of water and 5 0 - 1 0 0 ~1 injected onto the column for H P L C analysis. 4-DMDR was quantitated using a fluorescence set at an excitation wavelength of 245 nm with a 550 nm emission cutoff filter (A.B.I. Analytical, Kratos Division). The analytical column used was a uBOND A P A K Phenyl column (3.9 m m x 15 cm, Waters Associates, Milford, MA). The mobile phase consisted of citrate buffer (0.1 M, p H 4.5)-methanolacetonitrile (2:1:1) at a flow rate of 1 ml/min.
Results Fifteen patients were entered into the study. One of them was not eligible because of his prior history of myocardial infarction but was evaluated for both response and toxicity. Patient characteristics are shown in Table 2. Patients received a median of two courses of therapy (range 1-12) with the cumulative dose range from 50 to 712.5 m g / m 2. Five patients received only 1 course of treatment but had rapid progression of their diseases. Two of them had significant neutropenia ( < 1000/cumin) but others had mild toxicities. One patient with a diagnosis of adenocarcinoma achieved a partial response with a duration of 14 weeks. Two patients had minor responses with a duration of 14 and 24 weeks. Stable disease occurred in three patients for 21, 22, and 27 weeks. The remaining patients had progressive disease. Median survival from onset of therapy for all patients was 33 weeks (range 3 - 7 3 + weeks).
Toxicity All patients tolerated the treatment well, and hematologic toxicities were tolerable (Table 3). Neu-
Table 2.
Patient characteristics
Total No. of Pts. Median age (range) Sex: Male/female Histology: Adenocarcinoma Squamous cell carcinoma Large cell carcinoma Bronchoalveolar cell carcinoma Adenosquamous carcinoma Tumor sites:Lung Skin/subcutaneous tissue Bone Adrenal Liver Lymph nodes Others
15 58 (35-63 Yrs) 10/5 9 2 2 1 1 15 5 4 3 2 2 3
tropenia ( < 1,000/mm 3) and thrombocytopenia ( < 100,000/mm 3) occurred in 16~ (9/57) and 11 ~ (6/57) of all treatment courses respectively. One patient developed a treatable pneumonia during a neutropenic period. Three patients had correctable arrhythmia (two with atrial fibrillation and one with accelerated junctional rhythm). Two of these patients received additional 4-DMDR treatment under close observation but without further problems. One did not receive further 4-DMDR therapy. No evidence of decreased ejection fraction determined by multigated cardiac scan was observed. Other toxicities are shown in Table 4.
Clinical pharmacokinetic studies The assay for 4-DMDR was linear from 3 to 20 ng/ml, with 3 n g / m l the lower limit of detection. No interfering peaks were present in the chromatograms obtained using drug-free plasma. Plasma 4-DMDR levels of patients that received the drug were apparently below the limit of detection. This was true even after the fifth dose. In addition, the occurrence of myelosuppression in several patients could not be associated with higher or detectable plasma 4-DMDR concentrations.
$76 Table 3. Hematologic toxicities Median lowest counts x lOVmm 3
Dose
mg/m2/ course
No. of courses
Absolute granulocytes (range)
Platelets (range)
37.5 50 60-62.5 70-75
2 28 16 11
2.3 3.2 2.2 1.8
181 323 182 185
(1.6-3.1) (0.1-11.9) (0.5-3.9) (0-3.3)
(137-226) (96-738) (94-406) (62-371)
Table 4. Other toxicities No. of courses with toxicities Dose
mg/mV course 37.5
No. of courses 2
50
28
60-62.5
16
70-75
11
Grade
Nausea/ vomiting
Malaise
Anorexia
Diarrhea
Alopecia
Stomatitis
1 2 1 2 1 2 1 2
0 0 10 12 5 8 3 6
0 0 6 2 8 0 6 2
0 0 4 0 8 0 5 0
1 0 4 2 1 3 0 0
0 0 3 0 1 0 2 0
0 0 1 0 2 0 1 2
Discussion In this study, 4-DMDR was found to have only limited activity in E-NSCLC patients who had received neither prior chemotherapy nor radiotherapy. This evaluation confirmed the limited activity of this drug in previously untreated E-NSCLC [7]. The latter study used 4-DMDR as a single dose from 40 to 50 m g / m 2 and found that one of 11 patients had an " i m p r o v e d " major response lasting 5.2 months [7]. The dose schedule used in the present study indicates that the drug has tolerable toxicity. Nausea and vomiting occurred even with routine antiemetic drug administration but were tolerable. These results are in agreement with other studies [4, 6, 9 - 1 3 ] that showed nausea and vomiting were c o m m o n and that a more aggressive use of antiemetic drugs should be considered. Mucositis was u n c o m m o n in our study, and none occurred in three previously
