Dose-limiting Toxicities In Cycle Research Articles

A phase I, pharmacokinetic and pharmacodynamic dose escalation trial of weekly paclitaxel with interferon-α2b in patients with solid tumors

Paclitaxel and interferon have demonstrated anti-angiogenic activity in vitro and in vivo. The toxicity, pharmacokinetics, and pharmacodynamics of paclitaxel with interferon-alpha2b (IFN-alpha2b) were assessed in patients with solid tumors to assess the feasibility of this novel anti-angiogenic regimen. IFN-alpha2b (1 million units) was administered twice daily by subcutaneous injection. Paclitaxel was given weekly over 1 h starting at 30 mg/m2 and increased to 50 mg/m2. Cycles were repeated every 4 weeks. Nineteen patients with a variety of solid tumors were enrolled. Dose-limiting toxicity in cycle 1 was observed at 50 mg/m2. Eleven patients were treated at 40 mg/m2 with no undue toxicity. Pharmacokinetic parameter comparison studies were completed in 11 patients who received days 1 and 29 paclitaxel. Mean paclitaxel clearance and area under the curve (0-infinity) were not statistically different from days 1 to 29. There was a 50% increase in the average Cmax from days 1 to 29. There was also a 73% decrease of matrix metalloproteinase-9 (MMP-9) levels in these 11 patients from days 1 to 29 (p < 0.0005). All three patients with cutaneous angiosarcomas experienced clinically meaningful remissions. In addition, minor responses were observed in one patient with heavily pretreated ovarian cancer and another with adrenocortical carcinoma. This trial details the inability to dose escalate to the maximum tolerated dose of weekly paclitaxel when combined with low-dose interferon. However, this low-dose regimen caused a significant decrease in MMP-9 and demonstrated anti-cancer activity in cutaneous angiosarcomas.

Bortezomib Plus Docetaxel in Advanced Non-small Cell Lung Cancer and Other Solid Tumors: A Phase I California Cancer Consortium Trial

This phase I study was performed to determine the dose-limiting toxicity and maximum tolerated dose (MTD) of docetaxel in combination with bortezomib in patients with advanced non-small cell lung cancer (NSCLC) or other solid tumors. Patients were enrolled in cohorts of three over six dose levels. Each treatment cycle was 3 weeks long and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11). Dose escalation and MTD determination were based on the occurrence of dose-limiting toxicities in cycle 1 only. A total of 36 patients were enrolled, 26 of whom had NSCLC. All patients received at least one dose of study drug at one of five dose levels. The MTD of the combined regimen was determined to be 1.0/75 mg/m bortezomib/docetaxel. The combination was generally well tolerated. Toxicities were manageable, and no additive toxicities were observed. The most common adverse events were fatigue (67% of patients), nausea (50%), diarrhea (39%), and neutropenia (39%). Two patients with NSCLC achieved a partial response, and seven (19%) patients achieved stable disease (including six patients with NSCLC). The combination of bortezomib and docetaxel was feasible and well tolerated in patients with advanced NSCLC or other solid tumors. The recommended phase II dose is bortezomib 1.0 mg/m on days 1, 4, 8, and 11 plus docetaxel 75 mg/m on day 1, cycled every 21 days. Therapeutic doses of docetaxel and bortezomib are achievable for this combination.

Performance of outpatient regimen of S-1 in combination with fractional cisplatin for advanced or recurrent gastric cancers: a phase I study

