Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours

Background:

Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab.

Methods:

Patients with advanced solid tumours received increasing doses of continuous oral olaparib (100, 200 and 400 mg b.i.d. capsule formulation) in combination with bevacizumab (10 mg kg⁻¹ intravenous q2w).

Results:

In all, 12 patients enrolled and received treatment. The most common adverse events (AEs) related to olaparib were grade 1/2 nausea and fatigue. No haematological parameters were reported as AEs. No serious AEs related to olaparib or dose-limiting toxicities (DLTs) were reported. Three patients discontinued due to AEs, two patients discontinued both olaparib and bevacizumab and one patient discontinued olaparib. Five patients received combination treatment for over 6 months. There was no evidence that bevacizumab affected olaparib.

Conclusion:

The combination of olaparib 400 mg b.i.d. with bevacizumab 10 mg kg⁻¹ q2w was generally well tolerated with no DLTs. This combination could be considered for future clinical investigation.     

A phase I,dose-finding study of sunitinib in combination with irinotecan in patients with advanced solid tumours

Background:

Sunitinib is a multitargeted, oral tyrosine kinase inhibitor with antitumour and antiangiogenic activity. We investigated the safety and pharmacokinetics of sunitinib in combination with irinotecan in patients with advanced, refractory solid tumours.

Methods:

Sunitinib was initially administered once daily at 37.5 mg per day on days 1–14 of a 21-day cycle, in which irinotecan 250 mg m⁻² was given on day 1. In a second cohort, the sunitinib dose was reduced to 25 mg per day. Blood samples were collected for pharmacokinetic studies.

Results:

In the sunitinib 37.5 mg per day cohort, 3 out of 10 evaluable patients had objective responses, but dose-limiting toxicities (DLTs) of neutropenia, pneumococcal sepsis, and fatigue were observed. There were no DLTs in the sunitinib 25 mg per day cohort. Paired observations of pharmacokinetic parameter values of sunitinib and irinotecan alone vs the combination did not reveal significant drug–drug interactions. The maximum tolerated dose was defined as sunitinib 25 mg per day (days 1–14) with irinotecan 250 mg m⁻² (day 1), but no activity was observed at this dose.

Conclusion:

Although a higher sunitinib dose of 37.5 mg per day (days 1–14) with irinotecan showed preliminary evidence of antitumour activity, this dose was poorly tolerated. Therefore, this particular combination will not be pursued for further studies.     

A phase I/II study of neoadjuvant liposomal doxorubicin,paclitaxel, and hyperthermia in locally advanced breast cancer

Purpose: The prognosis for locally advanced breast cancer (LABC) patients continues to be poor, with an estimated five-year survival of only 50–60%. Preclinical data demonstrates enhanced therapeutic efficacy with liposomal encapsulation of doxorubicin combined with hyperthermia (HT). Therefore this phase I/II study was designed to evaluate the safety and efficacy of a novel neoadjuvant combination treatment of paclitaxel, liposomal doxorubicin, and hyperthermia.

Materials and methods: Eligible patients received four cycles of neoadjuvant liposomal doxorubicin (30–75 mg/m²), paclitaxel (100–175 mg/m²), and hyperthermia. They subsequently underwent either a modified radical mastectomy or lumpectomy with axillary node dissection followed by radiation therapy and then eight cycles of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy.

Results: Forty-seven patients with stage IIB-III LABC were enrolled and 43 patients were evaluable. Fourteen patients (33%) had inflammatory breast cancer. Combined (partial + complete) clinical response rate was 72% and combined pathological response rate was 60%. Four patients achieved a pathologically complete response. Sixteen patients were eligible for breast-conserving surgery. The cumulative equivalent minutes (CEM 43) at T90 (tenth percentile of temperature distribution) was significantly greater for those with a pathological response. Four-year disease-free survival was 63% (95% CI, 46%–76%) and the four-year overall survival was 75% (95% CI, 58–86%).

Conclusions: Neoadjuvant therapy using paclitaxel, liposomal doxorubicin and hyperthermia is a feasible and well tolerated treatment strategy in patients with LABC. The thermal dose parameter CEM 43 T90 was significantly correlated with attaining a pathological response.     

