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Clinical Trials |
Department of Radiation Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4283 [D. I. R.]; Departments of Radiology [P. N.] and Internal Medicine [C. R. B., E. P. F.], University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235; Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232 [D. P. C.]; Division of Oncology, Stanford University, Stanford, California 94305 [B. L. L.]; and Pharmacyclics, Inc., Sunnyvale, California 94086 [R. M., J. E., S. Y., D. M., J. F. R.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Gd-Tex (NSC 695238) is a pentadentate aromatic metalloporphyrin developed as a sensitizer for radiation and chemotherapy (5) . Like many naturally occurring porphyrins, it has selective biolocalization in tumor and the ability to form long lived radicals by accepting solvated electrons generated by ionizing radiation in oxic or anoxic conditions (6) . In vitro studies have demonstrated dose-dependent radiation sensitization of human cancer cell lines. In vivo studies in single fraction and multifraction experiments of a variety of tumor models demonstrated dose-dependent radiation sensitization resulting in improved survival of tumor-bearing animals (6) .
Gd-Tex accumulates in tumor tissue with selective sparing of normal surrounding tissue. Animal studies using [56Gd] or [14C]Gd-Tex injected into tumor-bearing animals demonstrated rapid clearance of the drug from blood and normal tissues, with delayed clearance from tumors, which resulted in up to 8-fold greater concentrations in tumors compared with surrounding tissues (7) . Because Gd-Tex contains the paramagnetic metal ion gadolinium, its selectivity has been demonstrated by MRI of tumor-bearing animals. These studies show enhancement of tumors but not normal surrounding tissues. This persists for up to 48 h after single-dose administration (8) and is attributed to the hepatic and renal clearance of the drug. Because of the hepatic and renal clearance of the drug, liver and kidney enhancement has been observed as well. DLT in animals is hepatotoxicity. Gd-Tex has the potential to be a clinical tumor-selective radiation sensitizer. We report here the results of the Phase I clinical trial.
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PATIENTS AND METHODS |
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Eligibility criteria included: (a) Eastern Cooperative Oncology Group (ECOG) performance status, 0–2; (b) age, 
18 years; (c) serum creatinine, 
1.5 mg/dl; (d) aspartate transaminase and alanine transferase, twice the upper limit of institutional normal; (e) serum bilirubin, 2 mg/dl; (f) absolute granulocyte count, 1500/mm3; (g) the ability to complete a 14-day posttreatment follow-up; and (h) an expected survival of 3 weeks. Patients were not eligible if their radiotherapy fields involved entry-exit through the liver or kidneys, if they had received prior involved field XRT, if they were lactating or pregnant women, if they had received other investigational agents within 30 days, or if they had a medical or psychiatric illnesses that would preclude informed consent. No chemotherapy was allowed for 2 weeks before or 2 weeks after Gd-Tex administration.
Gd-Tex Dosage and Administration.
A single i.v. dose of Gd-Tex (Xcytrin, Pharmacyclics, Inc., Sunnyvale, CA), formulated in an aqueous solution of 5% (isotonic) mannitol at a concentration of 2.3 mg/kg, was administered at a rate of 1–32 ml/min during the 1st week of palliative radiation. Before Gd-Tex administration, patients were hydrated p.o. with 240 ml of clear liquids/h for each of 4 h and then with 500 ml D5W i.v. immediately before Gd-Tex infusion.
The starting dose of Gd-Tex was one-tenth of the human equivalent of the lethal-dose for 10% (LD10) for mice, or 0.6 mg/kg. The dose was increased in cohorts of 3–5 patients according to the following modified Fibonacci system: 0.9, 1.1, 2.0, 2.9, 4.0, 5.4, 7.1, 9.5, 12.6, 16.7, 22.3, and 29.6 mg/kg. Dose escalation progressed if none of 3 patients had any treatment-related grade 3 or grade 4 toxicity, using the Cancer Therapy Evaluation Program/National Cancer Institute (CTEP/NCI) Common Toxicity Criteria to score adverse events. If one patient experienced grade 3 or 4 toxicity, two additional patients were enrolled in the same cohort, and the dose was escalated if no additional patient had grade 3 or grade 4 toxicity. If two patients in a cohort experienced treatment-related grade 3 or grade 4 toxicity, the MTD would have been exceeded, and the dose below that cohort would have been declared the MTD. Thus the MTD was defined as the dose level below which 2 patients developed grade 3 or 4 toxicity and at which 3 of 3 or 4 of 5 patients completed the cohort without treatment-related grade 3 or grade 4 adverse events. The serious toxicity-limiting dose escalation was defined as the DLT. Patients returning for all scheduled follow-up visits including the final 14-day follow-up visit were considered to have successfully completed the study. All of the patients were included in the safety analysis.
XRT.