We designed an outpatient regimen consisting of fractional cisplatin in combination with S-1, a novel oral fluoropyrimidine derivative for the treatment of recurrent or advanced gastric cancer and conducted a phase I study to determine the dose limiting toxicities (DLTs) and recommended dose (RD). Escalating dosages of cisplatin (15, 20, and 25 mg/m(2), as levels 1, 2, and 3, respectively) were administered over 2 h on days 1, 8, and 15, with a fixed dose of S-1 for 3 consecutive weeks (days 1-21), repeated every 5 weeks. National Cancer Institute common toxicity criteria(NCI-CTC) grade 2 toxicities required treatment delay. Primary first cycle DLTs were defined as NCI-CTC grade 3 or 4 toxicities (except for hemoglobin levels, nausea, and vomiting). Nine patients were initially enrolled, and DLTs did not appear; however, one level-3 patient experienced grade 3 anemia. An additional three patients were enrolled in level 3 to confirm the toxicity profiles, and none experienced DLTs. Toxicity evaluations throughout a total of 62 cycles revealed that grade 1 or 2 hematological toxicities were common, although mostly transient, with recovery without specific treatment. One patient each in levels 1 and 3 required hospitalization due to grade 3 toxicities in the later cycles. Mean dose intensities for S-1 and cisplatin were both more than 91%. There were no treatment-related deaths. The preliminary response rate was 44%. It was concluded that the RD of cisplatin in this regimen was 25 mg/m(2) (level 3). S-1 in combination with fractional cisplatin is a promising regimen that allows repeated drug administration, in an outpatient setting, for advanced or recurrent gastric cancers. A phase II study of the RD is now under way.

A phase 1 dose escalation and pharmacokinetic (PK) trial of weekly docetaxel combined with daily erlotinib in adult cancer patients

2038 Background: This study aimed to define the maximum tolerated dose (MTD) of weekly docetaxel combined with daily erlotinib. Methods: 25 patients (pts) with no more than one prior therapy for metastatic disease and no prior taxane exposure were enrolled. All pts received 150 mg of oral erlotinib daily and docetaxel over 30 mins on days 1, 8 and 15 every 28 days with oral dexamethasone premedication (4 mg day before, of and after infusion). Plasma for PK of doecetaxel and erlotinib were obtained on day 1 of cycle (C) 2. A “3+3” design was used. In addition to the standard definitions of dose limiting toxicity (DLT) occurring in cycle 1, inability to give two docetaxel doses in C1 was deemed dose limiting. Erlotinib was given for a maximum of 12 cycles and docetaxel up to 6 cycles. Results: 91 cycles (Range: 1 to 12) have been administered to 22 evaluable pts. DLT in cycle 1: 0 of 3 pts treated at 20 mg/m2; 1 of 6 pts at 25 mg/m2: Grade (Gde) 4 enterocolitis with small bowel perforation; Another pt developed Gde 3 pulmonary toxicity (interstitial pneumonitis) in C3 that responded to corticosteroids. 0 of 3 pts treated at 30 mg/m2 had a DLT in cycle 1. 0 of 3 pts treated with 35 mg/m2 experienced a DLT and this cohort was then expanded to 10 pts. At this dose level, 3 pts required dose reduction in C2 (2 for Gde 3 neutropenia and one for Gde 3 mucositis), 1 pt was dose reduced in C 4 due to chronic diarrhea and 1 pt required a dose reduction in C3 due to Gde 1 elevation of bilirubin. 1 pt at this dose level was not evaluable due to Gilbert’s disease and was removed from study. Of the 22 evaluable pts, Gde 1/2 acneiform rash occurred in 8/12 pts respectively. The rash was ameliorated by dexamethasone premedication. Gde 1/2/3 diarrhea was observed in 10/8/2 pts. PK evaluation of docetaxel and erlotinib are ongoing. Activity included a partial response (PR) lasting 6+ months in a pt with non-small lung cancer, a PR lasting 12 + months in a pt with hepatoma and PR in 2 of 2 pts with cholangiocarcinoma lasting 4+ and 8+ months. Conclusion: Docetaxel at 35 mg/m2 and erlotinib at 150 mg daily can be given in combination but many patients require docetaxel reduction to 30 mg/m2 for subsequent cycles. Interesting activity has been seen in hepatobiliary carcinomas. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis

A phase 1/2 study of STA-4783 in combination with paclitaxel and carboplatin in chemo-naïve advanced non-small cell lung cancer (NSCLC)