Phase I study of weekly paclitaxel and liposomal doxorubicin in patients with advanced solid tumours

The aim of this study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLT) of a weekly administration of paclitaxel and pegylated liposomal doxorubicin (Caelyx; Schering Plough Pharmaceutical) in patients with advanced solid tumours. 19 pretreated patients with solid tumours received escalated doses of pegylated liposomal doxorubicin (6-12 mg/m(2)) as a 1-h intravenous (i.v.) infusion followed by a fixed dose of paclitaxel (80 mg/m(2)) weekly for 4 consecutive weeks in cycles of 6 weeks. DLT was defined as grade 4 neutropenia or thrombocytopenia, febrile neutropenia, grades 3 or 4 non-haematological toxicity or treatment delay due to unresolved toxicity during cycle 1. The MTD was reached at the dose of pegylated liposomal doxorubicin of 10 mg/m(2)/week and paclitaxel of 80 mg/m(2)/week. The DLTs were treatment delay due to grade 3 neutropenia and grade 3 diarrhoea. A total of 55 chemotherapy cycles were administered, and grades 3-4 neutropenia occurred in seven cycles (13%); the non-haematological toxicity was mild with grades 2/3 diarrhoea occurring in 4 (7%), grades 2-4 asthenia in 11 (20%) and grade 2 mucositis in 7 (13%) cycles. There was no case with more than a 10% LVEF decrease after a median of 3 (range 2-6) administered cycles/patients. One patient with breast cancer and 1 with ovarian cancer experienced a major partial response. The weekly administration of pegylated liposomal doxorubicin at the dose of 10 mg/m(2) in combination with paclitaxel at the dose of 80 mg/m(2) for 4 consecutive weeks, in cycles of 6 weeks which represent the recommended doses for further phase II studies, is a well tolerated regimen, which merits further evaluation in tumours known to be sensitive to taxanes and/or anthracyclines.     

Nonpeghylated liposomal doxorubicin combination regimen (R-COMP) for the treatment of lymphoma patients with advanced age or cardiac comorbidity

Doxorubicin is the most effective single agent in the treatment of non-Hodgkin's lymphoma (NHL). Its use is limited because of the cardiac toxicity primarily in elderly patients (pts) and in pts with history of cardiac disease. Liposomal doxorubicin has been proven to reduce cardiotoxicity. The aim of this retrospective study was the use of nonpeghylated liposomal doxorubicin (NPLD) in term of efficacy, response rate and incidence of cardiac events. We retrospectively collected the experience of 33 Hematological Italian Centers in using NPLD. Nine hundred and forty-six consecutive pts treated with R-COMP (doxorubicin was substituted with NPLD, Myocet) were collected. Median age was 74 years, the reasons for use of NPLD were: age (466 pts), cardiac disease (298 pts), uncontrolled hypertension (126 pts), other reasons (56 pts). According to clinicians' evaluation, 49.9% of pts would not have used standard doxorubicin for different situations (age, cardiomyopathy, previous use of doxorubicin, and uncontrolled hypertension). Overall 687 pts (72.6%) obtained a complete remission (CR). About 5% (n = 51) of subjects developed major cardiotoxic events including heart failure (N = 31), ischemic heart disease (N = 16), acute heart attack (N = 3), and acute pulmonary oedema (N = 1). After a median follow-up of 32 months, 651 pts were alive and the overall survival (OS) was 72%. After a median observation period of 23 months disease free survival (DFS) was 58%. Either in univariate or in multivariate analysis OS and DFS were not significantly affected by age or cardiac disease. Our findings strongly support that including R-COMP is effective and safe when the population is at high risk of cardiac events and negatively selected. Moreover, the use of this NPLD permitted that about half of our population had the opportunity to receive the best available treatment.     

A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors

Purpose  Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors. Methods  Patients received bortezomib, 0.9–1.5 mg/m², on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m², on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination. Results  A total of 37 patients with four median prior therapies were treated. Frequent grade 1–2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m², and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m². Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m² levels, bortezomib at 1.3 mg/m² and PLD at 30 mg/m² are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs. Conclusions  A regimen of bortezomib, 1.3 mg/m² on days 1, 4, 8, and 11 with PLD, 30 mg/m², on day 4 of a 21-day cycle, was safe in this study, and merits further investigation. Supported in part by grants from the following: Millennium Pharmaceuticals, Inc., General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health(RR00046), National Cancer Institute SPORE in Breast Cancer (5-P50-CA58223-09A1 H.S. Earp), National Inst. of Health (K23-RR16536 ECD), Leukemia and Lymphoma Society (6096-07 RZO), and National Cancer Institute (RO1 CA102278 RZO).     

