High-dose recombinant interleukin-2 alone: a regimen with limited activity in the treatment of advanced renal cell carcinoma.

Sixteen patients with metastatic renal cell carcinoma were treated with high-dose bolus recombinant interleukin-2 (rIL-2) alone at a dose and schedule identical to those that produced a 35% response rate among 72 patients in a trial reported by the Surgery Branch, National Cancer Institute (NCI), Bethesda, Md, in which rIL-2 plus lymphokine-activated killer (LAK) cells was used for the treatment of renal cell carcinoma. Patients received two 5-day cycles of 100,000 Cetus U/kg (600,000 IU/kg) of rIL-2 infused intravenously over 15 minutes every 8 hours; each treatment cycle was separated by 1 week. No objective responses were seen. The toxicity of rIL-2 given alone at these high doses was similar to that noted with high-dose rIL-2-LAK cell therapy. The lack of responses seen in this trial also differed from the 21% response rate observed by the NCI Surgery Branch, using rIL-2 alone at an identical schedule and dose in 56 patients with renal cell carcinoma. Only minor differences in such recognized prognostic variables as performance status, tumor burden, and rIL-2 dose intensity were noted between this study and other trials reported by the NCI Surgery Branch and by the IL-2-LAK Working Group. Our analysis indicates that, because of the smaller number of patients in our trial, not enough subjects were included with the ideal characteristics to attain the 21% response rate seen in the NCI study. However, the precise nature of these characteristics remains unclear.

Comparative in vivo and in vitro activation of human natural killer cells by two recombinant alpha-interferons differing in antiviral activity.

Natural killer (NK) cell activation by two interferon-alpha subtypes, interferon-alpha A and interferon-alpha D, was examined in vitro and in vivo in eight cancer patients. When assessed in vitro, NK cells in six of eight patients lysed K562 target cells to a greater extent when incubated with interferon-alpha A (1 ng/ml) than with the same concentration of interferon-alpha D. However, when patients were evaluated collectively, no significant difference was detectable in the effectiveness of the two subtypes in enhancing NK cell activity. Patients received the same interferons given as four injections which were randomized with respect to subtype and were separated by intervals of six or more days. NK cell activity was consistently elevated in peripheral mononuclear cells sampled 24 hr but not seven days after injection as compared to peripheral mononuclear cells sampled just prior to each injection (p less than 0.001 for both subtypes). At a given dose level, both interferon subtypes resulted in comparable NK cell activation. However, a negative correlation existed between the amount of interferon administered and the magnitude of enhancement (p less than 0.05). In 16 separate paired determinations, there were eight in which NK cell activity was lower after the second injection of an interferon dose than after the first injection of the same dose (15 or 45 micrograms, irrespective of subtype), and eight in which the alternate pattern occurred. Thus, repeated injection in the same patient of one or the other dose resulted in no consistent changes in the extent of NK cell stimulation. Since the two interferons have a 20-fold difference in specific antiviral activity for human amnion cells and up to an 80-fold difference in human fibroblasts, either different mechanisms are involved in antiviral and NK cell-stimulatory activity, or activities of these two subtypes for cells of different histogenesis vary. Greater NK cell-stimulatory activity therefore occurred at the lowest tested doses, a dose which was less than 10% of previously reported maximally tolerated doses of these interferons.

Phase I trial of human lymphoblastoid interferon with whole body hyperthermia in advanced cancer.

Laboratory studies have shown a potentiation of the biological effects of interferons (IFN) by elevated temperatures (39.5-40.5 degrees C). Based on such observations a Phase I clinical trial involving 17 cancer patients was conducted to assess the toxicity and biological effects of combining whole body hyperthermia (WBH) (40.5 degrees C for 75 min) and IFN. The study design incorporated a treatment schedule which allowed comparisons of WBH alone, to IFN administered i.m., to combinations of the two modalities. Human lymphoblastoid IFN was given for 6 days in weeks, 2, 4, and 6. At least 4 patients were entered at each of three IFN dose levels (1 x 10(6) units/m2; 3 x 10(6) units/m2; 10 x 10(6) units/m2). WBH was delivered on day 1 of week 1, day 6 of week 4, and days 4 and 6 of week 6. IFN was administered 1 h prior to WBH. The schedule used allowed for the development of tachyphylaxis to IFN-induced fever. Maximum temperatures were not significantly higher 24 h post-IFN/WBH than after a comparable number of days of human lymphoblastoid IFN alone. There was no statistically significant difference in toxicity assessments, hematological and hepatic blood parameters, serum IFN levels, or biological response modulation (i.e., 2',5'-oligoadenylate synthetase activity; beta 2-microglobulin levels; natural killer cell cytotoxicity, using K562 target cells and Chang cells) 24 h posttreatment between human lymphoblastoid IFN alone or combined modality therapy. No cumulative toxicity was observed in 6 patients receiving maintenance therapy for up to 1 year. Prior preclinical observations, together with the clinical safety reported in this study, encourage further investigation into the interactions between IFNs and hyperthermia.

