Phase II trial of the CDK4 inhibitor PD0332991 in CDK4-amplified liposarcoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10002-10002 ◽  
Author(s):  
Mark Andrew Dickson ◽  
Mary Louise Keohan ◽  
William D. Tap ◽  
Cristina Antonescu ◽  
Jonathan Landa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Stable Disease ◽  
Systemic Therapy ◽  
Promising Result ◽  
Progression Free Survival ◽  
Median Number ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Cdk4 Inhibitor

10002 Background: CDK4 is amplified in approximately 90% of well-differentiated/de-differentiated liposarcomas (WD/DDLS). The selective CDK4/CDK6 inhibitor PD0332991 (PD) inhibits growth and induces senescence in liposarcoma cell lines and xenografts. In a phase I trial of PD, several patients with progressive WD/DDLS had prolonged stable disease for several years. To determine the safety and efficacy of PD, a phase II study was performed. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age≥18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥1+). Pts received oral PD 200mg daily for 14 consecutive days in 21-day cycles. The primary endpoint was progression-free survival (PFS) at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD would be considered to have activity in WD/DDLS. Results: Of 44 patients screened (42/44 CDK4 amplified; 41/44 RB+), 29 were enrolled and 27 were evaluable for the primary endpoint. Median age was 65 (range 37-83); 52% were male; ECOG scores were 0 (69%) or 1 (31%), and the median number of prior regimens was 1 (range 1-5). PFS at 12 weeks was 70% (19/27 patients; 90% CI 56-100%), and thus the study significantly exceeded its primary endpoint. At the data cutoff, the median PFS was 18 weeks. Seven patients remain on study with stable disease at 18-48 weeks of followup. Grade 3 and 4 events included anemia (grade 3, 14%), thrombocytopenia (grade 3, 17%; grade 4, 14%), neutropenia (grade 3, 41%; grade 4, 7%) and febrile neutropenia (3%). Dose reductions were required in 24% of patients. Conclusions: Among patients with WD/DDLS with CDK4 amplification and RB expression who had actively progressing disease despite prior systemic therapy, treatment with the CDK4 inhibitor PD0332991 was associated with improved PFS. A randomized phase 3 trial is planned.

Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Mark Andrew Dickson ◽  
William D. Tap ◽  
Mary Louise Keohan ◽  
Sandra P. D'Angelo ◽  
Mrinal M. Gounder ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Promising Result ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Eligibility Criteria ◽  
Well Differentiated ◽  
Grade 3

10512 Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ≥ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (≥1+). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ≥40% and not promising as ≤20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting > 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.

MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
T. J. Hobday ◽  
J. Rubin ◽  
K. Holen ◽  
J. Picus ◽  
R. Donehower ◽  
...  
Keyword(s):  
Growth Factor ◽  
Neuroendocrine Tumors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Uncontrolled Hypertension ◽  
Eligibility Criteria ◽  
Grade 3

4504 Background: Treatment options for metastatic NET, including islet cell carcinoma (ICC) and carcinoid tumor (CT), are limited. These tumors frequently express vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet derived growth factor receptor receptor-β (PDGFR-β). Sorafenib, a small-molecule inhibitor of the VEGFR-2 and PDGFR-β tyrosine kinase domains, is a rational targeted therapy to evaluate in NET. Methods: Eligibility criteria included: ECOG PS = 2, = 1 prior chemotherapy, good organ function and signed informed consent. Prior interferon and prior or concurrent octreotide at a stable dose were allowed. Pts unable to take oral medications, with uncontrolled hypertension or with symptomatic coronary artery disease were excluded. Pts received sorafenib 400 mg po BID. Primary endpoint was response by RECIST in two cohorts (ie, CT and ICC) using separate 2-stage phase II designs. Results: 93 pts were enrolled: (50 CT, 43 ICC). For pts evaluable for the primary endpoint, 4 of 41 (10%) CT pts and 4 of 41 (10%) ICC pts had a PR. There were 3 minor responses (MR = 20–29% decrease in sum of target lesion diameters) in CT pts and 9 MRs in ICC pts for PR+MR rate of 17% for CT pts and 32% for ICC pts. For pts evaluable, 6-month progression-free survival was observed in 8/20 CT and 14/23 ICC pts. Grade 3–4 toxicity occurred in 43% of pts, with skin (20%), GI (7%) and fatigue (9%) most common. Translational studies from tumor tissue will be presented. Conclusions: Sorafenib at 400 mg po BID has modest activity in metastatic neuroendocrine tumors, with frequent grade = 3 toxicity. Supported by NOI CM6225. No significant financial relationships to disclose.

