Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies.

PURPOSE: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. STUDY DESIGN: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). RESULTS: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks. CONCLUSION: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.     

Phase II trial of perillyl alcohol in patients with metastatic colorectal cancer

Purpose. This is a phase II study of perillyl alcohol in the treatment of patients with metastatic colorectal carcinoma. The primary endpoint is time to progression. Secondary objectives are to evaluate objective response rate and toxicity. Patients and Methods. Eligible patients had metastatic adenocarcinoma of the colon or rectum. Patients received perillyl alcohol orally at a dose of 1200 mg/m². Dose escalation to 1,600mg/m² was allowed. Results. Twenty-seven patients were enrolled. The median time to progression was 1.8 months (range 1 to 3 mo). Four patients received less than one cycle and were not evaluable for response. Of the remaining 23, all had progressive disease. There were no complete or partial responses. Toxicity was relatively mild, with fatigue, nausea and anemia predominating. Three patients withdrew from therapy for toxicity (grade 3 belching, bloating; grade 2 nausea, fatigue, vomiting, anorexia and increase perspiration; grade 1 anorexia). Discussion. Despite preclinical evidence of anticancer activity, oral perillyl alcohol administered at this dose and formulation does not appear to have clinical antitumor activity when used for patients with advanced colorectal carcinoma.     

Phase II trial of acivicin in patients with advanced colorectal carcinoma

Acivicin, an amino acid antibiotic, was administered to 36 adult patients with previously treated metastatic colorectal cancer. The starting dose for good-risk patients was 15 mg/m2/day day given as a short intravenous infusion on 5 consecutive days every 3 weeks. Patients previously treated with radiation therapy, mitomycin, or nitrosoureas and those with inadequate bone marrow reserve received 12 mg/m2 on the same schedule. In 33 evaluable patients, one partial response occurred. Sixteen patients had stable disease with a median time to disease progression of 15 weeks (range 9-27) and a median survival of 8 months. The median survival of the whole group was, however, less than 6 months. Myelotoxicity was mild and resulted in no significant complications. Nonhematological toxicity primarily consisted of nausea, vomiting, drowsiness, depression, and altered mentation. Acivicin given by this schedule is inactive at these dose levels in previously treated patients with colorectal carcinoma.     

Phase II evaluation of 4'epi-doxorubicin in patients with metastatic colorectal carcinoma

Thirty-four evaluable patients with metastatic colorectal carcinoma (13 rectal primary and 21 colonic primary, 4 pretreated and 30 untreated) received 4'epi-doxorubicin at the dose of 75 mg/m2 i.v. once every 21 days, for a minimum of 2 courses. Symptomatic toxicity (mainly confined to gastrointestinal complaints) was short-lived and easily managed. Hematologic toxicity was mild. Transient electrocardiographic abnormalities were found in 50% of patients, without signs of significant cumulative cardiotoxicity. Three previously untreated patients achieved a partial response (lasting 16, 12 and 12 weeks, respectively) with a response rate of 9% (3%-23%, 95% confidence interval). More interestingly, all responsive patients had rectal cancer: further studies of 4'epi-doxorubicin confined to the rectal localization seem warranted.     

Phase II trial of 10-Edam in patients with advanced colorectal carcinoma

10-Edam (10-ethyl-10-deaza-aminopterin), an antifolate derivative, was administered to 14 chemotherapy-naive patients with advanced colorectal carcinoma. The drug was given weekly by intravenous route at an initial dose of 80 mg/m2, with escalation or attenuation according to tolerance. Mucositis was dose limiting and occurred in 11 of 14 patients (78.6%). Removal from the study was required in one patient due to progressive pulmonary fibrosis that was histologically identical to methotrexate-induced lung damage. Toxicity was otherwise mild to moderate and included diarrhea, constipation, abdominal discomfort, anorexia, nausea/vomiting, rash, and fatigue. There were no responses to 10-Edam in this study, 95% confidence interval (0-0.23). Stable disease was achieved in four patients; the remaining 10 patients demonstrated progression within 9 weeks of initiating systemic therapy. 10-Edam employed at this dosage and schedule was not effective as a treatment against advanced colorectal carcinoma.     

Phase II study of capecitabine in patients with fluorouracil-resistant metastatic colorectal carcinoma.

