A phase II study of CI-980 in previously untreated extensive small cell lung cancer: an Ohio State University phase II research consortium study

CI-980, (ethyl (S)-(5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b] pyrazine-7-yl) carbamate 2-hydroxyethansulfonate (1:1)), is a water-soluble mitotic inhibitor. It acts by binding to the colchicine-binding site on tubulin, a site different from that of the vinca alkaloids, inhibiting tubulin polymerization. Cells exposed to CI-980 accumulate in M phase and die. In preclinical tumor models, CI-980 showed a broad spectrum of activity, including in multi-drug resistant tumor cell lines, with activity at least equal to that of vincristine. Extensive small cell lung cancer, despite its responsiveness to chemotherapy, is usually an incurable disease with survival in patients of less than one year. Due to the preclinical activity of CI-980 and its similar mechanism of action to drugs effective in small cell lung cancer, a phase II trial in extensive small cell lung cancer was initiated by The Ohio State University Phase II Research Consortium. A "window of opportunity" design was chosen where a short six-week trial of the drug was given unless there was significant objective response. Twelve patients were entered in the study and underwent a total of 16 cycles of chemotherapy. The median age of the patients was 54 years old (range 34-71) and performance status was ECOG 0 (four patients), ECOG 1 (seven patients), and ECOG 2 (one patient). The patients were treated with a 72-hr infusion at a dose of 4.5 mg/m2/day. Toxicity was predominantly myelosuppression with granulocytopenia (nine episodes), and anemia (seven episodes). There were no objective responses with 11 patients being removed from study due to progressive disease. Evaluation of leukocyte microtubule structure in peripheral blood revealed microtubule depolymerization, which was seen after treatment (t = 72 hr) and was reversible within 24 hr of stopping the drug. We conclude that despite antitumor activity demonstrated in preclinical studies, CI-980 does not have biological activity in previously untreated small cell lung cancer at this dose and infusion protocol.     

Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin's lymphoma: A phase II randomized study

Background:It is unclear whether the purine analogs fludarabine(Flu) and cladribine (CdA) are non-resistant. Patients and methods:Sixty patients with relapsed or refractorylow-grade NHL were randomly allocated to initial treatment with either Flu 25mg/m², or CdA 0.14 mg/kg, each for five consecutive days every fourweeks. Upon treatment failure, eligible patients were crossed over to theother study drug. Results:Overall response and CR were 68% and 48%with Flu, and 72% and 38% with CdA, respectively. Forresponders, actuarial three-year progression-free survival was 58% withFlu and 52% with CdA. Treatment with both drugs was well tolerated,with toxic effects primarily hematological. Two patients (8%) in theFlu group and 15 patients (47%, P = 0.001) in the CdA groupwere taken off study because of persistent hematological toxicity. After crossover, none of seven refractory patients responded, while eight of ninepreviously responsive patients achieved second responses. Conclusions:Our study confirms that Flu and CdA have similarresponse rates and durations. However, further studies are required tooptimize the CdA schedule and dosage in order to ameliorate its toxic profilewhile maintaining antitumor activity. The two drugs appear to becross-resistant.     

A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma

Bryostatin 1 is a naturally occurring macrocyclic lactone with promising antitumour and immunomodulatory function in preclinical and phase I clinical investigations. In this phase II study, 17 patients with progressive non-Hodgkin's lymphoma of indolent type (NHL), previously treated with chemotherapy, received a median of 6 (range 1-9) intravenous infusions of 25 microg/m(2) bryostatin 1 given once weekly over 24 hours. In 14 evaluable patients no responses were seen. Stable disease was attained in one patient for 9 months. The principal toxicities were myalgia and phlebitis. Treatment was discontinued early because of toxicity alone (phlebitis) in 2 patients, toxicity in addition to progressive disease in 3 patients (myalgia and phlebitis n = 2; thrombocytopenia n = 1) and progressive disease in 5 patients. The results fail to demonstrate efficacy of this regimen of bryostatin 1 in the treatment of NHL. In light of preclinical data that demonstrate synergy between bryostatin 1 and several cytotoxic agents and cytokines, clinical studies to investigate bryostatin 1 in combination are warranted. We also present data to demonstrate that central venous lines may be used in future studies to avoid phlebitis.     

