Showing papers on "Phases of clinical research published in 1993"
TL;DR: The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months and the minimal effective dose was 2 mg/kg/day, which is a promising drug for patients with AIDS or ARC.
Abstract: 2',3'-didehydro-3'-deoxythymidine (d4T) is a pyrimidine analogue and inhibitor of reverse transcriptase with potent in vitro activity against human immunodeficiency virus (HIV). A phase I trial of d4T was conducted in 41 HIV-infected patients, 12 with AIDS and 29 with AIDS-related complex (ARC). Thirty-six patients were evaluatable. The maximum tolerated dose was 2 mg/kg/day. The dose-limiting toxicity was sensory peripheral neuropathy, which occurred in 20 patients (55%). Four patients (11%) developed hepatotoxicity. Five (14%) developed anemia requiring a transfusion but not discontinuation of drug. The mean +/- SE plasma elimination half-life at all dose levels was 1.2 +/- 0.09 h. Increased or stable absolute CD4 counts were seen in most patients. The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months. d4T is a promising drug for patients with AIDS or ARC. This clinical trial is continuing to determine the minimal effective dose.
180 citations
TL;DR: The study demonstrated that chemoprevention trials can be performed through the network of the Community Clinical Oncology Program (CCOP) and evaluated the toxicity and efficacy of alpha-tocopherol in patients with oral leukoplakia.
Abstract: BACKGROUND Oral leukoplakia is an important model for developing chemoprevention approaches for lesions in the upper aerodigestive tract. These lesions most often result from exposure to carcinogens such as tobacco and alcohol and may precede development of invasive cancer. The potent antioxidant alpha-tocopherol (vitamin E) has prevented the development of cancers of the oral cavities in animal models. PURPOSE The objectives of this study were to evaluate the toxicity and efficacy of alpha-tocopherol in patients with oral leukoplakia and to assess the feasibility of performing chemoprevention trials through the network of the Community Clinical Oncology Program (CCOP). METHODS A single-arm phase II study using the nontoxic agent alpha-tocopherol to treat oral premalignant leukoplakia was performed at seven institutions affiliated with the CCOP through The University of Texas M. D. Anderson Cancer Center. Patients with symptomatic leukoplakia or dysplasia were treated orally with alpha-tocopherol (400 IU) twice daily for 24 weeks. Follow-up was performed at 6, 12, and 24 weeks after the start of treatment to assess toxicity and response, and serum alpha-tocopherol levels were determined at baseline and at 6 and 24 weeks. RESULTS Of the 43 patients who have completed 24 weeks of treatment, 20 (46%) had clinical responses and nine (21%) had histologic responses. Mean serum alpha-tocopherol levels were 16.1 micrograms/mL at baseline and increased to 34.29 micrograms/mL after 24 weeks of treatment. Patient-recorded drug calendars, as well as serum drug levels, indicated excellent patient compliance; an average of 95% of the prescribed pills were taken. Treatment was extremely well tolerated; no grade 3 or 4 toxic effects were reported. CONCLUSIONS Administration of alpha-tocopherol resulted in both clinical and histologic responses in premalignant leukoplakia lesions. The study also demonstrated that chemoprevention trials can be performed through the CCOP. The major problems were that a high percentage of patients were not assessable for response, some patients withdrew because expenses were not reimbursable, and there was limited participation within the CCOP network. These problems may reflect difficulties inherent in the implementation of multi-institutional chemoprevention trials. IMPLICATIONS The efficacy of alpha-tocopherol alone and in combination with other chemopreventive agents for carcinogenesis in the upper aerodigestive tract should be explored in future trials.
139 citations
TL;DR: Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible.
