Dose-escalating study of continuative low dose of oral vinorelbine in patients with advanced breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1128-1128
Author(s):  
A. Felici ◽  
M. Russillo ◽  
S. Di Segni ◽  
A. Fabi ◽  
G. Ferretti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Low Dose ◽  
Metastatic Breast ◽  
Pharmacokinetic Analysis ◽  
Weekly Dose ◽  
Oral Vinorelbine ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

1128 Background: Low and continuative dose of antineoplastic drugs has been shown to have an antiangiogenic activity. The rapid absorption and relatively short half-life of the oral formulation of vinorelbine are favorable pharmacokinetic characteristics to test a continuative low-dose schedule. Methods: Patients with measurable metastatic breast cancer were treated with escalating dose of oral vinorelbine from 50 mg/m2 per week to 90 mg/m2 per week until progressive disease or unacceptable toxicity. These patients were administered one third of the total weekly dose 3 times per week, every other day. A pharmacokinetic analysis was planned at the first 3 weeks of drug assumption. Results: Of twenty-two patients included in the study, 3 were treated at 50 mg/m2/w (level 1), 5 at 60 mg/m2/w (level 2), 3 at 70 mg/m2/w (level 3), 8 at 80 mg/m2/w (level 4), and 3 at 90 mg/m2/w (level 5); we are still enrolling patients at this level. The median age was 59 years (range 23–75). The median number of prior lines of chemotherapy and hormonal therapy was 2 (range 0–4 for CT and 0–5 for OT). Fifteen of 22 patients had visceral metastasis. No dose-limiting toxicities have been observed until now. The main toxicities were: asymptomatic neutropenia grade 4 in two patients (1 in level 4 and 1 in level 5), asthenia grade 3 in 7 patients (1 at level 1, 2 at level 2, 1 at level 3, 3 at level 4), neurotoxicity grade 3 in two patients (one at level 2 and one at level 4). One patient experienced an intestinal sub-occlusion and hospitalization was required with no permanent side effects. One patient had a partial response, five a stable disease, fourteen progressed and two are not evaluated yet. At 1 year, five of the twenty evaluable patients are died by disease. Samples of twenty patients were collected for pharmacokinetic analysis that will be presented at the meeting. Conclusions: The continuative split 3 times per week oral vinorelbine is feasible, and at 90 mg/m2/w we have not reached yet the maximum tolerated dose. No significant financial relationships to disclose.

Docetaxel and capecitabine for previously treated metastatic colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13579-13579
Author(s):  
T. E. O’Brien ◽  
E. Newton ◽  
J. Trey ◽  
E. Crum
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Low Dose ◽  
Metastatic Breast ◽  
Human Colon Cancer ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Level 2

13579 Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 & 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m2, C=1000mg/m2; Level 2: D= 15 mg/m2, C= 1100 mg/m2; Level 3: D= 20 mg/m2, C= 1100 mg/m2; Level 4: D=20mg/m2, C=1250mg/m2. Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual. No significant financial relationships to disclose.

Phase I study of panobinostat (LBH589) and letrozole in post-menopausal women with metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13501-e13501 ◽  
Author(s):  
Winston Tan ◽  
Jacob B Allred ◽  
Alvaro Moreno-Aspitia ◽  
Donald W. Northfelt ◽  
James N. Ingle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

A phase I study of modified irinotecan (CPT-11) plus cisplatin (CDDP) [m-IP] against paclitaxel/carboplatin [TC] -resistant and recurrent ovarian cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13015-13015
Author(s):  
T. Suzuki ◽  
M. Morishita ◽  
M. Matsuura ◽  
T. Fujimoto ◽  
R. Tanaka ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I Study ◽  
Phase Ii Study ◽  
Recurrent Ovarian Cancer ◽  
Hematological Toxicity ◽  
Prior Chemotherapy ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