Phase I study of the halichondrin B analogue eribulin mesylate in combination with cisplatin in advanced solid tumors

Background:

Eribulin mesylate is a synthetic macrocyclic ketone analogue of Halichondrin B that has demonstrated high antitumor activity in preclinical and clinical settings. This phase I study aimed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics in combination with cisplatin (CP) in patients with advanced solid tumours.

Methods:

Thirty-six patients with advanced solid tumours received eribulin mesylate 0.7–1.4 mg m⁻² and CP 60–75 mg m⁻². Eribulin mesylate was administered on days 1, 8, and 15 in combination with CP day 1 every 28-day cycle. The protocol was amended after dose level 4 (eribulin mesylate 1.4 mg m⁻², CP 60 mg m⁻²) when it was not feasible to administer eribulin mesylate on day 15 because of neutropenia; the treatment schedule was changed to eribulin mesylate on days 1 and 8 and CP on day 1 every 21 days.

Results:

On the 28-day schedule, three patients had DLT during the first cycle: grade (G) 4 febrile neutropenia (1.0 mg m⁻², 60 mg m⁻²); G 3 anorexia/fatigue/hypokalemia (1.2 mg m⁻², 60 mg m⁻²); and G 3 stomatitis/nausea/vomiting/fatigue (1.4 mg m⁻², 60 mg m⁻²). On the 21-day schedule, three patients had DLT during the first cycle: G 3 hypokalemia/hyponatremia (1.4 mg m⁻², 60 mg m⁻²); G 4 mucositis (1.4 mg m⁻², 60 mg m⁻²); and G 3 hypokalemia (1.2 mg m⁻², 75 mg m⁻²). The MTD and recommended phase II dose was determined as eribulin mesylate 1.2 mg m⁻² (days 1, 8) and CP 75 mg m⁻² (day 1), on a 21-day cycle. Two patients had unconfirmed partial responses (PR) (pancreatic and breast cancers) and two had PR (oesophageal and bladder cancers).

Conclusions:

On the 21-day cycle, eribulin mesylate 1.2 mg m⁻², administered on days 1 and 8, in combination with CP 75 mg m⁻², administered on day 1 is well tolerated and showed preliminary anticancer activity.     

Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours

Objective: A combination regimen of temozolomide (TMZ) and pegylated liposomal doxorubicin has been evaluated in the treatment of brain metastases from solid tumours. Study design: Nineteen consecutive patients (pts) have been enrolled in a prospective phase II trial and treated with TMZ 200 mg/m² (days 1–5) and pegylated liposomal doxorubicin 35 mg/m² (day 1) every 28 days. The study was prospectively projected according to the Simon’s two-stage optimal design. Results: Major toxicities have been grade III neutropenia and thrombocytopenia in one patient (pt) and grade III erythrodisesthesia in two pts. Three pts achieved a complete response (CR) and four a partial response (PR), for an overall response rate of 36.8% (95% CI: 19.1–59.2), which exceeded the target activity in the study design. A significant improvement in quality of life was demonstrated by FACT-G analysis. The median Progression Free Survival (PFS) was 5.5 (95% CI: 2.7–8.2) months while the median Overall Survival (OS) was 10.0 months (95% CI: 6.3–13.7). Conclusions: The TMZ/pegylated liposomal doxorubicin regimen was well tolerated with an encouraging activity in brain metastases from solid tumours.     

Phase 1 clinical study of pegylated liposomal doxorubicin (JNS002) in Japanese patients with solid tumors

BACKGROUND: Pegylated liposomal doxorubicin (PLD, JNS002) is a formulation of doxorubicin encapsulated polyethylene-glycol coated liposomes with prolonged circulation time and unique toxicity profile. This phase 1 study was aimed at investigating the maximum tolerated dose (MTD), recommended dose, toxicity, pharmacokinetics, and antitumor activity in Japanese patients with solid tumors. METHODS: Patients with solid tumors not amenable to standard forms of treatment were eligible. PLD was administered as an intravenous infusion every 4 weeks. Dose escalation of PLD was planned from 30 to 60 mg/m(2) in 10 mg/m(2) increments. The pharmacokinetics of total doxorubicin (encapsulated plus non-encapsulated) in plasma were examined for the first cycle of treatment. RESULTS: Fifteen patients, aged 49-69 (median; 56) years with advanced solid tumors were enrolled. The major non-hematological toxicities were hand-foot syndrome (HFS), rash and stomatitis. Myelosuppression, especially leukopenia and neutropenia were major hematological toxicities. Although HFS was not severe, a delay of doses for subsequent cycles was required with multiple dosing. The peak plasma concentration and the area under the concentration time curve of PLD increased proportionally to the dose. Objective response was observed in one patient and the normalization of tumor marker values in another. These two patients had been diagnosed with ovarian cancer. CONCLUSION: The recommended dose for phase 2 clinical studies of PLD in Japanese patients was 50 mg/m(2) every 4 weeks. The encouraging results prompted us to plan a subsequent clinical study of PLD against ovarian cancer.     

