The phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m2 and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104.
Patients with advanced solid tumours received PR-104 as a 1-hour intravenous infusion on days 1, 8 and 15 every 28 days with assessment of pharmacokinetics on cycle 1 day 1. Twenty-six patients (pts) were enrolled (16 male/10 female; median age 58 yrs, range 30 to 70 yrs) who had received a median of two prior chemotherapy regimens (range, 0 to 3) for melanoma (8 pts), colorectal or anal cancer (3 pts), NSCLC (3 pts), sarcoma (3 pts), glioblastoma (2 pts), salivary gland tumours (2 pts) or other solid tumours (5 pts). PR-104 was administered at 135 mg/m2 (3 pts), 270 mg/m2 (6 pts), 540 mg/m2 (6 pts), 675 mg/m2 (7 pts) and 900 mg/m2 (4 pts) for a median of two treatment cycles (range, 1 to 7 cycles) and five infusions (range, 1 to 18) per patient.
Dose-limiting toxicities (DLTs) during cycle one included grade four thrombocytopenia at 540 mg/m2 (1 of 6 pts) and grade four thrombocytopenia and neutropenia at 900 mg/m2 (2 of 4 pts). At an intermediate dose of 675 mg/m2, there were no DLTs among a total of seven patients given 12 treatment cycles but all experienced moderate to severe (grade 2 to 4) haematological toxicity. Thrombocytopenia was delayed in its onset and nadir, and its recovery was protracted and incomplete in many patients. There were no complete or partial tumour responses. PR-104-induced thrombocytopenia and neutropenia correlated with plasma AUC of PR-104, PR-104A and an oxidative semi-mustard metabolite (PR-104S1), but no more strongly than with PR-104 dose-level. There was no significant correlation between plasma AUC for the reduced metabolites and myelotoxicity.
Thrombocytopenia, and to a lesser extent neutropenia, was the DLT of weekly PR-104. The MTD was 675 mg/m2/week. PR-104 given weekly may be a suitable protocol for further clinical evaluation as a short course of treatment with fractionated radiotherapy or haematopoietic stem cell support, as its duration of dosing is restricted by delayed-onset and protracted thrombocytopenia.
This phase I trial was designed to determine the safety and maximum tolerated dose (MTD) of tipifarnib in combination with gemcitabine and cisplatin in patients with advanced solid tumours. Furthermore, the pharmacokinetics of each of these agents was evaluated. Patients were treated with tipifarnib b.i.d. on days 1–7 of each 21-day cycle. In addition, gemcitabine was given as a 30-min i.v. infusion on days 1 and 8 and cisplatin as a 3-h i.v. infusion on day 1. An interpatient dose-escalation scheme was used. Pharmacokinetics was determined in plasma and white blood cells. In total, 31 patients were included at five dose levels. Dose-limiting toxicities (DLTs) consisted of thrombocytopenia grade 4, neutropenia grade 4, febrile neutropenia grade 4, electrolyte imbalance grade 3, fatigue grade 3 and decreased hearing grade 2. The MTD was tipifarnib 200 mg b.i.d., gemcitabine 1000 mg m−2 and cisplatin 75 mg m−2. Eight patients had a confirmed partial response and 12 patients stable disease. No clinically relevant pharmacokinetic interactions were observed. Tipifarnib can be administered safely at 200 mg b.i.d. in combination with gemcitabine 1000 mg m−2 and cisplatin 75 mg m−2. This combination showed evidence of antitumour activity and warrants further evaluation in a phase II setting.
farnesyltransferase inhibitor; phase I study; pharmacokinetics
The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study.
Patients and Methods
Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m2 on days 1, 8, and 15 with cisplatin 50 mg/m2 on days 1 and 15 (arm A); gemcitabine 1,500 mg/m2 at a rate of 10 mg/m2/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m2 with docetaxel 40 mg/m2 on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m2 with irinotecan 100 mg/m2 on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival.
Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens.
Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.