13015 Background: CPT-11/CDDP is effective regimen for ovarian cancer. Particularly against ovarian cancer resistant to prior chemotherapy, a 40% response rate was reported (Sugiyama T Cancer Letters, 1998). However, every 4 weeks treatment with CPT-11 day 1, 8, and 15, administration on day 15 was skipped in about 60% due to toxicity, and the relative dose intensity of IP was 66.7% in non-small cell lung cancer (Saito H Am J Clin Oncol 2006). We planed Phase I study, in consideration of the effect of prior chemotherapy in TC-resistant ovarian cancer, a modified CPT-11 (day 1, 8) and CDDP (day 1) for every 4 weeks treatment (m-IP). The aim of this study conducted to examine the dose limiting toxicity (DLT), to evaluate the maximum tolerated dose (MTD), and define the recommended dose (RD) for a phase II study. Methods: Patients with TC-resistant ovarian cancer having a PS 0–1, age 30–75 years, normal organ functions, and written informed consent. CPT-11 was administered intravenously over 90 minutes on day 1 and day 8, plus CDDP was day 1, repeated every 4 weeks. The dose escalation schedule was defined: Doses of CPT-11/CDDP (mg/m2) were 60/60 at level 1, 70/60 at level 2 and 70/70 at level 3. DLT were determined as Grade 4 hematological toxicity and = Grade 3 non-hematological toxicity occurred, and when dosing on day 8 was delayed for more than 8 days due to toxicity. Results: Nine patients were enrolled (level 1/2/3: 3/3/3). DLTs, at level 1 and 2, no patients developed. At level 3, grade 3 nausea and vomiting and delayed treatment on day 8 due to anorexia, were observed in all of 3 patients. Therefore, MTD was determined to be level 3 and RD was determined to be level 2 (CPT-11: 70mg/m2, CDDP: 60mg/m2). Major =Grade 3 toxicities observed were leukopenia, neutropenia, nausea, and vomiting. No Grade 4 hematological toxicities were observed. Diarrhea was mild. Antitumor effect at RD was observed in 1 patient with CR, 1 patient with PR and 1 patient with PD. Conclusions: The MTD of m-IP was CPT-11 70mg/m2 and CDDP 70mg/m2 (level 3), the RD was CPT-11 70mg/m2 and CDDP 60mg/m2 (level 2). Preliminary response are promissing associated with tolerable toxicity for TC-resistant and recurrent ovarian cancer. A Phase II study is currently conducted. No significant financial relationships to disclose.

A phase IB trial of 5-azacitidine (5AC) and suberoylanilide hydroxamic acid (SAHA) in patients with metastatic or locally recurrent nasopharyngeal carcinoma (NPC) and NK-T cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e17017-e17017
Author(s):  
Wen Son Hsieh ◽  
Eng Huat Tan ◽  
Wan-Teck Lim ◽  
Ross A. Soo ◽  
Anthony T. C. Chan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Load ◽  
Dose Level ◽  
Clinical Benefit ◽  
Tumor Tissue ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e17017 Background: Epigenetic up-regulation of EBV and cellular genes via demethylation and histone deacetylase inhibition can induce EBV lytic replication enhancing immune mediated tumor killing and up-regulation of tumor suppressor genes resulting in tumor apoptosis. Methods: Patients (Pt) with relapsed or refractory NPC and NK-T cell lymphomas were enrolled to determine safety, tolerability, pharmacokinetics (PK), pharmacodynamics and preliminary anti-tumor activity using a dose escalation design. 5AC was administered on days 1 to 10 sub-cutaneously while SAHA was administered on days 1 to 14 orally. PK for SAHA, EBV viral load, characterization of circulating EBV, Immunohistochemistry (IHC) and EBV promoter methylation analysis in tumor tissue were performed. Results: 11 pt have been treated (M:F 8:3, median age 48, R: 35-71) at 3 dose levels – 5AC 50 mg/m2 and SAHA 200 mg b.i.d. (dose level 1), 5AC 37.5 mg/m2 and SAHA 200 mg q. am and 100 mg q. pm (dose level 2), and 5AC 25 mg/m2 and SAHA 100 mg b.i.d (dose level 3). Median number of previous treatment regimens was 3 (R:1-6). Dose limiting toxicities (DLT) were seen in 2/2 pts at dose level 1: grade 4 thrombocytopenia (1 pt), grade 3 nausea, vomiting and fatigue (2 pts), and grade 5 hepatic failure (1 pt). Two of six patients at dose level 2 experienced DLT: grade 3 fatigue (1 pt) and worsening of pre-existing Sweet’s Syndrome (1 pt). Common AEs (G1/2) included fatigue (73%), cough (64%), anorexia (55%), and injection site reaction (45%). One minor response was seen and 5 pt had prolonged stable disease (>16 weeks), including one patient for 88 weeks. Analysis of post-treatment tumor biopsies showed demethylation of EBV lytic cycle gene promoters after treatment. SAHA PK, IHC results for EBV gene expression in tumor tissue, EBV viral load and characterization of circulating EBV will be presented. Conclusions: 5AC/SAHA appears to be tolerable at dose level 3 with suggestion of clinical benefit. Analysis of post-treatment tumor and blood samples suggests that modulation of EBV gene expression may play a role in the mechanism underlying clinical benefit. Continued accrual at dose level 3 is ongoing. Clinical trial information: NCT00336063.

