Phase I/II study of albumin-bound nab-paclitaxel plus gemcitabine administered to Chinese patients with advanced pancreatic cancer

Purpose

The primary objective of this study was to evaluate the dose-limiting toxicities (DLTs) and identify the maximum-tolerated dose (MTD) and recommended dose of nab-paclitaxel plus gemcitabine as a first-line treatment in Chinese patients with advanced pancreatic ductal adenocarcinoma (PDA).

Methods

Patients with previously untreated advanced PDA were treated with nab-paclitaxel followed by gemcitabine (1,000 mg/m²) administered intravenously for 30 min on days 1 and 8 and repeated every 21 days.

Results

Patients received nab-paclitaxel at the following dose levels: 80 mg/m² (n = 3), 100 mg/m² (n = 6), and 120 mg/m² (n = 12). The DLTs evaluated were elevated alanine aminotransferase and febrile neutropenia. However, there had no two out of three to six patients experienced DLTs, the MTD was not met. A total of 93 cycles were administered. The most common grade 3/4 toxicities were neutropenia (9.52 %), thrombocytopenia (4.76 %), and sensory neuropathy (4.76 %). For 12 patients receiving 120 mg/m², the overall response rate and disease control rate were 41.67 and 83.33 %, respectively, and the median progression-free survival and overall survival were 5.23 and 12.17 months, respectively.

Conclusions

Treatment with albumin-bound nab-paclitaxel (120 mg/m²) plus gemcitabine has a favorable safety profile with an encouraging antitumor effect in Chinese patients.     

A phase I study of Triapine® in combination with doxorubicin in patients with advanced solid tumors

Purpose

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine^® administered in combination with doxorubicin.

Study design

Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine^® IV on days 1–4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m² and Triapine^® 25 mg/m². PK analysis was performed at various time-points before and after treatment.

Results

Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m², Triapine^® 45 mg/m²), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m²) with Triapine^® 45 mg/m². The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine^® were reduced to 45 and 25 mg/m², respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer.

Conclusions

Pretreated patients with advanced malignancies can tolerate the combination of Triapine^® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m² on day 1 and Triapine^® 25 mg/m² on days 1–4 of a 21-day cycle.     

A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies

Purpose

To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies.

Patients and methods

Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m² by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m² was given concurrently as an IV infusion on days 1–5 of each cycle.

Results

Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m² on day 1, 14 mg/m² on days 1 and 3, and 20 mg/m² on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m²; no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m² on day 1, the level was escalated to 14 mg/m² on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m² on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks.

Conclusion

Obatoclax mesylate administered at 14 mg/m² IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m² IV on days 1–5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.     

Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors

Purpose

Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib.

Methods

Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1–5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m². The pharmacokinetics of topotecan was evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib.

Results

Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m². Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib.

Conclusions

The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.     

The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors

Purpose

3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.

Methods

The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1–3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m² and 3-AP 85 mg/m² per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.

Results

Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m² per day and irinotecan 200 mg/m². DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.

Conclusions

The MTD for this combination was 3-AP 60 mg/m² per day on days 1–3 and irinotecan 200 mg/m² on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.     

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

A Phase I trial of dose escalation of topotecan combined with whole brain radiotherapy for brain metastasis in lung cancer

Objective

The aim of this study was to define the maximum-tolerated dose (MTD) and observe the toxicity of escalating topotecan combined whole brain radiotherapy for brain metastasis in lung cancer.

Methods

Patients with brain metastasis of lung cancer received conventional fractionation radiotherapy, with 5 daily fractions of 2 Gy per week, the total radiation dose was 40 Gy, while the larger lesions were boosted to 50–60 Gy. The initial dose of topotecan was 1.0 mg/m². Escalation dose was 0.25 mg/m². Every cohort contained at least 3 patients. If no dose-limiting toxicity (DLT) was observed, the next dose level was opened for entry. These courses were repeated until DLT appeared. MTD was declared as one dose level below which DLT appeared.

Results

Eighteen patients were recruited. Two cases of grade 3 leucopenia/neutropenia was observed as DLT at the level of topotecan 2.0 mg/m². MTD of topotecan was defined as 1.75 mg/m². The major side effects were leucopenia/neutropenia, nausea and vomiting.

Conclusion

Topotecan combined with whole brain radiotherapy for brain metastasis in lung cancer is well tolerated. Maximum-tolerated dose of topotecan is 1.75 mg/m², once a week of a total of four.     