Docetaxel and ifosfamide have shown significant activity against a variety of solid tumours. This prompted a phase I trial on the combination of these drugs. This phase I study was performed to assess the feasibility of the combination, to determine the maximum tolerated dose (MTD) and the side effects, and to propose a safe schedule for further phase II studies. A total of 34 patients with a histologically confirmed solid tumour, who were not pretreated with taxanes or ifosfamide and who had received no more than one line of chemotherapy for advanced disease were entered into the study. Treatment consisted of docetaxel given as a 1-h infusion followed by ifosfamide as a 24-h infusion (schedule A), or ifosfamide followed by docetaxel (schedule B) every 3 weeks. Docetaxel doses ranged from 60 to 85 mg m(-2) and ifosfamide doses from 2.5 to 5.0 g m(-2). Granulocytopenia grade 3 and 4 were common (89%), short lasting and ifosfamide dose dependent. Febrile neutropenia and sepsis occurred in 17% and 2% of courses respectively. Non-haematological toxicities were mild to moderate and included alopecia, nausea, vomiting, mucositis, diarrhoea, sensory neuropathy, skin and nail toxicity and oedema. There did not appear to be any pharmacokinetic interaction between docetaxel and ifosfamide. One complete response (CR) (soft tissue sarcoma) and two partial responses (PRs) were documented. A dose of 75 mg m(-2) of docetaxel combined with 5.0 g m(-2) ifosfamide appeared to be manageable. Schedule A was advocated for further treatment.
Pazopanib plus gemcitabine combination therapy was explored in patients with advanced solid tumors.
In a modified 3 + 3 enrollment scheme, oral once-daily pazopanib was administered with intravenous gemcitabine (Days 1 and 8, 21-day cycles). Three protocol-specified dose levels were tested: pazopanib 400 mg plus gemcitabine 1,000 mg/m2, pazopanib 800 mg plus gemcitabine 1,000 mg/m2, and pazopanib 800 mg plus gemcitabine 1,250 mg/m2. Maximum-tolerated dose was based on dose-limiting toxicities during treatment Cycle 1. In the expansion phase, six additional patients were enrolled at the highest tolerable dose level.
Twenty-two patients were enrolled. At the highest dose level tested (pazopanib 800 plus gemcitabine 1,250), patients received >80 % of their planned dose and the regimen was deemed safe and tolerable. The most common treatment-related adverse events included fatigue, neutropenia, nausea, and decreased appetite. Neutropenia and thrombocytopenia were the most common events leading to dose modifications. Pharmacokinetic interaction between pazopanib and gemcitabine was not observed. One objective partial response at the highest dose was observed in a patient with metastatic melanoma. Prolonged disease stabilization (>12 cycles) was reported in three patients (metastatic melanoma, cholangiocarcinoma, and colorectal carcinoma).
Combination pazopanib plus gemcitabine therapy is tolerable, with an adverse event profile reflective of that associated with the individual agents. There was no apparent pharmacokinetic interaction with pazopanib plus gemcitabine co-administration, although patient numbers were limited. Further investigation of combined pazopanib plus gemcitabine is warranted.
Anti-angiogenesis; Combination therapy; Gemcitabine; Melanoma; Pazopanib; Pharmacokinetics; Phase I; Solid tumors
Capecitabine and docetaxel are both active against a variety of solid tumours, while their toxicity profiles only partly overlap. This phase I study was performed to determine the maximum tolerated dose (MTD) and side-effects of the combination, and to establish whether there is any pharmacokinetic interaction between the two compounds. Thirty-three patients were treated with capecitabine administered orally twice daily on days 1–14, and docetaxel given as a 1 h intravenous infusion on day 1. Treatment was repeated every 3 weeks. The dose of capecitabine ranged from 825 to 1250 mg m–2twice a day and of docetaxel from 75 to 100 mg m–2. The dose-limiting toxicity (DLT) was asthenia grade 2–3 at a dose of 1000 mg m–2bid of capecitabine combined with docetaxel 100 mg m–2. Neutropenia grade 3–4 was common (68% of courses), but complicated by fever in only 2.4% of courses. Other non-haematological toxicities were mild to moderate. There was no pharmacokinetic interaction between the two drugs. Tumour responses included two complete responses and three partial responses. Capecitabine 825 mg m–2twice a day plus docetaxel 100 mg m–2was tolerable, as was capecitabine 1250 mg m–2twice a day plus docetaxel 75 mg m–2. © 2000 Cancer Research Campaign