Phase II study of bevacizumab in combination with cisplatin and docetaxel as first-line treatment of patients (p) with metastatic non-squamous non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19023-e19023
Author(s):  
N. Ferrer ◽  
M. Cobo ◽  
A. Paredes ◽  
M. Méndez ◽  
J. Muñoz-Langa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Median Number ◽  
Line Treatment ◽  
Eligibility Criteria ◽  
Platinum Based Chemotherapy ◽  
History Of ◽  
Grade 3 ◽  
Number Of Cycles

e19023 Background: Bevacizumab (B), in addition to platinum-based chemotherapy, is indicated for 1st-line treatment of p with advanced NSCLC other than predominantly squamous cell histology. B has been shown to improve progression free survival (PFS) and overall survival (OS) when combined with cisplatin/gemcitabine and carboplatin/paclitaxel, respectively. However, there are limited data on the safety and efficacy of B in combination with other widely used chemotherapy doublets for NSCLC. This is a single-arm, open- labeled, single-stage phase II trial of cisplatin (C), docetaxel (D) and B for NSCLC. Methods: Eligibility criteria: chemo- naïve, stage IIIB wet or IV, non-squamous NSCLC, PS 0–1, no brain metastases and no history of gross hemoptysis. P received D (75 mg/m2), C (75 mg/m2), and B (15 mg/kg iv) on day 1 every 3 weeks for up to 6 cycles, followed by B 15 mg/kg alone every 3 weeks until disease progression or toxicity. Primary endpoint: PFS. Results: 50 p were enrolled (enrollment completed): 24% female, median age 60 (36–74), PS 1: 64%, adenocarcinoma: 72%; stage IV: 92%. Two p did not start treatment. Median follow-up is 5.3 months (range 0–13.6). Median number of cycles of B was 7 (range 0–18). 56% completed 6 cycles of treatment; 24% received ≥ 12 cycles of B. Most frequent grade ≥ 3 toxicities: diarrhea (14.6%), fatigue (14.6%), dyspnea (9.8%), anorexia (4.9%), alopecia (4.9%), esophagitis (4.9%), constipation (4.9%), mucositis (12.2%), proteinuria (4.9%); hematological toxicities: neutropenia (22%), febrile neutropenia (9.8%), leucopenia (14.6%), lymphopenia (4.9%). Of interest, 41.5% developed grade <3 epistaxis and 17% hypertension (1 p grade 3). One p died due to hemoptysis. 46 p were evaluable for response: 29 PRs (ORR: 63%). 18 of 48 p have experienced progression or death with a median SLP of 7.8 months (95% CI: 6.6-NR). Median OS is 13.5 months (95% CI: 12.7–13.6; 81.2% p censored); 1-year survival is 83.9% (95% CI: 67.4%-92.5%). Conclusions: Treatment with C, D and B, followed by maintenance B in 1st line of advanced non-squamous NSCLC shows an acceptable toxicity profile and promising efficacy. Final results will be presented. [Table: see text]

Bevacizumab (B), cisplatin, and vinorelbine in chemotherapy-naive patients (p) with nonsquamous non-small cell lung cancer (NSCLC): A Galician Lung Cancer Group phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19089-e19089
Author(s):  
L. Leon ◽  
S. Vázquez ◽  
J. M. Gracia ◽  
M. Lázaro ◽  
J. L. Fírvida ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Survival Data ◽  
Safety Profile ◽  
Progression Free Survival ◽  
Median Number ◽  
Stage Iiib ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Number Of Cycles

e19089 Background: Bevacizumab, an anti-VEGF monoclonal antibody, improves response rates and prolongs survival in p with non squamous NSCLC when combined with carboplatin-paclitaxel or cisplatin-gemcitabine. This single-arm, open-labeled phase II trial aims to evaluate the efficacy and safety profile of B in combination with another widely used chemotherapy doublet for NSCLC: cisplatin and vinorelbine. Methods: Chemotherapy-naïve p diagnosed with stage IIIB or IV non squamous NSCLC received cisplatin (80 mg/m2), vinorelbine (25 mg/m2 IV days 1 and 8) and B (15 mg/kg IV) on day 1 every 3 weeks for up to 6 cycles followed by B 15 mg/kg alone every 3 weeks until disease progression. Main eligibility criteria were: PS 0–1, no brain metastases, no history of hemoptysis, stable cardiac condition and no full dose anticoagulation. Primary endpoint was progression-free survival and secondary endpoints were RR, duration of response, OS, 1-year survival and safety profile of the combination. Results: 38 p have been enrolled in the study and data of 27 p have been included in this analysis. P characteristics were: male 66.7%; median age 57 years (range 41–74); ECOG PS 0/1 (%) 33.3/66.7; adenocarcinoma/other (%) 74.1/25.9; stage IIIB/IV (%) 25.9/74.1. Median number of cycles for B/cisplatin/vinorelbine was 4.0 (range 1–6) and median number of cycles for B maintenance was 2 (range 1–4). 17 p were evaluable for response according to RECIST criteria: PR 29.4% and SD 41.2%. With a median follow-up of 3.9 months (range 0.7–11.1), median PFS was 4.6 months (95% CI: 2.6–6.6) and median OS has not been reached yet. Hematological toxicities were: 1 p gr. 3 anemia; 2 p gr. 3 and 2 p gr. 4 leucopenia; 10 p gr. 3, 1 p gr. 4 neutropenia and 3 p febrile neutropenia. Most common grade 3/4 non hematological toxicities were: vomiting (1p gr. 4), high blood pressure, asthenia and hyperglycemia. 1 p experienced gr. 4 abdominal pain, 1 p. gr. 4 constipation, 1 p. gr. 4 nausea and 1 p gr. 4 respiratory infection. No grade 3/4 hemoptysis were reported. Conclusions: This interim analysis shows that B in combination with cisplatin and vinorelbine is safe and well tolerated and has a promising activity in chemo-naïve p with non squamous NSCLC. Survival data will be updated. [Table: see text]

scholarly journals Phase II Trial of the CDK4 Inhibitor PD0332991 in Patients With Advanced CDK4-Amplified Well-Differentiated or Dedifferentiated Liposarcoma