PURPOSE: Capecitabine is an oral fluoropyrimidine converted to fluourouracil (FU) preferentially in tumor tissue. It has proven clinical activity against colorectal cancer when used as first-line therapy. The objectives of this study were to assess the safety and efficacy of capecitabine in patients with metastatic colorectal carcinoma who progressed despite previous FU therapy. PATIENTS AND METHODS: According to the group sequential analysis design of this study, accrual would stop if no responses were observed in the first 20 patients treated. If one or more objective responses were confirmed, the trial would be expanded. Patients received capecitabine 1,250 mg/m(2) twice a day for 14 days, every 3 weeks. Tumor lesions were assessed every 6 weeks, and patients were followed for survival every 3 months after completing treatment. RESULTS: Twenty-three patients were enrolled onto the study; 22 fulfilled all the eligibility criteria. No objective responses were observed among the 22 eligible patients; 11 patients (50%) had stable disease for a median duration of 141 days (range, 88-289 days). The Kaplan-Meier estimate of median time to disease progression was 64 days (95% CI, 41 to 134 days). The median survival time estimate was 389 days (95% CI, 267 to 637 days). The most frequent treatment-related adverse events were hand-foot syndrome, diarrhea, and nausea or vomiting. There were no grade 4 toxicities and no treatment-related deaths. CONCLUSION: Single-agent capecitabine in patients with metastatic colorectal carcinoma refractory to FU showed no objective responses and clinical benefit that was, at best, modest. The use of capecitabine in combination with other treatments in this patient population is under investigation.     

Phase II study of oxaliplatin in japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines

BACKGROUND: Although oxaliplatin (L-OHP) combined with infusional 5-fluorouracil (5-FU) and leucovorin (LV) is one of the standard chemotherapy regimens for metastatic or recurrent colorectal cancer, its introduction to Japan has been delayed. Phase I studies of L-OHP monotherapy in Japan showed no dose-limiting toxicity at the internationally recommended dose of 130 mg/m2 every 3 weeks, as well as no racial differences in pharmacokinetics as compared with Western subjects. This study aimed to clarify the efficacy and safety of L-OHP monotherapy in patients with metastatic colorectal cancer refractory to fluoropyrimidines. METHODS: Patients with metastatic colorectal cancer who had failed to respond to fluoropyrimidine-based chemotherapy received L-OHP at a dose of 130 mg/m2 every 3 weeks. RESULTS: Sixty patients were enrolled. Two ineligible patients and one untreated patient were excluded from analysis. The median number of treatment cycles was 4 (range, 1-6). The overall response rate was 9% (5/57, 95% CI: 4-19%). The median time to progression was 2.7 months, and the median survival time was 11.1 months. Grade 3 major toxicity comprised thrombocytopenia (12%) and nausea (11%). There was no grade 4 toxicity. All patients experienced mild to moderate sensory neurotoxicity without functional impairment interfering with activities of daily living. CONCLUSIONS: The efficacy and toxicity of L-OHP in Japanese patients with metastatic colorectal cancer refractory to fluoropyrimidines is apparently similar to those in Western patients.     

Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer.

PURPOSE: To evaluate the antitumor activity, safety, immune response, and replication of CI-1042 (ONYX-015), an E1B 55-kd gene-deleted replication-selective adenovirus, administered intravenously to patients with metastatic colorectal cancer PATIENTS AND METHODS: Eighteen patients with metastatic colorectal cancer for whom prior chemotherapy failed were enrolled onto an open-label, multicenter, phase II study. CI-1042 was administered intravenously at a dose of 2 x 1012 viral particles every 2 weeks. Patients were evaluated for tumor response and toxicity; in addition, blood samples were taken for adenovirus DNA and neutralizing antibody analysis. RESULTS: Common toxicities included flu-like symptoms, nausea, and emesis. All 18 patients eventually were removed from study because of progressive disease. Seven patients were assessed as having stable disease after 2 months of treatment, whereas two patients were considered to have stable disease after 4 months. Detectable circulating CI-1042 DNA was identified in 36% of patients 72 hours after last infusion, which is suggestive of ongoing viral replication. CONCLUSION: In this phase II study, intravenous CI-1042 was administered safely to patients with advanced colorectal cancer. Toxicity was manageable, consisting primarily of flu-like symptoms. Stable disease was experienced by seven patients for 11 to 18 weeks.     

Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer.