Abstract: Background Previous studies indicate that suramin may be an active agent for treatment of solid tumors. The clinical use of suramin is complicated by a broad spectrum of toxic effects and complex pharmacology. Studies have suggested that the dose-limiting neurotoxicity of this agent is closely related to sustained plasma drug concentrations of 350 micrograms/mL or more. Purpose This phase I clinical trial in patients with solid tumors was designed to determine whether plasma concentrations resulting in both antitumor activity and manageable toxicity could be achieved with short, intermittent infusions of suramin. Methods Thirty-seven patients, including 33 with metastatic, hormone-refractory prostate cancer, collectively received 43 courses of suramin designed to maintain a plasma concentration range of 200-300, 175-275, or 150-250 micrograms/mL. Patients received a test dose of 200 mg and an initial loading dose of 1000 mg/m2 on day 1 of therapy. Subsequent suramin doses and schedules were individually determined using a strategy of adaptive control with feedback, which used a maximum a posteriori Bayesian algorithm to estimate individual pharmacokinetic parameters. Patients were treated until dose-limiting toxicity or progressive disease developed. Results Thirty-five of the 37 study patients and 31 of the 33 with prostate cancer were assessable for toxicity and response. Treatment was discontinued in 28 patients because of dose-limiting toxicity consisting of a syndrome of malaise, fatigue, and lethargy; recurrent reduction in creatinine clearance of 50% or more; or axonal neuropathy. Evidence of major antitumor activity was observed in patients with prostate cancer treated at all three plasma drug concentrations. Measurable responses (one complete response and five partial responses) were noted in six of 12 patients with measurable disease. Twenty-four (77%) of 31 patients had a reduction in prostate-specific antigen of 50% or more, and 17 (55%) of 31 had a reduction of 75% or more. Twenty (83%) of 24 patients reported reduction in pain. Conclusions Suramin can be safely administered as an intermittent bolus injection by use of adaptive control with feedback to control plasma drug concentrations; toxicity is significant but manageable and reversible. Suramin is active against hormone-refractory prostate cancer. Implications Future trials should address the role and necessary extent of therapeutic drug monitoring; the optimal plasma drug concentration range and duration of therapy; and the activity of suramin in combination with other agents, in earlier stages of prostate cancer, and in other tumor types.
125 citations
TL;DR: Topotecan is an interesting new topoisomerase I inhibitor exerting antitumor activity in this phase I trial, and leucocytopenia is dose-limiting.
118 citations
TL;DR: The feasibility of pre‐irradiation chemotherapy has not been explored in patients with poor prognosis, and some improvement has been noted in recent trials using higher doses of hyperfractionated radiation therapy (HRT).
Abstract: Background. Fewer than 20% of children with intrinsic brain stem tumors survive longer than 2 years. Although some improvement has been noted in recent trials using higher doses of hyperfractionated radiation therapy (HRT), the feasibility of pre-irradiation chemotherapy has not been explored in these patients with poor prognosis.
Methods. Between February 1988 and March 1989, 37 patients were entered onto a Phase II Pediatric Oncology Group study for evaluating the feasibility, response, and toxicity of treating children with high-risk brain stem tumors with chemotherapy followed by HRT (66 Gy). Chemotherapy consisted of four cycles of cisplatin (100 mg/m2) plus cyclophosphamide (3 g/m2).
Results. Of 32 eligible patients, 65% improved clinically during the first 2–3 cycles of chemotherapy; 75% of those improving were weaned from steroids. On neuroradiology review of scans before and after chemotherapy, 3 patients had partial responses (PR, > 50% shrinkage), 23 had stable disease (SD), and 6 had progressive disease (PD). The median survival was 9 months. The three patients who attained a PR on chemotherapy were among the longest survivors at 38 plus, 44 plus, and 40 months. Toxicities included profound but brief marrow suppression, transient electrolyte-renal dysfunction, and ototoxicity. Brain stem swelling from intravenous fluids caused transient deterioration in two patients. Six patients developed an unusual syndrome of transient marrow suppression after HRT.
Conclusions. This study suggests that pre-irradiation chemotherapy can be successfully added to the treatment of patients with brain stem tumors with both clinical and objective responses noted, but that other agents must be identified to overcome the apparent development of drug resistance and to improve survival. Cancer 1993; 72A404-13.
92 citations
TL;DR: It has been concluded that ONCONASE was well tolerated by the majority of patients, demonstrated a consistent and reversible clinical toxicity patterns, did not induce most of the toxicities associated with most ofThe chemotherapeutic agents and, in view of its demonstrated objective clinical activity observed in patients harboring resistant solid tumors, the Phase II clinical trials are currently ongoing.
