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Results of a Randomized Study of IM862 Nasal Solution in the Treatment of AIDS-Related Kaposi’s Sarcoma

From the Department of Medicine, Division of Hematology, Kenneth Norris Cancer Hospital and Research Institute, University of Southern California School of Medicine, Los Angeles, CA; and Department of Medicine, Division of Hematology, Massachusetts General Hospital, Harvard Medical Center, Boston, MA.

Address reprint requests to Parkash S. Gill, MD, Norris Cancer Hospital and Research Institute, 1441 Eastlake Ave, MS-34, Los Angeles, CA 90033; email parkashg{at}hsc.usc.edu

ABSTRACT

PURPOSE: Although advances have been made in the treatment of AIDS-related Kaposi’s sarcoma (AIDS-KS) with systemic chemotherapy, less toxic therapies are needed. IM862 is a naturally occurring peptide with antiangiogenic properties and was thus studied in patients with AIDS-KS.

PATIENTS AND METHODS: IM862 was given as intranasal drops at a dose of 5 mg. Patients were randomized to two dosing schedules given in repeated cycles until disease progression or unacceptable toxicity: 5 days of therapy followed by 5 days off (n = 18) and every other day dosing (n = 26).

RESULTS: Forty-two male patients and two female patients with a median age of 38 years (range, 22 to 53 years) were accrued. Twenty-one patients (47%) had more than 50 mucocutaneous lesions, 14 (32%) had lymphedema, and none had visceral involvement. Thirty-three patients (75%) had received prior systemic chemotherapy. Twenty-four patients (55%) had CD4⁺ lymphocyte count 200/mm³. All but five patients were being treated with concurrent protease inhibitor(s), for a median of 10 months (range, 0 to 24 months). Major responses were documented in 36%, with five complete and 11 partial remissions, occurring after a median of 6 weeks (range, 3 to 26 weeks) and lasting a median of 33+ weeks (range, 12+ to 95+ weeks). Twenty-one patients had stable disease for periods of 7 to 72+ weeks. Adverse effects to IM862 were limited to mild and transient headache, fatigue, tingling, and nausea. No hematologic adverse effects attributed to treatment were reported.

CONCLUSION: IM862 given as intranasal drops is well tolerated and has antitumor activity in patients with AIDS-KS. A randomized double-blinded study to define the activity of IM862 in patients with AIDS-KS is in progress.

KAPOSI’S SARCOMA (KS) is the most common malignancy in patients infected with the human immunodeficiency virus (HIV), occurring as the AIDS-defining diagnosis in approximately 15% of patients with AIDS.¹ KS most commonly involves the skin, but in more advanced stages, tumor-associated lymphedema is common, and at least one third of AIDS-related KS (AIDS-KS) patients have life-threatening visceral disease of the lungs and gastrointestinal tract.²

The optimal treatment for patients with AIDS-KS must take into consideration both the extent of disease and the status of underlying immune function. Systemic agents with therapeutic efficacy include interferon alpha (INF) and cytotoxic chemotherapy.^3-8 INF is most effective in patients with good immune function but has minimal activity in patients with CD4⁺ lymphocyte counts of less than 100/mm³.³ Cytotoxic chemotherapy is generally reserved for patients with widespread mucocutaneous or visceral disease. Although both INF and cytotoxic chemotherapy have antitumor activity in AIDS-KS, neither modality is curative. Moreover, these agents are associated with cumulative toxicities that prohibit long-term use. Therefore, other agents are needed in the treatment of AIDS-KS that are safe, easily administered, and well tolerated over prolonged periods of time.

IM862 is a dipeptide of L-glutamyl-L-tryptophan that was initially isolated from the thymus. IM862 has been synthesized synthetically, and preclinical studies have shown that the dipeptide inhibits angiogenesis in chorioallantoic membrane assays.⁹ IM862 has also inhibited tumor growth in xenograft models, but no direct cytotoxicity has been observed on the tumor cells. IM862 mediates these effects by inhibiting production of vascular endothelial growth factor (VEGF) and by activation of natural killer (NK) cell function. In animal studies with IM862 in which the intranasal, subcutaneous, intravenous, and intramuscular administration routes were compared, no difference in antitumor activity was observed among these different routes of administration.¹⁰ The intranasal administration route showed a bioavailability of 71%, and thus the intranasal route of administration was adapted in human trials.⁹

Two different dose schedules of IM862 administered intranasally to patients with AIDS-KS were tested to determine the antitumor effects and define the side effects.

