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G Patient Summaries, Lilly Trial H3X-MC-PPPA

UNIVERSITY OF TEXAS GALVESTON SITY

Three patients were treated at the Galveston study center (patients 21-23). Patient 21 is a 42-year-old man with known chronic HBV infection since 1990. His only symptoms were persistent fatigue. He had previously undergone a 6-month course of interferon therapy which failed to clear his infection. During the final week of interferon therapy he had a grand mal seizure, for which he has since taken phenytoin. At entry into the PPPA trial physical examination and chest radiograph were normal; screening labs met study requirements. He had a liver biopsy on April 16, 1993, which showed a lymphocytic portal infiltrate but no piecemeal necrosis, fatty metamorphosis or cirrhosis. Treatment with FIAU was started on May 14, 1993, at a dose of 0.05 mg/kg bid. At study entry AST (27 U/L) and ALT (41 U/L) were in the normal range, but serum HBV DNA was 2,752 pg/mL. On his 21st day of FIAU he had 2 tonic seizures, and FIAU was discontinued for 5 days because of concern that they may have been FIAU related. When phenytoin levels were found to be subtherapeutic, his dose was increased to provide adequate levels, and no further seizures occurred. At the time of his 5th weekly study visit on June 18 he complained of fatigue that interfered with his daily activities (attributed by the patient to the increased dosage of phenytoin). On June 26 FIAU was discontinued because of suspected toxicity at another study site.

During the 43 days of FIAU therapy there was some evidence of a therapeutic response with a drop of serum HBV from 2752 to 916 pg/ml. During the trial the AST levels remained normal (25-28 U/L) as did the ALT levels (38-42 U/L). Because of the toxicity in patients at another study site the patient had repeated transaminase measurements at intervals of 1-2 weeks (for the next 2 months) and then at monthly intervals for 4 more months (last measurement on January 12, 1994). Five days after discontinuing FIAU his serum HBV DNA level rose to 1,722 pg/ml, and thereafter remained between 1,399 and 4,486 pg/ml. AST levels repeatedly ranged from 25-30 U/L and ALT likewise remained in the normal range. Lactate levels, performed at weekly intervals during the 2 months following cessation of therapy with FIAU, were always in the 1.0-1.9 mmole/L range, (normal 0.3-2.6 mmole/L). He had no complaints (other than maxillary sinusitis in Nov. 1993) and his physical examinations remained unremarkable. A biceps muscle biopsy to assess subclinical FIAU myopathy was normal by light microscopy and histochemical staining of mitochondria.

Patient 22 is a 37-year-old man with HBV infection, known since 1988. His only complaints were mild fatigue and arthralgias. He had known about interferon but had been unwilling to undergo that type of therapy. Physical examination was unremarkable except for spider angiomata on his upper back and over both deltoid areas. Chest radiograph was normal,



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Review of the Fialuridine (FIAU) Clinical Trials G Patient Summaries, Lilly Trial H3X-MC-PPPA UNIVERSITY OF TEXAS GALVESTON SITY Three patients were treated at the Galveston study center (patients 21-23). Patient 21 is a 42-year-old man with known chronic HBV infection since 1990. His only symptoms were persistent fatigue. He had previously undergone a 6-month course of interferon therapy which failed to clear his infection. During the final week of interferon therapy he had a grand mal seizure, for which he has since taken phenytoin. At entry into the PPPA trial physical examination and chest radiograph were normal; screening labs met study requirements. He had a liver biopsy on April 16, 1993, which showed a lymphocytic portal infiltrate but no piecemeal necrosis, fatty metamorphosis or cirrhosis. Treatment with FIAU was started on May 14, 1993, at a dose of 0.05 mg/kg bid. At study entry AST (27 U/L) and ALT (41 U/L) were in the normal range, but serum HBV DNA was 2,752 pg/mL. On his 21st day of FIAU he had 2 tonic seizures, and FIAU was discontinued for 5 days because of concern that they may have been FIAU related. When phenytoin levels were found to be subtherapeutic, his dose was increased to provide adequate levels, and no further seizures occurred. At the time of his 5th weekly study visit on June 18 he complained of fatigue that interfered with his daily activities (attributed by the patient to the increased dosage of phenytoin). On June 26 FIAU was discontinued because of suspected toxicity at another study site. During the 43 days of FIAU therapy there was some evidence of a therapeutic response with a drop of serum HBV from 2752 to 916 pg/ml. During the trial the AST levels remained normal (25-28 U/L) as did the ALT levels (38-42 U/L). Because of the toxicity in patients at another study site the patient had repeated transaminase measurements at intervals of 1-2 weeks (for the next 2 months) and then at monthly intervals for 4 more months (last measurement on January 12, 1994). Five days after discontinuing FIAU his serum HBV DNA level rose to 1,722 pg/ml, and thereafter remained between 1,399 and 4,486 pg/ml. AST levels repeatedly ranged from 25-30 U/L and ALT likewise remained in the normal range. Lactate levels, performed at weekly intervals during the 2 months following cessation of therapy with FIAU, were always in the 1.0-1.9 mmole/L range, (normal 0.3-2.6 mmole/L). He had no complaints (other than maxillary sinusitis in Nov. 1993) and his physical examinations remained unremarkable. A biceps muscle biopsy to assess subclinical FIAU myopathy was normal by light microscopy and histochemical staining of mitochondria. Patient 22 is a 37-year-old man with HBV infection, known since 1988. His only complaints were mild fatigue and arthralgias. He had known about interferon but had been unwilling to undergo that type of therapy. Physical examination was unremarkable except for spider angiomata on his upper back and over both deltoid areas. Chest radiograph was normal,