A phase II study of human rDNA alpha-2 interferon in patients with low grade non-Hodgkin's lymphoma

Summary Thirty five patients with a diagnosis of non-Hodgkin's lymphoma of low histological grade were treated with 2×10⁶/m² of human rDNA alpha 2 IFN-a₂ by subcutaneous injection. Treatment was continued until progressive disease was documented or one year of therapy had been given. None of the patients had to stop treatment because of toxicity and no treatment delays or suspensions of therapy were necessary as a consequence of myelosup-pression. Thirty four patients were evaluable and seventeen (50%) obtained an objective response (2 CR, 15 PR) with a median duration of eleven months. Sixteen patients were untreated prior to receiving interferon but were felt to need some form of therapy rather than be suitable for a watch policy. Eleven of these patients responded (69%) with 95% confidence limits lying between 41% and 89%. No other pretreatment factors appeared to affect the liklihood of response. Single agent IFN-₂ has significant activity in the low grade non-Hodgkin's lymphomata and warrants further investigation in this disease.     

Pegylated liposomal doxorubicin as single-agent treatment of low-grade non-Hodgkin's lymphoma: a phase II multicenter study

The purpose of this study was to determine the objective response rate, median duration of response, time to disease progression, and survival time and to evaluate the safety of pegylated liposomal doxorubicin in previously treated patients with low-grade non-Hodgkin's lymphoma. Thirty-two patients with low-grade non-Hodgkin's lymphoma were treated and analyzed. Pegylated liposomal doxorubicin 30 mg/m2 was administered intravenously as a single dose on day 1 of each 3-week cycle. Patients had an Eastern Cooperative Oncology Group performance status of 0-1 and had stage II-IV disease. The median baseline left ventricular ejection fraction was 60%, and the median age was 68 years. In 29 evaluable patients, there were 3 (10%) complete responses, 6 (21%) partial responses, 11 (38%) patients with stable disease, and 9 (31%) with progressive disease. The median number of cycles was 4 (range, 1-22 cycles). The median duration of response (complete response plus partial response) was 11.0 months (range, 2.3-37.0 months). The estimated median time to progression was 5.6 months (range, 1.1-40.5 months) and the estimated median survival was 29.6 months (range, 3.9-41.6 months). Treatment-related toxicities grade = 3 included neutropenia (25%) and palmoplantar erythrodysesthesia (9%). Only 1 clinically significant cardiac toxicity was observed. There were 17 deaths; none were treatment related. Single-agent pegylated liposomal doxorubicin 30 mg/m2 every 3 weeks, is associated with antitumor activity in the treatment of low-grade non-Hodgkin's lymphoma, as shown by an objective response of 31%, and produced no significant cardiac or hematologic toxicity. Based on these results, pegylated liposomal doxorubicin should be further evaluated in combination with other agents in low-grade non-Hodgkin's lymphoma.     

A phase II protection study of BB-10010 in patients with high grade non-Hodgkin's lymphoma undergoing intensive chemotherapy

The aim of this study was to determine whether administration of BB-10010, a synthetic stem cell inhibitor, would allow more intensive chemotherapy to be administered to patients with newly diagnosed high grade NHL. Thirteen patients were randomised to receive BB-10010 concurrently with dose-intensified BEMOP/CA chemotherapy (7 patients) or chemotherapy alone (6 patients). Although the mean neutrophil count of BB-10010 treated patients was higher following cycles 1, 2 and 3 of chemotherapy compared with those receiving chemotherapy alone, there was no difference in the mean number of cycles tolerated, blood component usage and hospital admissions due to infections. No specific toxicity of BB-10010 was identified. Whilst BB-10010 can be administered safely, it does not improve the ability of patients to tolerate intensive chemotherapy for high grade NHL.     

A phase II multicenter study of CAMPATH-1H antibody in previously treated patients with nonbulky non-Hodgkin's lymphoma