Phase I/II and pharmacokinetic study of S-1 and oxaliplatin in previously untreated advanced gastric cancer

Background

We aimed to determine the maximum-tolerated dose (MTD) of S-1 when given with oxaliplatin, to evaluate S-1 pharmacokinetics, and to determine the efficacy and safety of this regimen as a first-line treatment for advanced gastric cancer (AGC).

Methods

Oxaliplatin was fixed at a dose of 130 mg/m² on day 1 (D1). S-1 was administered from D1 to D14 of a 3-week cycle, and escalated by 10 mg/m² per day from 70 mg/m² per day up to 100 mg/m² per day. Pharmacokinetic analyses were performed following a single dose of S-1 on D-5 and D1 of the first cycle.

Results

In phase I (n = 18), MTD was not defined. In phase II (n = 47) with the planned maximum dose, partial response was achieved in 26 patients (55.3%) and stable disease in 14 patients (29.8%). The median time to progression was 6.6 months (95% CI 4.0–9.2 months) and the median overall survival was 12.5 months (95% CI 9.2–15.9 months). Frequent grade 3/4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), and leukopenia (13%). There was one grade 5 febrile neutropenia during the first cycle.

Conclusions

The pharmacokinetics of S-1 was not influenced by oxaliplatin. S-1/Oxaliplatin combination therapy is highly active against AGC and has a favorable toxicity profile.     

A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound, administered as a 24-h continuous infusion in patients with advanced solid tumors

Purpose

To determine the recommended/maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profile of tasisulam sodium (hereafter tasisulam), a novel anticancer agent.

Methods

In this phase I study, tasisulam was administered as a 24-h continuous intravenous infusion on day 1, every 28 days, to patients with advanced solid tumors. A flat-dosing schema was planned for four cohorts of 3–6 patients: 600, 1,200, 2,000, and 2,500 mg.

Results

Twenty-six patients were enrolled. No dose-limiting toxicities (DLTs) were observed until cohort 3 (grade 3 hyperbilirubinemia). Interim PK analyses of this and another ongoing phase I study suggested that a lower dose after cycle 1 was necessary for doses ≥2,500 mg because of the long half-life of tasisulam (~14 days). Therefore, a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg was implemented for cohort 4; one patient developed DLT (grade 4 neutropenia), and another developed grade 3 thrombocytopenia in cycles 2 and 3. These findings, together with PK data, which indicated a disproportionate increase in free drug relative to total tasisulam concentrations at doses >2,500 mg, led to the determination of the 2,500-/1,750-mg regimen as the MTD. Eight patients had stable disease, and two patients unconfirmed partial responses.

Conclusions

When administered as a flat-dose, 24-h infusion, the MTD of tasisulam was a loading dose of 2,500 mg followed by a chronic dose of 1,750 mg, every 28 days. Consistent with the profile of the 2-h infusion in clinical development, bone marrow suppression was the major DLT.     

A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

Background

Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.

Methods

LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m² IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.

Results

Twenty-four patients were treated for 1–30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m². Two out of two patients experienced grade 4 neutropenia at the 132 mg/m² dose level. When an additional three patients were treated at the expanded 110 mg/m² dose level, two experienced grade 4 neutropenia. The 85 mg/m² dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m² with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %.

Conclusion

LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m² without G-CSF or 110 mg/m² with G-CSF.     

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors

Purpose

To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors.

Patients and methods

Patients received escalated doses of paclitaxel (starting dose: 100 mg/m²), gemcitabine (starting dose: 800 mg/m²) and oxaliplatin (starting dose: 50 mg/m²) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle.

Results

Twenty-seven patients (median age 65 years) with performance status 0–1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m², gemcitabine 1,150 mg/m² and LOHP 70 mg/m². The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected.

Conclusions

The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m², gemcitabine 1,000 mg/m² and oxaliplatin 70 mg/m² every 2 weeks. The regimen is generally well tolerated and merits further evaluation.     

A phase I study of paclitaxel, cisplatin, and fluorouracil (TCF) for advanced gastric cancer

Purpose

A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol^®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP.

Methods

The doses of TXL and CDDP were fixed at 80 and 25 mg/m², respectively, while that of 5-FU was increased by 100 mg/m² in each cohort from 300 mg/m² (level 1) to a maximum of 600 mg/m² (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks.

Results

A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%.

Conclusions

Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m², respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun.     

