Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies

This phase I study wasconducted to determine the dose limitingtoxicity, maximum tolerated doses, andrecommended phase II doses of thecombination of JM-216 and paclitaxel. Patients received paclitaxel intravenouslyover one hour on day 1 of each cycle. OralJM-216 was administered on days 1–5starting after the paclitaxel infusion. Cycles were repeated every 21 days. Patients were accrued at nine differentdosing combinations. JM-216 doses rangedfrom 10–80 mg/m²/day and werecombined with paclitaxel doses of 150, 175,or 200 mg/m². Forty-three patientswere treated with 146 cycles of therapy. Dose-limiting toxicity, consisting offebrile neutropenia and grade 3thrombocytopenia, was encountered in 2patients at the seventh dose level (JM-21680 mg/m²/day + paclitaxel175 mg/m²). Two intermediate doselevels were explored. The first level(JM-216 70 mg/m²/day + paclitaxel175 mg/m²) produced dose-limitingthrombocytopenia in 1 of 6 patients. However, two additional patients alsodemonstrated delayed recovery fromthrombocytopenia following treatment. As aresult, a second intermediate dose level(JM-216 60 mg/m²/day + paclitaxel200 mg/m²) was filled with sixpatients. No dose-limiting toxicities werereported in any patients at this doselevel. The combination of oral JM-216 andpaclitaxel is well-tolerated with minimalnon-hematologic and reversible hematologictoxicity. The recommended dose for phaseII study is JM-216 60 mg/m²/day for 5days and paclitaxel 200 mg/m² on day 1repeated every 21 days. Higher doses ofJM-216 are associated with more severethrombocytopenia and delayed hematologicrecovery resulting in subsequent dosingdelays.     

5-Fluorouracil vs. epirubicin vs. 5-fluorouracil plus epirubicin in advanced gastric carcinoma

From January, 1985, through January, 1987, 165 patients with advanced gastric cancer were randomized to receive epirubicin (E) alone (90 mg/m² day 1), 5-Fluorouracil (5-FU) alone (500 mg/m² days 1–5), or the combination of E (90 mg/m² day 1) and 5-FU (400 mg/m² days 1–5). Courses were repeated every four weeks. Patients were stratified by extent (locally advanced vs. metastatic), evaluability (measurable vs. non-measurable) and by history of prior radiotherapy (yes vs. no). Randomization to single arm epirubicin was stopped after 26 patients were enrolled. Objective responses occurred in only 1/16 (6%) of the patients treated with E alone, 1/40 (5%) with 5-FU alone and 4/33 (12%) with both 5-FU and E. There were no significant differences in all eligible patients with respect to time to progression or overall survival in the three treatment arms. Toxicity was primarily hematologic and more pronounced in the combination arm. Neither 5-FU alone, epirubicin alone, or the combination have a major impact in the treatment of gastric carcinoma.     

Gemcitabine and mitoxantrone in metastatic breast cancer: A phase-I-study

Background: Gemcitabine and mitoxantrone are active agents for the treatment of metastatic breast cancer. Due to different modes of action and a favorable toxicity profile they are suitable for combination therapy. This phase I trial was initiated to determine the optimal doses for the combination in patients with metastatic breast cancer. Secondary objectives included the evaluation of the safety and efficacy of the regimen. Patients and methods: Patients with metastatic breast cancer were treated with gemcitabine (1000–1400 mg/m²) on days 1, 8 and 15 and mitoxantrone (10–14 mg/m²) on day 8. Treatment was repeated every 4 weeks for a maximum of 8 cycles. Doses were assigned at registration according to the escalation scheme. Results: Twenty-six patients received a total of 93 cycles at 5 different dose levels. The maximum tolerated doses were 1200 mg/m² gemcitabine and 14 mg/m² mitoxantrone with grade 4 neutropenia being the dose limiting toxicity. Recommended phase II doses, however, are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m² based on a similar median dose intensity and a more favorable toxicity profile. Predominant toxicity was myelosuppression. Most common non-hematological toxicities were nausea, vomiting, alopecia and elevation of liver enzymes. Twenty-one patients were assessable for response. Four patients achieved a partial response accounting for an overall response rate of 19%. In addition, 12 patients (57%) had stable disease and 5 patients (24%) failed to response to the treatment. Median duration of response and duration of clinical benefit were 14 and 9 months, respectively. Conclusion: In this phase I study of gemcitabine and mitoxantrone, the DLT was neutropenia. Recommended phase II doses are gemcitabine 1200 mg/m² and mitoxantrone 12 mg/m².     