CAMPATH-1H is a humanized antilymphocyte monoclonal antibody (mAb) directed against the CD52 antigen expressed on normal and malignant lymphocytes. We report the results of a multicenter phase II trial using intravenous CAMPATH-1H in previously treated patients with nonbulky non-Hodgkin's lymphoma (NHL) or minimal residual NHL. Sixteen previously treated patients with nonbulky NHL and two patients with minimal residual NHL, were treated with CAMPATH-1H. Changes in peripheral blood lymphocyte subsets were analyzed by multiparameter flow cytometric techniques in eleven patients. The 18 patients enrolled in the studies received CAMPATH-1H for a median duration of 6 weeks (range, 3 to 14 weeks), and a median cumulative dose of 470 mg (range, 180 to 1185 mg). Two of the sixteen patients with nonbulky NHL achieved a complete response (CR) and one patient achieved a partial response (PR). One of the two patients with minimal residual NHL achieved a molecular CR. Infusional complications were seen with the majority of patients but were more common with initial infusions. Significant hematologic toxicity was also observed with grade (3/4) thrombocytopenia (n=10), grade (3/4) neutropenia (n=4) and grade 3 anemia (n=3). Due to excessive infectious complications observed with the patients enrolled, the trials were terminated early. Anti-tumor activity was demonstrated in a small subset of previously treated low-grade lymphoma patients with nonbulky or minimal residual disease. Future studies evaluating the effect of different drug schedules, modes of mAb administration, and concurrent use of prophylactic antibiotics/antiviral/antifungal agents to optimize anti-tumor activity and limit infectious toxicities are planned.     

A phase II study of topotecan in patients with relapsed small-cell lung cancer

An early phase II study of topotecan produced favorable results in a small number of untreated and previously treated patients with small-cell lung cancer (SCLC). This multicenter study was conducted in patients with relapsed SCLC at 19 medical institutions in Japan. Topotecan 1.0 mg/m2/day was administered for 5 consecutive days every 3 weeks. Fifty-three patients were enrolled in the study. One patient was withdrawn before the commencement of study treatment, and 2 patients were unable to continue study treatment due to an interruption in the supply of study medication. The response rate was 26.0% in 13 of the 50 evaluable patients who were eligible and completed protocol-specified treatment and procedures. The median time to progression and overall survival were 133 days and 262 days, respectively. The most frequently reported toxicity was reversible myelosuppression, such as leukopenia, neutropenia, anemia (decreased hemoglobin), and thrombocytopenia. Nonhematological toxicity was also reported but the incidence of grade 3/4 symptoms was low. The results of this study indicate that topotecan is effective against relapsed SCLC with good tolerability.     

A phase II study of mitoxantrone in malignant lymphoma

A phase II study of mitoxantrone (MIT) was performed in 13 cases of refractory malignant lymphoma, 1 of Hodgkin's disease and 12 of non-Hodgkin lymphoma. The twelve non-Hodgkin lymphomas were previously treated with adriamycin. MIT was diluted in 50 approximately 100 ml saline solution and intravenously administered by drip infusion in 15 approximately 30 minutes. The dose of MIT was 3 mg/m2/day for 5 days (A) or 10 approximately 14 mg/m2/day, for 1 day (B). There were 2 CR, 1 MR, 1 NC and 2 PD among 8 cases treated by schedule A, and two cases were not evaluable. With schedule B, there was 1 MR among 5 cases, and four cases were not evaluable. In the 7 evaluable cases, remission rate was 2/7 (29%) with remission durations of 6+ weeks and 55 weeks. The dose limiting toxicity was granulocytopenia but no serious infection was observed. With schedule A, it was difficult to repeat the treatment every 3 weeks because of the delay in granulocyte recovery. Gastrointestinal toxicities were observed in about half of the treatment courses but they were mild in degree. A prolongation of QTc (greater than 0.44) was observed in 3 cases (4 treatment courses) among 9 cases (10 treatment courses) whose baseline QTc values were within normal limits. Baseline QTc values were above the normal limit in 4 cases and in two of them, QTc showed further prolongation after MIT treatment. No arrhythmia or congestive heart failure was observed.     

A phase II study of epirubicin in malignant lymphoma

A new anthracycline analog, epirubicin (4'-epi-Adriamycin) was evaluated at eleven institutes in a phase II clinical study in patients with malignant lymphoma. Epirubicin was administered intravenously mainly with using the following two regimens; 50 to 60 mg/m2 every three weeks and 40 mg/m2 weekly. A total of 46 cases were entered into the study and 41 cases were evaluable. Clinical responses, complete plus partial remissions, were observed in 27 cases (65.9%) with 8 of these showing complete remission. There was no significant difference of response between the two regimens. Response rates taking into account previous chemotherapy were 90.9% (10/11) in previously nontreated cases, 61.9% (8/13) in cases previously treated with non-anthracyclines and 52.9% (9/17) in cases treated with anthracyclines. The major adverse effect was bone marrow suppression; leukopenia was observed in 83.8%, anemia in 60.5% and thrombocytopenia in 15.4%. Other adverse effects frequently observed were anorexia (59.0%), nausea-vomiting (48.8%) and alopecia (55.6%). These adverse effects seemed milder than those produced by doxorubicin. The results indicated that epirubicin seemed to be a markedly useful drug against malignant lymphoma.     