American cancer society Phase I trial of naturally produced beta-interferon.

Naturally produced beta-interferon was evaluated following i.m. and i.v. administration to 18 patients with advanced cancer. Fever (mean +/- S.E. = 38.1 degrees +/- 1.7 degrees), enhancement of natural killer cell cytotoxicity, and depression of the white blood cell count occurred following a single i.m. injection in the absence of detectable serum antiviral activity. Fever, rigors, and fatigue were dose-limiting toxicities following daily i.v. administration of 10 million units. Tachyphylaxis, as reported following repetitive administration of alpha-interferons, did not occur. Side effects, depression of the white blood cell count, and enhancement of natural killer cell cytotoxicity were similar when beta-interferon was administered daily as a 10-min bolus or as a 6-hr infusion. However, while natural killer cell cytotoxicity increased progressively over 10 days of bolus injections, it was maximal after the initial 6-hr infusion of beta-interferon. Administration of 10 million units of beta-interferon divided equally between a 10-min bolus injection and a 3-hr infusion was well tolerated and resulted in high initial peak and lower sustained serum interferon levels. Based on pharmacokinetic criteria, this schedule of administration can be recommended for further study in Phase II trials. However, in light of the biological activity of beta-interferon following i.m. administration, the level of beta-interferon in the serum may have limited value as a predictor of antitumor response, toxicity, or biological response modification.

Randomized trial of recombinant alpha 2b-interferon with or without indomethacin in patients with metastatic malignant melanoma.

alpha-Interferon has antitumor activity in a variety of malignancies but is frequently associated with unacceptable toxic side-effects. The routine use of agents potentially capable of reducing these side-effects has not been recommended out of concern for possible reductions in the therapeutic activity of interferon. We conducted a prospective randomized trial of alpha-interferon given with or without indomethacin to patients with malignant melanoma to determine what effect, if any, indomethacin might have on the toxic, immunomodulatory, and therapeutic properties of interferon in this disease. 53 patients were stratified according to performance status and randomized to receive alpha 2b-interferon, 20 million units per m2 i.v., 5 days per week for 4 weeks followed by 10 million units per m2 s.c. three times per week, either with or without indomethacin, 25 mg orally three times a day. The overall major response rate was 13% (three complete responders and three partial responders among 47 evaluable patients) and was the same on both arms. The mean maximal temperature elevation induced by interferon was significantly reduced (from 102.1 to 100.7, P = 0.0002) by indomethacin, but the incidence and severity of interferon-related fatigue, reduction in performance status, headache, depression, confusion, elevations in liver function tests, and myelosuppression were no different in either arm of the study. Indomethacin did not reduce the frequency of dose reductions for toxic side-effects and did not permit the administration of higher interferon doses. Peripheral blood natural killer activity was significantly enhanced in patients during maintenance therapy whether or not they received indomethacin. Indomethacin appeared to inhibit augmentation of natural killer activity during high dose induction therapy. Immunological changes did not correlate with response status. We conclude that indomethacin can reduce the fever associated with interferon therapy in patients with malignant melanoma without interfering with its therapeutic or chronic immunomodulatory activities. Since fever is rarely the dose-limiting toxicity of interferon, indomethacin is of marginal benefit to patients with malignant melanoma receiving interferon at the doses outlined in this study.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

PURPOSE: To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. CONCLUSION: Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer.

PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.

Comparison of the biologic effects of two recombinant human interferons alpha (rA and rD) in humans.