scholarly journals Phase I Study of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and Etoposide) in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1748-1748 ◽  
Author(s):  
Dai Chihara ◽  
Yasuhiro Oki ◽  
Luis Fayad ◽  
Emily Wesson ◽  
Charnelle Ruben ◽  
...  
Keyword(s):  
Dose Level ◽  
Overall Response Rate ◽  
Bone Marrow Involvement ◽  
Median Number ◽  
Cell Transplant ◽  
Salvage Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Background: Despite recent approval of 4 new drugs for relapsed PTCL, an unmet need remains for new therapies. Survival of relapsed/refractory PTCL patients is improved by stem cell transplant particularly if patients are in CR prior to transplant (Smith 2013). ICE (ifosfamide, carboplatin and etoposide) is commonly used salvage regimen which produces CR rates ranging from 7% to 23% in patients with PTCL (Zelenetz 2003, Mikesch 2013). Romidepsin is a HDAC inhibitor which showed overall response rate of 25% with CR rate of 15% in a large phase II trial for relapsed/refractory PTCL (Coiffier 2012). To further improve outcomes particularly in CR rates pre-transplant, we conducted a phase I study of romidepsin in combination with standard ICE in patients with relapsed/refractory PTCL. Methods: The primary objective of this trial is to determine the toxicity profile and to identify the maximum tolerated dose of the romidepsin in combination with standard ICE. A statistical design of modified toxicity probability interval method was used (Ji 2010). Romidepsin was administered intravenously on days 1 and 4 of ICE, at 8mg/m2 (dose level 1), 10mg/m2 (level 2), or 12mg/m2 (level 3). All patients received G-CSF support. Patients could receive next cycle of treatment on day 14 if ANC was > 1 and platelets were ≥ 75,000 with ≥ 20,000 allowed if patients had bone marrow involvement with PTCL at time of enrollment. Results: As the time of the data cut off (August 2014), a total of 9 patients were registered (4 PTCL-NOS, 4 AITL, 1 NK/TCL) and 7 were assessable for toxicity and response (Cheson 2007). Two patients were consented but did not received treatment. Median age of patients was 60 (range 59-70) years, 5 patients had primary refractory disease and 5 patients had advanced stage disease at the time of enrollment. Median number of prior regimens was 1 (range 1-2) and 1 patient had received a prior front-line consolidative ASCT. At the time of data cut off a total of 7 patients were treated with 2, 4 and 1 patients respectively at dose level 1, 2 and 3, respectively. Median number of treatment cycles were 2 (range 1-4). The common non-hematologic toxicity of grade 3/4 was fatigue (71%), nausea (43%), shortness of breath (29%), and vomiting (14%). With a total of 15 cycles overall given, grade 3/4 thrombocytopenia and neutropenia occurred in 87% and 40% of the cycles and febrile neutropenia occurred once in 1 patient. Dose limiting toxicities occurred in a 70 year-old female treated at dose level 2 with renal failure which was considered to be associated with ifosfamide and etoposide and in 67 year-old male with bone marrow involvement who previously had a front-line consolidative ASCT 6 months earlier and was treated at dose level 3 with persistent grade 3/4 thrombocytopenia. The overall response rate was 71% (5/7, 95%CI: 22-96%) with all in CR. Two patients who received dose level 1 underwent allogeneic transplant and one patient in dose level 2 underwent autologous stem cell transplant but all patients relapsed after transplant. Median duration of response was 7.2 months and six of the 7 patients experienced further disease progression. Summary: In conclusion, romidepsin plus ICE is an effective salvage regimen but with a higher rate of thrombocytopenia and neutropenia as anticipated than with romidepsin or ICE alone. Even though romidepsin plus ICE produces a high CR rate, early relapse despite this even when followed by transplant indicates the crucial need to develop methods to detect minimal residual disease and approaches to best address this. Enrollment continues to this trial. Disclosures Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding.