Phase I study of axitinib combined with paclitaxel,docetaxel or capecitabine in patients with advanced solid tumours

Background:

Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy.

Methods:

A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m^–2 weekly), docetaxel (100 mg m^–2 every 3 weeks) or capecitabine (1000 or 1250 mg m^–2 b.i.d., days 1–14).

Results:

Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand–foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents.

Conclusions:

Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.     

Phase II study of CLAD (cyclophosphamide, liposomal doxorubicin and dexamethasone) in patients with advanced multiple myeloma and historical comparison to CAD (cyclophosphamide, doxorubicin and dexamethasone)

The purpose of this study was to assess the efficacy and safety of pegylated liposomal doxorubicin in combination with cyclophosphamide and dexamethasone (CLAD). In this prospective open-label phase II study, 60 patients with advanced multiple myeloma (MM) received three weekly cycles of CLAD, consisting of cyclophosphamide 200 mg/m2 i.v. d1-4, pegylated liposomal doxorubicin 20 mg/m2 i.v. d1 and dexamethasone 40 mg p.o. d1-4 for a maximum of six cycles in absence of disease progression. Efficacy and toxicity was compared to our immediate historical cohort of 46 patients treated with cyclophosphamide, dexamethasone and conventional doxorubicin (CAD). A total of 239 cycles of CLAD and 209 cycles of CAD, respectively, were given. The objective response rate was 71% (CLAD) and 74% (CAD). Non-cumulative hematological toxicity was predominant in both regimens. It was found that CLAD is an active and well-tolerated treatment regimen for MM. Response rate is comparable to other anthracycline containing regimens like CAD with an advantage in hematological toxicity and lower infectious complications, and a presumed advantage of lower cardiotoxicity.     

Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar

Valspodar, a P-glycoprotein modulator, affects pharmacokinetics of doxorubicin when administered in combination, resulting in doxorubicin dose reduction. In animal models, valspodar has minimal interaction with pegylated liposomal doxorubicin (PEG-LD). To determine any pharmacokinetic interaction in humans, we designed a study to determine maximum tolerated dose, dose-limiting toxicity (DLT), and pharmacokinetics of total doxorubicin, in PEG-LD and valspodar combination therapy in patients with advanced malignancies. Patients received PEG-LD 20-25 mg m(-2) intravenously over 1 h for cycle one. In subsequent 2-week cycles, valspodar was administered as 72 h continuous intravenous infusion with PEG-LD beginning at 8 mg m(-2) and escalated in an accelerated titration design to 25 mg m(-2). Pharmacokinetic data were collected with and without valspodar. A total of 14 patients completed at least two cycles of therapy. No DLTs were observed in six patients treated at the highest level of PEG-LD 25 mg m(-2). The most common toxicities were fatigue, nausea, vomiting, mucositis, palmar plantar erythrodysesthesia, diarrhoea, and ataxia. Partial responses were observed in patients with breast and ovarian carcinoma. The mean (range) total doxorubicin clearance decreased from 27 (10-73) ml h(-1) m(-2) in cycle 1 to 18 (3-37) ml h(-1) m(-2) with the addition of valspodar in cycle 2 (P=0.009). Treatment with PEG-LD 25 mg m(-2) in combination with valspodar results in a moderate prolongation of total doxorubicin clearance and half-life but did not increase the toxicity of this agent.     