A phase II study of oral idarubicin (4-demethoxidaunorubicin) in previously untreated elderly patients with non-Hodgkin's lymphoma

Eighteen untreated elderly patients (median age 75 years) with non-Hodgkin's lymphoma (NHL) entered a phase II study with oral Idarubicin (4-demethoxidaunorubicin) at a dosage of 30-35 mg/m2 on day 1 and every 3 weeks thereafter. The medium number of cycles administered was three (range one to nine). We obtained one (6%) complete response and four (25%) partial responses in 16 evaluable patients. Toxicity was mild and no cardiotoxicity was found. At this dosage Idarubicin showed little anticancer activity in NHL.     

Phase II study of sequential topotecan and etoposide in patients with intermediate grade non-Hodgkin's lymphoma: a National Cancer Institute of Canada Clinical Trials Group study

Preliminary results indicate that inhibitors of the nuclear enzyme topoisomerase (topo) I, such as topotecan, may be active in non-Hodgkin's lymphoma (NHL). Pre-clinical studies have shown sequential administration of a topo I and II inhibitor has supra-additive anti-tumor effects in some model systems, and that greater cytotoxicity occurs if the topo I inhibitor is given first. We enrolled, 22 eligible patients with relapsed or refractory intermediate grade NHL in a phase II study ofsequential administration of topotecan 1.25 mg/m2 days 1-5 and etoposide 50 mg po b.i.d. days 6-12, every 28 days without G-CSF. Most patients had diffuse large B-cell lymphoma and all had received only one prior regimen (CHOP, 20 patients, or equivalent, 2 patients). Patients with stable or responding disease were allowed to proceed to high-dose therapy and autologous stem-cell transplant after 2 cycles of therapy. The 22 patients received a total of 62 cycles of topotecan + etoposide (median 2, range 1-6), and 4/22 completed all six planned cycles. Hematologic toxicity was significant and resulted in incomplete etoposide dosing in half of all cycles in 16/22 patients. Nineteen of twenty-two patients had grade 3/4 neutropenia, 12 had grade 3/4 thrombocytopenia, and 6 grade 3/4 anemia. Eleven patients had at least one episode of febrile neutropenia or had documented infection. Non-hematologic toxicity was mild. Four patients had a partial response (PR) (18.2%), nine had stable disease and seven progressed; three patients with stable disease went on to ABMT. The combination of topotecan and etoposide as given in this study has modest activity in relapsed/refractory aggressive histology NHL, and produces marked myelosuppression. Other doses and schedules combining topo I and II inhibitors, or topo I inhibitors with alkylating agents, should be explored with the addition of hematopoietic growth factors in this patient population.     

A phase II clinical trial of oral VP 16-213 in advanced non-Hodgkin's lymphoma

A phase II clinical trial of oral VP 16-213, a semisynthetic podophyllotoxin, was undertaken in twenty nine patients with advanced non-Hodgkin's lymphoma. All patients had received extensive prior chemotherapies including adriamycin, cyclophosphamide, vinka alkaloids and/or bleomycin and has become refractory to these drugs. The dosage of VP 16-213 was 200 mg/day p.o. bid for 5 days at 3 to 4-week intervals. There were 3 CRs (10.3%) and 6 PRs (20.7%) with a median duration of remission of 16 weeks ranging from 7 to 185+ weeks. Leukopenia less than 4 X 10(3)/cm3 and thrombocytopenia less than 100 X 10(3)/cm3 were seen in 80% and 26.7% of cases, respectively. Alopecia (100%), anorexia (44%) and nausea (26%) were observed but these were well tolerated. We conclude that the oral administration of VP 16-213 has considerable antitumor activity with no cross-resistance to vinka alkaloids, anthracyclines and alkylating agents.     