Abstract: ONCONASE(R) (ONC), previously known as P-30 Protein, is a novel amphibian protein isolated from Rana pipiens eggs/early embryos (1) which demonstrates cytostatic and cytotoxic activity against several human tumor cell lines in vitro, as well as anti-tumor activity in vivo. Animal toxicology studies in rats and dogs revealed dose-dependent weight loss, some skeletal muscle and myocardial degenerative changes, a decrease in albumin and bilirubin levels in rats, and a dose-related elevation of serum transaminases and alkaline phosphatase in both species. A human weekly schedule Phase I study of intravenous bolus ONC was initiated, with dose levels ranging from 60 mug/m2 (anticipated human dose) to 960 mug/m2. Five patients were treated per dose level, without dose escalations within the same patients. Dose levels were doubled in new groups of patients with a variety of relapsing and resistant tumors. A correlation was noted between the dose level and the number of doses (cumulative effect), and the toxicities observed. The dose limiting toxicity was renal as manifested by proteinuria with edema, +/- azotemia and fatigue. Other side effects included flushing, myalgias, transient dizziness, and decreased appetite. Two patients, one at 480 mug/m2 and another at 960 mug/m2 levels, developed reversible hypotensive reactions preceded by flushing. The maximum tolerated dose (MTD) appears to be 960 mug/m2. Incidental findings included some objective responses in non-small cell lung, esophageal, and colorectal carcinomas. It has been concluded that ONCONASE was well tolerated by the majority of patients, demonstrated a consistent and reversible clinical toxicity patterns, did not induce most of the toxicities (such as, e.g., myelosuppression and alopecia) associated with most of the chemotherapeutic agents and, in view of its demonstrated objective clinical activity observed in patients harboring resistant solid tumors, the Phase II clinical trials have been initiated and are currently ongoing.
79 citations
TL;DR: Results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen.
Abstract: BACKGROUND Therapy with high-dose cyclophosphamide, cisplatin, and carmustine (BCNU) plus autologous bone marrow transplantation has been extensively studied as treatment for patients with stage II or III breast cancer who have a 70% or greater risk of developing metastatic disease. This therapy is being used in a cooperative intergroup phase III clinical trial. In the cyclophosphamide-cisplatin-BCNU regimen, cyclophosphamide and BCNU, but not cisplatin, have been reported to cause acute lung injury, suggesting that either cyclophosphamide or BCNU may contribute to this injury. PURPOSE The purpose of this study was to analyze clinical and pharmacokinetic data from our ongoing phase II trials and to determine whether there is an association between BCNU pharmacokinetics and acute lung injury following cyclophosphamide-cisplatin-BCNU therapy. METHODS We performed a retrospective study of 38 patients treated following induction therapy or relapse, 29 with stage II-IV breast cancer and nine with intermediate and high-grade stage III-IV non-Hodgkin's lymphoma. These patients received therapy with cyclophosphamide at a dose of 1875 mg/m2 daily as a 1-hour intravenous infusion for 3 days, cisplatin at 55 mg/m2 per day as a 72-hour continuous intravenous infusion, and BCNU at 600 mg/m2 as a 2-hour infusion immediately following completion of the cisplatin infusion. Data from analysis of blood samples were used to calculate pharmacokinetic parameters for BCNU, and acute lung injury was determined on the basis of pulmonary function test results and histologic examination of lung biopsy specimens. RESULTS Our analysis showed that 20 (53%) of the 38 patients developed pulmonary injury following treatment. Twelve (60%) of the 20 had values for area under the curve (AUC) for BCNU concentration x time that exceeded 600 (micrograms/mL) x minute, whereas only two (11%) of the 18 without pulmonary injury had values above this level (P < .03). Thus, 12 (86%) of 14 patients with BCNU AUC greater than 600 (micrograms/mL) x minute developed lung injury. CONCLUSIONS These results suggest that BCNU exposure greater than 600 (micrograms/mL) x minute is associated with increased risk of acute lung injury after cyclophosphamide-cisplatin-BCNU therapy and may be a major cause of pulmonary drug injury following this regimen. IMPLICATIONS Strategies aimed at more uniform drug exposure or selective neutralization of chlorethylisocyanate, one of the two major hydrolysis products of BCNU, might reduce the incidence of acute lung injury following this regimen without major compromise of antitumor effect.
76 citations
TL;DR: The immunologic interactions between chemotherapy and IL‐2 and an outpatient interleukin‐2 regimen were assessed to improve the antitumor efficacy and assess the immunologic interacted with chemotherapy.
Abstract: Background. Based on prior experience with dacarbazine (DTIC) and an outpatient interleukin-2 (IL-2) regimen, the current study was conducted to improve the antitumor efficacy and assess the immunologic interactions between chemotherapy and IL-2.