PATIENTS AND METHODS

Eligibility Criteria
A phase II clinical trial of IM862 was conducted in patients with AIDS-KS. Patients were required to have serologic evidence of HIV infection and biopsy-proven KS, with at least five measurable lesions with or without lymphedema. Patients with visceral involvement were excluded. Other inclusion criteria included an absolute granulocyte count greater than 1,000/mm³, platelet count greater than 75,000/mm³, bilirubin 1.5 mg/dL, and serum creatinine less than 1.5 times the upper limit of normal. Prior systemic therapy including chemotherapy had to be stopped 4 weeks before starting IM862. The protocol and informed consent were approved by the institutional review boards of the Los Angeles County-University of Southern California Medical Center (Los Angeles, CA) and Massachusetts General Hospital, Harvard University (Boston, MA), and all patients gave informed consent before treatment.

Patient Evaluation
Patients underwent a complete physical examination, Karnofsky performance status evaluation, complete blood counts, serum chemistries, and toxicity assessment every 2 weeks for the first 2 months of treatment and then monthly thereafter. Patients were staged according to the AIDS Clinical Trials Group–based tumor, immune, systemic (TIS) staging system.¹¹ KS evaluations consisted of counting as many as 50 cutaneous lesions and assessing their character as raised or flat. If there were more than 50 cutaneous lesions, a representative anatomic area was selected and the lesions were counted and characterized. In addition, five discrete, nodular indicator lesions were selected, and the sum of the products of their largest perpendicular diameters was recorded. All adverse events were graded using the Southwest Oncology Group toxicity criteria.¹²

Treatment Plan
All patients with AIDS-KS who were entered onto the study received IM862 at a dose of 5 mg in 0.7 mL of diluent administered as nasal drops. Patients were randomized to the following treatment schedules: tier 1, 5 days of treatment followed by 5 days of rest; tier 2, a single dose on every other day of therapy. Treatment regimens were repeated for a total of 90 days. The first five patients treated at Massachusetts General Hospital received an initial dosing schedule of either 5 days treatment followed by 10 days rest (n = 2) or 10 days of treatment followed by 20 days of rest (n = 3). Because of the occurrence of progressive disease in two patients during the rest periods, the remaining three patients and subsequent four patients accrued at this site were treated with the every-other-day dosing schedule. The data from these nine patients were pooled in the tier 2 schedule. Patients were allowed concurrent use of antiretroviral agents, protease inhibitors, and prophylaxis against opportunistic infections. Patients were monitored for response to therapy and toxicities and underwent laboratory studies every 2 weeks for the first 8 weeks and then monthly thereafter for a total of 90 days. After day 90, patients with stable disease or better were permitted to continue on the same regimen with monthly follow-up.

Efficacy Criteria
Mucocutaneous response to therapy was evaluated using the AIDS Clinical Trials Group criteria.¹¹ Complete response was defined as resolution of all disease for 4 weeks or more without evidence of new disease. In patients with residual pigmentation, all lesions had to be completely flat with pathologic remission documented in a representative lesion. Partial response was defined as a reduction in the product of the bidimensional measurements of target lesions by 50% or more or complete flattening of 50% or more lesions, without evidence of new disease, lasting for 4 weeks or more. Progressive disease was defined as the development of new lesions, increase in the bidimensional measurements by 25% or more, development of new or worsening of existing tumor-associated edema, or development of visceral disease. Stable disease was defined as not fulfilling complete response, partial response, or progressive disease criteria.