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Review of the Fialuridine (FIAU) Clinical Trials and screening laboratories met the study criteria. A pre-study liver biopsy as showed a lymphoplasmacytic infiltrate, piecemeal necrosis and prominent focal portal fibrosis. At the time of starting FIAU (0.125 mg/kg p.o. bid) on June 8, 1993, the level of serum HBV DNA was 3715 pg/ml, and liver function tests showed an AST level of 76 and an ALT of 115. On June 15, his second study visit, his only complaints were of a metallic taste in his mouth which he attributed to FIAU, and persistent pain at the site of liver biopsy done 2 weeks earlier (the latter improved over the next week). Serum HBV DNA was 1,981 pg/ml, and AST and ALT were essentially unchanged. On June 22, after 2 weeks of FIAU, his HBV DNA level had dropped to 904 pg/mL, and AST and ALT were 81 and 114 U/L, respectively. FIAU was discontinued on June 27 because of the events at NIH. Following cessation of FIAU he was followed with weekly visits for the next 2 months, monthly visits for the next 4 months, and at trimonthly intervals thereafter (last recorded visit October 31, 1994). During the first 2 months of follow-up the HBV DNA levels progressively fell to < 0.7 pg/ml. He felt well and his level of fatigue returned to what it had been before taking FIAU. There were no symptoms of peripheral neuropathy. During this period his only findings on examination were mild hepatic tenderness which cleared in 3 weeks. AST and ALT levels, which had reached 95 and 135 U/L, respectively, at the time of drug cessation, subsequently declined to 31 and 35 U by 2 months later. Follow-up included lactate determinations, which were always within the normal range. During long term (2-14 mos. after discontinuance of FIAU) follow-up, HBV DNA remained < 2.2 pg/ml for 5 months, but at 8 months and at 10 months had reached levels of 4,057 and 229 pg/ml, respectively. AST (22-49 U/L) and ALT (21-66 U/L) remained in the normal range. At the most recent (October 31, 1994) follow-up visit he complained of a few episodes of nausea, and he was referred for consideration of interferon therapy. Patient 23 is a 62-year-old man whose chronic HBV infection followed a blood transfusion in 1985. His only symptoms possibly referable to HBV infection were pruritus and early morning nausea. He had a history of coronary artery bypass surgery, performed in 1981 and 1985. His medications consisted of oral propranolol and diltiazem. Physical examination was unremarkable. Chest radiograph showed a slightly enlarged heart. Screening laboratory testing met study criteria. Liver biopsy had been performed earlier (February 15, 1993) and revealed a chronic portal inflammatory infiltrate, focal piecemeal necrosis, fatty metamorphosis and portal fibrosis (without overt cirrhosis). At the time (June 10, 1993) of starting FIAU (0.125 mg/kg p.o. bid) the serum HBV level was at 4,736 pg/ml, and the AST and ALT levels were mildly elevated at 95 and 169 U/L, respectively. A week later, at his second study visit, he complained of early morning nausea (which he considered probably his baseline) for which compazine was prescribed. At that visit the serum HBV DNA level had dropped to 228 pg/ml and the AST and ALT levels had risen to 146 and 230 U/L, respectively. On the 3rd study visit (June 24) he had no complaints and had taken compazine on only 3 separate occasions. HBV DNA was 106 pg/ml; AST had almost doubled (179 U/L) and ALT was similarly elevated (288 U/L). Two days later, FIAU was discontinued, after a total of 16 days, again because of the serious toxicity noted at another study site. Nine days after stopping FIAU (July 6) he complained of several days of nausea (more than his baseline) and of lower extremity weakness. He was admitted to the hospital for