scholarly journals A randomized phase II trial evaluating the addition of low dose, short course sunitinib to docetaxel in advanced solid tumours

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yvonne L. E. Ang ◽  
Gwo Fuang Ho ◽  
Ross A. Soo ◽  
Raghav Sundar ◽  
Sing Huang Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Low Dose ◽  
Negative Impact ◽  
Objective Response ◽  
Metastatic Breast ◽  
Solid Tumours ◽  
Breast Cancer Patients ◽  
Short Course ◽  
Grade 3

Abstract Background We previously reported that low-dose, short-course sunitinib prior to neoadjuvant doxorubicin-cyclophosphamide (AC) normalised tumour vasculature and improved perfusion, but resulted in neutropenia and delayed subsequent cycles in breast cancer patients. This study combined sunitinib with docetaxel, which has an earlier neutrophil nadir than AC. Methods Patients with advanced solid cancers were randomized 1:1 to 3-weekly docetaxel 75 mg/m2, with or without sunitinib 12.5 mg daily for 7 days prior to docetaxel, stratified by primary tumour site. Primary endpoints were objective-response (ORR:CR + PR) and clinical-benefit rate (CBR:CR + PR + SD); secondary endpoints were toxicity and progression-free-survival (PFS). Results We enrolled 68 patients from 2 study sites; 33 received docetaxel-sunitinib and 35 docetaxel alone, with 33 breast, 25 lung and 10 patients with other cancers. There was no difference in ORR (30.3% vs 28.6%, p = 0.432, odds-ratio [OR] 1.10, 95% CI 0.38–3.18); CBR was lower in the docetaxel-sunitinib arm (48.5% vs 71.4%, p = 0.027 OR 0.37, 95% CI 0.14–1.01). Median PFS was shorter in the docetaxel-sunitinib arm (2.9 vs 4.9 months, hazard-ratio [HR] 2.00, 95% CI 1.15–3.48, p = 0.014) overall, as well as in breast (4.2 vs 5.6 months, p = 0.048) and other cancers (2.0 vs 5.3 months, p = 0.009), but not in lung cancers (2.9 vs 4.1 months, p = 0.597). Median OS was similar in both arms overall (9.9 vs 10.5 months, HR 0.92, 95% CI 0.51–1.67, p = 0.789), and in the breast (18.9 vs 25.8 months, p = 0.354), lung (7.0 vs 6.7 months, p = 0.970) and other cancers (4.5 vs 8.8 months, p = 0.449) subgroups. Grade 3/4 haematological toxicities were lower with docetaxel-sunitinib (18.2% vs 34.3%, p = 0.132), attributed to greater discretionary use of prophylactic G-CSF (90.9% vs 63.0%, p = 0.024). Grade 3/4 non-haematological toxicities were similar (12.1% vs 14.3%, p = 0.792). Conclusions The addition of sunitinib to docetaxel was well-tolerated but did not improve outcomes. The possible negative impact in metastatic breast cancer patients is contrary to results of adding sunitinib to neoadjuvant AC. These negative results suggest that the intermittent administration of sunitinib in the current dose and schedule with docetaxel in advanced solid tumours, particularly breast cancers, is not beneficial. Trial registration The study was registered (NCT01803503) prospectively on clinicaltrials.gov on 4th March 2013.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