IFN-alpha (rD) was investigated to determine the relationship between antiviral activity in vitro and the modulation of biologic effects in vivo. Eight patients with malignancy were given 15 and 45 micrograms weekly injections of IFN-alpha (rA) and IFN-alpha (rD). The frequency of side effects was much lower with IFN-alpha (rD) injections. This was objectively documented both in incidence of side effects (20 versus 45, p less than 0.01) and mean maximum temperature (1 degree C lower with IFN-alpha (rD), p less than 0.002). A bovine cell line, MDBK, was used to measure interferon concentrations in the serum. Geometric mean peak titers and time-to-peak titers were similar with the two recombinant interferon preparations. Although IFN-alpha (rD) has relatively less antiviral activity on human cells, its effect on the total granulocyte count, natural killer (NK) cell cytotoxicity, and 2'5'-A activity was comparable to IFN-alpha (rA). Mean NK cell percent specific 51Cr release was enhanced by both interferons (after 15 micrograms doses, mean percent NK cell cytotoxicity IFN-alpha (rD) preinjection, 10.5% +/- 2.3%; post-injection, 27.2% +/- 4.5%; IFN-alpha (rA), preinjection, 14.4% +/- 3.2%, postinjection, 25.1% +/- 5%). Species-specific antiviral activity of an interferon does not necessarily predict other biologic properties following in vivo administration.

Phase I study in cancer patients of a replication-defective avipox recombinant vaccine that expresses human carcinoembryonic antigen.

PURPOSE: A phase I clinical trial in patients with advanced carcinoma was conducted, using a replication-defective avipox vaccine containing the gene for the human carcinoembryonic antigen (CEA). The canarypox vector, designated ALVAC, has the ability to infect human cells but cannot replicate. PATIENTS AND METHODS: The recombinant vaccine, designated ALVAC-CEA, was administered intramuscularly three times at 28-day intervals. Each cohort of six patients received three doses of either 2.5 x 10(5), 2.5 x 10(6), or 2.5 x 10(7) plaque-forming units of vaccine. RESULTS: The vaccine was well tolerated at all dose levels and no significant toxicity was attributed to the treatment. No objective antitumor response was observed during the trial in patients with measurable disease. Studies were conducted to assess whether ALVAC-CEA had the ability to induce cytolytic T-lymphocyte (CTL) responses in patients with advanced cancer. Peripheral blood mononuclear cells (PBMCs) from patients with the MHC class I A2 allele were obtained before vaccine administration and 1 month after the third vaccination. Peripheral blood mononuclear cells were incubated with the CEA immunodominant CTL epitope carcinoembryonic antigen peptide-1 and interleukin 2 and quantitated using CTL precursor frequency analysis. In seven of nine patients evaluated, statistically significant increases in CTL precursors specific for CEA were observed in PBMCs after vaccination, compared with before vaccination. CONCLUSION: These studies constitute the first phase I trial of an avipox recombinant in cancer patients. The recombinant vaccine ALVAC-CEA seems to be safe and has been demonstrated to elicit CEA-specific CTL responses. These studies thus form the basis for the further clinical exploration of the ALVAC-CEA recombinant vaccine in phase I/II studies in protocols designed to enhance the generation of human T-cell responses to CEA.

Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study.

Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end of treatment (14 months), and at 6-month intervals during follow-up. Before treatment, all patients had hypercellular marrows with hairy cels replacing normal marrow elements; all showed at least a 95% clearing of their hairy cell infiltrate by 6 months of therapy. However, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral samples in all patients. All patients have completed treatment with a median duration of follow-up off therapy of 27 months (range, 15 to 31 months). To date, all peripheral counts and serum soluble interleukin-2 receptor (sIL2R) levels remain stable, and no patient has had progression of the hairy cell infiltrate in the bone marrow. Although no patient achieved a pathologic complete response, alternating monthly cycles of dCF and rIFN-alpha 2a produced durable partial remissions (PRs) in all patients. Continued follow-up is required to determine the length of such remissions.

Metastatic malignant melanoma treated with combined bolus and continuous infusion interleukin-2 and lymphokine-activated killer cells.

Fifty patients with advanced melanoma received high-dose bolus and continuous infusion interleukin-2 (IL-2) with lymphokine-activated killer (LAK) cells in an attempt to improve the therapeutic index of this active but toxic therapy. Treatment began with up to nine bolus doses of IL-2 administered over 3 days. After 1 day of rest, patients underwent daily leukapheresis for 4 days, and the leukocytes were cultured with IL-2 in vitro to prepare LAK cells. Continuous infusion IL-2 was begun 1 day after the last leukapheresis and continued for up to 148 hours; LAK cells were administered on days 1, 2, and 4 of the infusion. Responding patients were eligible to receive up to two additional cycles of therapy at 3-month intervals. Most patients completed each cycle without dose reduction. One patient had a complete response and six patients had partial responses (14% response rate). The complete responder and three of the partial responders (8%) remain free from disease progression with follow-up of 21 to 24 months. Of these four patients with durable remissions, one had extensive liver and lymph node metastases, one had lymph node, pleural, and parenchymal lung metastases, and two had disease limited to lymph nodes or subcutaneous tissues. Seventeen patients (34%) required pressors for hypotension, three patients (6%) developed hemodynamically significant arrhythmias, and six patients (12%) developed dyspnea at rest, but none required intubation and there were no treatment-related deaths. Unacceptable toxicity developed in two patients during bolus IL-2 administration and therapy was aborted; both returned to baseline status within 4 days of discontinuing IL-2. Fever, oliguria, and elevated creatinine or transaminase levels occurred frequently but were also transient. Despite less frequent severe toxicity with this modified regimen, these results confirm the ability of IL-2 and LAK cell therapy to induce durable remissions in some patients with advanced melanoma.

Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines.

The National Cancer Institute (NCI) Extramural IL2/LAK Working Group treated 93 patients with 114 cycles of high-dose intravenous (IV) interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells in three phase II trials. Thirty-six patients had metastatic melanoma, 35 had metastatic renal cell cancer, and 22 had colorectal cancer. All patients had a Karnofsky performance status greater than or equal to 80% and normal laboratory tests and organ function, and had received no more than one prior form of immunotherapy or chemotherapy. Objective responders were eligible to receive up to two additional courses of therapy at 12-week intervals. The most frequent toxicities were a capillary leak syndrome resulting in marked extravascular fluid shifts, and hypotension requiring treatment with large volumes of IV fluids and vasopressor agents. Laboratory and clinical evidence of hepatic and renal dysfunction were virtually universal. Intensive care-level support was routinely provided and the toxicity observations confirmed the need for this level of care. The life-threatening toxicities were cardiac and pulmonary. Five of the 27 patients who experienced significant respiratory compromise required intubation and mechanical ventilatory support. Twenty patients developed cardiac arrhythmias, the majority of which were supraventricular. There was a single episode of ventricular tachycardia requiring cardioversion. Four patients had transient cardiac ischemia, and an additional four had myocardial infarctions, one of which was fatal. With these exceptions, all toxicities were rapidly reversible. The occurrence of only a single therapy-related death and a very low incidence of other irreversible or life-threatening events is comparable to the level of toxicities often observed in other phase II trials. Although the intensity of this regimen limits this approach to a subset of cancer patients with excellent performance status and adequate organ function, because of the frequency and apparent durability of complete responses, this treatment warrants further investigation.

Phase II evaluation of thalidomide in patients with metastatic breast cancer.

PURPOSE: To determine the efficacy, safety, pharmacokinetics, and effect on serum angiogenic growth factors of two dose levels of thalidomide in patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-eight patients with progressive metastatic breast cancer were randomized to receive either daily 200 mg of thalidomide or 800 mg to be escalated to 1,200 mg. Fourteen heavily pretreated patients were assigned to each dose level. Each cycle consisted of 8 weeks of treatment. Pharmacokinetics and growth factor serum levels were evaluated. RESULTS: No patient had a true partial or complete response. On the 800-mg arm, 13 patients had progressive disease at or before 8 weeks of treatment and one refused to continue treatment. The dose was reduced because of somnolence to 600 mg for five patients and to 400 mg for two and was increased for one to 1,000 mg and for four to 1,200 mg. On the 200-mg arm, 12 patients had progressive disease at or before 8 weeks and two had stable disease at 8 weeks, of whom one was removed from study at week 11 because of grade 3 neuropathy and the other had progressive disease at week 16. Dose-limiting toxicities included somnolence and neuropathy. Adverse events that did not require dose or schedule modifications included constipation, fatigue, dry mouth, dizziness, nausea, anorexia, arrhythmia, headaches, skin rash, hypotension, and neutropenia. Evaluation of circulating angiogenic factors and pharmacokinetic studies failed to provide insight into the reason for the lack of efficacy. CONCLUSION: Single-agent thalidomide has little or no activity in patients with heavily pretreated breast cancer. Further studies that include different patient populations and/or combinations with other agents might be performed at the lower dose levels.

Final analysis of the ECOG I-COPA trial (E6484) in patients with non-Hodgkin's lymphoma treated with interferon alfa (IFN-alpha2a) plus an anthracycline-based induction regimen.