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Review of the Fialuridine (FIAU) Clinical Trials evaluation (July 6-9). General physical and neurological examinations were unremarkable. AST was 124 U/L (normal range by impatient testing, 13-40 U/L) and ALT 252 (impatient normal range, 9-51 U/L). Lactate level was 1.1 mmol/L (normal 0.3-2.6). Electromyography and nerve conduction studies were normal. Symptoms improved and he was discharged. Over the next 2 months he was seen at follow-up at weekly intervals initially and then at 2 week intervals. A muscle biopsy was normal. HBV DNA started to rise (173 pg/mL) on July 1, reaching a peak of 750 pg/ml on August 24. AST was in the 62-83 U/mL range (outpatient testing normal, 10-78 U/mL), and ALT was in the 100-144 U/L range (outpatient testing normal, 5-95 U/mL). Lactate levels remained in the normal range. The next month (September 29), 3 months after discontinuing treatment, he had some intermittent epigastric pains for which he took antacids. No other complaints were noted and his examination was unremarkable. AST had risen to 250 U/L and ALT had risen to 333. On January 2, 1994, 6 months after cessation of FIAU, he was admitted to another hospital because of abdominal pain. A laparoscopic cholecystectomy was performed the following day after ultrasound demonstration of gallbladder sludge and thickening of the gallbladder wall and some ascites. Cholangiogram showed no stones and histologic examination of the gallbladder showed chronic cholecystitis. On January 27, 7 months after FIAU was stopped, he was again seen in follow-up. He was jaundiced, weak, and orthopneic, and ascites was present on physical examination. HBV DNA level was 50 pg/ml; AST 353 U/L; and ALT was 222. During hospital admission (January 31-February 12) therapeutic paracentesis showed fluid that was unremarkable. PT was 14.8 seconds; total bilirubin was 3.3 mg/dl, coming down to 2.0 mg/dl; AST and ALT were 408 and 262 U/L, coming down to 270 and 206, respectively, by the time of discharge. Abdominal CT showed ascites and a normal pancreas, but the serum amylase rose from 129 U/L (normal, 35-110) to 272 U/L at the time of discharge. Liver biopsy showed cirrhosis (mixed micro-macronodular pattern), slight microdroplet steatosis (amount of microdroplet steatosis considered nonspecific), and moderately active chronic active HBV hepatitis. During March-April the patient was followed as an outpatient continuing on diuretic therapy (spironolactone and furosemide) with control of his ascites and requiring only one further paracentesis. On his most recent follow-up (September 8, 1994) he was feeling well, and laboratory test results had not yet returned. TUFTS NEW ENGLAND MEDICAL CENTER SITE The first patient treated with FIAU at Tufts New England Medical Center is a 38 year old man with a past history of alcohol and parenteral drug abuse; his chronic compensated HBV hepatitis was diagnosed in 1990. Liver biopsy one week before starting FIAU showed chronic active hepatitis (focal inflammatory infiltrate as well as piecemeal necrosis and bridging). Secondary conditions included migraine, anxiety and depression. Treatment with FIAU (0.10 mg/kg/day in 2 divided doses) was begun on June 1, 1993 and continued through

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Review of the Fialuridine (FIAU) Clinical Trials June 28, (trial termination), for a total of 191 mg. Serum HBV DNA1 at study entry was 232 Eq/mL x 106 and over the next 4 weeks the level steadily dropped to 12 Eq/ml x 106 remaining at about this level over the next two months. Symptoms reported by the patient during the 4 weeks of treatment included: mild chills and myalgias for 24 hours on the second day of treatment; moderate diarrhea on the 10th to 12th days of treatment; and moderate vomiting for 2 days. During the month of FIAU treatment, the serum ALT level rose from the pretreatment value of 65 to 103 U/L on the 6th day, and then fell to 61 and 65 U/L during the 2nd and 3rd week. However, at 1 month the ALT was 122 and peaked at 206 U/L at 5 weeks after starting FIAU. The ALT then gradually dropped over the succeeding 7 weeks to 49 U/L. At 4-5 months after starting treatment ALT reached its nadir of 23 U/L, only to rise again to 211 U/L, at the end of 7 months. During the 6 months follow-up period, the patient reported several symptoms: mild abdominal pain (July 8-15); asthenia (July 8 to August 4); tremor of the hands (July 15 to August 10); anorexia and weight loss (July 21-August 8); and mild leg pain/numbness (starting October 22). Upon report of the last of these symptoms he was seen by a neurologic consultant who found evidence of a primary sensory neuropathy. Neurologic follow-ups on March 11, 1994 and on June 21, 1994 indicated that the patient continued to have numbness to the level of the knee and electric shock-like pains in the lower legs, preventing him from jogging or standing on his feet for any length of time, Subjectively the patient sensed that these symptoms had worsened over the 8 month period. Neurologic examinations showed loss of pain and cold perception up to the knees, absent ankle jerks, absence of vibration sense in the great toes, and some wasting of intrinsic foot muscles. Electrophysiologic studies indicated the presence of an axonal neuropathy with principally sensory involvement but some motor involvement as well. Over a 6 month period of neurologic evaluation it was felt that there had been neither significant changes on neurologic examination nor on nerve conduction studies, but subjectively the patient felt that the symptoms had worsened. The second patient in this trial is a 24-year-old male. Liver biopsy performed 5 days before starting the trial showed chronic active hepatitis with moderate portal area inflammation, abundant piecemeal necrosis and marked fibrosis. Treatment with FIAU (0.25 mg/kg/day in 2 divided doses) was begun on May 3, 1993 and continued through June 27 (trial terminated because of serious adverse events in FIAU study H3X-MC-PPPC). He received 55 days of therapy, representing a total dose of 963 mg of FIAU. Serum HBV DNA was 3034 Eq/mL x 106 at study entry, 271 at 7 days, and subsequently dropped to 110 by the end of the first month of treatment. At the end of the 55 days of treatment the HBV DNA level was 29 (1% of the baseline value). Over the next 7 weeks levels increased, ranging between 147 and 545 Eq/mL x 106 at the end of 8 months it was 978. The only adverse effect reported by the patient was one day's mild nausea 10 days prior to FIAU discontinuation. Serum ALT level on study 1   Measured by a new Chiron measurement system reported in Equivalents/ml x 106. For conversion from Equivalents to picograms:

