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Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology:
Clinical Science

A Phase II Study of Recombinant Human Interferon-α2a and Zidovudine in Patients with AIDS-Related Kaposi's Sarcoma

Fischl, Margaret A.; Finkelstein, Dianne M.*; He, Weili*; Powderly, William G.; Triozzi, Pierre L.; Steigbigel, Roy T.§; the AIDS Clinical Trials Group1

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Author Information

Department of Medicine, University of Miami School of Medicine, Miami, Florida; *Harvard School of Public Health, Boston, Massachusetts; Washington University, St. Louis, Missouri; the Ohio State University, Columbus, Ohio; and §State University of New York at Stony Brook, Stony Brook, New York, U.S.A.

Address correspondence and reprint requests to Dr. Margaret A. Fischl, University of Miami School of Medicine, Department of Medicine, R-60A, P.O. Box 016960, Miami FL 33101, U.S.A.

Manuscript received March 17, 1995; accepted October 5, 1995.

1For additional authors contributing to this study, see the Appendix.

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Abstract

Summary: To assess safety, antitumor response, and immunological and virological activity of interferon-α2a and zidovudine combination therapy in patients with AIDS-related Kaposi's sarcoma, we conducted an open-label, Phase II, multicenter study. Sixty-three patients with biopsy-proven Kaposi's sarcoma and no previous interferon-α therapy received zidovudine 600 mg/day and interferon-α2a 18 × 106 U/day. The median duration of follow-up was 49 weeks. Of 62 evaluable patients, 25 (40%; 95% confidence interval, 0.28-0.52) showed a complete (26%) or partial (15%) antitumor response. Eight of 30 patients (27%) with <100 CD4 cells/mm3 and 17 of 32 patients (53%) with ≥100 CD4 cells/mm3 had a response. The median time to response was 36 weeks. Of the 25 patients with a response, four developed tumor progression. The median duration of response was 22.4 weeks. Eight patients (13%) developed another AIDS-defining event and 13 (21%) died. The major toxicities included anemia (16%), neutropenia (27%), elevated serum transaminases (16%), weight loss (16%), malaise (14%), fatigue (14%), fever (10%), and headache (6%). Therapy with intermediate-dose interferon-α2a and zidovudine resulted in tumor regression in patients with AIDS-related Kaposi's sarcoma who had a wide range of CD4 cell counts; this therapy was relatively well tolerated.

Interferon-α is an effective treatment for patients with AIDS-related Kaposi's sarcoma who have pre-treatment CD4 cell counts of 200 cells/mm3 or more (1-11). High doses of interferon-α (20 × 106 U/m2 or more) induce regression in 28 to 45% of patients (1-3,6-11), whereas lower doses (<20 × 106 U/m2) have proven less effective, with response rates typically less than 10% (6-9). Improvements in response rates by the addition of cytotoxic chemotherapeutic agents to interferon-α have been limited by combined toxicities (12-15).

Zidovudine therapy improves disease-free survival, increases CD4 cell counts, and suppresses human immunodeficiency virus (HIV) replication (16-19). Zidovudine has no documented activity against Kaposi's sarcoma other than that mediated through immunological and virological responses (20). The combination of zidovudine and interferon-α has synergistic inhibitory activity against HIV in vitro (21,22) and has been associated with tumor regression in several preliminary studies (23-25).

Based on these data, we conducted a Phase II clinical trial to assess the safety and activity of combination therapy with intermediate doses of interferon-α2a and zidovudine in patients with AIDS-related Kaposi's sarcoma.

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METHODS

Study Sample

The study sample consisted of patients who had measurable, biopsy-proven Kaposi's sarcoma. The criteria for eligibility also included a Karnofsky status of ≥80 a hemoglobin level of ≥92 g/L, a neutrophil count of ≥1,200 cells/mm3, a platelet count of ≥90,000 platelets/mm3, a creatinine level of ≤1.5 mg/dl, serum transaminase levels less than 2.5 times the upper limit of normal, and serum positivity for anti-HIV antibodies. Patients were excluded if they had a serious opportunistic infection, cardiac or neurologic disease, non-nodal visceral Kaposi's sarcoma, zidovudine therapy 14 days before study entry, or previous therapy with interferon-α. Women who were pregnant or breast-feeding were also excluded. The use of other antiretroviral agents, systemic corticosteroids, cytotoxic chemotherapy, or radiation therapy was not allowed. Chemoprophylaxis for the prevention of Pneumocystis carinii pneumonia was permitted.

Patients were recruited from 14 AIDS Clinical Trials Units. The study was approved by Institutional Review Boards at each unit, and all patients gave written informed consent.