A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma

Summary Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patients with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of 6S-LV, 20 patients were randomly assigned to receive either 250 mg/m² 6S-LV or 500 mg/m² 6R,S-LV as a 2 hour IV infusion on day –2, and the other preparation on day –1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Cl_p, C_max, or terminal phase t_1/2 of 6S-LV. The overall response rate was 40% (C.I. 23–60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p=0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.     

A phase II trial of interferon alpha-2A plus fluorouracil in advanced renal cell carcinoma

Summary In vitro studies have documented the synergistic activity of interferon (IFN) and fluorouracil (5-FU) in human cancer cell lines, and recent clinical trials have demonstrated the efficacy of this combination in metastatic colon cancer. The current study was undertaken to evaluate the combination of IFN alpha-2a plus 5-FU in previously untreated patients with metastatic renal cell carcinoma. From May 1990 through August 1990, 14 patients with metastatic renal cell carcinoma were treated with 5-FU 750 mg/m² day continuous infusion IV days 1–5, followed by weekly IV infusions of 5-FU 750 mg/m² beginning on day 12. Patients concurrently received IFN alpha-2a 9×10⁶ IU subcutaneously 3 times per week beginning on day 1. The median age of patients treated was 57 (range 38–80) with a median Karnofsky performance status of 90 (range 60–100). Sites of metastases included lung only in 6 patients, liver only in 1 patient, 1 patient had bilateral disease at presentation, and the remaining patients had multiple sites of metastases. The median duration of therapy was 2 months. The predominant toxicities seen were stomatitis, nausea, flu-like symptoms and neurotoxicity. The only grade IV toxicity observed was severe vomiting in 1 patient, though 5 patients discontinued therapy within 2 months because of poor subjective response. With a minimum follow-up of 13 months no objective responses were seen. Thirteen of the 14 patients have had progressive disease and 11 have died. The median time to progression was 2 months (range 0.5–6 months) and the median survival was 5 months (range 2–14.5+months). We conclude that at this dose and schedule, IFN alpha-2a plus 5-FU is ineffective in the treatment of advanced renal cell carcinoma.From the Hoosier Oncology Group, the Walter Cancer Institute, Indianapolis, Indiana and the Department of Medicine, Indiana University, Indianapolis, USA.     

Mitoxantrone in refractory acute leukemia in children: A phase I study

Summary Nine children with acute non-lymphocytic leukemia (ANLL), ages 16 months to 16 years (median 7 years), and 15 children with acute lymphocytic leukemia (ALL), ages 10 months to 18 years (median 5 years), were treated with 5-day courses of mitoxantrone (Novantrone®; dihydroxyanthracenedione) as induction therapy. All the children had leukemia which was resistant to conventional therapy and all but one patient had received anthracycline therapy prior to the initiation of this trial. Three patients (two with ANLL, one with ALL) received the drug at a dose of 6 mg/m²/day i.v. for 5 days. Both patients with ANLL achieved partial remissions (PR) (105 and 87 days duration). The child with ALL failed to respond to two courses of the drug, and died of progressive disease 45 days after the institution of therapy. Twenty-one patients (14 with ALL, seven with ANLL) were treated with 8 mg/m²/day i.v. mitoxantrone for 5 days. There were three early deaths (all ALL) which were not felt to be secondary to drug toxicity. Four of the 18 children achieved complete remission (CR) (one ANLL — 35 days; three ALL — 39, 31 and 13 days). One child with ANLL achieved a PR (13 days) and one child with ALL showed improvement in his bone marrow status. Twelve children failed to respond to this therapy.Dose-limiting toxicity was not seen among the patients who received 6 mg/m²/day for 5 days. There were five patients who had mucositis and one patient who had nausea and vomiting among those patients who received 8 mg/m²/day for 5 days. Four of these children had significant decreases in the myocardial shortening fraction as measured by echocardiography. None of these patients had clinical signs of cardiotoxicity.The CR plus PR rate for both dose levels is 33%. Mitoxantrone appears to be an effective agent for remission induction in children with late stage ALL and ANLL. Toxicity was not a significant problem at the doses used in this trial.     