A Phase I/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 428-428 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Magdalini Migkou ◽  
Konstantinos Pamboukas ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Low Dose ◽  
Alkylating Agents ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 428 Lenalidomide (R) has significant activity in patients with multiple myeloma (MM). R has also shown activity in patients with AL amyloidosis, especially in combination with dexamethasone (D). However, AL patients are usually frail and R at the standard dose of 25 mg/day has been associated with significant toxicity. In MM patients, R with low dose D (Rd) has a better toxicity profile than the combination of R with high dose D. Alkylating agents, such as cyclophosphamide (C), are active in patients with AL and combinations of R with alkylating agents have given promising results in patients with MM. Thus, we designed a phase I/II trial of R, with low dose D and low dose C (RdC) in patients with AL. Primary objective of the study was to determine the maximum tolerated dose (MTD) for RdC and to assess hematologic response. Patients receive D 20 mg on days 1-4 (total 80 mg per cycle) , C on days 1-10, R on days 1-21 every 28 days, according to dose level (level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg). In the phase I part of the study, patients were observed for 2 cycles for determination of Dose Limiting Toxicity (DLT) according to a standard 3+3 design. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function were enrolled. All patients receive low-dose aspirin or LMWH if indicated. So far 23 patients have been enrolled in the study (16 in phase I, 7 in phase II). In the phase I study, 3 patients were enrolled in dose level 0, 7 in dose level 1 and 6 in dose level 2. Dose level 2, (R 15 mg, C 100 mg) is being further explored; 7 patients have been enrolled in phase II and accrual is ongoing. So far, 132 cycles of therapy have been administered; 8 patients have receive ≥6 cycles of RdC and 3 have completed 12 cycles of treatment. According to consensus criteria, heart was involved in 65%, kidneys in 61%, liver in 9% and 17% had AL-related peripheral neuropathy; 95% of the patients were Mayo stage II or III. Most patients (70%) were previously untreated. Among 7 pretreated patients, 2 had refractory disease, 2 had prior thalidomide and 5 had prior bortezomib. Hematologic response rates for patients who received at least 2 cycles of treatment, among all cohorts, was 64% and for the patients treated at dose level 2 was 75%. Median time to hematologic response was 2.5 months (range 0.9-4.8 months) for all patients and 1 month (range 0.9-2.9) for those treated at dose level 2. Organ responses have been recorded in 5 patients so far (3 cardiac and 3 renal responses, 1 patient had both cardiac and renal response). After a median follow-up of 7 months, 7 patients have died; 5 due to progressive heart amyloid, one patient had an acute MI followed by acute stent thrombosis and one died due to sepsis. The most common hematologic toxicities were anemia (grade 3/4 in 17%) and neutropenia (grade 3/4 in 17%). Most common non-hematologic toxicities were infection (grade ≥3 in 22%), fatigue (grade ≥3 in 9%), and rash (in 22%, grade 3 in 4%); also one patient suffered a stroke and one had DVT while on treatment with RdC. In parallel, and on a compassionate basis, AL patients with creatinine >2.5 mg/dL or on dialysis, were offered RdC with R dose adjusted according to CrCl. Initially R was given 15 mg every other day for CrCl <30 ml/min, or 15 mg thrice per week on the day after dialysis but due to toxicity R dose was reduced to 10 mg. So far, 13 patients have been treated with attenuated-dose RdC: 3 patients achieved a CR, one achieved a cardiac and one patient a liver response. However, the non-hematologic toxicity of the combination in patients with renal impairment was significant including fatigue (53%), infections (38%), rash (31%), diarrhea (15%), hyponatriemia (15%). Three patients discontinued treatment due to toxicity after the 1st cycle (including one early death due to non-neutropenic infection). In conclusion, RdC is an effective oral regimen for patients with AL amyloidosis, inducing significant rates of hematologic and organ responses. The recommended dose for RdC was R at dose of 15 mg, C at a dose of 100 mg and 20 mg of D and is further evaluated in the phase II of the study. Toxicity is manageable for patients with serum creatinine <2.5 mg/dL but can be significant for AL patients with more severe renal impairment. Lower doses of R, at 10 mg or less every other day or thrice per week should be used in these patients. Accrual in the phase II study is ongoing and updated results will be presented at the meeting. Disclosures: Dimopoulos: Celgene: Honoraria, Research Funding.