phase I; pharmacokinetics; capecitabine; docetaxel
The aim of this study is to define the maximum tolerated dose (MTD), safety, pharmacokinetics (PKs) and efficacy of ispinesib (SB-715992) in combination with docetaxel. Patients with advanced solid tumours were treated with ispinesib (6–12 mg m−2) and docetaxel (50–75 mg m−2). Docetaxel was administered over 1 h followed by a 1-h infusion of ispinesib on day 1 of a 21-day schedule. At least three patients were treated at each dose level. Blood samples were collected during cycle 1 for PK analysis. Clinical response assessments were performed every two cycles using RECIST guidelines. Twenty-four patients were treated at four dose levels. Prolonged neutropaenia and febrile neutropaenia were dose limiting in six and two patients, respectively. The MTD was ispinesib 10 mg m−2 with docetaxel 60 mg m−2. Pharmacokinetic assessment demonstrated concentrations of ispinesib and docetaxel, consistent with published data from single agent studies of the drugs. Seven patients (six hormone refractory prostate cancer (HRPC), one renal cancer) had a best response of stable disease (⩾18 weeks). One patient with HRPC had a confirmed >50% prostatic-specific antigen decrease. The MTD for ispinesib and docetaxel was defined and the combination demonstrated an acceptable toxicity profile. Preliminary PK data suggest no interaction between ispinesib and docetaxel.
docetaxel; kinesin spindle protein; mitotic kinesin; phase I; SB-715992
In preclinical models, non-cytotoxic suramin (concentrations <50 μM) potentiates the activity of multiple chemotherapeutic agents. The present study evaluated the safety and tolerability of suramin in combination with docetaxel or gemcitabine in previously chemotherapy-treated patients with advanced non-small cell lung cancer.
Patients received suramin intravenously in combination with either docetaxel on day 1 or gemcitabine on days 1 and 8, of each 21-day treatment cycle. After 3 cycles, patients with partial response (PR) or better continued on the same combination, whereas patients with stable disease (SD) or worse crossed-over to the other combination. Pharmacokinetic analyses were performed before and after each treatment.
Eighteen patients received a total of 79 courses (37 suramin plus docetaxel, 42 suramin plus gemcitabine). The dose-limiting toxicity (DLT) was febrile neutropenia, observed in three of six patients treated with suramin and docetaxel 75 mg/m2. No DLTs were observed with suramin plus docetaxel 56 mg/m2 or suramin plus gemcitabine 1,250 mg/m2. Common adverse events included neutropenia, thrombocytopenia, anemia, fatigue, nausea, vomiting, skin rash, hyperglycemia, and electrolyte abnormalities. The target plasma suramin concentration range of 10–50 μM was achieved in 90% of treatments. Discernable antitumor activity was noted in 11 patients (2 PR, 9 SD).
Non-cytotoxic suramin, in combination with docetaxel 56 mg/m2 or gemcitabine 1,250 mg/m2, was reasonably well-tolerated with a manageable toxicity profile. Target plasma concentrations were correctly predicted by our previously described dosing nomogram. The observed preliminary evidence of antitumor activity encourages evaluation of this strategy in efficacy trials.
Suramin; Docetaxel; Gemcitabine; Chemosensitizer; Modulator; Non-small cell lung cancer
This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies.
This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75–125 mg po BID) with gemcitabine (750–1,000 mg/m2 on days 1, 8, 15) and fixed cisplatin (75 mg/m2 day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered “heavily pretreated” and the protocol was amended to limit prior therapy and re-escalate lonafarnib in “less heavily pre-treated patients” on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed.
Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m2 days 1, 8, 15, and cisplatin 75 mg/m2 in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer.
Lonafarnib 75 mg BID, gemcitabine 750 mg/m2 days 1, 8, 15, and cisplatin 75 mg/m2 day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.
Lonafarnib; SCH66336; Cisplatin; Gemcitabine; Farnesyltransferase; Phase I; Pharmacokinetics
Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors.
In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m2 IV q21d to determine the MTDs of this treatment combination.
Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m2 q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m2 q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (±fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug–drug interactions with either schedule.
Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m2 IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug–drug interactions, and shows antitumor activity in patients with advanced solid tumors.
Sunitinib; Docetaxel; Solid tumors; Phase I; NSCLC; Antiangiogenesis
To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m−2, respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m−2, PCX 110 mg m−2 and GEM 1000 mg m−2 with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m−2, PCX 100 mg m−2 and GEM 1000 mg m−2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours.
doxorubicin; gemcitabine; paclitaxel; pharmacokinetics
Given the established individual activity of docetaxel and ifosfamide in anthracycline pretreated advanced breast cancer, the present phase I–II study aimed to define the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), and activity of the docetaxel–ifosfamide combination in this setting. Cohorts of three to six patients with histologically confirmed metastatic breast cancer after prior anthracycline-based chemotherapy were treated at successive dose levels (DLs) with escalated doses of docetaxel 70–100 mg m−2 over 1 h on day 1 followed by ifosfamide 5–6 g m−2 divided over days 1 and 2 (2.5–3.0 g m−2 day−1 over 1 h), and recycled every 21 days. G-CSF was added once dose-limiting neutropenia was encountered at a certain DL and planned to be incorporated prophylactically in subsequent higher DLs. In total, 56 patients with a median age of 54.5 (range, 32–72) years and performance status (WHO) of 1 (range, 0–2) were treated at five DLs as follows: 21 in phase I DLs (DL1: 3, DL2: 6, DL3: 3, DL4: 6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41 patients at DL4), which was defined as the level for phase II testing. All patients were assessable for toxicity and 53 for response. Dose-limiting toxicity (with the addition of G-CSF after DL2) was reached at DL5 with two out of three initial patients developing febrile neutropenia (FN). Clinical response rates, on an intention-to-treat basis, in phase II were: 53.6% (95% CI, 38.3–68.9%); three complete remissions, 19 partial remissions, seven stable disease, and 12 progressive disease. The median response duration was 7 months (3–24 months), median time to progression 6.5 month (0.1–26 month), and median overall survival 13 months (0.1–33 months). Grade 3/4 toxicities included time to progression neutropenia in 78% of patients–with 63% developing grade 4 neutropenia (⩽7 days) and in 12% of these FN, while no grade 3/4 thrombocytopenia was observed. Other toxicities included peripheral neuropathy grade 2 only in 12%, grade 1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and grade 2 fluid retention in 2% of patients. One patient in the study treated at phase II died as a result of acute liver failure after the first cycle. In conclusion, the present phase I–II study determined the feasibility of the docetaxel–ifosfamide combination, defined the MTD and demonstrated the encouraging activity of the regimen in phase II, thus warranting further randomised phase III comparisons to single-agent docetaxel or combinations of the latter with other active agents.
docetaxel; ifosfamide; breast cancer; phase I study
Satraplatin is an oral platinum with potential advantages over other platinum agents. This study investigated the combination of satraplatin and docetaxel in a phase 1 study of patients with advanced solid tumor malignancies followed by a phase 1b study in men with chemotherapy naïve metastatic castrate-resistant prostate cancer (CRPC).
In this single institution phase 1/1b study, patients received docetaxel on day 1 and satraplatin on days 1–5 of a 21-day cycle ± granulocyte colony stimulating factor (GCSF). For phase 1b, prednisone 10 mg daily was added.
Twenty-nine patients received treatment. Based on 3 dose limiting toxicities (DLT) (grade 4 neutropenia) in 13 patients at dose levels 1 and −1 (docetaxel 60 mg/m2 plus satraplatin 40 mg/m2 and docetaxel 60 mg/m2 plus satraplatin 50 mg/m2) GCSF was administered with subsequent cohorts. A dose level of docetaxel 60 mg/m2 plus satraplatin 50 mg/m2 with GCSF was the starting dose level for phase 1b. At the highest dose in the phase 1b (docetaxel 75 mg/m2 plus satraplatin 50 mg/m2) there were no DLTs.