Leucovorin, 5-fluorouracil,and gemcitabine: A phase I study

Gemcitabine is a chemotherapy agent with efficacy in the treatment of lung, pancreas, bladder and breast cancer. It inhibits DNA synthesis by interfering with cytidine triphosphate production and also inhibits the activity of ribonucleotide reductase. Gemcitabine may potentiate fluorouracil's inhibition of thymidylate synthase. This inhibition would be expected to be sequence dependent, occurring only if gemcitabine were administered following fluorouracil (5FU).The combination of leucovorin, 5-FU, and gemcitabine was assessed in this phase I trial. Eligibility requirements included refractory solid tumor malignancy; adequate hematologic, renal and hepatic reserve; no prior therapy with the combination of leucovorin and 5FU, or with gemcitabine; ECOG performance status 0–2, and signed informed consent.Eleven men and nine women were eligible. The median age was 52.5 years and the median performance status was 1. All but three patients had prior chemotherapy. The starting doses were leucovorin 20 mg/m², 5FU 255 mg/m² and gemcitabine 600 mg/m². 5FU and gemcitabine were escalated in tandem to 340 mg/m² and 800 mg/m² and thereafter to 425 mg/m² and 1000 mg/m², respectively. Gemcitabine administration always followed that of 5FU by 30 minutes. The median number of cycles was 2 (range 1–32). Two patients at the starting dose had disease progression within the first cycle with one death on day 28. One patient with cholangiocarcinoma had a partial response and remained on study for 40 months. There were no other responses.The maximum tolerated dose is leucovorin 20 mg/m², 5FU 340 mg/m², and gemcitabine 800 mg/m². The impact of drug sequence remains undetermined.     

Phase I study of combined alpha Interferon,alpha difluoromethylornithine (DFMO), and doxorubicin in advanced malignancy

Interferon (IFN) and conventional cytotoxic chemotherapeutic agents have been successfully combined in various studies. Alpha difluoromethylornithine (DFMO) is a novel antitumor agent which is an inhibitor of polyamine metabolism. A phase I study of IFN 24 × 10⁶ U/m²/day IM (days 3–7), DFMO 9 gm/m² p.o. daily (days 1–7), and a variable dose of doxorubicin starting at 20 mg/m² (day 6), of each 28 day cycle was performed. The aim of the study was to determine the maximally tolerable dose of doxorubicin in this combination. Three patients were treated with doxorubicin at 20 mg/m² and six patients at 40 mg/m². The dose limiting toxicities were neutropenia, fatigue and fever. All other toxicities were mild and there was no grade IV toxicity. A doxorubicin dose of 40 mg/m² produced tolerable toxicity and is recommended for phase II studies. No major antitumor effects were seen.     

Multiple resistance modulators combined with carboplatin for resistant malignancies: A pilot study

Background: Chemotherapy resistance is probably multifactorial; hence, we assessed the feasibility of adding to carboplatin 6 concurrent resistance modulators in 53 patients with resistant cancers.Methods: Pentoxifylline and dipyridamole were added to carboplatin 400 mg/m² in cohort 1, and metronidazole was also given in cohort 2. Mannitol and saline were administered in each cohort with the theoretical objective of improving carboplatin delivery to tumors by reducing blood viscosity. Because of excessive toxicity in cohort 2, cohort 3 received the same modulators as in cohort 2 but with a reduced dose of carboplatin (200 mg/m²). Subsequent patients had the following drugs added to those in the previous cohort: novobiocin (cohort 4), tamoxifen (cohort 5), ketoconazole (cohort 6). Cohort 7 patients received the 6 cohort 6 modulators along with carboplatin 300 mg/m².Results: Thrombocytopenia was excessive in early cohorts with a carboplatin dose of 400 mg/m², but was minimal at lower doses. Other toxicity was generally tolerable and reversible, particularly at carboplatin doses 300 mg/m², although gastrointestinal and neurological toxicity tended to worsen as additional modulators were added. No major responses (but 4 minor responses) were seen in this patient population with heavily pretreated or primarily resistant cancers.Conclusions: Acceptable doses for phase II studies are carboplatin 300 mg/m², 20% mannitol 250 ml plus normal saline 500 ml over 1 hr prior to carboplatin, pentoxifylline 700 mg/m²/day p.o. from 3 days before carboplatin to cessation of therapy, dipyridamole 100 mg/m² p.o. q6h × 6 days starting 24 hr before carboplatin, metronidazole (750 mg/m² p.o. 12 hr and immediately before, and 24 hr after carboplatin; 250 mg/m² suppository p.r. 12 hr and immediately before, and 6 and 24 hr after carboplatin; and 500 mg/m² i.v. right after carboplatin), novobiocin 600 mg/m² p.o. q12h × 6 days starting 24 hr before carboplatin, and tamoxifen 100 mg/m²/day plus ketoconazole 700 mg/m²/day × 3 days starting the day before carboplatin, with oral dexamethasone and ondansetron as antimetics.     