PURPOSE: This phase I clinical trial was designed to determine the maximum-tolerated dose and dose-limiting toxicities of the matrix metalloproteinase (MMP) inhibitor COL-3 in patients with refractory solid tumors. PATIENTS AND METHODS: Thirty-five patients with different cancer types were enrolled. COL-3 doses were escalated from 36 mg/m2/d in successive cohorts of at least three patients. Circulating levels of MMP-2, MMP-9, vascular endothelial growth factor, and basic fibroblast growth factor were assessed during treatment. Pharmacokinetic parameters were assessed for single and multiple doses of drug. RESULTS: Cutaneous phototoxicity was dose-limiting at 98 mg/m2/d. With the use of prophylactic sunblock, COL-3 was well tolerated at 70 mg/m2/d. The dose of 36 mg/m2/d was well tolerated without the use of sunblock. Other toxicities that did not seem to be related to dose or pharmacokinetics included anemia, anorexia, constipation, dizziness, elevated liver function test results, fever, headache, heartburn, nausea, vomiting, peripheral and central neurotoxicities, fatigue, and three cases of drug-induced lupus. Disease stabilization for periods of 26+ months, 8 months, and 6 months were seen in hemangioendothelioma, Sertoli-Leydig cell tumor, and fibrosarcoma, respectively. There was a potentially statistically significant relationship between changes in plasma MMP-2 levels and cumulative doses of drug when progressive disease patients were compared with those with stable disease or toxicity (P = .042). CONCLUSION: COL-3 induced disease stabilization in several patients who had a nonepithelial type of malignancy. Phototoxicity was dose-limiting. We recommend the dose of 36 mg/m2/d for phase II trials.     

Phase II trial of docetaxel (Taxotere(R)) in metastatic colorectal carcinoma

BACKGROUND:: Docetaxel (Taxotere^®) is prepared from a non-cytotoxic precursorextracted from the needles of the Taxus baccata. Preclinicalinvestigations have demonstrated that docetaxel is very activein colon adenocarcinoma murine models. Phase I studies revealedgranulocytopenia to be the dose-limiting toxicity. Initial clinicaltrials also demonstrated docetaxel's activity in ovarian, breast,and non-small cell lung cancer. Because of this encouragingpreclinical and clinical activity, we initiated a phase II studyof docetaxel in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS:: Docetaxel, 100 mg/m², was administered as a 1-hour intravenousinfusion every 21 days. Nineteen patients were entered on thetrial. All patients had measurable disease and had not receivedprior chemotherapy for metastatic disease. RESULTS:: No complete or partial responses were observed. Granulocytopeniawas the dose-limiting toxic effect. Seventeen patients had grade4 granulocytopenia; 8 of these patients received antibioticsfor neutropenic fevers. Twelve patients experienced hypersensitivityreactions, and 15 patients experienced cutaneous toxic reactions.One patient demonstrated evidence of fluid retention. CONCLUSIONS:: Administered at the stated dose and schedule, docetaxel haslittle activity against metastatic colorectal carcinomas. Thetoxicity profile, consisting of granulocytopenia, hypersensitivityreactions, cutaneous reactions, and edema, has been previouslydescribed in patients receiving docetaxel. docetaxel, Taxotere^®, paclitaxel, Taxol^®, colorectal carcinomas, colon carcinoma, rectal carcinoma     

Phase II study of paclitaxel in patients with metastatic breast carcinoma refractory to standard chemotherapy

BACKGROUND: The authors conducted a single institution Phase II clinical trial to determine whether paclitaxel had antitumor activity in patients with metastatic breast carcinoma that was refractory to standard chemotherapy. METHODS: Patients with metastatic breast carcinoma were eligible for the study if they had disease progression after at least 2 prior chemotherapy regimens. Patients who had received three prior regimens were treated in a separate cohort. All patients were required to have received doxorubicin in the past and were not eligible if they had received prior therapy with paclitaxel. The starting dose of paclitaxel for low risk patients was 175 mg/m2, administered as a 24-hour continuous infusion; the starting dose of paclitaxel was 150 mg/m2 for patients who had received > or = 3 prior regimens. Therapy was given every 3 weeks and continued for at least 2 courses unless there was evidence of rapidly progressing disease, for at least 3 courses if there was no change in disease and Grade 3 or 4 (based on National Cancer Institute toxicity criteria) toxicity was not noted, and for 6 courses beyond the maximum response in patients who demonstrated complete or partial responses and showed no evidence of disease progression. RESULTS: Sixty-eight of 69 patients entered in the study were evaluable for response: 35 patients who had received 2 prior chemotherapy regimens for Stage IV disease and 33 patients who had received > or =3 prior regimens. A partial response was observed in 7 patients who had received 2 prior regimens, for an objective response rate of 20% (95% confidence interval [95% CI], 14-26%). In the group who had received > or = 3 prior regimens, a total of 6 partial responses were observed, for an objective response rate of 18% (95% CI, 12-23%). The median response duration was 8.2 months (range, 2.7-10.1 months) for the group who had received 2 prior regimens and 5.8 months (range, 2.1-9.5 months) for patients who received > or = 3 prior regimens. Responses were noted in patients with anthracycline-resistant tumors. CONCLUSIONS: Paclitaxel was active in heavily pretreated patients with metastatic breast carcinoma, including anthracycline-resistant breast carcinoma.     