Methods. Thirty-two patients were registered onto a treatment program, which included DTIC 750 mg/m2 with cisplatin 100 mg/m2, each by intravenous bolus on day 1. Recombinant IL-2 was administered on an outpatient basis intravenously by 15–30-minute infusion (24.0 × 106 IU/m2) daily on days 12–16 and 19–23 of a 28-day cycle for three cycles and then every 42 days for responding patients.
Results. There were responses in 13 of the 32 registered patients (41% response rate), including five complete and eight partial remissions. Responses in the liver, lung, spleen, lymph nodes, and soft tissue sites were noted. The median duration of response was 8.0 months (range, 3.0–20.0+ months), and the overall median survival duration was 10.2 months. Three patients (9%) are alive, free of disease, without any treatment at 32.0+, 36.0+, and 42.0+ months after initiation of treatment. Only minor nephrotoxicity was observed, and treatment delays were rare.
Conclusions. Additional chemotherapeutic, hormonal, or biologic agents may be added to enhance efficacy further if they have toxicities that do not overlap.
75 citations
TL;DR: It is indicated that cisplatin is an anticancer agent worthy of further testing in patients with unresectable hepatocellular carcinoma, and patients whose serum level of alpha-fetoprotein (AFP) was high before treatment, 6 showed a > 50% reduction in serum AFP levels after treatment.
Abstract: A phase 2 study of cisplatin was performed in 28 previously untreated patients with unresectable hepatocellular carcinoma. The drug was given intravenously at a dose of 80 mg/m2/day every 4 weeks. Of 26 patients evaluated, 4 (15.4%) showed partial responses lasting for > 3 months, while no patient achieved a complete response. Of 22 patients whose serum level of alpha-fetoprotein (AFP) was high (> 400 ng/ml) before treatment, 6 (27.3%) showed a > 50% reduction in serum AFP levels after treatment. The current study indicates that cisplatin is an anticancer agent worthy of further testing in patients with this disease.
66 citations
TL;DR: In this small patient sample, liposomal daunorubicin was an effective and well tolerated agent in the treatment of Kaposi's sarcoma, with few mild symptoms of toxicity.
62 citations
TL;DR: The dose and schedule of gemcitabine employed results in only a modest response rate in patients with advanced renal carcinoma, and investigators should be aware of the possibility of dyspnea and bronchospasm developing shortly after gem citabine administration.
TL;DR: The authors conducted a multicenter Phase II study of combination therapy with 5′‐DFUR and CDDP to evaluate the therapeutic usefulness of this regimen in the treatment of unresectable and advanced gastric cancers with primary foci.
Abstract: Background. 5′-Deoxy-5-fluorouridine (5′-DFUR, doxifluridine) is a recently developed prodrug of oral 5-fluorouracil (5-FU), which is used clinically in Japan for the treatment of gastric, colorectal, and breast cancer. 5-FU has been reported to act synergistically with cisplatin (CDDP) in experimental and clinical studies. The authors conducted a multicenter Phase II study of combination therapy with 5′-DFUR and CDDP to evaluate the therapeutic usefulness of this regimen in the treatment of unresectable and advanced gastric cancers with primary foci. None of the patients had previously undergone chemotherapy. Their ages ranged from 27 to 75 years and performance status was grade 0 to 3.
Methods. 5′-DFUR (1400 mg/m2/d) was administered orally on days 1 through 4 and 15 through 18, and CDDP (80 mg/m2/d) was injected intravenously on day 5. This treatment cycle was repeated every 4 weeks. An independent panel of specialists evaluated the clinical response.
Results. Fifty-one patients were studied. Clinical evaluation of response was possible in 43 patients who met the protocol requirements. The overall response rate was 50.0% (14 of 28, 95% confidence limits, 30.7%–69.4%) for patients with measurable lesions. The median duration of response was 5.2 months (156 days). The overall median survival time was 8.9 months (268 days) for evaluated patients. Therapeutic toxicity of World Health Organization (WHO) grade ≧ 3 was manifested as anorexia and nausea or vomiting in 20.9% and 18.6% of the patients, respectively. However myelotoxicity and nephrotoxicity of WHO grades 3 and 4 occurred in less than 10% of the patient group. No drug-related mortality occurred.
Conclusions. Combined therapy with 5′-DFUR and CDDP is a safe and effective treatment regimen for advanced gastric cancers with primary foci which stresses the patient's quality of life, especially when used in an outpatient setting.