Trimetrexate in advanced carcinoma of the esophagus

Summary Twenty-four patients with advanced epidermoid carcinoma of the esophagus were treated with trimetrexate (TMTX), a lipid soluble non-classical antifol. Patients were given TMTX 8 mg/m² intravenously day 1–5 every 28 days. In nine of these patients the dose was escalated to 12 mg/m² day 1–5 every 28 days. Three patients had a partial response (95% confidence limit 3–32%) with a median response duration of 14 weeks. No hematologic toxicity was documented. Two patients developed moderate stomatitis and only 3 patients experienced any nausea or vomiting. The median survival of all patients is 12 weeks. It is concluded that a higher dose of TMTX should be studied in patients with esophageal cancer in order to assess the true therapeutic value of the agent at a dose closer to the median tolerated dose. A phase II ECOG study using TMTX 12 mg/m² intravenously day 1–5 every 21 days is currently being conducted.     

Radioimmunoassay for mitoxantrone,a new antitumor agent

A sensitive and specific radioimmunoassay for mitoxantrone in serum has been developed. The procedure allows direct measurement of mitoxantrone in unextracted serum samples, by using antisera from rabbits immunized with mitoxantrone-BSA antigen. Tritiated mitoxantrone of high specific radioactivity (ca. 15 Ci/mmol) was used as a radio-tracer ligand. The assay allows the detection of as little as 50 pg/ml and the quantitation of 75 pg/ml in 0.5 ml serum samples. Standard curves were linear in the concentration range of 75–2500 pg/ml, at antiserum dilutions of 1:15,000. The assay shows good reproducibility: coefficients of variation of 3–6% were obtained by analyzing five samples/concentration at 75, 100, 250, 500, and 1000 pg/ml. There was no cross reactivity with the major metabolite in human serum, having concentrations of up to 10,000 pg/ml. Serum samples collected at various time intervals from rats dosed intravenously with mitoxantrone (0.5 mg/kg), were analyzed for unchanged mitoxantrone by RIA. The drug concentrations decreased from 32 ng/ml at 0.5 h to 0.45 ng/ml by 24 h after dosing.Mitoxantrone, a dihydroxyanthracenedione derivative (1), is an antitumor agent currently used in clinical trials with very encouraging results, especially in metastatic breast cancer, and low incidence of adverse reactions (2–4). The drug is being administered intravenously at doses up to 14 mg/m². Preliminary pharmacokinetic studies (to be published separately) indicate rapid distribution, followed by slow clearance rates from the tissues.The sensitivity of the currently available (HPLC) methods (5, 6) is of about 5–20 ng/ml in serum. The purpose of this work was to develop a more sensitive method, such as radioimmunoassay, which can be utilized in pharmacokinetic studies to measure mitoxantrone levels in biological fluids, over extended periods of time after dosing.