Plasma and cerebrospinal fluid pharmacokinetics of topotecan in a phase I trial of topotecan, tamoxifen, and carboplatin, in the treatment of recurrent or refractory brain or spinal cord tumors

Purpose

This study was designed to ascertain the dose-limiting toxicities (DLT) and maximally tolerated doses of the combination of fixed-dose tamoxifen and carboplatin, with escalating doses of topotecan, and to determine the pharmacokinetics of topotecan in the plasma and cerebrospinal fluid.

Methods

Tamoxifen 100 mg po bid, topotecan 0.25, 0.5, 0.75, or 1.0 mg/m²/d IV, administered as a 72 h continuous infusion on days 1–3, followed by carboplatin AUC = 3, IV on day 3. Cycles were repeated every 4 weeks.

Results

Seventeen patients received 39 cycles of treatment: median 2, (range 1–5). The tumors included glioblastoma (6), anaplastic astrocytoma (2), metastatic non-small cell (3), small cell lung (2), and one each with medulloblastoma, ependymoma, and metastatic breast or colon carcinoma. The median Karnofsky performance status was 70% (range 60–90%) and age: 52 (range 24–75). Eleven patients were female and six male. Toxicities included thrombocytopenia (2), neutropenia without fever lasting 6 days (1), DVT (2), and emesis (1). Topotecan levels, total and lactone, were measured prior to the end of infusion in plasma and cerebrospinal fluid (CSF). At 1.0 mg/m²/d, the median CSF/plasma ratio was 19.4% (range 15.1–59.1%). The total plasma topotecan in two pts with DLTs was 4.63 and 5.87 ng/ml, in three without DLTs at the same dose level the mean total plasma topotecan was 3.4 ng/ml (range 3.02–3.83). Plasma lactone levels were 33% of the total; CSF penetration was 20% of the total plasma levels. 4/8 pts with high-grade gliomas had stable disease (median: 3 cycles (range 2–5)). Two had minor responses. One patient with metastatic non-small cell and one with small cell lung cancer had objective PRs.

Conclusions

The recommended phase II doses are: tamoxifen 100 mg po bid, topotecan 0.75 mg/m²/d IV continuous infusion for 72 h, followed by carboplatin AUC = 3 IV on day 3. Measurable topotecan levels, both total and lactone, are observed in the CSF.     

Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with advanced solid tumors

Purpose

Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin–brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN).

Methods

Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m²) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m². The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination.

Results

Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m²). Dose level 2 (brostallicin 7 mg/m² and cisplatin 75 mg/m²) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3–4 neutropenia was observed in 90.5% of patients, grade 3–4 thrombocytopenia in 38.1%, grade 3–4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 × 10⁹/L) for neutrophils was Day 14 (median; range 11–17) with recovery to an ANC of >1,500 3.5 days after nadir (median; range 2–4) at dose level 3. The cycle 1 nadir (median of 51,000 × 10⁹/L) for platelets occurred on Day 13 (median; range 10–15) with recovery to a platelet count of >100,000 4 days after nadir (median; range 2–8). No objective responses were observed, but seven patients had a long lasting (>18 weeks) stable disease.

Conclusions

Further studies of the combination of brostallicin and cisplatin are warranted.     

A phase IB dose-finding trial of liposomal doxorubicin in combination with capecitabine in patients with pretreated metastatic breast cancer

Purpose

Anthracyclines and fluoropyrimidines are very active in breast cancer, while liposomal doxorubicin has low cardiotoxicity. We conducted a dose-finding study of the combination of liposomal doxorubicin and capecitabine in patients with pretreated metastatic breast cancer.

Patients and methods

Patients received liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m² bid (level 0) or 1,000 mg/m² bid (level 1) on days 1–14 of each 21-day cycle to establish the maximum tolerated dose (MTD) and cardiac safety.

Results

Nine patients were enrolled and a total of 52 courses were delivered (median 6 cycles per patient [range 4–7]). Grade 4 neutropenia occurred in 15% of cycles, with one episode of febrile neutropenia; most nonhematological toxicities were mild or moderate. No formal MTD was established, and the study was closed because two cardiac events were observed at dose level 1 and another at dose level 0 in patients pretreated with epirubicin ≥ 560 mg/m².