TL;DR: The 3-week schedule seems as active as and less toxic than the weekly schedule, and no significant haematological toxicity, as usually reported with this drug, was observed.
TL;DR: A Phase II trial with a combination of recombinant IL‐2 (rIL‐2) and recombinant α‐IFN (α‐rIFN) in advanced RCC is initiated, with some evidence for additive or synergistic antitumoral activity of IL-2 and α-IFN in vitro and possibly in vivo.
Abstract: Background Both interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) have some efficacy in renal cell cancer (RCC) as single agents. Additionally, there is some evidence for additive or synergistic antitumoral activity of IL-2 and alpha-IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combination of recombinant IL-2 (rIL-2) and recombinant alpha-IFN (alpha-rIFN) in advanced RCC. Methods Thirty-six assessable patients with metastatic RCC were entered in this Phase II trial using a daily alternating schedule of alpha-rIFN and rIL-2. Over a period of 14 days, the patients received daily alternating treatment with 10 x 10(6) IU/m2 of recombinant alpha-2b-interferon subcutaneously and 18 x 10(6) IU/m2 of rIL-2 as a 1-hour intravenous infusion. This treatment schedule was repeated every sixth week up to a maximum of four cycles. After the second cycle, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with progressive disease were available for other strategies. Results Thirty-six patients entered the trial and were assessable for toxic effects. Thirty of 36 patients completed at least two cycles and were assessable for response. Nine patients achieved an objective response: 2 had complete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local relapse or bone metastases. A relapse-free survival length of 6 months or longer was seen in both patients with CR (12, 23 + months) and in four of seven patients with PR (6, 7, 12, 12 months). The toxicity was moderate and included fever and nausea in most patients, and hypotension, fatigue, skin rash, and arthralgia in a minority of the patients. No Grade 4 and only occasionally Grade 3 toxicity was observed. Fluid retention was negligible. The monitoring of immunologic parameters showed a significant rebound lymphocytosis including cytotoxic (CD56+) cells; in responders the peak of lymphocytosis occurred up to 1 week later than in nonresponders. Peripheral lymphocytes obtained after therapy showed only a slight increase of natural killer cell and lymphokine-activated killer cell activity. During therapy, there was a great release of secondary cytokines as tumor necrosis factor-alpha, gamma-interferon, and interleukin-6, with a peak level 2-4 hours after rIL-2 infusion. Conclusions In conclusion, daily alternating administration of alpha-rIFN and rIL-2 is effective in RCC with less toxicity, and the response rate is comparable to those of other immunotherapeutic schedules, including adoptive immunotherapeutic schedules, including adoptive immunotherapy and combinations of high-dose IL-2 and alpha-IFN.
TL;DR: Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity, with a lower than planned delivered dose-intensity, mainly due to mucositis.
Abstract: PURPOSEThe National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer.PATIENTS AND METHODSThe planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence.RESULTSMucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive.CONCLUSIONEdatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.
TL;DR: This new drug combination appears to be effective in advanced neuroblastoma, and its toxicity remains manageable, with no life-threatening complications.
Abstract: PURPOSEPatients older than 1 year with stage IV neuroblastoma who fail to achieve complete remission (CRem) have a particularly poor long-term prognosis. In an attempt to improve the outcome of these refractory patients, we tested a new drug combination.PATIENTS AND METHODSTwenty-nine children with advanced neuroblastoma (27 stage IV and two stage III) were entered onto this phase II study. All were refractory to conventional chemotherapy and had measurable disease at the time of the trial. The regimen was a combination of high-dose cyclophosphamide (2 g/m2/d) on days 2, 3, and 4, and etoposide (VP16; 50 mg/m2/d) by continuous intravenous (IV) infusion on days 1 to 5. A pharmacokinetic study of VP16 was conducted in eight patients to determine whether the goal of persistent plasma levels between 1 and 5 micrograms/mL was achieved.RESULTSPatients received a median of two courses, for a total of 58 courses. The median interval between each course was 32 days. In the 28 assessable patients, the overall respo...
TL;DR: Oral MIL is considerably toxic and has only marginal therapeutic activity in patients with colorectal cancer.