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Phase I trial of mitoxantrone and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with advanced solid malignancies

SummaryPurpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of high-dose mitoxantrone and document the toxicities and side effects of mitoxantrone when administered with GM-CSF.Patients and methods Twenty-three patients with advanced solid tumors were entered into a phase I and pharmacokinetic study. Mitoxantrone was administered at doses of 12, 21, 28, 32, 37, and 48 mg/m² on day 1; GM-CSF (5 g/kg once or twice daily) was administered on days 2 to 14. Therapy was repeated every 3 weeks. Dose escalation continued in sets of three patients until the dose limiting toxicity (DLT) was observed. The DLT was based on hematologic, non-hematologic, and cardiac toxicity, and delay of therapy by more than 1 week due to toxicity. Plasma samples were assayed for mitoxantrone concentrations using high performance liquid chromatography (HPLC).Results Twelve patients required either mitoxantrone dose reductions or delays. DLT of neutropenia was observed at a mitoxantrone dose of 48 mg/m²/day. Therefore, we conclude the MTD was 37 mg/m²/day. Myelosuppression appeared to be cumulative. Two patients were withdrawn from the study due to a drop in left ventricular ejection fraction (LVEF). Two of 23 patients experienced a partial response. The mean area under the curve (AUC) and peak mitoxantrone levels increased linearly with dose; triexponential elimination of mitoxantrone was observed. No statistically significant correlation was observed between either peak mitoxantrone level or AUC and duration of absolute neutrophil count (ANC) < 500/mm³.Conclusion The use of GM-CSF allows administration of mitoxantrone at a dose greater than three times that given in standard therapy; treatment is well tolerated. Further studies are needed to determine whether mitoxantrone has cumulative cardiac or hematologic toxicity.     

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

Summary The limiting toxicity of low dose continuous infusion 5-fluorouracil (200–300 mg/m²/day) is often palmarplantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42% –82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m²/day until toxicity or progressive disease forced discontinuation.The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42–92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6–61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups.Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.The five previously untreated patients who received pyridoxine for PPE continued 5-FU for a median of 6 months after development of the syndrome. The six previously untreated patients who did not receive pyridoxine when they developed PPE were able to continue 5-FU for a median of only 2.5 months after development of the syndrome. A similar number of clinical responders to 5-FU were present in both groups.Considering the high incidence of PPE and response in previously untreated colon cancer patients who receive protracted continuous 5-FU, prophylactic pyridoxine in conjunction with this treatment modality might be useful.     

Phase I study of eniluracil,oral 5-fluororacil and gemcitabine in patients with advanced malignancy

Purpose: The objectives of this trial wereto assess the maximal tolerated dose andtoxicity of the combination of oraleniluracil and 5-fluorouracil andintravenous gemcitabine. Patients and methods: Patients withhistologically confirmed, incurablemalignancy (solid tumor or lymphoma)refractory to standard therapy or for whichno standard therapy exists were enrolled. The treatment plan consisted of weeklygemcitabine for three weeks with twicedaily dosing of 5-FU and eniluracil for 21days beginning on day one of gemcitabine. Cycles repeated on an every four weekschedule. The initial cohort receivedgemcitabine 800 mg/m², oral 5-FU 0.6 mg/m²and eniluracil 6.0 mg/m². Results: Twenty-six patients were enrolled. Eight patients received less than 2 cyclesof therapy. Hematologic andgastrointestinal toxicity predominated,with 48% of courses resulted in grade oneor two neutropenia. Hematologic toxicitywas dose limiting. One treatment relateddeath occurred. Conclusions: The combination of eniluracil,5-fluorouracil and gemcitabine offers anoral alternative for 5-FU administration.The recommended phase II dose isgemcitabine 1000 mg/m², 5FU 1.2 mg/m² andeniluracil 12 mg/m².     

A phase I pharmacokinetic study of the P-glycoprotein inhibitor,ONT-093, in combination with paclitaxel in patients with advanced cancer