The Eastern Cooperative Oncology Group (ECOG) performed a prospectively randomized study (E6484) evaluating the use of interferon alfa 2a (IFN-alpha2a) in patients with aggressive low-grade or with intermediate-grade non-Hodgkin's lymphoma (NHL) accruing close to 300 patients between 1985 and 1988. Patients were eligible for study if they had bulky or symptomatic low-grade lymphoma or defined intermediate-grade subtypes. Of 291 patients enrolled, 249 were eligible for analysis. All patients were randomized to receive a four-drug cytotoxic chemotherapy regimen including cyclophosphamide, doxorubicin, vincristine and prednisone in 4-week cycles with or without IFN-alpha2a in addition (COPA vs I-COPA). Treatment was given for up to 8-10 months. This report, at a time when the median follow-up among survivors has reached 12 years, updates the analysis of time to treatment failure (TTF), duration of disease-free survival (DFS), and overall survival. Patients randomized to receive IFN-alpha2a had a prolonged TTF (P= 0.008; median 2.4 vs 1.6 years). DFS for those patients who had complete responses was also longer if IFN-alpha2a had been given (P = 0.035; median 2.7 vs 1.8 years). There was a clinically but not a statistically significant prolongation of overall survival by IFN-alpha2a (P= 0.107; median 7.8 vs 5.7 years). There were fewer deaths over time due to lymphoma in patients receiving IFN-alpha2a (67 vs 80 deaths). A subset analysis, based on disease histology (low-grade, follicular, intermediate-grade), revealed a significant prolongation of TTF in patients receiving IFN-alpha2a with either low-grade (P = 0.002; median 2.4 vs 1.6 years) or follicular (P= 0.01; median 2.5 vs 1.7 years) NHL but not intermediate grade (P = 0.622; median 2.3 vs 1.6 years) NHL. This analysis, performed approximately 12 years after closure of the study to accrual, supports the addition of interferon alfa to an induction cytotoxic chemotherapy regimen including cyclophosphamide and doxorubicin in the treatment of follicular NHL.

A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors.

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.

A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.

Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. Patients diagnosed with advanced, incurable malignancies who met standard Phase I criteria and who did not have a history of bleeding complications were enrolled, in cohorts of three, to receive PPS p.o. t.i.d., at planned doses of 180, 270, 400, 600, and 800 mg/m2. Patients were monitored at least every 2 weeks with physical exams and weekly with hematological, chemistry, stool hemoccult, and coagulation blood studies, and serum and urine samples for PPS and basic fibroblastic growth factor (bFGF) levels were also taken. The PPS dose was escalated in an attempt to reach the MTD. Eight additional patients were enrolled at the highest dose to further characterize the toxicity profile and biological in vivo effects of PPS. A total of 21 patients were enrolled in the three cohorts of doses 180 (n = 4), 270 (n = 3), and 400 (n = 14) mg/m2. The most severe toxicities seen were grade 3 proctitis and grade 4 diarrhea; however, 20 of the 21 patients had evidence of grade 1 or 2 gastrointestinal (GI) bleeding. These toxicities became evident at a much earlier time point as the dose was increased, but their severities were similar at all dose levels. There were no objective responses, although three patients had prolonged stabilization of previously progressing disease. Pharmacokinetic analysis suggested marked accumulation of PPS upon chronic administration. Serum and urine bFGF levels failed to show a consistent, interpretable pattern; however the data suggested an inverse relationship between PPS and bFGF levels in vivo. A MTD could not be determined using the daily t.i.d. dosing schedule due to the development of grade 3/4 GI toxicity (proctitis) at all dose levels studied. PPS, administered p.o. at doses of 400 mg/m2 t.i.d., did not cause significant systemic toxicity, but most patients developed moderate-to-severe GI toxicity within 1-2 months. The cause of the GI toxicity was unclear, but it was readily reversible upon cessation of the agent. The suggestion of an inverse relationship between PPS and bFGF supports further study of PPS as an antiangiogenic agent. The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.

A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.

PURPOSE: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers to: (a) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and (b) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions. EXPERIMENTAL DESIGN: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments. RESULTS: Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m(2)/day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m(2)/day (1/3 de novo patients, 5/8 total patients) and 538 mg/m(2)/day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3-11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m(2)/day but developed DLT at the same dose when de-escalated from 538 mg/m(2)/day. Other toxicities included grade 1-3 fatigue, grade 1-2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m(2)/day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and squalamine dose rate up to 384 mg/m(2)/day, with a prolonged terminal squalamine persistence in patient plasma (median t(1/2) = 18 h; range, 8-48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases. CONCLUSIONS: The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m(2)/day; however, patients without prior exposure to squalamine appeared to tolerate a dose rate of 384 mg/m(2)/day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.