Statistical Analysis
Study entry characteristics were examined to determine any possible correlates for response using Fisher’s exact test.¹³ An intent-to-treat analysis was used in this trial to assess response. The time to first response was calculated from the date of protocol initiation to the onset of partial or complete remission. Duration of response was calculated from the onset of partial or complete remission to disease progression in responding patients. Time to disease progression and time to treatment failure were calculated from beginning of therapy to first evidence of progression or loss to follow-up. Kaplan-Meier plots were constructed for all time-to-event analyses.¹⁴

RESULTS

Study Patients
Characteristics of patients at study entry are listed in Table 1. Forty-four patients with a median age of 38 years were accrued. The median duration of KS from diagnosis to study entry was 26 months. The median entry CD4⁺ lymphocyte count was 165 cells/mm³, and 24 patients (54%) had CD4⁺ lymphocyte counts of less than 200 cells/mm³. A prior AIDS-defining opportunistic infection (OI) was reported in 22 patients (50%), of whom 10 reported multiple prior AIDS-defining OIs. The most common OIs included Pneumocystis carinii pneumonia in 15 patients and cytomegalovirus retinitis in seven.

Of the 11 patients who were never treated with prior chemotherapy, six were naive to any treatment modality for KS. The remaining five received local therapies that consisted of intralesional treatments, radiation therapy, or INF. Two of these patients also received subcutaneous injections of human chorionic gonadotropin.

The majority of patients previously received prior cytotoxic chemotherapy with paclitaxel (n = 23); liposomal daunorubicin (n = 16); liposomal doxorubicin (n = 11); a combination of doxorubicin, bleomycin, and vincristine (n = 7); or more than one regimen given sequentially. Nineteen patients (43%) received two or more prior systemic chemotherapy regimens. All patients had evidence of active disease after treatment with cytotoxic chemotherapy before entry onto the study.

All but two patients were taking an antiretroviral regimen at study entry. Five patients were not being treated with protease inhibitor at study entry: three refused and two were resistant or intolerant to all commercially available protease inhibitors.

Tumor Response
Major (complete and partial) responses were documented in 16 patients (37%; 95% confidence interval, 22% to 52%; Tables 2 and 3 and Fig 1A through 1D), five of whom achieved a complete response. Characteristics of responders are listed in Table 4. The median time to response was 6 weeks (range, 3 to 36 weeks). Time to complete response, confirmed by biopsy, occurred after 20 to 26 weeks of therapy. Complete responses have been durable with the median duration of complete response in excess of 33 weeks (range, 12+ to 95+ weeks). No complete responder has relapsed after 72+ to 149+ weeks from initiation of treatment, and all five have been off treatment for a median of 18+ weeks (range, 5+ to 79+ weeks) with continued remission.

View larger version (79K): [in this window] [in a new window]   Fig 1. (A) Foot lesion (KS) at baseline evaluation. (B) Resolution of the lesion after 84 weeks of IM862 therapy. (C) Clusters of lower-extremity KS with lymphedema at baseline. (D) KS lesions after 56 weeks of IM862 treatment; lymphedema also resolved.

Twenty-one patients (48%) had stable disease for a median of 31+ weeks (range, 7 to 72+ weeks). Fourteen of these patients (32%) had stable disease for periods of 6 months or greater. Nine patients with stable disease as their maximal response eventually experienced disease progression; eight required treatment with systemic therapy. The duration of stable disease in these nine patients was 9 to 53 weeks; four of these patients had stable disease for 6 months or greater. Of the remaining 11 patients with stable disease, five remain on therapy, four patients remain in stable disease off treatment after periods of 4 to 52 weeks, and two have been lost to follow-up. The overall median time to disease progression from onset of therapy for all patients is 309 days.

No significant differences in response rates were observed when comparing the two treatment arms: 33% for tier 1 (5 days of treatment followed by 5 days rest) versus 38% for tier 2 (every-other-day schedule) (P = .76). Similarly, there was no significant difference in response rate when stratifying by no prior chemotherapy (45%) compared with those patients who received prior systemic chemotherapy (33%) (P = .49).

Five (36%) of 14 patients with tumor-related lymphedema had a major response to therapy, with complete resolution of tumor-associated edema in three (Fig 1D). Three additional patients had symptomatic improvement in lymphedema, and all three continue on therapy with stable disease.

When stratifying by CD4⁺ lymphocyte count, no significant difference was observed in response rates. Thus seven (29%) of 24 patients with baseline CD4⁺ lymphocyte counts of less than 200/mm³ had a major response to therapy compared with nine (45%) of 20 responders with a CD4⁺ lymphocyte count of greater than 200/mm³ (P = .35).