Conclusions

The recommended dose for phase II studies is liposomal doxorubicin 60 mg/m² on day 1 plus capecitabine 825 mg/m²/bid on days 1–14 of each 21-day cycle. Despite the lower cardiotoxicity of liposomal doxorubicin, the risk of cardiac damage persists in anthracycline-pretreated individuals and mandates close cardiac monitoring and careful evaluation of the overall cumulative dose.     

A phase I study of oral ixabepilone in patients with advanced solid tumors

Background

Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors.

Patients and methods

Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1–5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects.

Results

The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine.

Conclusions

The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.     

A phase I study of larotaxel (XRP9881) administered in combination with carboplatin in chemotherapy-naïve patients with stage IIIB or stage IV non-small cell lung cancer

Purpose

This primary objective of this phase I dose-escalation study was to define the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of larotaxel administered in combination with carboplatin in chemotherapy-naïve patients with advanced/metastatic non-small cell lung cancer (NSCLC).

Methods

Eighteen patients with stage IIIB or IV NSCLC, in cohorts of three to six evaluable patients, were to receive every 3 weeks: larotaxel beginning at 45 mg/m² administered as a 1-h infusion, followed after 30 min by carboplatin (area under the concentration–time curve (AUC) = 6 mg/mL × min, later AUC = 5) as a 1-h infusion. Dose escalation of larotaxel up to 90 mg/m² was permitted according to DLT occurrence. Patients received ondansetron as prophylactic anti-emetic premedication.

Results

In view of the toxicity encountered, the carboplatin dose was decreased for the later part of the study to AUC = 5 mg/mL × min. Eight of 18 treated patients experienced DLTs in the first cycle, including neutropenia and associated complications, diarrhea and fatigue. The MTD of the combination was defined as larotaxel 60 mg/m² with a carboplatin AUC of 6 mg/mL × min. Neutropenia, reported at grade 3/4 in 15/18 patients (83%), was the most common severe adverse event, reaching grade 4 in 14 patients (78%). Eleven patients (61%) experienced grade 3/4 non-hematological toxicity, predominantly dehydration, fatigue, infection, nausea and vomiting. One patient (6%) achieved a partial response and 11 (61%) had stable disease.

Conclusions

The combination of larotaxel and carboplatin is feasible and shows modest activity in chemotherapy-naïve patients with advanced/metastatic NSCLC. The principal toxicity was grade 3/4 neutropenia.     

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

Phase I study of sorafenib in combination with docetaxel and prednisone in chemo-na?ve patients with metastatic castration-resistant prostate cancer

Purpose

We performed a dose-escalation study to investigate the safety of sorafenib in combination with docetaxel and prednisone in chemo-na?ve patients with metastatic castration-resistant prostate cancer (mCRPC).

Methods

Six patients were included per dose level. Following docetaxel infusion on day 1 (75?mg/m²/q3?weeks), sorafenib was administered at 200?mg BID on days 2?C19 (dose level 1), at 200?mg BID on days 1?C21 (dose level 2), at 400?mg BID on days 2?C19 (dose level 3), at 400?mg BID on days 1?C21 (dose level 4). Maximal tolerated dose (MTD) was exceeded if ??2 patients experienced dose-limiting toxicities (DLT) during cycle 1. The recommended phase 2 dose for sorafenib was defined as one dose level below MTD. If MTD was not reached, the highest feasible dose would be selected to treat an expanded cohort to confirm safety.

Results

Two DLTs were observed during sorafenib dose-escalation consisting of grade 4 febrile neutropenia (dose level 2) and grade 3 hand-foot syndrome (HFS) (dose level 3). Our pharmacokinetic results showed an increased exposure to docetaxel across all dose levels during sorafenib comedication. The main grade ??3 toxicities were neutropenia (35?%), HFS (27?%), and febrile neutropenia (19?%). The prostate-specific antigen (PSA) response rate was 74?%. Median overall survival was 25.2?months.

Conclusion

Three-weekly docetaxel and prednisone could be combined with sorafenib at 400?mg BID on days 1?C21 without reaching MTD. However, we observed a pharmacokinetic interaction between sorafenib and docetaxel, associated with significant toxicities, raising concerns about the safety of this combination in mCRPC.     

A phase I trial to determine the safety, pharmacokinetics, and pharmacodynamics of intercalated BMS-690514 with paclitaxel/carboplatin (PC) in advanced or metastatic solid malignancies

Purpose

A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy.

Experimental design

Patients received fixed doses of P (200 mg/m²) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4–19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D).

Results

The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease.

Conclusions

The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.