Background: ONT-093 is an orally bioavailable inhibitor of P-glycoprotein (P-gp). In pre-clinical studies, ONT-093 could inhibit P-gp and reverse multidrug resistance at nM concentrations with no effect on paclitaxel pharmacokinetics. Phase I trials of ONT-093 in normal human volunteers showed no dose-limiting toxicities at serum concentrations associated with biologic activity achieved with doses ranging from 300 to 500 mg. Methods: Phase I pharmacokinetic trial of ONT-093 in doses from 300 to 500 mg administered before and after intravenous paclitaxel doses of 150 to 175 mg/m² repeated every 21 days. All patients received paclitaxel alone on cycle 1. Results: 18 patients were enrolled onto 4 dose levels. Toxicity of the combination included neutropenia, arthralgia, myalgia, and peripheral neuropathy. Four of 6 patients receiving 500 mg doses of ONT-093 and paclitaxel at 175 mg/m² (dose level 4) had higher-grade neutropenia with cycle 2, with 1 patient experiencing febrile neutropenia. Plasma pharmacokinetic parameters of paclitaxel were unchanged between cycle 1 and 2 for dose levels 1 to 3, but at dose level 4, 45–65% increases in paclitaxel AUC were observed in 4 of the 6 patients. Mean C_max of ONT-093 was 9 μM (range 5–15 μM) which were 3- to 5-fold higher than in single agent studies of ONT-093. Conclusions: Doses of ONT-093 achieving serum concentrations associated with biological activity were well tolerated in combination with standard doses of paclitaxel. Toxicities of the combination in this schedule were mainly attributable to paclitaxel and dose-limiting toxicity was limited to febrile neutropenia. There was an apparent pharmacokinetic interaction between paclitaxel and ONT-093, possibly related in part to the excipient, Cremophor, present in the paclitaxel formulation.     

Phase I trial of fluorouracil modulation by n-phosphonacetyl-l-aspartate and 6-methylmercaptopurine ribonucleoside (MMPR), and leucovorin in patients with advanced cancer

The results of several clinical trials support the hypothesis that biochemical modulation may enhance the antitumor activity of 5-Fluorouracil (5-FU). We have performed a phase I trial using a combination of three different biochemical modulators at the optimal dose established in previous clinical trials. The modulators include: phosphonacetyl-l-aspartate (PALA), which may increase 5-FU incorporation into RNA; leucovorin, which potentiates thymidylate synthase inhibition; and 6-methylmercaptopurine riboside (MMPR), which promotes the intracellular retention of fluorinated nucleotides. The treatment regimen consisted of PALA 250 mg/m² day 1, followed 24h later by MMPR 150 mg/m² as an iv bolus, and the initiation of a 24 hour infusion of 5-FU along with leucovorin 50 mg/m². This regimen was repeated weekly. Doses of 5-FU were escalated in cohorts of four or more patients from 2,000 to 2,600 mg/m². Among 20 patients entered, the majority had colorectal cancer, and most had received prior 5-FU treatment. Toxicity was predominantly gastrointestinal, and diarrhea was dose-limiting at a 5-FU dose of 2600 mg/m². There were three partial remissions observed, two of whom had colorectal cancer. Emerging data that casts doubt on the modulation value of PALA at this dose and schedule suggests that revision of this regimen be considered before Phase II trial.     

Raltitrexed (tomudex) administration in patients failing multiple prior chemotherapy regimens in advanced colorectal cancer: a pilot study

Purpose: To evaluate efficacy of Raltitrexed, a specificthymidilate synthase inhibitor, in patients with advancedcolorectal cancer (ACC) failing multiple prior chemotherapyregimens (e.g. 5-FU+LV, CPT-11, etc). Methods: 20 patients with ACC; 13 males/7 females,median age 64 (range: 53–69), median Karnovsky PS: 80 (70–90), and sites of metastases; liver: 16, lung: 6, lymph nodes:9, peritoneal: 8 and a life expectancy of at least 3 months,were entered in the present pilot study of Raltitrexedadministration. All patients had progressed after priorchemotherapy with 5-FU+LV and subsequently CPT-11, and somehad received further infusional 5-FU. Raltitrexed wasadministered at a dose of 3 mg/m² i.v. every 21 days. Results: 3 patients obtained stable disease (SID), 15%,with tumor marker decline (CEA, CA-19.9). Time-to-progressionwas 4.8 months (2.2–7) and survival 7.4 months (6.0–7.8).Toxicity was in general not severe and consisted mainly ofmyelosuppression; neutropenia (WHO) grade 2: 45% and grade 3:22%, and anemia grade 1–2: 40%. Conclusion: Response to treatment with Raltitrexed islimited in patients with ACC failing multiple priorchemotherapy regimens, however, a limited percentage ofpatients with SD derived clinical benefit.     