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Study Design and Treatment

The study was an open-label, multicenter study. The dose of study medications was based on the findings of two previously published Phase I studies (24,25). Zidovudine was supplied by Burroughs Wellcome Co. (Research Triangle Park, NC, U.S.A.) and was given as one 100-mg capsule every 4 h (600 mg/day). Interferon-α2a was supplied by Hoffmann-La Roche (Nutley, NJ, U.S.A.) in 5-ml vials as a sterile lyophilized powder for reconstitution containing 18 × 106 U. Interferon-α2a was given as a s.c. injection once per day at a dose of 18 × 106 U. Patients who achieved a complete tumor response continued to receive zidovudine at the same dose and schedule and interferon-α2a at the same dose three times per week on nonconsecutive days.

If a serious (≥grade 3) toxicity occurred, zidovudine, interferon-α2a, or both were withheld until the toxicity grade returned to a lower-grade toxicity or pretreatment values. Zidovudine was initially withheld for serious anemia, and interferon-α2a was initially withheld for serious fatigue or moderate (grade 2) systemic, renal, neurologic, pulmonary, or cardiac toxicities except for fever and headache. Interferon-α2a was restarted at a dose of 9 million U once per day, and zidovudine was restarted as one 100-mg capsule every 6 h (400 mg/day). Patients with life-threatening toxicities (grade 4) other than anemia, neutropenia, or hepatic; a recurrent serious toxicity despite a modification in study medication; an opportunistic infection requiring therapy; or tumor progression had study medication permanently discontinued.

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Patient Evaluation

Patients had clinical and laboratory evaluations at enrollment, weekly through week 16, and every 8 weeks thereafter. Patients had tumor evaluations at weeks 4, 8, 12, 28, 36, and 52 and every 3 months thereafter. Responses of Kaposi's sarcoma were graded according to standardized criteria as a complete, partial, no response (stable), or progression. Patients with 4 or more weeks of therapy were considered evaluable for antitumor responses. A complete response was defined as the absence of clinically detectable disease persisting for a minimum of 1 month and confirmed by biopsy. A partial response was defined as a 50% or greater reduction in the sum of the product of the bidirectional measurement of measured lesions or the number of total lesions or the complete flattening of 50% or more of nodular lesions, all persisting longer than a month without the occurrence of new lesions. No response was defined as <25% increase or decrease in measured lesions without the occurrence of new lesions. Progression was defined as a ≥25% increase in measured lesions or the occurrence of new lesions after at least 4 weeks of therapy. Response duration was calculated as the difference between the time of first response (partial or complete) and the time of relapse.

CD4 cells from peripheral blood were enumerated using monoclonal antibodies and flow cytometry. Sera from patients, frozen at -70°C, were assayed simultaneously for HIV p24 antigen by an enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, IL, U.S.A.). Positive p24 antigen results were defined as 25 pg/ml or more.

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Statistical Analysis

Time-to-event distributions were estimated using Kaplan and Meier estimates. The Mantel-Haenszel test, Cox regression model, and logistic regression were used to determine pretreatment characteristics associated with antitumor responses. To determine changes in laboratory parameters over time, a linear regression model was fitted for data for each patient and summary statistics were calculated. All analyses were based on an intent-to-treat approach.

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RESULTS

Sixty-three patients were enrolled in the study between July 1989 and February 1991. All patients were white; 14 patients were Hispanic. The mean age (±SD) was 37.0 ± 7.9 years. Fifty-eight patients were homosexual or bisexual, and five had a history of injection drug use. Fifteen patients (24%) had a previous AIDS-defining opportunistic infection. The mean (±SD) pretreatment CD4 cell count was 181 ± 157 cells/mm3 (Table 1). Seventeen patients had detectable levels of serum p24 antigen before treatment. Eleven patients (17%) had <10 cutaneous Kaposi's sarcoma lesions; 37 (59%) had 10 to 50 lesions; and 15 (24%) had >50 lesions.

Table 1
Table 1
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The median duration of follow-up was 49 weeks. Forty-one patients discontinued study medication. The reasons for discontinuation of study medication included HIV disease progression (32 cases), death (one case), toxicity (three cases), self-withdrawal (four cases), and other (one case). The median duration of study treatment was 28 weeks.

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Antitumor Responses

One patient was not evaluable for response because of early treatment termination at week 3. Twenty-five patients (40%; 95% confidence interval (CI), 0.28-0.52) showed a complete or partial response as a best response (Table 2). The estimated median time from study entry to a partial response was 16 weeks (range, 8-36 weeks) and to a complete response was 36 weeks (range, 16-44 weeks). Thirty-one patients (49%) without a complete or partial response progressed; 19 initially had no change, and 12 had progression as the first measurable response. The median time to progression from study entry was 38 weeks (range, 4-36 weeks). Of the 25 patients who responded, four relapsed (two each with a partial or complete response) and two died without disease progression. The median duration of response was 22.4 weeks (range, 28-52 weeks).

