Bridging the Gap: Conference Record [Abstract book, International Conference on AIDS (12th: 1998: Geneva, Switzerland)]

318 Abstracts 22278-22281

12th World AIDS Conference

ment was 270. A single planned interim analysis was performed for the first 82
patients.
Results: Accrual was ceased after the interim analysis showed a significant
difference in treatment arms which met the trial's stopping rule (alpha < 0.005).
Patients assigned active gel (n = 36) were significantly more likely than placebo
assignees (n = 46) to respond (either CCR or PR) to treatment (41.7% vs 6.5%,
p = 0.00027). Therapy was well tolerated with toxicity limited to local cutaneous
irritation. Treatment arms (active vs placebo) were well matched for ethnicity, age,
gender (all subjects were male), mean (~ SE) CD4 cell count at baseline (197 ~
29 vs 161 ~ 25), proportion receiving any antiretroviral (ARV) therapy on study
(95% vs 100%), any protease inhibitor (72% vs 87%) and any triple (or greater)
ARV combination (78% vs 94%).
Conclusion: In this international study, topical treatment of cutaneous KS
lesions with 0.1% 9-cis-retinoic acid gel was associated with a six-fold improvement in response rate when compared to vehicle gel (42% vs 7%, p = 0.00027).
Therapy was well tolerated with toxicity limited to local skin irritation.
S22278 Phase 2 study (Protocol L1057-28) of PanretinTM capsules
(LGD1057, ALRT1057) for AIDS-related Kaposi's sarcoma
Alvin Friedman-Kien1, M. Conant2. The No. Am. Panretin Gel KS Study Group;
1New York University Medical Center, Dept of Dermatology, 550 First Street,
New York, NY 1006; 2Private Medical Practice, San Francisco, USA
Background: A Phase 2, multicenter, open label clinical trial of a Minimax twostage design was conducted to evaluate the safety, tolerability and anti-tumor
effects of PANRETIN (9-cis-retinoic acid) Capsules in patients with AIDS-related
Kaposi's sarcoma (KS).
Methods: PANRETIN Capsules (9-cis-retinoic acid) were administered orally to
HIV-positive patients with biopsy proven KS in once daily doses of 60 mg/m2/day
escalating to 100 mg/m/day (and to 140 mg/m2/day prior to protocol revision). Six
indicator mucocutaneous lesions were assessed every two weeks.
Results: Five study centers enrolled 57 patients, all male, with a median age of
40 years (range 25 to 62). The median number of KS lesions was 22 (range 6 to
155). Over a median duration of treatment of 15.1 weeks, (range 0.1 to 61.9), the
overall response (complete or partial) rate determined by applying AIDS Clinical
Trial Group (ACTG) criteria to each patient's 6 indicator lesions was 37% (21/57)
for the intent-to-treat dataset, and 57% (21/37) for the protocol-defined evaluable
patient dataset. One patient had a clinical complete response. The median time to
response was 8.7 weeks (range 2.3 to 21.1). For the 21 responders, 1 relapsed,
9 continue on treatment, and the remaining 11 were still in response at withdrawal from the study, the median duration of response (from start of treatment
to relapse or last lesion assessment) was 33.1 weeks (range 12.4 to 61.7). 53%
(30/57) had prior systemic anti-KS therapy, and 71% (5/7) of patients refractory
to prior systemic anti-KS chemotherapy responded. Responding patients had a
median CD4 count of 195 cells/mm3 (range 4 to 383), which did not differ from
the entire 57 patient data set. 89% of patients were concurrently taking three or
more antiretroviral agents (ARV), with 94% of these including a protease inhibitor,
and there was no statistical association between degree of concurrent ARV and
response (p = 0.52). The most frequent drug-related adverse events, which were
generally mild to moderate, included headache (70%), dry skin (51%), rash (47%),
alopecia (42%), exfoliative dermatitis (peeling/flaking) (33%), and hyperlipidemia
(32%). Two patients developed pancreatitis at 140 mg/m2/day; one recovered
and the other died of an unrelated, disseminated fungal infection.
Conclusions: PANRETIN Capsules have substantial anti-tumor activity in
AIDS-related KS, producing durable responses which appear to be independent
of baseline CD4 counts and concurrent antiretroviral therapy. Responses were
seen in patients refractory to prior systemic anti-KS chemotherapy. Adverse
events were not unusual for retinoid therapy, and the safety profile appears
manageable, especially with the final dosing range of 60 to 100 mg/m2/day.
22279 | Antitumor activity of interleukin-4 toxin in nude mice
implanted with AIDS-associated Kaposi's sarcoma tumor
Syed R. Husainl1, R.J. Kreitman22, I. Pastan22, R.K. Puri33. 1DCGT, CBER,
FDA, 8800 Rockville Pike, HFM-530 Bethesda, MD 20892; 2Laboratory of
Molecular Biology, NCI, NIH Bethesda MD; 3DCGT, CBER, FDA 8800 Rockville
Pike, HFM 530 Bethesda MD, USA
Objectives: To assess the antitumor activity of a circularly permuted Pseudomonas exotoxin [IL-4(38-37)-PE38KDEL] against IL-4 receptor positive
AIDS-KS tumors implanted in nude mice.
Methods: AIDS-KS cells, KS-Y1 (10 x 106) were injected s.c. in the right flank
of 4-week old nude mice resulting in the development of tumors in 2 out of 5
mice. The tumors were excised and re-implanted s.c into mice to consistently
generate solid tumors in all injected mice. The efficacy of IL-4(38-37)-PE38KDEL
was assessed by its administration through different routes and dosing schedule.
Results: We have found that AIDS-KS cell cultures express high affinity IL-4R.
KS-Y1, an AIDS-KS cell line also expressed large number (-~1800 sites/cell) of
high affinity (kd = 137 pM) IL-4R. The in vitro protein synthesis inhibition assay