reported studies using 4-DMDR doses between 10 and 50 m g / m 2 [7, 10, 12]. Mucositis occurred in 8-17~ of patients who received higher doses (50-60 m g / m 2) [4, 13]. Alopecia was mild in our study but varied in other studies [4,6,7, 11, 12]. Although several studies [4,6,7,12,13] had shown significant myelosuppression from this drug, we and other investigators [11] did not find it to be a limiting toxicity at doses between 45 and 50 m g / m 2. The discrepancy could be due to a healthier patient population (i.e., previously untreated in these two studies), whereas most other studies were of previously treated patients. It is possible that our dose schedule, with the dose divided over a 5-day period, could influence the degree of toxicity; the other study found significant myelotoxicity even in previously untreated patients when 4-DMDR was given as a single dose [7]. Cardiotoxicity in humans so far has been uncommon. No clinical evidence of congestive heart fail-
$77 ure or reduction of left ventricular ejection fraction (LVEF) occurred in the present study. Other investigators [4, 6, 7, 9 - 1 3 ] did not observe congestive heart failure in their patients with the highest cumulative 4-DMDR dose of 800 m g / m 2. No diminution in resting LVEF, determined by either radionuclide left ventriculograms or echocardiogram, was found [4,7, 10, 12]. Lionetto et al. [9] observed a greater than 10% decrease in LVEF (11% and 19%) in two patients who received 135 and 450 m g / m 2 of 4-DMDR respectively, but with final values of LVEF > 50% and without clinical signs of cardiotoxicity. Correctable cardiac arrhythmias occurred in 20% of our patients. The cause-and-effect relationship with 4-DMDR is uncertain, since two patients continued to receive more 4-DMDR without recurrence of cardiac arrhythmias. Bonfante et al. [4] reported a 66% incidence of E K G abnormalities in their patients who received oral 4-DMDR treatment. However, only 37.5% of the abnormalities were arrhythmias (atrial premature beats, 22~ ventricular premature beats, 12.5%; sinus arrhythmias 3%). Other E K G abnormalities could be due to nonspecific changes. No E K G abnormalities were found in other studies [6, 11,13]. Cardiac toxicities of this drug need to be investigated further in a larger number of patients for a longer duration of follow-up time. At this dose schedule (10 m g / m 2 P O / d a y x 5 days), we did not observe a detectable plasma level of 4-DMDR. Berman e t al. [12] detected a level of 4-DMDR in plasma of about 20 n g / m l in a patient who took a single dose of 50 m g / m ~ of 4-DMDR orally but the level decreased to 2 n g / m l after 48 hours. In other studies, after a single oral dose of 4 0 - 6 0 m g / m 2 or 50 m g / m 2 in three divided doses of oral 4-DMDR over 24 hours, the mean peak plasma levels were between 6.3 and 13.2 n g / m l [11, 13]. The mean plasma 4-DMDR half-lives were short (3.2 + 0.4, and 8.75 hours) in two studies [11, 13]. Our dose schedule, which divided the drug to be given over a 5-day period, could result in an undetectable plasma level. A modification of the assay technique such as that suggested by Smith [14], which reports the limit of sensitivity of a modified assay to be 0.25 ng/ml, m a y be required to determine the pharmacokinetics of 4-DMDR more accurately in future studies.
Our study shows the limited efficacy of 4-DMDR given at the dose of 10 m g / m 2 / d a y • 5 days in previously untreated E-NSCLC patients. However, because the toxicities are mild and the drug has a short half-life, it is possible that increasing the dose of 4-DMDR given in a 5-day schedule could increase therapeutic efficacy. The discrepancies of the results of bioavailability of this agent administered orally indicates that further studies are needed. Evaluation of the activity of this drug in this disease with intravenous route to ensure a proper dose of 4-DMDR is needed.
Acknowledgements This study was partially supported by grant from Adria Laboratories, Columbus, Ohio 43216. We thank Paul Y. Holoye, M.D., Alan M. Kramer, M.D., Isaiah W. Dimery, M.D., Bonnie S. Glisson, M.D., Jin Soo Lee, M.D., David T. Cart, M.D., and William K. Murphy, M.D. for their collaboration, James A. Neidhart, M.D., and Waun Ki Hong, M.D. for their valuable comments and suggestions, and Pamela Ansley and Cynthia Argo for their secretarial assistance. This study was presented in part at the annual meeting of the American Association for Cancer Research, New Orleans, May 25, 1988.
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Address for offprints: T. Umsawasdi, Department of Medical Oncology, Box 80, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