Protease Inhibitor Use
All but five patients entered on the study were receiving a concurrent protease inhibitor. The median duration of protease inhibitor use before study entry was 10.0 months (range, 0 to 24 months) and was similar between the treatment arms. Twenty-four patients (54%) had been on a protease inhibitor for 6 months or more before study entry. There was no significant difference in the response rate when stratifying patients who received a protease inhibitor for 6 (38%) versus those who received a protease inhibitor for less than 6 months (33%; P = .76). One of five patients who were never started on a protease inhibitor had a partial response to therapy.

Effect on IM862 on HIV Viral Load
Serial measurements of HIV viral load were performed for 30 patients. No consistent trends were observed. Of the responding patients, 11 had serial HIV viral load evaluations. Five responders showed one log or greater decline in HIV viral load, two patients maintained persistently nondetectable levels, and one patient showed no change in viral load over time. In contrast, three responding patients had increases in HIV viral load over time. All three of these patients remain in response despite the increase in viral load.

Effect on IM862 on Plasma VEGF Levels
Serial evaluations of plasma were performed on the first 15 patients to determine the effects of IM862 on levels of VEGF. Preliminary results showed no significant trends in VEGF levels over time, and no significant correlation with tumor response was seen, primarily because over time the majority of VEGF levels in individual patients remained within normal limits of the assay (data not shown).

Adverse Events
Adverse events due to IM862 are listed in Table 5. All nonhematologic adverse events were mild to moderate in severity, and all were transient. The most common adverse events were headache, which was reported in 12 patients (35%), and fatigue, which was reported in three (11%). Headaches generally occurred shortly after drug administration and were transient. Other side effects reported were uncommon, occurring in less than 10% of patients, and consisted of tingling, nausea, diarrhea, and altered tastes. There were no treatment delays or dose modifications secondary to adverse events. No patient had a related grade 3 or 4 hematologic adverse event. Only one patient was removed from study because of adverse events, which consisted of severe sinusitis that was deemed to be possibly related to drug treatment. To date, only one patient, who was removed from study early for disease progression, has died; death occurred 6.5 months from the onset of therapy as a result of multiple opportunistic infections and KS.

Several recent advances have been made in the understanding of the factors that affect the growth of KS. Several cytokines have been identified as autocrine growth factors for KS, including interleukin-1, interleukin-6, and oncostatin-M.^15-18 KS cells are also known to produce several angiogenic factors, such as basic fibroblast growth factor, VEGF, and interleukin-8.^19-21 The progressive understanding of the factors that affect the growth of KS has allowed for the evaluation of novel compounds for the treatment of KS, which include antiangiogenic compounds.

Several antiangiogenic compounds have been studied in patients with AIDS-KS. Two of the first antiangiogenic compounds studied in AIDS-KS were pentosan polysulfate^22,23 and tecogalan sodium.^24,25 Minimal to no antitumor activity was seen with pentosan when it was administered as either an intravenous infusion weekly or a subcutaneous injection three times weekly.^22,23 Similarly, in two phase I studies with tecogalan sodium using either once-weekly or once-every-three-weeks intravenous dosing schedules, no objective responses were reported, although a minority of patients reported reduction and symptomatic relief of tumor-associated edema.^24,25 The dose-limiting grade 4 toxicity of tecogalan sodium was prolongation of activated prothrombin time; other common side effects of this drug included transient fevers, chills, and headache in more than one half of the patients.

Another antiangiogenic agent studied in AIDS-KS was a fumagillin analog, TNP-470.²⁶ In phase I studies using a weekly intravenous schedule, partial remissions were seen in 18% of patients with AIDS-related KS. These remissions were, however, short in duration, and the toxicity profile was erratic, with the occurrence of CNS bleeding. All of these previous angiogenic compounds were studied in patients before the availability of protease inhibitors. Other antiangiogenic agents that are currently being evaluated in the treatment of AIDS-KS include inhibitors of VEGF and matrix metalloproteinases.²⁷

We have studied IM862 given intranasally using two different dosing schedules. In vitro studies of IM862 have shown antiangiogenic properties with potent inhibition of chorioallantoic membrane assays stimulated with either basic fibroblast growth factor or VEGF.⁹ In addition, the peptide may have other mechanisms for antitumor activity. For example, IM862 seems to exert antitumor activity by modulating NK cell function. Thus when NK cells in immunodeficient mice were depleted using specific antibodies, the tumor inhibitory effect of the peptide was reduced in murine tumor xenograft models (unpublished data). Pharmacokinetic studies have previously shown that IM862 has a short half-life, lasting minutes in duration.¹⁰ Despite the short half-life, however, responses that were observed in animal studies as well as this study suggest that IM862 may induce an inhibitor of angiogenesis that has longer lasting effects.