Table 2
Table 2
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Pretreatment CD4 cell counts were significantly associated with a complete or partial response (P = 0.01). Eight of 30 patients (27%) with a CD4 cell count of <100 cells/mm3 had a response compared with 17 of 32 patients (53%) with a CD4 cell count of ≥100 cells/mm3 (Table 3). The number of Kaposi's sarcoma lesions, the presence of oral cavity lesions, detectable levels of serum p24 antigen, and Karnofsky performance score were not significantly associated with antitumor response. The same pretreatment variables were also evaluated as possible prognostic factors for tumor progression. Only the pretreatment CD4 count was significantly associated with progression (p = 0.002). Among patients who had progression, time to progression was significantly shorter for those with CD4 cell counts of <100 cells/mm3 compared with those with counts of ≥100 cells/mm3.

Table 3
Table 3
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Adverse Events

Twenty-three patients had a serious hematologic toxicity, and 10 patients had a serious elevation in serum transaminases (Table 4). The most frequent serious signs or symptoms were weight loss (16%), malaise (14%), fatigue (14%), and fever (10%). During therapy, assessments showed a slight decrease in hemoglobin levels, a moderate decrease in neutrophil counts, and no significant change in serum alanine aminotransferase levels.

Table 4
Table 4
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Thirty-four patients (54%) had an interruption, reduction, or discontinuation of study medication. Modification in study medication typically occurred during the first 12 weeks of therapy. Three patients discontinued study medication because of toxicity. Using a Cox proportional hazard model on the time until a dose-limiting toxicity, no differences in the tolerance of treatment or modification of study medication were noted for patients with a CD4 cell count of <100 cells/mm3 and those with ≥100 cells/mm3.

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HIV Disease Progression and Survival

Eight patients developed an AIDS-defining opportunistic infection during the study. Opportunistic infections included Mycobacterium avium-complex infection (two cases), M. tuberculosis (two cases), P. carinii pneumonia (one case), cytomegalovirus infection (one case), other atypical mycobacterial infection (one case), and Candida esophagitis (one case).

Thirteen patients (21%) died. Causes of death included Kaposi's sarcoma (seven cases), respiratory failure (one case), bronchopneumonia (one case), M. avium-complex (one case), and P. carinii pneumonia (one case). The estimated median survival time was 106 weeks (Fig. 1).

Fig. 1
Fig. 1
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CD4 Cells and p24 Antigen

An initial decrease in CD4 cell counts was seen and persisted during follow-up without a further decline in the CD4 cell count. The median decline in absolute CD4 cell counts at week 4 was 18 cells/mm3. Only a minimal increase in the percent of CD4 cells was noted over time (p = 0.26). Seventeen patients had detectable levels of serum HIV p24 antigen before treatment. Twelve patients (71%) had a 50% or greater decline in antigen levels that persisted throughout treatment

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DISCUSSION

Interferon-α monotherapy had demonstrated activity in the treatment of patients with AIDS-related Kaposi's sarcoma, depending on the dose of interferon used. Low doses (1-20 × 106 U) are associated with only minimal responses (3-11%; 6-9), whereas higher doses (20-50 × 106 U) are associated with more reasonable responses (28-45%) (1-3,6-11). However, patients with CD4 cell counts of <200 cells/mm3, a prior history of opportunistic infections, systemic symptoms, visceral disease, or large tumor burdens are less likely to have tumor regression, and tumor responses in these subgroups fall below 10 to 30% (1-11). Although zidovudine does not have direct activity against Kaposi's sarcoma (20), its use in combination with interferon-α may result in enhanced anti-HIV activity (21,22), which may also result in better antitumor responses. Preliminary data suggest that antitumor responses are achievable with lower doses (8-18 × 106 U/day) of interferon-α when combined with zidovudine (23-25).

An intermediate dose of interferon-α2a and zidovudine in our study resulted in antitumor responses of 40%. This rate falls in the upper range of reported responses (28 to 45%) for high doses of interferon-α (20-50 × 106 U/day) and suggests an enhanced response for this combination. Moreover, antitumor responses were noted across several subgroups that have been associated with lower response rates. Patients with large tumor burden (>50 cutaneous lesions) had a response rate of 33% compared with 43% among those with ≤50 cutaneous lesions. Patients with detectable levels of p24 antigen had a response rate of 65% compared with 32% among those without detectable antigen.