Liposomal encapsulated doxorubicin (Caelyx) in the treatment of relapsed aggressive non-Hodgkin's lymphoma: a phase II study

Aggressive non-Hodgkin's lymphoma (NHL), such as diffuse large B-cell lymphoma, can be cured in approximately 50% of cases, but those cases that recur and are not amenable to high-dose chemotherapy rely on palliative chemotherapy to improve symptoms and prolong life. Anthracyclines are associated with a high response rate in aggressive NHL but extended treatment results in cardiotoxicity. Liposomal encapsulated doxorubicin has been shown in other tumor types to allow for extended treatment with doxorubicin, but is associated with a low cardiac risk. The present study aimed to assess the response rate, survival and cardiac risk of patients with relapsed aggressive NHL treated with liposomal encapsulated doxorubicin. Eighteen patients with relapsed aggressive NHL were treated with liposomal encapsulated doxorubicin (40 - 50 mg/m2) for a planned six cycles. Some 83% of patients had diffuse large B-cell or mantle cell NHL. Four patients had a partial response (23%), whereas five patients had stable disease. None had a complete response. Eight patients progressed when receiving the liposomal encapsulated doxorubicin therapy. The median survival time was 34 weeks, and the median progression-free survival was 15.7 weeks. Overall survival was 50% at 6 months and 39% at 12 months. Progression-free survival was 33% at 6 months and was 28% at 12 months. The mean ejection fraction pre- and post-liposomal encapsulated doxorubicin treatment remained the same. Only one patient had a drop in ejection fraction to <50%. Liposomal encapsulated doxorubicin offers another choice to patients seeking palliation from their lymphoma recurrence with a response rate of 23% that was well tolerated and had a minimal cardiotoxic risk.     

Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study.

PURPOSE: Determine response rate, time to disease progression, and toxicity of the proteasome inhibitor PS-341 in patients with stage IV renal cell cancer. PATIENTS AND METHODS: PS-341 1.5 mg/m(2) was administered intravenously twice weekly for 2 weeks every 21 days. Dose escalation to 1.7 mg/m(2) ensued in the absence of grade 3 to 4 toxicities. Re-evaluation took place after three cycles. To assess proteasome inhibition, patients were randomly assigned to tumor core biopsy either before the first dose or after the third cycle of PS-341. Additionally, whole blood was collected at the same time intervals. RESULTS: Twenty-three patients were enrolled; 21 were assessable for response. Two patients were never treated (one patient refused treatment and one had insufficient tumor for biopsy). Eighteen patients completed at least three cycles of therapy; three patients experienced disease progression after two cycles. Grade 4 toxicities were arthralgia, diarrhea, and vomiting. Grade 3 toxicities included thrombocytopenia with one hemorrhage, anemia, febrile neutropenia, gastrointestinal toxicity, pain, fatigue, neuropathy (one sensory, one mixed sensorimotor), and electrolyte disturbances. Grade 1 to 2 neuropathy occurred in seven patients. One case of thrombosis and one case of pleural effusion occurred. Only one objective response was seen. Proteasome activity was measured by specific chymotryptic activity (SpA) and chymotryptic/tryptic activity (ChT:T). After PS-341, there was a decrease in mean whole blood SpA and ChT:T (P =.07 and.11, respectively). CONCLUSION: Evidence is lacking for clinically significant activity of PS-341 in metastatic renal cell cancer. Insufficient biopsy and whole blood sample numbers preclude conclusions regarding proteasome inhibition within tumor. Further evaluation in this disease setting is not recommended.     

A University of Chicago consortium phase II trial of SB-715992 in advanced renal cell cancer

BACKGROUND: Advanced renal cell cancer (RCC) continues to have a poor overall prognosis despite new FDA-approved therapies. Although taxane-based therapies are generally ineffective in RCC, research into the role of the von Hippel-Lindau protein has shown an association with microtubule dynamics. Mitotic kinesins are a class of molecular motors that also interact with microtubules and are required for proper mitotic function. SB-715992 is a new agent that inhibits the function of a mitotic kinesin known as kinesin spindle protein and leads to cell death. PATIENTS AND METHODS: Twenty patients with previously treated advanced RCC were enrolled on this phase II trial of SB-715992, with response rate as a primary endpoint. RESULTS: No patients responded with complete or partial remission. Six patients had stable disease, and 1 patient continues on therapy after 12 cycles. Common toxicities included anemia (80%), elevated creatinine (70%), lymphopenia (45%), fatigue (50%), hyperglycemia (50%), and dyspnea (45%). Reported grade 3/4 toxicities included dyspnea, fatigue, neutropenia with skin infection, dizziness, hyperuricemia, and hypertension. CONCLUSION: This dose and schedule of SB-715992 does not appear to have a significant cytotoxic effect for patients with previously treated advanced RCC.