The combination of satraplatin and docetaxel is feasible in solid tumor malignancies. In advanced malignancies, the recommended phase 2 dose is docetaxel 60 mg/m2 IV day 1 with satraplatin 40 mg/m2/d PO days 1–5, without G-CSF, and Docetaxel 70 mg/m2 IV day 1 with Satraplatin 50 mg/m2/day PO days 1–5, with G-CSF support, repeated in 3-week cycles. For patients with CRPC the recommended phase 2 dose is docetaxel 75 mg/m2 IV day 1 with satraplatin 50 mg/m2/d PO days 1–-5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles.
Satraplatin; Docetaxel; Phase 1; Castrate-resistant; Prostate; Cancer
This phase Ib trial assessed safety, tolerability, and maximum tolerated dose (MTD) of figitumumab (CP-751,871), a fully human monoclonal antibody targeting the insulin-like growth factor type 1 receptor (IGF-IR), in combination with docetaxel.
Patients with advanced solid tumours were treated with escalating dose levels of figitumumab plus 75 mg m–2 docetaxel every 21 days. Safety, efficacy, pharmacokinetics (PKs), and biomarker responses were evaluated.
In 46 patients, no dose-limiting toxicities were attributable to the treatment combination. Grade 3 and 4 toxicities included neutropaenia (n=28), febrile neutropaenia (n=11), fatigue (n=10), leukopaenia (n=7), diarrhoea (n=5), hyperglycaemia, lymphopaenia, cellulitis, DVT, and pain (all n=1). The MTD was not reached. Four partial responses were observed; 12 patients had disease stabilisation of ⩾6 months. Pharmacokinetic and biomarker analyses showed a dose-dependent increase in plasma exposure, and complete sIGF-IR downregulation at doses of ⩾3 mg kg–1. Pharmacokinetics of docetaxel in combination was similar to when given alone. Out of 18 castration-resistant prostate cancer patients, 10 (56%) had ⩾5 circulating tumour cells (CTCs) per 7.5 ml of blood at baseline: 6 out of 10 (60%) had a decline from ⩾5 to <5 CTCs and 9 out of 10 (90%) had a ⩾30% decline in CTCs after therapy.
Figitumumab and docetaxel in combination are well tolerated. Further evaluation is warranted.
figitumumab (CP-751,871); insulin-like growth factor type 1 receptor (IGF-IR); chemosensitisation; monoclonal antibody; docetaxel
Gemcitabine and docetaxel have a broad spectrum of clinical activity in patients with carcinoma. The Sarcoma Alliance for Research Through Collaboration conducted a phase II trial of gemcitabine in combination with docetaxel in children and adults with recurrent Ewing sarcoma (EWS), osteosarcoma (OS), or unresectable or recurrent chondrosarcoma. The primary objective was to determine the objective response rate using Response Evaluation Criteria in Solid Tumors (RECIST).
Gemcitabine (675 mg/m2 i.v. over 90 minutes on days 1 and 8) was administered in combination with docetaxel (75 mg/m2 i.v. over 1 hour on day 8) every 21 days. All patients received filgrastim or pegfilgrastim. A Bayesian formulation was used to determine the probability of achieving the target response rate for each subtype—0.35 for EWS and OS or 0.20 for chondrosarcoma. If the probability of achieving the target response rate was <0.05, the combination was considered inactive. Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0.
Fifty-three eligible patients were enrolled in the three subtype groups—OS (n = 14), EWS (n = 14), and chondrosarcoma (n = 25). Toxicities included neutropenia, thrombocytopenia, fatigue, dyspnea, bronchospasm, edema, neuropathy, and liver function abnormalities. Dose modification for toxicity was required for eight patients during cycle 1 and 16 patients in subsequent cycles. Seven patients withdrew from therapy as a result of toxicity. No complete responses were observed. Partial responses were observed in OS (n = 1), EWS (n = 2), and chondrosarcoma (n = 2) patients.
Gemcitabine in combination with docetaxel was associated with a probability of reaching the target 35% response rate of <5% in OS patients and 5.6% in EWS patients; the probability of reaching a 20% response rate in chondrosarcoma patients was 14%.
The Bayesian formulation permitted estimation of the probability of achieving the target response rate for each subtype after each response evaluation. By allowing multiple looks at the data, this design stopped the trial after considering the probability of achieving the target response rate and accrual rate. Because this design did not specify a rule for declaring the treatment as “active,” a direct comparison with a standard two-stage phase II design is not appropriate. The decision to close the EWS and chondrosarcoma subtype arms was based, in part, on slow accrual and was supported by the low probability of achieving the target response rate. The rate of enrollment, rather than the statistical design, had a significant effect on the trial duration.