Figitumumab in patients with refractory metastatic colorectal cancer previously treated with standard therapies: a nonrandomized,open-label,phase II trial

Purpose

Figitumumab (CP-751,871) is a human IgG2 monoclonal antibody that binds and down-regulates insulin-like growth factor receptor-1 (IGF-1R) and inhibits activation of this receptor by IGF-1 and IGF-2. This nonrandomized, open-label, single-arm, phase II trial evaluated the antitumor activity and safety of figitumumab in patients with metastatic colorectal cancer that was refractory to ≥2 systemic therapies.

Methods

Cohorts A and B received intravenous figitumumab 20 and 30 mg/kg in 3-week cycles, respectively. Both received loading doses (20 or 30 mg/kg) on days 1 and 2 of cycle 1. The primary endpoint was 6-month survival (null hypothesis for each cohort, H₀: p_{6 mo surv} = 0.45). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response, safety, and pharmacokinetics.

Results

A total of 168 patients (Cohort A, n = 85; Cohort B, n = 83) received figitumumab. Estimated 6-month survival was 49.4 % (95 % CI 38.8–60.0) in Cohort A and 44.1 % (95 % CI 33.4–54.9) in Cohort B. Median OS was 5.8 and 5.6 months, respectively; median PFS was 1.4 months in both cohorts. No objective partial or complete responses occurred. The respective rates of treatment discontinuation due to treatment-related adverse events (AEs) were 5 and 7 %. The most common grade 3/4 nonhematologic AEs in both cohorts were hyperglycemia and asthenia. No grade 4 hematologic laboratory abnormalities occurred. Most deaths were reported as due to progressive disease; none were due to figitumumab.

Conclusion

Six-month survival data do not support further study of figitumumab 20 or 30 mg/kg in this patient population.     

Phase II trial of doxil for patients with metastatic melanoma refractory to frontline therapy.

Treatment options for patients with stage IV melanoma are limited. Based on differences in the toxicity and activity profiles of pegylated liposomal doxorubicin (doxil) compared to standard doxorubicin, we have conducted a phase II trial of doxil for patients with metastatic melanoma. Doxil was administered as a 60-90 min intravenous infusion every 21 days. The starting dose was 60 mg/m2 for the initial nine patients, but was subsequently reduced to 50 mg/m2 for the remainder due to toxicity issues. Thirty-two patients were enrolled in the trial. Ninety-one percent had received prior systemic therapy. There were no complete responses and two partial responses for an overall response rate of 6%. The dominant side effects included hand-foot syndrome, rash (occasionally severe), and stomatitis, consistent with reports from other trials using similar doses and schedules. We conclude that doxil does not demonstrate sufficient activity in metastatic melanoma to warrant further investigation into its use in this setting.     

A phase II trial of docetaxel and estramustine in patients with refractory metastatic breast carcinoma