7106 Background: STA-4783 (S) is a bis-thiobenzoylhydrazide that induces heat shock protein 70 (hsp 70). S significantly enhanced the antitumor activity of paclitaxel (P) in xenograft models, where single agent S had no activity. P with S given IV over 3 hours q 3 weeks was studied in a Phase 1 trial (ASCO 2004 Abstract 3124). Treatment was well-tolerated and maximum tolerated dose (MTD) was not reached. A Phase 1/2 trial was initiated in chemo naïve patients with advanced NSCLC. Methods: Phase 1 (safety/PK/MTD) was followed by a Phase 2 randomized two-arm portion. Two dose levels were evaluated in Phase 1: Cohort 1 carboplatin (C) AUC 6, P 175 mg/m2, and S 233 mg/m2; and if MTD was not observed, Cohort 2 was enrolled with the C AUC 6, P 200 mg/m2, and S 266 mg/m2. Dosing was IV q 3 weeks for up to 6 cycles in the absence of dose limiting toxicity or progression. In the Phase 2 portion 86 patients are planned to be randomized 1:1 to C AUC 6 + P 200 mg/m2 q 3 weeks or the CPS dose selected in Phase 1. The Phase 2 primary endpoint is time to progression, with secondary endpoints of response rate, survival, and quality of life. Study pharmacodynamic parameters include natural killer (NK) cell activity and hsp70 level. Results: Sixteen patients were treated in Phase 1, 7 in cohort 1 and 9 in cohort 2. No first cycle dose-limiting toxicities were seen in either cohort. Phase 1 AEs included (usually Grade 1–2) arthralgia and myalgia, peripheral neuropathy, rash, nausea and vomiting, fatigue, alopecia, edema, dehydration, constipation, and decreased blood counts. Eleven patients completed 6 cycles of therapy. Eight patients (50%) achieved a partial response (PR). Seven of the 8 patients with evaluable samples showed increased NK cell activity. Given the safety profile of cohort 2, this CPS dose level was used in Phase 2. As of submission, seventy patients have been randomized to Phase 2. Conclusions: CPS is well-tolerated at the dose levels studied, and the overall safety profile of CPS appears similar to that of CP alone. CPS has shown encouraging clinical activity, and the correlative NK activity data suggest that S is biologically active in vivo. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta

A dose escalation and pharmacokinetic (PK) trial of weekly docetaxel combined with daily erlotinib in adult cancer patients

2119 Background: Docetaxel is a taxane with a broad range of clinical activity. Erlotonib is an oral tyrosine kinase inhibitor of the epidermal growth factor receptor (HER1/EGFR). This study aims to define the maximum tolerated dose (MTD) of both drugs when docetaxel is given weekly. Methods: 14 evaluable patients (pts) with only one prior therapy for metastatic disease and no prior taxane exposure have been enrolled to date. All pts received 150 mg of oral erlotonib daily and intravenous infusion of docetaxel over 30 min. on days 1, 8 and 15 every 28 days with oral dexamethasone premedication (4mg day before, of and after infusion). The PK profile of docetaxel was defined on day 1 of cycle 2. A standard “3+3” design was used. In addition to the standard definitions of dose limiting toxicity (DLT) occurring in cycle 1, inability to give repeated doses in cycle 1 was deemed dose limiting. Results: 45 cycles (133 weekly doses of docetaxel) have been adminstered to 14 pts. 0 of 3 pts treated at 20 mg/m2 experienced a DLT. 1 of 6 pts treated at 25 mg/m2 had a DLT event: grade 4 enterocolitis with small bowel perforation; 1 pt developed grade 3 pulmonary toxicity (interstitial pneumonitis) in cycle 3 that responded to corticosteroids. 0 of 3 pts treated at 30 mg/m2 had a DLT in cycle 1. Accrual to 35 mg/m2 is ongoing (1 pt has completed cycle 1 without DLT). Grade 1/2 acneiform rash occurred in 4/8 pts respectively. Grade 1/2 diarrhea was observed in 7/2 pts. No pts had a neutrophil or platelet count fall below 1,500 and 100,000 respectively in cycle 1. 11 pts have had a PK evaluation and the docetaxel clearance on day 1 of cycle 2 was 66 L/hr or 31.5 L/hr/m2 (Coefficient of variation-CV: 35%/29%) and volume of distribution was 8.94 L (CV: 26%). Conclusion: Weekly docetaxel and erlotinib in combination do not alter the profile or the intensity of the toxicities of either drug when given as single agents. Accrual to the 35 mg/m2 docetaxel cohort is ongoing to further define the toxicity and PK profile. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis

Phase I evaluation of the weekly 24 hour intravenous administration of aviscumine, a recombinant ribosome-inactivating protein, in patients with refractory solid tumors

3106 Background Aviscumine is a recombinant E.coli-derived type II ribosome-inactivating protein with potent antitumor activity in vitro and in vivo. The drug targets terminal a2–6-sialylated structures (CD75s). In a previous Phase I study (EORTC 16002), the drug exhibited a short t½ after 1 h i.v. infusion. Methods In the current Phase I study, Aviscumine was therefore administered weekly as a 24 h central i.v. infusion in patients (pts) with refractory solid tumors to determine safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and PK. Pts had histologically or cytologically verified disease, were =18 yrs old, had an ECOG PS =2 and adequate bone marrow, liver and renal function. DLT was any non-hematological gr 3–4 toxicity (CTC version 2.0), ANC below 500/ml for =7 days, febrile neutropenia or thrombocytopenia °4. MTD was defined as dose where >20% of pts had DLT in cycle 1. Results Since February 2003, 11 pts (8 male, 3 female) were enrolled. Median age was 63 yrs (41–77). Tumor types ...

Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer

BackgroundTZT-1027 is a synthetic dolastatin 10 analog with antineoplastic properties in various cell lines and tumor xenografts. The purpose of this phase I study was to evaluate the safety and toxicity, maximum tolerated dose, pharmacokinetics and pharmacodynamics, clinical and metabolic antitumor activity ofTZT-1027 when given as a 1-h intravenous infusion every 3 weeks in patients with refractory solid tumors. Patients and methodsPatients had a histologically verified refractory tumor with measurable disease,were ≥18 years old, had an Eastern Cooperative Oncology Group performance status <2 and adequate bone marrow, liver, renal and cardiac function. Dose-limiting toxicity was defined as platelets <25 × 109/l, neutrophils <0.5 × 109/l for >5 days, febrile neutropenia ≥38.5°C with grade 4 (National Cancer Institute–common toxicity criteria) neutropenia, or grade 3/4 non-hematological toxicity excluding nausea and vomiting. The last dose was the dose where ≥2 out of six patients experienced dose-limiting toxicity in cycle one. The maximum tolerated dose was one dose level below with less than two of six patients with dose-limiting events. ResultsTwenty-one non-selected, fully evaluable patients were enrolled. The majority were male (19) and the median age was 55 years (range 39–67). Dose levels of TZT-1027 ranged from 1.35 to 3.0 mg/m2. The median number of cycles was two (range 1–4). Dose-limiting toxicities were observed in three patients at the 3.0 mg/m2 dose level, including neutropenia, fatigue and a short lasting, reversible peripheral neurotoxic syndrome. The most common toxicities per patient were fatigue, anorexia, alopecia, nausea, constipation, leukopenia and neutropenia. Based on RECIST criteria, the best response was stable disease in seven patients. The pharmacokinetic evaluation revealed a T1/2 of ∼7 h and linear kinetics. ConclusionsThe recommended dose of TZT-1027 for the 3-weekly administration is 2.7 mg/m2. Neutropenia, fatigue and a reversible peripheral neurotoxic syndrome are dose-limiting with this schedule. TZT-1027 maybe associated with neurological side-effects in patients previously exposed to neurotoxic compounds such as oxaliplatin.