A Phase 1 Trial of Vorinostat and Pegylated Liposomal Doxorubicin In Relapsed or Refractory Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2816-2816
Author(s):  
Frederick Lansigan ◽  
Stuart Seropian ◽  
Dennis L. Cooper ◽  
Von Potter ◽  
Noelle Sowers ◽  
...  
Keyword(s):  
Dose Level ◽  
Phase 1 ◽  
Pegylated Liposomal Doxorubicin ◽  
Cell Transplant ◽  
Heavily Pretreated ◽  
Level 3 ◽  
Refractory Lymphoma ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 2816 Background: Vorinostat is a histone deacetylase inhibitor with activity in lymphoma and leukemia. Vorinostat has been reported to act synergistically with topoisomeraseII inhibitors such as anthracyclines (Ac) by facilitating an open chromatin configuration thus enhancing double-strand DNA breaks and apoptosis. We conducted a phase 1 study of escalating doses of vorinostat with pegylated liposomal doxorubicin (V+PLD) in patients with relapsed or refractory lymphoma. The primary objective was to determine the maximum tolerated dose (MTD). Other endpoints included safety, tolerability, and activity of V+PLD. Methods: Patients age ≥18 years with relapsed or refractory lymphoma were enrolled sequentially into 1 of 3 dosing levels using a standard 3+3 design for up to 8 cycles. The study was conducted in accordance with the Declaration of Helsinki, good clinical practice and regulatory guidelines. Vorinostat 200 (dose level 1), 300 (dose level 2), or 400mg (dose level 3) twice daily on days 1–7 and PLD 30mg/m2 on day 3 of a 21-day cycle were administered to eligible and consenting patients. CTCAE v.3.0 was used to determine toxicities, and the revised criteria for malignant lymphoma were used to determine response. Results: 14 patients have been enrolled; 2 men and 12 women; median age 69 years [range 27–88]; median prior therapies (4) [1-11]; prior Ac (13); median prior Ac dose (300mg/m2) [108-440mg/m2]; prior HDACi (1); Dose level 1 (7); Dose level 2 (4); Dose level 3 (3). Lymphoma subtypes included: Hodgkin's lymphoma (HL)(4), peripheral T-cell lymphoma (3), diffuse large B-cell lymphoma (DLBCL)(5), grey zone lymphoma (1), lymphoplasmacytic lymphoma (1). Median number of study cycles was two [1-8](2). Grade 3–4 hematologic toxicities included: neutropenia (3) and thrombocytopenia (1). Grade 3–4 non-hematologic toxicities included: fatigue (2), nausea (1), anorexia (1), dehydration (1), AST/ALT elevation (1), amylase/lipase elevation (1). No cardiac toxicities were observed. There was one death attributed to disease progression. Partial responses (PR) were documented in two HL patients, stable disease (SD) in one HL and one DLBCL patient. Three patients continued therapy beyond 2 cycles. One HL patient with a PR tolerated 8 cycles despite a prior anthracycline dose of 350mg/m2 and 9 prior systemic treatments including ABVD, ICE, GND, DICEP, BEAM and autologous stem cell transplant, Gem and C-MOPP. Another HL patient with a PR after 2 cycles is currently on cycle 3 at dose level 3 and had 5 prior treatments including autologous transplant. One other HL patient with SD discontinued therapy after 2 cycles to proceed with alternative chemotherapy including allogeneic stem cell transplant. One patient with cutaneous DLBCL obtained a skin response but had overall stable disease and completed 6 cycles before disease progression; prior treatment included R-CHOP, R-ICE, CEPP, and GemOx. In addition, one patient with lymphoplasmacytic lymphoma had a clinical response after 1 cycle but therapy was discontinued because of neutropenia and her disease progressed. Conclusions: The combination of V+PLD is well tolerated even among older and heavily pretreated patients. There were no cardiac toxicities even in patients heavily pretreated with anthracyclines. The MTD has not been reached and enrollment to dose level 3 is ongoing. Disease control was achieved in 4 of 14 patients (2 PR and 2 SD). Of interest, 3 of 4 patients with HL achieved disease control (2 PR and one SD), and treatment with vorinostat in combination with anthracycline-based therapy warrants further investigation in HL. Disclosures: Lansigan: Merck: Speakers Bureau. Off Label Use: Vorinostat in combination with pegylated doxorubicin is considered experimental in lymphoma. Foss:Merck: Speakers Bureau.

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