Abstract: Background: Treatment results in advanced colorectal cancer (CC) remain unsatis-factory and palliative, with 5-fluorouracil with or without calcium folinate being the only drug able to induce clinically acceptable response rates.Patients and Methods: A clinical phase II study is presented with an oral formulationof the phospholipid derivative miltefosine (MIL) in patients with advanced colorec-tal cancer. Patients were stratified according to pretreatment. Only non-pretreatedor pretreated patients who had received 5-fluorouracil with or without calcium folinate were accepted. MIL was given as capsule twice daily at a single dose of 50 mg for the 1st week with dose escalation to 150 mg (50 mg × 3) in the 2nd week and subsequently in case of good tolerability. Nine weeks were considered the minimal duration of treatment.Results: 54 patients were evaluable for toxicity and 44 were evaluable for response. A short-lived partial response was observed in one pretreated female patient with multiple lung lesions, a ‘no change’ status in 14 patients, including 8 nonpretreated patients (42%) and 6 pretreated patients (24%). Side effects were distinct, with loss of appetite, nausea and vomiting up to grade 4 WHO and weight loss of more than 5 kg in 3 months in a considerable number of patients. Furthermore, an increase of leukocyte and platelet counts was observed during the first 2 months of treatment. Conclusion: Oral MIL is considerably toxic and has only marginal therapeutic activity in patients with colorectal cancer.
TL;DR: The FLEP regimen is an active combination in advanced gastric cancer with moderate toxicity that warrants further testing in a phase III trial.
TL;DR: Oral administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma, and myelotoxicity was the most frequent observed toxicity.
Abstract: Piritrexim is a lipid-soluble antifolate which, like methotrexate, has a potent capacity to inhibit dihydrofolate reductase. We performed a multicentre phase II study with piritrexim in patients with locally advanced or metastatic breast cancer. Twenty-four patients of which sixteen had received prior chemotherapy, were initially treated with 25 mg piritrexim orally administered trice daily for four days, repeated weekly, with provision for dose escalation or reduction according to observed toxicity. Of twenty-one patients evaluable for tumour response, one patient achieved a partial response which lasted for 24 weeks. Three patients had stable disease during 12 weeks of treatment, seventeen had progressive disease. Pirtrexim was generally well tolerated, in eighteen patients the dose could be escalated. Myelotoxicity was the most frequent observed toxicity of this piritrexim regimen. Leucopenia and thrombocytopenia grade 3/4 occurred in 38% of the patients sometime during treatment. Pharmacokinetic analysis of piritrexim in three patients during the first treatment cycle, revealed peak levels 1 to 2 h after an oral dose, with a trend towards a higher peak plasma levels and AUCs on the fourth dosing day compared with the first dosing day. In conclusion, orally administered piritrexim appears to be a regimen with little activity in patients with locally advanced or metastatic breast carcinoma.
TL;DR: LND, a new drug with an innovative mechanism of action, might potentiate anticancer activity, without increasing toxicity, in patients with advanced non‐small cell lung cancer.
Abstract: Background. Combination chemotherapy with conventional antiproliferative drugs is becoming the treatment of choice for patients with advanced non-small cell lung cancer (NSCLC), a good performance status, and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anticancer activity, without increasing toxicity. Methods. In a Phase I1 study, 46 patients with advanced NSCLC were assigned to receive chemotherapy with the methotrexate, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (MACC) regimen, as originally described, plus LND, 150 mg orally, three times per day. Treatment was continued until progression of disease, occurrence of unacceptable toxic effects, or refusal by the patient (the median duration of MACC treatment was 6 weeks: 7 weeks for LND). Resuits. For the whole group of patients, actual dose intensities (DI) of MACC and LND were 95% and 67% of those projected (median values), respectively. There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient. On the contrary, there was no correlation between the duration of treatment with LND and its DI. The DI of LND and MACC were not correlated with each other. In all, seven objective responses (only partial responses) were observed. The overall median survival time was 42 weeks (confidence limits [CL], 20-52). The median survival length of patients receiving the full dose of LND (450 mg daily for at least 1 week) was 46 weeks (CL, 28-67), as compared with the median survival of 19 weeks (lower
Journal Article•
TL;DR: Mitomycin, ifosfamide, and cisplatin have demonstrated the best single-agent activity thus far in patients with non-small cell lung cancer (NSCLC), the most common malignant disease in the western world.