One of the first five fractions of palliative XRT was delivered between 2 and 5 h after the completion of the Gd-Tex infusion. At least two parallel opposed or wedge pair X-ray beams were used to deliver 2, 2.5, or 3 Gy once daily to the planning target volume. Computerized dosimetry was performed for all patients. Dose gradient was maintained below 5%. Total doses ranged between 30 Gy in 10 fractions and 60 Gy in 30 fractions. The kidneys and liver were excluded from the irradiated volume. The spinal cord dose was limited to 40 Gy at 2 Gy/day or 30 Gy at 3 Gy/day. No X-ray entry-exit through the liver or kidneys was allowed.
MRI.
Axial MRI scans of the brain, upper abdomen, and the site to be irradiated were obtained on all of the patients who could be scheduled and who could complete the study. Imaging was performed with a 1.5 Tesla device using the body or head coil. Axial T1 weighted spin echo, turbo spin echo, or fast field echo images were obtained of the site to be irradiated, the liver, and the kidneys before and after the administration of Gd-Tex. The slice thickness ranged from 6 to15 mm. Images were obtained before, and within one h after, the administration of Gd-Tex. Additional delayed images were obtained in some patients up to 14 h after injection. The same MRI equipment and identical parameters were used for the pre- and post-Gd-Tex scans for each patient. Regions of interest were created in the tumors imaged as well as in the normal hepatic and renal parenchyma. Enhancement was scored if there was a 20% increase in signal intensity in the images obtained post-Gd-Tex administration as compared with the pre-Gd-Tex images.
Pharmacokinetics.
Plasma samples were obtained at baseline and over the first 1.5 h after dosing in patients treated with 0.6–2.0 mg/kg, and at 1, 4, and 24 h after drug infusion in the remainder of the patients. Additional time points were obtained from some patients. All of the blood samples were anticoagulated with K3EDTA. The plasma layer was separated by centrifugation and stored frozen until the time of analysis. The concentration of gadolinium was determined in each plasma sample by ICP-AES using a validated method. The ICP-AES analysis was performed by MDS Harris Laboratories in Lincoln, Nebraska. Gadolinium concentrations in plasma were converted to units of µg-equiv/ml before pharmacokinetic analysis. A µg-equiv was defined as the quantity of Gd-Tex (intact parent compound) in µg that would contain an amount of gadolinium metal equivalent to what was measured by ICP-AES. The lower limit of quantitation for this assay was determined to be 3.7 µg-equiv/ml. The interday relative error and precision of the assay were determined to be 7.4 and 7.5%, respectively, during the validation.
For the patients with early sampling time points, plasma concentration versus time profiles were fit to a 1-compartment, open, linear pharmacokinetic model with zero order input and first order elimination. Pharmacokinetic parameter estimates were obtained using nonlinear weighted least squares regression analysis using WinNonlin Version 2.0 (Pharsight Corporation, Mountain View, CA), with the regression weighted to 1/Cp, where Cp equals the measured plasma concentration of Gd-Tex.
For patients sampled at 1, 4, and 24 h, it was not considered appropriate to use a compartment model because contributions from 
, ß, and 
elimination phases could contribute to the Gd-Tex concentrations measured at these time points. Therefore, noncompartmental analysis was used to determine the area under the plasma concentration versus time curve between 1 and 24 h (AUC1–24 h) using the logarithmic trapezoidal method of integration. Because plasma samples for several patients were not obtained at exactly 1 h or 24 h, the logarithm of the plasma concentration at these time points was extrapolated/interpolated for some patients. The percentage of extrapolated area for each patient was less than 9%.
To test for a nonlinear relationship between AUC1–24 h and dose, the data were fitted to a power function described as AUC1–24 h = A(dose)B, and the function was transformed by taking logarithms of both sides to yield Ln(AUC1–24 h) = Ln(A) + BLn(dose). After calculating the value of B, Student‘s t test was used to see whether B was significantly different from 1.0.
Follow-up Evaluation.
Patients were followed for 4 h after infusion, then seen again at 24 h, 48 h, 72 h, 7 days, and 14 days after infusion. Follow-up safety information was obtained through day 30 after infusion.
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RESULTS |
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. The most common tumor was lung cancer. The most frequently irradiated sites were the thorax and the brain. The majority of patients had a good performance status at baseline evaluation. All but three of the patients were ambulatory and capable of total self care.
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Dose Escalation
The Gd-Tex dose was escalated in 13 cohorts from 0.6 mg/kg to 29.6 mg/kg. The number of patients and doses of Gd-Tex administered in each cohort is shown in Table 2
. The 10th cohort was expanded to four patients because the patient who died did not complete the 30-day follow-up. The 11th cohort was expanded to five patients per protocol because one patient experienced a treatment-related grade 3 rise in bilirubin. No further grade 3 or 4 toxicity was observed in the additional patients enrolled at that dose. Dose escalation continued according to the escalation rules. Dose escalation was discontinued after the 13th cohort when a pattern of dose-related renal toxicity became apparent. The MTD defined per protocol was 22.3 mg/kg.