To define maximum tolerated dose (MTD), clinical toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered in combination with docetaxel once every 21 days in patients with advanced solid tumor malignancies.
Docetaxel was administered over 1 h at doses of 55, 70, and 75 mg/m2. 17-AAG was administered over 1–2 h, following the completion of the docetaxel infusion, at escalating doses ranging from 80 to 650 mg/m2 in 12 patient cohorts. Serum was collected for pharmacokinetic and pharmacodynamic studies during cycle 1. Docetaxel, 17-AAG, and 17-AG levels were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored in peripheral blood mononuclear cells by immunoblot.
Forty-nine patients received docetaxel and 17-AAG. The most common all-cause grade 3 and 4 toxicities were leukopenia, lymphopenia, and neutropenia. An MTD was not defined; however, three dose-limiting toxicities were observed, including 2 incidences of neutropenic fever and 1 of junctional bradycardia. Dose escalation was halted at docetaxel 75 mg/m2-17-AAG 650 mg/m2 due to delayed toxicities attributed to patient intolerance of the DMSO-based 17-AAG formulation. Of 46 evaluable patients, 1 patient with lung cancer experienced a partial response. Minor responses were observed in patients with lung, prostate, melanoma, and bladder cancers. A correlation between reduced docetaxel clearance and 17-AAG dose level was observed.
The combination of docetaxel and 17-AAG was well tolerated in adult patients with solid tumors, although patient intolerance to the DMSO formulation precluded further dose escalation. The recommended phase II dose is docetaxel 70 mg/m2 and 17-AAG 500 mg/m2.
17-AAG; Geldanamycin; Hsp90; Docetaxel; Phase I
To determine the maximum tolerated dose (MTD) of trabectedin plus gemcitabine administered on a weekly schedule in patients with advanced solid tumors.
Patients with ECOG performance status 0–1 and adequate organ function were enrolled. On days 1, 8, and 15 of a 28-day cycle, patients received gemcitabine (starting dose, 800 mg/m2) followed by trabectedin (starting dose, 0.3 mg/m2). Strict liver function test treatment criteria were employed to avoid hepatic toxicity seen in previous trabectedin studies. Plasma samples were collected during cycles 1 and 2 for pharmacokinetic analyses.
Fifteen patients received ≥1 dose, with a median of two treatment cycles (range 1–10). The most common drug-related toxicity was hepatic. Dose reductions were required for trabectedin in four (27%) patients and gemcitabine in six (40%) patients. Cycle delays/dose holds were required in 11 (73%) patients and doses above trabectedin 0.4 mg/m2 and gemcitabine 1,000 mg/m2, which is the recommended phase II dose, were not feasible. Seven patients maintained stable disease after two cycles. Gemcitabine and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
Given the lack of pharmacokinetic interaction and potential efficacy of trabectedin and gemcitabine combination therapy, further study is warranted with alternate schedules.
Dose-finding; Phase I; Gemcitabine; Pharmacokinetics; Trabectedin
The objective of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of S-1, an oral fluorouracil derivative, combined with gemcitabine, the current standard treatment for advanced pancreatic cancer (APC). The subjects were histopathologically proven APC patients with distant metastasis. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this was repeated every 21 days. Doses of each drug were planned as follows: level 1: 800/60, level 2a: 800/80, level 2b: 1000/60, level 3: 1000/80 (gemcitabine (mg m−2)/S-1 (mg m−2 day−1)). In all, 21 patients with APC were enrolled. The main grade 3–4 toxicities observed during first cycle were neutropenia (33%), anaemia (10%), thrombocytopenia (14%) and anorexia (10%). There were no DLT observed in level 1. Three of six patients in level 2a had DLT and this level was considered the MTD. In all, 12 patients in level 2b had no DLT and this level was selected as the recommended dose. Applicable responses were one complete response and nine partial responses (48%). As toxicities were well tolerated and antitumour activities seem to be promising, this combination can be recommended for further phase II studies with APC.