Abstract: Mitomycin, ifosfamide, and cisplatin have demonstrated the best single-agent activity thus far in patients with non-small cell lung cancer (NSCLC), the most common malignant disease in the western world. For this reason, we initiated a phase II study, giving these three agents in combination (designated MIC) to 74 patients with inoperable NSCLC. Sixty-six patients were evaluable for response, of whom 30 (45%) demonstrated a partial response and 7 (11%) a complete response. These results, along with those obtained in two other phase II trials of MIC in NSCLC, promoted us to begin a large-scale, multicenter, phase III study of MIC in patients with inoperable limited-stage NSCLC. In this ongoing study, patients have been randomized to receive treatment with MIC and radiotherapy or radiotherapy alone. We hope to resolve the issue of whether a survival advantage is conferred on NSCLC patients treated with radiotherapy in combination with this promising chemotherapeutic regimen.
TL;DR: Future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration, in view of fazerabine's narrow range of toxicities.
Abstract: Fazarabine (Arabinofuranosyl-5-azacytosine) is a synthetic pyrimidine nucleoside which combines the arabinose sugar of cytosine arabinoside with the triazine base of 5-azacytidine. It has demonstrated activity against a variety of human solid tumor xenografts including colon, lung and breast cancers. Eighteen patients with refractory metastatic colon cancer were enrolled in a phase II trial of fazarabine. The drug was administered as a 72 hr continuous infusion every 3–4 weeks; the starting dose was 2 mg/m2/hr as established in a previous phase I study. The major toxicity was neutropenia, as predicted from the phase I study. The median time to nadir for cycle 1 was 20 days, with a median granulocyte count of 437/μl (range 36–1600/μl); recovery was within 2–4 days, with only one incidence of fever and neutropenia in 42 cycles. Especially noted for their absence were thrombocytopenia, nausea, vomiting and stomatitis. No objective clinical responses were seen; one patient had stabilization of rapidly growing liver metastases for a period of 7 months. In view of fazarabine's narrow range of toxicities, future dose intensification trials utilizing fazarabine in combination with hematopoietic growth factors are worthy of consideration.
TL;DR: 10-EDAM is an inactive agent in metastatic melanoma and this multicentre phase II study to determine the efficacy and toxicity of this agent in patients with metastatics melanoma found no objective responses and 1 toxic death.
TL;DR: This schedule of the combination of cisplatin and methotrexate did not improve response rate or survival compared with previous studies of this two-drug combination.
TL;DR: Toxicity, predominantly hematologic with significant neutropenia and thrombocytopenia, was quite severe and it is concluded that this drug is not active against adenocarcinoma of the pancreas.
Abstract: Amonafide is a new synthetic anticancer agent whose mechanism of action is through inhibition of macromolecular synthesis as well as DNA intercalation. The Southwest Oncology Group (SWOG) has investigated this drug in a phase II study of pancreas cancer. Thirty-six patients were registered on this study: of these 29 were eligible for response evaluation, and 20 received the two cycles required for making a response assessment. Patients met the standard phase II criteria of no prior chemotherapy, measurable disease and a SWOG performance status of 2 or less. Toxicity, predominantly hematologic with significant neutropenia and thrombocytopenia, was quite severe. Four treatment related deaths were encountered. No responses were seen in thirty-six patients studied. We conclude that this drug is not active against adenocarcinoma of the pancreas.
TL;DR: The bioreductive alkylating agent porfiromycin may be safely administered at a dose of 40 mg/M2 to patients undergoing radiation therapy for squamous cell carcinoma of the head and neck.