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. A total of four patients experienced serious adverse events. At 9.5 mg/kg, one patient experienced grade 3 nausea and vomiting. At 16.7 mg/kg, one patient developed hemolytic anemia. Above the MTD, at 29.6 mg/kg, one patient developed serious dyspnea, myalgia, photophobia, asthenia, and grade 3 acute renal failure. Another patient developed grade 2 acute renal failure. There were no serious hepatic, pulmonary, or cardiovascular toxicities observed. Adverse events are discussed by body system.
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Dermatological Toxicity.
The most frequently reported adverse event was transient green discoloration of skin, mucosa, feces, and urine in all of the patients receiving Gd-Tex doses 7.1 mg/kg. The discoloration was attributed to the dark green color of the study drug and resolved completely over 72–96 h. Patients accepted this well as long as they and their families were prepared for it. One patient treated at the 22.3 mg/kg dose level developed a vesicular rash on the palms of his hands after administration of Gd-Tex. A biopsy was consistent with pseudoporphyria or porphyria cutanea tarda. However, a quantitative urine porphyrin analysis was not consistent with porphyria cutanea tarda. The rash was self-limited. Two patients reported pruritus—one at the MTD and the other at a dose above the MTD.
Gastrointestinal Toxicity.
Treatment-related dose-dependent nausea and vomiting, the second most frequently reported adverse event, was observed in 28% of the patients, including all of the patients in the 7.1- and 9.5-mg/kg dose groups. All of the patients treated at 12.6 mg/kg or higher were premedicated with oral antiemetics (dexamethasone, 10 mg, and prochlorperazine, 10 mg), which prevented the nausea until the MTD was exceeded. Above the MTD, grade 2 nausea and vomiting were seen again in one patient. Diarrhea was observed after eight treatments but was not dose-dependent. Although one patient each in the 1.1-, 2.0-, 4.0-mg/kg cohorts, two patients in the 9.5-mg/kg cohort, and three patients in the 12.6-mg/kg cohort reported possibly treatment-related diarrhea, no patients in cohorts receiving above 12.6 mg/kg reported diarrhea.
Hematological Toxicity.
One patient with a previously unknown history of G6PD deficiency treated at 16.7 mg/kg developed hemolytic anemia, manifested by a drop in hematocrit and a grade 3 rise in total bilirubin. There was no treatment-related neutropenia, thrombocytopenia, or anemia.
Hepatic Toxicity.
Transient grade 1 and grade 2 rises in transaminases peaking at 48 h after dose was observed in fewer than five patients and resolved within 7 days in all of the cases.
Radiation Toxicity
All in-field XRT toxicities were mild, expected, and commensurate with dose. There was no increase in normal tissue toxicity within the XRT treatment volume. There were no grade 3 or 4 toxicities within the radiation ports. All of the unusual or potentially serious toxicities seen in this trial and described above were systemic.
MRI Results
MRI images were used to document the biodistribution of Gd-Tex. Tumor and normal tissue enhancement was measured in the irradiated sites as well as in the brain, liver, kidneys, muscle, and lungs. Fig. 1
shows the contrast enhancement as a percent increase from baseline, averaged per cohort. At doses up to 4.0 mg/kg, some but not all of the tumors enhanced after Gd-Tex administration, with signal intensities increasing up to 31%. At doses above 4.0 mg/kg, every tumor that was evaluable-enhanced significantly, with signal intensities increasing from 24 to 113%. Other sites demonstrating increased enhancement were the kidney and the liver, the two organs in which Gd-Tex is cleared. There was no significant enhancement of the normal brain at any of the doses (-3 to 12% contrast enhancement). There was no significant contrast enhancement in muscle at doses up to 12.6 mg/kg. At and above the MTD, there was moderate contrast enhancement in muscle (25–28% contrast enhancement). The lungs did not enhance visibly, although the percent change in very low signal intensities at 0.9 and 29.6 mg/kg calculated to be 35% and 70% respectively. Fig. 2
shows an MRI scan of the brain of a patient with a brain metastasis from non-small cell lung cancer on study before (A) and after (B) the injection of Gd-Tex. Enhancement of the tumor but not the normal brain is seen, indicating that Gd-Tex is selectively taken up and retained by the metastasis. Signal enhancement of tumors was seen as late as 14 h after a single Gd-Tex administration.