BACKGROUND: The similarity between the mechanism of action between docetaxel and estramustine generated the hypothesis of synergistic antimicrotubule effects and cytotoxicity when the two agents are combined. In addition, it has been demonstrated that estramustine binds P-glycoprotein in vitro and, thus, may prevent the efflux of taxanes in tumors that over-express P-glycoprotein. To further evaluate the combinations clinical efficacy and safety, a trial was performed in heavily pretreated patients with metastatic breast carcinoma (MBC). METHODS: Thirty-six patients with MBC were treated with estramustine 900 mg/m(2) per day divided into 3 doses given on Days 1-3 and docetaxel 70 mg/m(2) given by intravenous administration over 1 hour on Day 3 after the first dose of estramustine, every 21 days. Patients may have received any number of prior chemotherapy regimens for MBC. RESULTS: Nine partial responses were observed in 31 assessable patients, for an objective response rate of 29% (95% confidence interval, 14-48%). The median progression free survival was 4 months (range, 1-41 months), and the median overall survival was 17 months (range, 2-45 months). Severe toxicities (Grade 3 or 4) were neutropenia, hypophosphatemia, and thrombosis. Seventy-five percent of patients experienced either an improvement or no change in quality of life. CONCLUSIONS: The combination of docetaxel and estramustine produced responses in heavily pretreated women with MBC while maintaining quality of life.     

Phase II trial of sagopilone, a novel epothilone analog in metastatic melanoma

Background:

Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing.

Methods:

A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0–2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⁻², was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity.

Results:

Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⁻² indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%).

Conclusion:

Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.     

Phase II trial of a paclitaxel and carboplatin combination in Asian patients with metastatic nasopharyngeal carcinoma

Purpose: An earlier phase II trial of paclitaxel in patients with metastatic nasopharyngeal carcinoma (NPC) demonstrated a response rate of 22%. Hence we proceeded to study the combination of paclitaxel and carboplatin in these patients.Patients and methods: The 21-day regimen was as follows: i.v. paclitaxel 175 mg/m2 over three hours preceded by standard premedications, followed by i.v. carboplatin dosed at AUC of six infused over one hour. Only chemotherapy-naïve patients with histological diagnoses of undifferentiated carcinoma of the nasopharynx, systemic metastases and radiologically measurable lesions were eligible.Results: Thirty-two patients were accrued to this study. Twenty patients (62%) had at least two sites of metastasis. The main grade 3–4 toxicity was neutropenia (31%). Nine patients (28%) developed neutropenic sepsis, which caused the demise of one of them. Twenty-four patients (75%) responded to treatment, with one (3%) attaining a complete response. The median time to progression of disease was seven months and the median survival was 12 months. At one year, 52% of the patients were alive.Conclusions: The combination of paclitaxel and carboplatin is an active regimen in NPC. Its convenience of administration and good tolerability make it an attractive alternative regimen to consider for patients with metastatic disease.     

Phase II trial of irinotecan in combination with amifostine in patients with advanced colorectal carcinoma

BACKGROUND: Irinotecan is effective in patients with advanced colorectal carcinoma in both first-line and salvage settings but its use can be limited by serious side effects. Amifostine has been shown to reduce the incidence of cisplatin-induced cumulative renal toxicity in patients with advanced ovarian carcinoma and nonsmall cell lung carcinoma. In the current pilot Phase II trial, the authors examined the potential role of amifostine as a protective agent against irinotecan-induced diarrhea and myelosuppression and evaluated an every-2-weeks regimen as an alternative schedule for the administration of irinotecan in patients with previously treated metastatic colorectal carcinoma. METHODS: All patients received amifostine, 740 mg/m2, followed by irinotecan, 250 mg/m2, every 2 weeks. A 6-week cycle of chemotherapy (every 2 weeks for 3 treatments) was chosen to assess toxicity and response. The main objective of the current study was to evaluate the impact of amifostine on gastrointestinal and hematologic toxicity. RESULTS: A total of 22 patients entered the current study. Six of these 22 patients (27%) had WHO Common Toxicity Criteria Grade 3 or 4 diarrhea, including 2 patients (9%) with Grade 4 diarrhea. Eight of 22 patients (36.3%) developed Grade 3 or 4 neutropenia (Grade 4 in 4 of the 22 patients [18%]). Dose reduction was required in 25% of the treatment cycles. Five of the 22 patients (23%) withdrew from the trial due to amifostine toxicity. Of the 15 patients who were evaluable for response, 4 patients (26.6%) had achieved a partial response and 9 (60%) had stable disease as their best response.CONCLUSIONS: The combination of irinotecan with amifostine in patients with previously treated metastatic colorectal carcinoma did not appear to reduce irinotecan toxicity. Amifostine did not appear to interfere with the cytotoxic effect of irinotecan. The results of the current study did demonstrate efficacy and safety of the every-2-weeks irinotecan schedule that was comparable to other established regimens and these results support its feasibility as a reasonable alternative in this disease setting.