Antitumor responses were also seen over a wider range of CD4 cell counts than those reported with interferon-α alone, as noted in two previously published Phase I studies (24,25). In addition, the rate of tumor regression in patients with higher CD4 cell counts in our study (≥100 cell/mm3) was greater (53%) than reported with higher doses of interferon-α alone (28-45%). Although the rate of tumor regression was lower in patients with a CD4 cell count of <100 cells/mm3, the rate of response (27%) was higher than reported with interferon-α alone in this patient subgroup (<10%) (6). Thus, the addition of zidovudine to intermediate doses of interferon-α appears not only to enhance antitumor responses but to extend responses to a larger group of patients. Similarly enhanced responses (immunological and virological) have been seen with combination nucleoside therapy in patients with HIV disease without Kaposi's sarcoma (25-27). Zidovudine therapy may also downregulate the endogenous interferon system in patients with advanced HIV disease (28) and enhance the potential effectiveness of exogenous interferon.

Our study also showed that combined therapy can be safely administered. The major adverse effects noted are typical of the general toxicities observed with interferon-α and included malaise, fatigue, and weight loss. Hepatic toxicity has been observed with interferon-α and zidovudine therapy. The incidence of hepatic toxicity in our study (16%) was not different from that reported with interferon-α or zidovudine alone. In addition, increases in serum transaminase levels responded promptly to study medication modification and were not dose limiting. Neutropenia was the most common toxicity associated with combined therapy. The incidence of neutropenia (27%) was not different from that reported with zidovudine monotherapy in patients with advanced HIV disease (16). For patients with less severe HIV disease (17,18), this incidence is higher than expected and may reflect additive toxicity from the use of combination therapy. As noted with monotherapy, toxicities tended to occur early in treatment, and most toxicities could be managed with a modification in the dose of either or both drugs. Only three patients required discontinuation of study medication because of a toxicity.

Our study confirms that combined therapy with an intermediate of interferon-α2a and zidovudine can be tolerated and results in tumor regression in patients with nonvisceral AIDS-related Kaposi's sarcoma. Because the study population was limited to patients with nonvisceral disease, the effects of this combination in patients with visceral Kaposi's sarcoma could not be determined. Combined therapy with interferon-α2a and zidovudine also appears to induce antitumor responses in patients with a broader range of CD4 cell counts, including some patients with CD4 cell counts ≤100 cells/mm3. Thus, the combination of zidovudine and interferon-α2a should be considered for the treatment of patients with nonvisceral HIV-related Kaposi's sarcoma regardless of the CD4 cell count.

Acknowledgment: This study was supported in part by grants from the National Institute of Allergy and Immunology AIDS Clinical Trials Group.

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APPENDIX

Other participants in the conduct of this study are listed below: Sharon Maiewski, P.A.-C, Elisa Dale, B.S.N., University of Miami School of Medicine, Miami, FL; Linda Millar, Harvard School of Public Health, Boston, MA; Mary Gould, R.N., Lee Ratner, M.D., Ph.D., Washington University School of Medicine, St. Louis, MO; Michael F. Para, M.D., Richard Gower, R.N., B.S.N., The Ohio State University, Columbus, OH; Ruth Tenzler, B.S.N., Jack Fuhrer, M.D., SUNY Stony Brook, New York, NY; Donna Mildvan, M.D., Stephen C. Malamud, M.D., Beth Israel Medical Center, New York, NY; Bruce Dezube, M.D., Beryl Chapman, R.N., Clyde Crumpacker, M.D., Harvard-Beth Israel, Boston, MA; Judith Feinberg, M.D., Antoinette Hood, M.D., Charles P. Raines, R.N., Johns Hopkins Hospital, Baltimore, MD; Steven A. Miles, M.D., Ronald T. Mitsuyasu, M.D., Judith Carden, R.N., UCLA AIDS Center, Los Angeles, CA; Deborah McMahon, M.D., Monto Ho, M.D., George Pazin, M.D., University of Pittsburgh, Pittsburgh, PA; Richard S. Schulof, M.D., Ph.D., Jane L. Cortless, R.N., B.S.N., Susan F. le Lacheur, PC-C, M.P.H., George Washington University, Washington, D.C.; W. Christopher Ehmann, M.D., M. Elaine Eyster, M.D., Pennsylvania State University-Hershey Medical Center, Hershey, PA; George F. McKinley, M.D., Michael H. Grieco, M.D., Brenda Kolatch St. Luke's/Roosevelt Hospital Center, Columbia University, New York, NY; John M. Bennett, M.D., University of Rochester, Rochester, NY; Mary Ellen Rybak, M.D., Sarah H. Cheeseman, M.D., University of Massachusetts, Boston, Massachusetts; and Richard A. Koup, M.D., Aaron Diamond AIDS Research, New York, NY. Cited Here...

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REFERENCES

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Keywords:

Kaposi's sarcoma; Interferon-α; Zidovudine

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