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The plasma concentration versus time profiles for five patients sampled at early time points are shown in Fig. 3(A)
. The pharmacokinetic data from these patients were fit to a 1-compartment, open, linear model and a median (interquartile range) value for the plasma elimination half-life was determined as 0.78 h (0.74–0.79 h). Although the sampling scheme was not sufficiently detailed to resolve an distribution and a ß elimination phase, 0.78 h still represents a reasonable estimate of an upper limit for the half-life because any ß phase contribution would increase the 1-compartment model-derived value of the elimination half-life.
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, representative plasma concentration versus time profiles have been plotted for three individuals selected from the second group of 18 patients. Patients in this group received doses ranging from 5.4 to 29.6 mg/kg. Blood samples were drawn at 1, 4, and 24 h after administration of Gd-Tex. The area under the plasma concentration versus time curve (AUC1–24 h) for each patient was compared with the estimated value of AUC1–24 h for an efficacious dose of Gd-Tex in mice (23 mg/kg). For each patient, AUC1–24 h was greater than the corresponding value in mice. Thus, the Gd-Tex levels achieved in humans exceed those achieved in mice at an efficacious dose.
AUC1–24 h was plotted versus dose for each patient to determine whether a nonlinear relationship existed between these two variables. As shown in Fig. 4
, a trend toward nonlinearity (concave up) was observed between AUC1–24 h and dose. However, a fit of the data to a power function revealed that this trend was not statistically significant.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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4.0 mg/kg, independent of tumor type. A general dose-response relationship between signal intensity and drug concentration was observed; however, the heterogeneity of tumors examined and sites imaged precluded the description of a quantitative relationship. A dose-response relationship was also seen with respect to the percent of patients with tumor enhancement at a given dose. Enhancement was noted in primary as well as in metastatic tumors alike. Unlike conventional MRI contrast agents, the signal enhancement after Gd-Tex administration persisted for up to 14 h after single i.v. injection, despite rapidly falling plasma levels with a median half-life of 7.4 h. This is thought to be caused by the intracellular uptake and retention of Gd-Tex in tumor cells, demonstrated in preclinical studies. Gd-Tex could, thus, allow for selective radiosensitization of tumors in patients based on its selective localization in tumors. Gd-Tex also has the potential to be studied in the context of an initial and follow-up diagnostic tumor imaging agent and to delineate the tumor for MRI-based three-dimensional treatment planning, including stereotactic radiosurgery. We recommend the use of 16.7 mg/kg as the maximum single dose of Gd-Tex, although this is not the MTD to obviate the grade 2 renal toxicity seen at the MTD. The dose-limiting nonoliguric acute tubular necrosis responded to renal diet and fluid restriction in both patients. Because texaphyrins are highly lipoprotein-bound, dialysis was not indicated to increase the elimination of Gd-Tex.
Patients with differing tumor histologies and irradiated sites were included in this trial, which was adequate to assess the intended systemic and preliminary loco-regional Phase I end points. Future radiation site-specific Phase I trials will be necessary to fully evaluate potential toxicities within irradiated volumes in different body areas. Enhancement demonstrated in normal renal and hepatic parenchyma confirms the initial impression that the liver and kidneys should be excluded from the irradiated volume. We recommend that the drug not be used in patients with G6PD deficiency, and that it be used selectively and with great care in those with porphyrias. Adequate initial renal function is essential.
In conclusion, Gd-Tex plasma concentrations exceeding that reported for radiosensitization can be achieved at well-tolerated doses below the MTD. Using MRI, Gd-Tex selectively biolocalizes in tumors. These results are also consistent with the finding that normal tissue radiation toxicity was not increased. The nonlinear character of tumor enhancement, however, did not permit a reliable correlation with plasma concentration in this study, and continues as a subject of ongoing research.
Multiple dose administration of Gd-Tex will be necessary to realize its potential as a useful clinical radiation sensitizer. Radiation site-specific Phase I trials with multiple dosing of Gd-Tex are ongoing under the sponsorship of the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute. The optimal dose and schedule of Gd-Tex and integration with XRT will be determined by the MRI, pharmacokinetic, and clinical data derived from these trials as well as this one. Ultimately, a Phase III trial randomizing patients to site-specific XRT with or without Gd-Tex will be necessary to determine the clinical efficacy of this new drug as a clinical radiation sensitizer.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by a research Grant from Pharmacyclics, Inc., Sunnyvale, CA. 
2 To whom requests for reprints should be addressed, at Department of Radiation Oncology-2 Donner, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, PA 19104-4283. Phone: (215) 662-4204; Fax: (215) 349-5445.
3 The abbreviations used are: XRT, radiation therapy; Gd-Tex, gadolinium texaphyrin; MRI, magnetic resonance imaging; MTD, maximum tolerated dose; DLT, dose-limiting toxicity; ICP-AES, Inductively Coupled Plasma Atomic Emission Spectroscopy; AUC, area under curve; G6PD, glucose 6 phosphate dehydrogenase.
Received 8/17/98; revised 12/29/98; accepted 12/29/98.
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