demonstrated that IL-4(38-37)-PE38KDEL was highly cytotoxic to KS-Y1 cells
(IC50, 8.1 ~ 1.9 ng/ml). Three intratumoral injections of IL-4 toxin (750 pg/kg) on
alternate days (QOD) resulted in a complete regression of s.c. tumors. Similar
treatment with lower doses (250 and 500 tg/kg) but multiple injections (n = 6)
also eradicated the tumors completely. Lymphopenia induced by KS growth was
reversed by IL-4 toxin therapy. The QOD x 3 intraperitoneal injections inhib
ited tumor growth in a dose-dependent manner with the highest dose exhibiting
complete response.
Conclusion: IL-4(38-37)-PE38KDEL may be an useful drug for the treatment
of AIDS-KS and its antitumor activity should be further explored.
22280 1 A phase II study of oral thalidomide in patients with
AIDS-related Kaposi's sarcoma (KS)
Robert Yarchoan1 2, Richard F. Little2, K. Wyvill2, L. Welles2, J.M. Pluda2,
W. Figg2, G. Tosato2. 1Building 10 Room 12N226, 9000 Rockville Pike,
Bethesda, MD; 2National Cancer Institute, Bethesda, MD, USA
Background: Thalidomide has been shown to inhibit angiogenesis (D'Amato,
Folkman et al. PNAS 91: 4082, 1994). Angiogenesis has been shown to be
important in the pathogenesis of KS, and we thus hypothesized that KS might be
amenable to treatment with thalidomide.
Methods: Phase II dose titration trial. Oral thalidomide was administered for
up to 52 wks initially at 200 mg/day with escalation every two wks as tolerated
to a maximum of 1000 mg/day. KS which was progressive over the two months
prior to enrollment was required. The AIDS Clinical Trails Group KS criteria, with
minor modification, was utilized to assess responses.
Results: Thirteen patients (pts.), median (range) age 39 (31-49) years; entry
median (range) CD4 count 255 (14-646) cells/mm3 have accrued to date. 8
pts. were poor and 5 were good risk as assessed using the TIS staging (JCO
7:1201, 1989) for KS. Overall response rate was 36% (95% Cl: 7.6%-64.4%),
with 4 of 11 pts achieving partial response (PR) (3 of the 4 poor risk by TIS
criteria). Of responding pts., 3 were on stable anti-HIV therapy (2 on double nucleoside therapy, one on a 3-drug regimen). One pt. began 3-drug therapy while
on thalidomide but prior to attaining PR. Two responding pts had prior systemic
cytotoxic chemotherapy. Responses were documented at weeks four (3/11) and
eight (1/11) at daily doses of 300 mg, 400 mg (2 pts.), and 800 mg. Two pts.
with PR have not progressed at 50 and 30 weeks, while two pts. achieving a PR
progressed after 16 and 49 weeks. Two pts. progressed without achieving a PR
after 16 and 24 weeks. Five pts. have had stable disease to date at 52 (1 pt), 32
(1 pt.), 22 (1 pt.) and 12 (2 pts.) weeks. Toxicity requiring treatment termination
occurred in 3 pts.: grade 3 rash with fever that recurred with drug rechallenge (1
pt.); myositis (1 pt.); and depression (1 pt). Three pts. had grade 3 neutropenia
on study. Five pts. had sedation which resolved with dose reduction. Inducible