Abstract: Purpose: A phase I toxicity trial aimed at defining an appropriate dose of the bioreductive alkylating agent porfiromycin to be used in conjunction with radiation therapy in patients with squamous cell carcinoma of the head and neck. Methods and Materials: A total of 21 patients were entered into this phase I clinical trial. All patients had locally advanced squamous cell carcinoma of the head and neck and were treated with radiation therapy with or without surgical intervention. Porfiromycin was administered on days 5 and 47 of the course of radiation therapy. The initial dose of the drug was 50 mg/M2, but due to hematological toxicity the dose was lowered to 40 mg/M2. The final 12 of the 21 patients in this phase I clinical trial was treated at the dose of 40 mg/M2. Radiation therapy was directed at the primary site and regional lymph nodes as clinically indicated with conventional fractionations of 200 cGy/day to total doses in excess of 6,000 cGy. Results: Five patients were treated at the initial dose of 50 mg/M2, but due to excessive hematologic toxicity the dose was reduced to 45 mg/M2 for 4 patients and lowered again to 40 mg/M2 for the final 12 patients of the study. As expected, the major toxicity was hematological with thrombocytopenias and neutropenias. There were no clinically evident bleeding episodes secondary to thrombocytopenia and no neutropenic deaths during the course of the study. Of the 21 patients treated in the series, 10 remain alive no evidence of disease (NED) with a median follow-up of 18.5 months. Four of the alive NED patients have been followed for over 2 years. Conclusions: The bioreductive alkylating agent porfiromycin may be safely administered at a dose of 40 mg/M2 to patients undergoing radiation therapy for squamous cell carcinoma of the head and neck. Based on the results of this phase I trial, we have now mounted a phase III clinical trial in patients with all stages of squamous cell carcinoma of the head and neck, comparing radiation therapy with porfiromycin to radiation therapy with mitomycin C. There is no radiation therapy without drug in this phase III clinical report. © 1994 Wiley-Liss, Inc.
TL;DR: This intensive course treatment with three anticancer agents appears to promote the regression of gastric, lung, and gynecologic cancers.
Abstract: This phase II study was designed to assess the therapeutic potential of intensive course treatment with three anticancer agents: 50 mg of cisplatin on day 1, 40 mg/m2 of epirubicin on day 2, and 250 mg of 5-fluorouracil on days 2 through 5. Drug courses were repeated every 2 weeks and most patients received between 4 and 6 courses. Thirty-five patients with measurable advanced solid cancers entered the study. They consisted of 16 gastric, 5 colorectal, 4 gallbladder, 3 pancreatic, 3 lung, 2 esophageal, 1 uterine, and 1 ovarian cancers. Of the 35 patients, 29 were evaluated for therapeutic effect of the regimen, and the overall response rate was 31.0% (5 CR + 4 PR/29). A 33.3% rate of tumor regression, consisting of 2 complete responses (CR) and 3 partial responses (PR) out of 15 patients (2 CR + 3 PR/15), was seen for gastric cancers. For the other types of tumors the responses were achieved in 2 lung cancers (1 CR + 1 PR/3). 1 uterine cancer (1 CR/1), and 1 ovarian cancer (1 CR/1). The esophageal, colorectal, pancreatic, and gallbladder cancers were unresponsive to this regimen. Toxicities of the drug treatment were clinically tolerable and consisted of general malaise, nausea, vomiting, stomatitis, alopecia, and leucopenia. However, two patients died of uncontrollable metabolic acidosis after 1 and 2 courses, respectively. This intensive course treatment appears to promote the regression of gastric, lung, and gynecologic cancers.
TL;DR: The Early Breast Cancer Trialists' Collaborative Group overview analysis confirmed the benefits of both polychemotherapy and tamoxifen in broad subgroups of patients, and it remains a challenge, however, to quantify the risk of relapse and the benefit of therapy for individual patients.
Abstract: The use of systemic (drug) therapy postoperatively reduces the risk of relapse and death for patients with resectable invasive breast cancer. The Early Breast Cancer Trialists' Collaborative Group overview analysis confirmed the benefits of both polychemotherapy and tamoxifen in broad subgroups of patients. It remains a challenge, however, to quantify the risk of relapse and the benefit of therapy for individual patients. If the ipsilateral lymph nodes are free of metastases and the tumor is infiltrating ductal or lobular in histology and less than 1 cm in diameter, the risk of relapse is low, so the benefits of standard treatments are too small to warrant routine use. For node-negative patients with larger tumors or for those with positive lymph nodes, the benefits of therapy are significant, although many of these individual patients will not relapse. Hence, better prognostic methods, improving the accuracy of predicting an individual patient's risk, could allow for more rational treatment recommendations. The most widely used polychemotherapy combination incorporates three drugs: cyclophosphamide, methotrexate, and fluorouracil. The substitution or inclusion of doxorubicin, which is somewhat more toxic than the cyclophosphamide, methotrexate, and fluorouracil regimen, is justifiable in subsets of patients at higher risk of relapse, eg, those with metastatic involvement of four or more axillary lymph nodes. Because higher dose intensity (the amount of drug given per unit time) of chemotherapy improves relapse-free survival, phase II clinical trials are testing various dose-intensification strategies, and phase III trials are underway to determine their comparative efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)