Phase I–II trial of mitoxantrone in acute leukemia: an interim report

Summary We evaluated the effect of mitoxantrone (Novantrone®; dihydroxyanthracenedione) in the treatment of refractory acute leukemia and acute leukemia in relapse. In this study, 70 patients are currently evaluable. Of the 25 patients who received mitoxantrone 10 mg/m² × 5, two of 10 with ANLL in relapse, one of five with ALL in relapse achieved complete remission, and one of seven with blastic phase CML responded. At a dose of 12 mg/m² × 5, nine of 22 patients with ANLL in relapse, one of five patients with blastic phase CML and none of the nine patients with ALL responded. At this dose all remissions occurred after one course of treatment. None of the patients with ANLL or ALL refractory to primary therapy achieved a remission. Toxicities encountered with both dose levels were comparable. However, second courses at 12 mg/m² × 5 led to severe stomatitis and prolonged cytopenia. We conclude that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m² per day × 5 is the optimal dose schedule. A randomized trial comparing daunorubicin with mitoxantrone in combination with cytarabine in untreated patients with ANLL should answer whether mitoxantrone is less toxic and whether it should replace daunorubicin in standard induction therapy in ANLL.See Table 1     

A phase I and pharmacokinetic study of VNP40101M,a new alkylating agent,in patients with advanced or metastatic cancer

Summary Purpose: VNP40101M is a new alkylating agent that demonstrated broad anti-tumor activity in murine tumor models. A phase I trial was initiated to determine the toxicities, maximum tolerated dose, and pharmacokinetics of VNP40101M by short IV infusion. Study design: The starting dose was 3 mg/m² every four weeks, and was escalated in successive cohorts as follows: 6, 12, 24, 40, 60, 80, and 100 mg/m². Beyond 100 mg/m², dose increments were 25%. Initially, 1–2 patients were assigned to a dose level. Intra-patient dose escalation was permitted. With the first instance of a drug-related grade 2 adverse event, all dose levels required assessment of 3–6 patients. Pharmacokinetic parameters were assessed in the first cycle and any cycle with a change in dose. Results: Twenty-six patients in 13 dose levels ranging from 3–305 mg/m² were evaluated. Dose-related thrombocytopenia was the major toxicity, with the nadir occurring at a median of day 27. At 305 mg/m², six of eight patients developed grade 3 thrombocytopenia, including one event that met the definition for DLT. Other dose-related toxicities included moderate granulocytopenia, anemia, and a mild infusion-related syndrome consisting of acute headache and facial flushing. The granulocyte nadir occurred at a median of day 34, and recovery of both thrombocytopenia and neutropenia to < grade 2 occurred at a median of day 43. VNP40101M peak plasma concentrations and AUC were linear with dose. The elimination half-life was short and estimated to be approximately 15 minutes. Conclusions: The MTD and recommended dose for phase II trials is 305 mg/m² every six weeks. Phase II trials in less heavily pre-treated patient populations are warranted.Supported by Vion Pharmaceuticals, Inc.     

A phase I clinical trial of spicamycin derivative KRN5500 (NSC 650426) using a phase I accelerated titration "2B" design

The spicamycin derivative KRN5500 was considered as a potential anti-cancer agent based on in vitro and preclinical studies. A Phase I study involving 24 cancer patients in whom tumors were refractory to all other conventional therapies was conducted to determine the dose limiting toxicity, maximum tolerated dose, effectiveness, and pharmacokinetic parameters of this drug administered by 1-h IV infusion daily for five consecutive days every 3 weeks. Using an accelerated dose titration strategy, 8.4 mg/m²/d × 5 days was the maximum administered dose. Severe gastrointestinal and hepatic toxicities were observed at doses at or above 4.3 mg/m²/d × 5. The recommended Phase II dose is 4.3 mg/m²/d × 5. The distribution of KRN5500 followed a two-compartment model, and clearance did not decrease significantly over the dose range 0.8–8.4 mg/m²/d × 5. No significant correlation was observed between plasma levels and toxicity. No tumor responses were observed among the 14 patients evaluable for response.