protein-10, TNF-, and interleukin-6 were measured but overall no clear trends
were observed.
Conclusion: Thalidomide is well tolerated at doses of up to 1000 mg/day and
appears to be active in KS. In some cases it appears to induce durable responses.
This trial is ongoing. Further study will help define the potential role of thalidomide
in the therapy of KS.
22281 A phase I dose escalation study of
2'-/-fluoro-2',3'-dideoxyadenosine (F-DDA, lodenosine)
in patients with symptomatic HIV infection
Robert Yarchoan12, Richard Little2, J.A. Lietzau2, L. Welles2, J.M. Pluda2,
J.A. Kelley3, H. Mitsuya4. 1NCI/DCS/HAMB 9000 Rockville Pike, Building 10,
Room 12N226, Bethesda, MD 20892; 2National Institutes of Health/National
Cancer Institute/HIV & AIDS Malignancy Branch, Bethesda, MD; 3National
Institutes of Health/Na'tl Cancer Institute/Lab of Medicinal Chemistry, Bethesda,
MM 4 National Institutes of Health/Na'tl cancer Institute/Medicine Branch,
Bethesda, MD, USA
Background: Originally synthesized and developed in the Laboratory of Medicinal Chemistry and the Developmental Therapeutic Program of the NCI (Marquez,
V.E., et al. Biochemical Pharmacology, 1987, 36, 2719), F-ddA (lodenosine) is an
acid-resistant, fluorinated purine reverse transcriptase inhibitor (RTI) that has little
in vitro cross-resistance with other RTIs. It is active even in strains with Q151M
that are resistant to multiple RTIs.
Objectives and Design: Phase-1 dose-escalating trial to study the toxicity,
pharmacokinetics, and activity of F-ddA administered over 12 weeks. Eligibility
requirements included: symptomatic HIV infection; CD4 < 500 cells/mm3; and no
anti-HIV drugs for 3 weeks prior to entry.
Results: 25 patients (pts), median (range) CD4 cells 219 (5-662) cells/mm3,
have been entered to date on 5 dose levels ranging from 0.2 to 3.2 mg/kg twice
daily. 19 pts had received more than 6 months of prior antiretroviral therapy. Oral
bioavailability was - 75% fasting and ~65% non-fasting. The 8 pts tested to date
on the highest 2 doses (1.6 and 3.2 mg/kg twice daily) had a median decrease in
viral HIV RNA of -0.49 log10 copies/ml (range -0.17 to -0.84, p < 0.01) at week
6. Trends downward in viral load were also seen at the 0.4 and 0.8 mg/kg doses,
and a trend upward was seen in the CD4 counts at the highest doses. Twelve pts.
reported increased energy. Adverse events including asymptomatic transaminase
elevations, neutropenia, hyperglycemia, and hyperamylasemia were all of unclear
relationship to F-ddA.
Conclusion: F-ddA has excellent bioavailability, is well tolerated, and has
anti-HIV activity on a twice-daily dose schedule, even in pts with extensive prior
therapy. The long intracellular half-life of the active triphosphate moiety of F-ddA

suggests that the drug may have utility even if given once daily, and further studies
will explore such a regimen as well as its use in combination therapy.