Phase I clinical study of infusional 5-fluorouracil with oxaliplatin and gemcitabine (FOG regimen) in patients with solid tumors

BackgroundThe aim of this study was to determine the maximum tolerated dose, recommended phase II dose (RPTD) and toxicities of the FOG regimen (infusional 5-fluorouracil, oxaliplatin, gemcitabine). Patients and methodsPatients with advanced solid tumors were treated in an accelerated titration scheme. 5-Fluorouracil was administered intravenously at 200 mg/m2/day for 14 days and repeated every 21 days (one cycle). Gemcitabine was administered on days 1 and 8 over 30 min at 450–650 mg/m2. Oxaliplatin was administered on day 1 over 2 h at 85–130 mg/m2. For cycles 1, 3 and beyond, gemcitabine followed oxaliplatin; for cycle 2, gemcitabine preceded oxaliplatin. ResultsForty-five and 39 patients were assessable for toxicity and response, respectively. Cycle 1 dose-limiting toxicities (DLT) included neutropenia, thrombocytopenia and diarrhea. No DLT was observed in cycle 1 at the first four dose levels (DL). At DL-5, two of four (50%) patients experienced DLT in cycle 1. Expanding DL-4, nine of 26 (35%) patients experienced DLT in cycle 1. Because recurrent grade 3 toxicities were observed in three of six (50%) patients at DL-3, DL-2 was considered the RPTD. At the RPTD, three patients had a partial response (response rate 23%). ConclusionsThe RPTD for the 5-fluorouracil–oxaliplatin–gemcitabine combination is 200/100/450 mg/m2. This novel regimen has demonstrated activity in advanced solid tumors and merits further investigation.

Phase I Trial of Paclitaxel, Carboplatin, and Methotrexate With Granulocyte Colony-Stimulating Factor and Leucovorin in Advanced Transitional Cell Carcinoma

Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients 60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.

Phase I Trial of Paclitaxel, Carboplatin, and Methotrexate With Granulocyte Colony-Stimulating Factor and Leucovorin in Advanced Transitional Cell Carcinoma

Advanced transitional cell carcinoma (TCC) of the urothelial tract is usually fatal despite high response rates to platinum-based chemotherapy regimens. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has demonstrated marked single-agent activity in TCC, and combinations of carboplatin and paclitaxel have been well tolerated in other solid tumors. Methotrexate is also active in TCC. Due to unexpectedly severe myelosuppression and mucositis when methotrexate and paclitaxel were combined, we undertook a phase I trial of paclitaxel, carboplatin, and escalating doses of methotrexate with granulocyte colony-stimulating factor and leucovorin support in advanced TCC to determine the feasibility of this combination. Nineteen previously untreated patients with locally advanced or metastatic TCC were eligible. Median age was 62 years. In sequence, paclitaxel 200 mg/m2 (3-hour infusion), carboplatin dosed to an area under the concentration-time curve of 6 mg/mL x min, and methotrexate 10 mg/m2, increasing in 10-mg/m2 increments, were administered on day 1 every 21 days. Granulocyte colony-stimulating factor 300 microg/d or 480 microg/d (in patients <60 kg or >60 kg, respectively) was administered on days 2 through 11 and leucovorin 15 mg orally every 6 hours for 3 days. At this time, the methotrexate dose has been escalated to 50 mg/m2. There were no dose-limiting toxicities in cycle 1. Sixty-eight cycles have been administered (range, one to eight cycles; median, three cycles). Significant hematologic toxicity including neutropenic sepsis (two episodes) occurred in subsequent cycles, but was infrequent. The major nonhematologic toxicity was neuropathy. Sixteen patients are evaluable for response. One patient has achieved a complete response, seven are partial responders, seven have stable disease, and one progressed on therapy. The overall response rate is 50% (95% confidence interval, 25% to 75%). The combination of paclitaxel, carboplatin, and methotrexate holds promise to be well tolerated and active in advanced TCC.