S-1; gemcitabine; metastatic pancreatic cancer; phase I study
Fixed-dose rate gemcitabine plus docetaxel is active as second-line therapy for metastatic uterine leiomyosarcoma. We sought to determine the activity of this regimen as first-line treatment.
Eligible women with advanced uterine leiomyosarcoma were treated with gemcitabine 900 mg/m2 over 90 minutes, days one and eight, plus docetaxel 100 mg/m2 on day eight, with granulocyte growth factor support day nine of a 21-day cycle. Patients with prior pelvic radiation received lower doses. Patients were treated until progression or unacceptable toxicity. Response was assessed every other cycle by RECIST.
Forty-two women enrolled, with 39 evaluable for response. Objective responses were observed in 15 of 42 patients (35.8% overall; complete response 4.8%, partial response 31%, 90% confidence interval 23.5 to 49.6%), with an additional 11 (26.2%) having stable disease. Nineteen of 38 (50%) received six or more cycles of study treatment. Myelosuppression was the major toxicity: neutropenia grade 3 in 5%, grade 4 in 12%; anemia grade 3 in 24%; thrombocytopenia grade 3 in 9.5%, grade 4 in 5%. One patient had a grade 3 allergic reaction, 17% had grade 3 fatigue. One possibly-related grade 4 pulmonary toxicity was observed. The median progression-free survival (PFS) was 4.4 months (range 0.4 to 37.2+ months). Among 15 women with objective response, median response duration was six months (range 2.1 to 33.4+ months). Median overall survival was 16+ months (range: .4 − 41.3 months)
Fixed-dose rate gemcitabine plus docetaxel achieves high objective response rates as first-line therapy in metastatic uterine leiomyosarcoma.
gemcitabine; docetaxel; uterine leiomyosarcoma
The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m2 intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m2/day to 2750 mg/m2/day as a continuous infusion from day 1–3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m2 on day 1 and ifosfamide 2750 mg/m2/day on days 1–3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m2 on day 1 and ifosfamide 2500 mg/m2/day continuous infusion on days 1–3.
British Journal of Cancer (2002) 87, 846–849. doi:10.1038/sj.bjc.6600542 www.bjcancer.com
© 2002 Cancer Research UK
ifosfamide; docetaxel; malignancy; toxicity; G-CSF
Doxorubicin-based treatment is standard therapy for metastatic uterine leiomyosarcoma. There is no standard second-line therapy. We determined activity of fixed-dose rate gemcitabine plus docetaxel as second-line treatment for metastatic uterine leiomyosarcoma.
Eligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy were treated with gemcitabine 900 mg/m2 days one and eight over 90 minutes, plus docetaxel 100 mg/m2 on day 8 of a 21-day cycle with granulocyte growth factor. Patients with prior pelvic radiation received lower doses. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT).
Forty-eight of 51 women were evaluable for response (one wrong histology, two never treated). Prior therapy was doxorubicin-based in 90%, and ifosfamide-based in 6%. The overall objective response rate is 27%, with complete response in 6.3% (3/48), and partial response in 20.8% (10/48). An additional 50% (24/48) had stable disease (median duration 5.4 months). The median number of cycles per patient was 5.5 (range 1–22); 73% of patients remained progression-free at 12 weeks and 52% at 24 weeks. The predominant toxicity was uncomplicated myelosuppression: thrombocytopenia grade 3 (29%), grade 4 (10.4%); neutropenia grade 3 (12.5%), grade 4 (8.3%) anemia grade 3 (20.8%), grade 4 (4.2%). While pulmonary toxicity was reported, no patient had drug-related pneumonitis/hypoxia-type toxicity. Median progression-free survival (PFS) was 5.6+ months (range 0.7 – 27+ months). The median duration of objective response was 9+ months (range 3.9 – 24.5+ months).