Combination of pegylated liposomal doxorubicin (PLD) and paclitaxel in patients with advanced soft tissue sarcoma: a phase II study of the Hellenic Cooperative Oncology Group

Patients with soft tissue sarcoma (STS), even after complete local disease control, often relapse locally or with distant metastases. This multicenter phase II study was conducted to evaluate the safety and efficacy of the combination of pegylated liposomal doxorubicin (PLD) and paclitaxel, as first-line treatment in patients with advanced STS. In all, 42 patients with locally advanced or metastatic STS, median age 54 years and median Eastern Cooperative Oncology Group performance status (PS) 1 were treated with PLD 45 mg m(-2) and paclitaxel 150 mg m(-2), every 28 days for a total of six cycles. Histological types included mainly leiomyosarcomas (43%), malignant fibrous histiocytomas (14%) and liposarcomas (12%). At study entry, 69% of patients had distant metastases. Overall response rate was 16%, including one complete (CR 2%) and six partial responses (PRs 14%), while an additional 14 patients had disease stabilization (SD 33%). At median follow-up 41.5 months, median time to progression (TTP) was 5.7 months with median overall survival (OS) 13.2 months. Grade 3-4 toxicities included neutropenia (17%), anaemia (15%), neurotoxicity (5%) and palmar-plantar erythrodysesthesia (9%). There were no treatment-related deaths. The combination of PLD and paclitaxel is a safe and well-tolerated regimen demonstrating modest efficacy as first-line treatment in patients with advanced STS.     

A phase I combination dose-escalation study of eribulin mesylate and gemcitabine in patients with advanced solid tumours: a study of the Princess Margaret Consortium

Background:

Eribulin mesylate is a synthetic microtubule inhibitor that showed cytotoxic synergy in combination with gemcitabine preclinically. This combination was assessed in a Phase I dose-finding trial in patients diagnosed with advanced solid tumours who had received up to two prior chemotherapy regimens for metastatic disease (CP cohort).

Methods:

Dose escalation was performed in a 3+3 design to identify the recommended phase II dose (RP2D). Two additional expansion cohorts in women with gynaecologic cancers at the RP2D (G), and further dose escalation of metastatic chemotherapy-naive patients (CN), were evaluated.

Results:

45 patients were treated: 21 (CP), 10 (G) and 14 (CN). The initial combination of eribulin and gemcitabine was administered on days 1, 8, and 15 of a 28-day cycle; however, due to 2 out of 6 dose-limiting haematological toxicities at the first dose level, a reduced dose-intense schedule was assessed. The RP2D was defined at 1.0 mg m⁻² eribulin and 1000 mg m⁻² gemcitabine day 1 and 8 q3 weeks. No other significant toxicities were observed in the G expansion cohort. Neutropenia prevented further dose escalation in the CN cohort. Objective responses were seen in all three cohorts – 2/21 (CP), 1/10 (G) and 2/14 (CN).

Conclusions:

The combination of eribulin and gemcitabine was well tolerated at the RP2D.     

Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer

In total, 70 patients were enrolled into this phase II study, to evaluate the activity of the pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) combination in recurrent ovarian cancer patients. PLD, 30 mg m(-2), was administered on day 1 by 60' i.v. infusion, followed by GEM, 1000 mg m(-2), given by 30' i.v. on days 1 and 8; cycles were repeated every 21 days. In all, 67 patients are so far evaluable for response. Seven complete responses (10.4%, 95% CI: 3.1-17.7), 16 partial responses (23.9%, 95% CI: 13.7-34.1), 26 disease stabilisations (38.8%, 95% CI: 27.1-50.5) and 18 progressions (26.9%, 95% CI: 16.3-37.5) have been registered. Within the resistant population (n=36), the response rate was 25% (95% CI: 10.9-39.1). Within the group of platinum-sensitive patients (n=31), the response rate was 45.2% (95% CI: 27.7-62.7). A total of 443 courses are evaluable for toxicity. Grade 3-4 hematological toxicity was registered in 30 patients (42.8%), mainly represented by neutropenia (35.6%); palmar-plantar erythrodysesthesia affected 24 patients (34.2%), but it was of grade 3 in only seven of them (10%).     

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors

PURPOSE: To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. METHODS: Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. RESULTS: The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. CONCLUSIONS: This is a quite well-tolerated regimen which merits further evaluation in phase II studies.     

Phase I safety and pharmacokinetic study of SU-014813 in combination with docetaxel in patients with advanced solid tumours

Background

In pre-clinical models enhanced anti-tumour activity was observed when SU-014813, an oral multi-targeted tyrosine kinase inhibitor was combined with docetaxel. This synergy might be explained by improvement of the penetration of cytotoxic agents into tumours as a result of both VEGFR and PDGFR inhibition. We assessed the maximal tolerated dose (MTD), evaluated the pharmacokinetics and preliminary anti-tumour efficacy of oral SU-014813 administered continuously in combination with docetaxel to patients with advanced solid tumours.