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Review of the Fialuridine (FIAU) Clinical Trials entry was 88 U/L and remained between 73 and 84 at weekly measurements over the first month of therapy. On the day of cessation of FIAU therapy the ALT was 161 (increased to 1.8-fold of baseline). Over the next 2 1/2 weeks it rose to a peak of 241 U/L (increase of 2.7-fold) and then gradually fell reaching a level of 64 at 8 months after the start of the study. When the study was stopped on June 27, 1993, because of his 55 day course of FIAU totalling 963 mg, he was offered the option of hospitalization for observation and I.V. thymidine rescue therapy from possible subsequent manifestations of FIAU toxicity. On return from vacation on July 6 he agreed to hospital admission. Serum lactate levels were normal and muscle biopsy showed normal results. He was asymptomatic on admission and received 8 gm/m2 (14 gm) of thymidine for 7 days via continuous I.V. infusion as FIAU washout treatment. Also, he received carnitine and thiamine as part of the rescue therapy. During the subsequent 6 month follow-up period, fatigue (noted on study visits at 17 days and 5 weeks after the last dose of FIAU) and headaches (noted on study visits 17 days, 6 wks and again 5 months after stopping FIAU) were reported. The fatigue was short-lived, lasting 1 day on the first occasion and 11 days on the second. The headache lasted 1 or 2 days except on the last occasion when it persisted in a mild form for 11 days. Headaches had been present for some years in the past, and he had taken tylenol (325 mg) for them intermittently since 1989. SUMMARY OF TRIAL H3X-MC-PPPA Five patients were enrolled in the study and received either 0.10 or 0.25 mg/kg/day FIAU in bid aliquots in liquid form. The 90-day planned treatment was halted prematurely by the Sponsor because of major adverse events that occurred in FIAU Study H3X-MC-PPPC that was taking place concurrently. The 5 patients received FIAU for 17-56 days. Serum HBV DNA levels decreased significantly in all patients during the first week of therapy and remained markedly lower throughout the treatment period. This reduction in the level of this marker of HBV disease is considered a favorable response to therapy. Three of the 5 patients had transient ALT elevations shortly after the reduction in HBV DNA which were considered by the investigators, quite reasonably, as a reflection of immune activation (causing a hepatocellular reaction) and a favorable response to therapy. There have been no deaths of study subjects, nor were there any serious adverse events during the course of FIAU therapy. All patients had asthenia at some time and 4 of 5 experienced some nausea (3 reported emesis). Two patients in the 0.25 mg/kg/day group experienced dizziness. Abdominal pain, anorexia, diarrhea, or myalgia occurred once in both treatment groups. During the 6-month post-therapy follow-up, one patient was hospitalized 3 times (once each for nausea, cholecystectomy, and liver biopsy). One patient developed symptoms of peripheral neuropathy 5 or 6 months after his last dose of FIAU. The neuropathy was confirmed on neurologic consultation and by nerve conduction studies. None of the patients in this study developed the severe FIAU toxicity (hepatic failure, lactic acidosis, pancreatitis) observed in trial H3X-MC-PPPC. Three patients did develop mild transient amylase elevations but there was no clinical evidence of pancreatitis.