Fixed-dose rate gemcitabine plus docetaxel is active second-line therapy for uterine leiomyosarcoma.
uterine leiomyosarcoma; gemcitabine; docetaxel
The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m−2 (day 1) (arm A); docetaxel 75 mg m−2 (day 8) and gemcitabine 1250 mg m−2 (days 1,8) (arm B) or docetaxel 25 mg m−2 and gemcitabine 800 mg m−2 (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P=0.102, P=0.056, P=0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% CI: 10.5–20.6); arm B 18.1 months (95% CI: 15.9–20.3); arm C, 13.7 months (95% CI: 12.8–14.6). Neutropenia was the predominant grade 3–4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P=0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.
ovarian cancer; docetaxel; carboplatin; gemcitabine; triple-agent therapy; sequential therapy
The aim of the study was to determine the maximal tolerated dose (MTD) of gemcitabine every two weeks concurrent to radiotherapy, administered during an aggressive program of sequential and simultaneous radiochemotherapy for locally advanced, unresectable non-small cell lung cancer (NSCLC) and to evaluate the efficacy of this regime in a phase II study.
33 patients with histologically confirmed NSCLC were enrolled in a combined radiochemotherapy protocol. 29 patients were assessable for evaluation of toxicity and tumor response. Treatment included two cycles of induction chemotherapy with gemcitabine (1200 mg/m2) and vinorelbine (30 mg/m2) at day 1, 8 and 22, 29 followed by concurrent radiotherapy (2.0 Gy/d; total dose 66.0 Gy) and chemotherapy with gemcitabine every two weeks at day 43, 57 and 71. Radiotherapy planning included [18F] fluorodeoxyglucose positron emission tomography (FDG PET) based target volume definition. 10 patients were included in the phase I study with an initial gemcitabine dose of 300 mg/m2. The dose of gemcitabine was increased in steps of 100 mg/m2 until the MTD was realized.
MTD was defined for the patient group receiving gemcitabine 500 mg/m2 due to grade 2 (next to grade 3) esophagitis in all patients resulting in a mean body weight loss of 5 kg (SD = 1.4 kg), representing 8% of the initial weight. These patients showed persisting dysphagia 3 to 4 weeks after completing radiotherapy. In accordance with expected complications as esophagitis, dysphagia and odynophagia, we defined the MTD at this dose level, although no dose limiting toxicity (DLT) grade 3 was reached.
In the phase I/II median follow-up was 15.7 months (4.1 to 42.6 months). The overall response rate after completion of therapy was 64%. The median overall survival was 19.9 (95% CI: [10.1; 29.7]) months for all eligible patients. The median disease-free survival for all patients was 8.7 (95% CI: [2.7; 14.6]) months.
After induction chemotherapy, the maximum tolerated dose and frequency of gemcitabine was defined at 500 mg/m2 every two weeks in three cycles during a maximum of 7 weeks of thoracic radiotherapy for the phase II study. This regimen represents an effective and tolerable therapy in the treatment of NSCLC.
Purpose: Satraplatin is a third generation oral platinum, which has demonstrated antitumor activity. The aim of this phase I study was to determine the maximum tolerated dose (MTD) of the combination of satraplatin and gemcitabine in patients previously treated with chemotherapy and in patients without prior chemotherapy. Patients and Methods: Two separate MTDs were planned in two different patient groups (those with and without prior chemotherapy treatment). Dose escalations were planned in cohorts of three patients. Tumor measurements were obtained every two cycles. Assessment of response was performed according to Response Evaluation Criteria in Solid Tumors (RECIST criteria v.1.0). Results: Thirty subjects were enrolled. A MTD of gemcitabine 1000 mg/m2 days 1 and 8 plus satraplatin 60 mg/m2 days 1–3, every 21 days was determined in the prior chemotherapy group. No MTD could be determined for the no prior chemotherapy group treated with this schedule. Five patients completed 12 treatment cycles; 22 serious adverse events (SAE) were observed. Although not an entry criteria, overall confirmed response was observed in 17 (24%) evaluable patients (complete response, CR = 1 and partial response, PR = 3) and in 3/7 (43%) patients with measure prostate cancer lesions. Conclusions: In this phase Ib study, the combination of satraplatin and gemcitabine demonstrated to be safe and efficacious in particular in patients with prostate cancer.
satraplatin; oral platinum; phase I study; prostate cancer; solid tumors; chemotherapy
The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m2 on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m2 on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ≤33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m2. Forty-six patients were enrolled and 45 received ≥1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy.
Motesanib; Breast cancer; Angiogenesis; VEGF; Chemotherapy