Compared with other antiangiogenic agents studied thus far, the antitumor activity observed with IM862 is promising. Major responses were observed in 16 patients (36%), with stable disease achieved in 21 patients (48%). In addition, major responses were also seen in four patients with tumor-related lymphedema. Also, responses to treatment are associated with prolonged durability, with complete remissions lasting a median of 33+ weeks (range, 12+ to 95+ weeks). Notably, stable disease on this therapy was also associated with durability, lasting a median of 31+ weeks (range, 7 to 72+ weeks); 14 patients (67%) experienced stable disease that lasted for 6 months or more. It should also be noted that the majority of these patients who had prior exposure to systemic chemotherapy were able to improve or maintain their responses to treatment with this less toxic treatment modality.

IM862 was well tolerated, and no severe adverse effects were reported. Thus far, toxicities were limited to transient grade 1 or 2 headaches, which were reported in 35% of patients. Other side effects were reported in less than 10% of patients. Only one severe adverse event, which consisted of sinusitis, was reported on this study; this was deemed to be possibly related to drug treatment.

The use of highly active antiretroviral therapies has been shown to have significant effects in reducing the incidence of KS in patients with HIV infection.²⁸ There have been anecdotal reports of KS regressions occurring with protease inhibitor use.^29,30 In contrast, in one study in which liposomal all-trans retinoic acid was used in the treatment of patients with AIDS-KS, only 7% of patients (two of 29) on a concurrent protease inhibitor had a major response to therapy; this was similar to the 4% response rate that was observed in patients who did not receive a protease inhibitor.³¹ No large prospective clinical studies have been reported to date that show direct anti-KS activity with protease inhibitors. A careful evaluation of protease inhibitor use was examined in this study to determine if these agents had any confounding effects on observed responses. The median prior duration of protease use was 10 months and was similar between the two treatment arms. Twenty-one patients had exposure to two or more prior protease inhibitors. When stratifying by protease inhibitor use of greater than 6 months compared with less than 6 months, there was no difference in major response rate. Moreover, serial evaluations to determine the effects of IM862 showed no consistent effect on HIV viral load, as noted in the responding patients. Although it cannot be ruled out definitively, responses to IM862 are not likely to be attributed to highly active antiretroviral therapy with protease inhibitors.

To date, no curative therapies have been found for AIDS-KS, and disease progression generally occurs within a few weeks to months once therapy is stopped. Treatment is therefore required to be continued over a prolonged period of time. Systemic chemotherapy agents cannot be given for prolonged periods because there is a risk of cumulative toxicities. IM862, which is safe and well tolerated over prolonged periods of time, is therefore an attractive alternative in patients with cutaneous KS. Our results also show that IM862 is as efficacious in patients with a CD4⁺ lymphocyte count of less than 200/mm³, with response rates that are similar to those achieved in patients with CD4⁺ lymphocyte counts of greater than 200/mm³.

In conclusion, IM862 administered as intranasal drops at a dose of 5 mg every other day or every day for 5 days alternating with 5 days without treatment is well tolerated and is safe over a prolonged period of time. Both dosing schedules tested resulted in major response in patients irrespective of the extent of immunosuppression. Further studies are being conducted to optimize the dose and dosing schedule of IM862 in other malignancies. A large randomized, placebo-controlled study is also in progress in the treatment of patients with AIDS-related KS.

ACKNOWLEDGMENTS

We thank the following people for invaluable assistance with this trial: Dharshika Dharmapala, Serena Vergara, Miki Ilaw, Lasika Seneviratne, Sheryl Todd, Phil Syrdal, and Lawrence Green.

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Submitted September 7, 1999; accepted December 9, 1999.

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