Methods

In this phase I study successive patient cohorts received docetaxel 60 or 75 mg/m² every 3 weeks in combination with chronic daily dosing of SU-014813. Dose limiting toxicity was assessed both in the first and second treatment cycle.

Results

Twenty-five patients were entered on study of which 24 started treatment. Dose limiting toxicities were prolonged neutropenia, neutropenic fever, fatigue and diarrhoea. Other toxicities included fatigue, alopecia, nausea, vomiting, anorexia, rash, hypertension and hair discolouration. The recommended phase II dose was determined to be docetaxel 75 mg/m² in combination with SU-014813 50 mg/day. There was no clinically relevant pharmacokinetic drug-drug interaction. Two patients (8%) achieved a partial response (PR) and 7 patients (29%) had stabilisation of their disease (SD) >6 months, for a clinical benefit rate of 37.5%. The activity observed in patients with melanoma and sunitinib refractory gastrointestinal stromal tumours (GIST) was particularly noteworthy.

Conclusions

Oral SU-014813 50 mg/day with docetaxel 75 mg/m² is a clinically feasible regimen with a manageable safety profile and anti-tumour activity. Further development is warranted in patients with melanoma and GIST.     

Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours

Background:

Preclinical studies suggest that histone deacetylase (HDAC) inhibitors may restore tumour sensitivity to retinoids. The objective of this study was to determine the safety, tolerability, and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of the HDAC inhibitor entinostat in combination with 13-cis retinoic acid (CRA) in patients with solid tumours.

Methods:

Patients with advanced solid tumours were treated with entinostat orally once weekly and with CRA orally twice daily × 3 weeks every 4 weeks. The starting dose for entinostat was 4 mg m⁻² with a fixed dose of CRA at 1 mg kg⁻¹ per day. Entinostat dose was escalated by 1 mg m⁻² increments. Pharmacokinetic concentrations of entinostat and CRA were determined by LC/MS/MS. Western blot analysis of peripheral blood mononuclear cells and tumour samples were performed to evaluate target inhibition.

Results:

A total of 19 patients were enroled. The maximum tolerated dose (MTD) was exceeded at the entinostat 5 mg m⁻² dose level (G3 hyponatremia, neutropenia, and anaemia). Fatigue (G1 or G2) was a common side effect. Entinostat exhibited substantial variability in clearance (147%) and exposure. CRA trough concentrations were consistent with prior reports. No objective responses were observed, however, prolonged stable disease occurred in patients with prostate, pancreatic, and kidney cancer. Data further showed increased tumour histone acetylation and decreased phosphorylated ERK protein expression.

Conclusion:

The combination of entinostat with CRA was reasonably well tolerated. The recommended phase II doses are entinostat 4 mg m⁻² once weekly and CRA 1 mg kg⁻¹ per day. Although no tumour responses were seen, further evaluation of this combination is warranted.     

Weekly paclitaxel combined with pegylated liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors.

BACKGROUND: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx trade mark ) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination. METHODS: A phase I study was performed with an initial dose of 50 mg/m(2) wPTX and 30 mg/m(2) PLD. The paclitaxel dose was escalated in increments of 10 mg/m(2) and PLD in increments of 5 mg/m(2) until the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels. RESULTS: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m(2) for PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar-plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD was mild: skin toxicity grade 1-2 developed at high cumulative doses and vascular thrombotic events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median 53.5% increase of PLD area under the concentration curve (range 4.4%-219%). CONCLUSIONS: The combination of PLD/wPTX constitutes an active chemotherapy regimen with mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m(2). Patients should be monitored for a potentially increased risk of thromboembolic events.     

Pilot study with pegylated liposomal doxorubicin for advanced or unresectable hepatocellular carcinoma.

We performed a pilot-study on pegylated liposomal doxorubicin (PLD) for advanced hepatocellular carcinoma. Seventeen patients received 40 mg/m(2) PLD intravenously every 4 weeks. A clinical benefit response was achieved in 50% (complete remission 7%, minor remission 7%, stable disease 36%). Toxicities were moderate. In view of these encouraging findings, further studies appear warranted.