2013 ◽  
Vol 31 (16) ◽  
pp. 2024-2028 ◽  
Author(s):  
Mark A. Dickson ◽  
William D. Tap ◽  
Mary Louise Keohan ◽  
Sandra P. D'Angelo ◽  
Mrinal M. Gounder ◽  
...  
Keyword(s):  
Phase Ii ◽  
Systemic Therapy ◽  
Progression Free Survival ◽  
Open Label ◽  
End Point ◽  
Open Label Phase ◽  
Well Differentiated ◽  
Grade 3 ◽  
Cdk4 Inhibitor

Purpose CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS. Patients and Methods Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active. Results We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response. Conclusion Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.

Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter's Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2860-2860
Author(s):  
Petra Jenke ◽  
Barbara Eichhorst ◽  
Raymonde Busch ◽  
Nadine Anheier ◽  
Ulrich Duehrsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Research Funding ◽  
Progression Free Survival ◽  
Response Rates ◽  
Median Number ◽  
Response Evaluation ◽  
Free Survival ◽  
Richter's Transformation ◽  
Grade 3

Abstract Abstract 2860 Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter's transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin's lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial. Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated guidelines (Hallek et al., Blood 2008). Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m2, adriamycin 50mg/m2 and vincristine 1, 4mg/m2 d1; prednisone 100mg/m2 d1–5). Rituximab was added starting with the 2nd cycle (375mg/m2 on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response. Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT. A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%. All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos. The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p<0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001). Conclusion: CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients. Disclosures: Eichhorst: Hoffmann La Roche: Honoraria, Research Funding, Travel Grants; Mundipharma: Research Funding, Travel Grants; Gilead: Consultancy. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau. Bergmann:Celgene: Honoraria. Stilgenbauer:Hoffmann La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel Grants. Fink:Hoffmann La Roche: travel grants. Fischer:Hoffmann La Roche:. Wendtner:Hofmann-La Roche: Consultancy, Honoraria, Research Funding. Hallek:Roche: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Honoraria.

Oral metronomic chemotherapy using cyclophosphamide in metastatic patients (pts) after standard treatment: Results of a randomized phase II trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13519-e13519
Author(s):  
S. Clisant ◽  
A. Adenis ◽  
E. Dansin ◽  
C. Desauw ◽  
M. Degardin ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Randomized Study ◽  
Sample Size Calculation ◽  
Metronomic Chemotherapy ◽  
Median Number ◽  
Disease Rate ◽  
Progression Rate ◽  
Severe Toxicity ◽  
Eligibility Criteria ◽  
Grade 3

e13519 Background: Oral metronomic chemotherapy (OMC) has antiangiogenic properties and megestrol acetate (MA) is an orexigen used to maintain the general condition in critically ill pts. Anecdotal responses have been reported with each treatment. We hypothesized that each treatment offer disease control without significant severe toxicity. Methods: This multi-center-randomized study was aimed to assess the efficacy and tolerance of both treatments. Primary endpoint was stable disease rate at 2 months: 2mSD (RECIST). Main eligibility criteria were as follows: non-breast cancer, pts with progressive disease refractory to standard therapies or without established standard care, ECOG=0–1, neither hypercalcemia nor hypoalbuminemia. Pts were randomized to receive MA 160 mg b.i.d or OMC 50 mg b.i.d until severe toxicity or progression. The sample size calculation was based on Simon Minimax design (α=10%, β =90%, P0=5%, P1=20%). The second stage was allowed because at least 2mSD were seen among 12 first pts. Results: 88 pts were included from 9/2006 to 12/2008 (44 in each arm). Median age was 61 (22–84). Most common primaries were: colorectal cancer (30 pts), soft tissue sarcoma (17), lung cancer (13), head & neck (8) and unknown primaries (4). The median number of previous lines of treatment was 4 (0–10). As of 28 December 2008, 80 pts are assessable for primary endpoint: 6/40 pts (15%) experienced 2mSD in OMC arm whereas 2/40 pts (5%) in MA arm. Three long-lasting SD (6 months +) are currently being observed in 3 pts receiving OMC (2 sarcomas and 1 RCC). No Grade 3 or 4 toxicity was notified. Treatment was discontinued in 1 case because of MA- induced deep venous thrombosis. Conclusions: OMC and MA offer SD in patients with advanced, refractory and progressive tumors, without any significant toxicity. The non-progression rate with OMC (15%) is in a same range of efficacy that was recently reported with new targeted therapy or anti-angiogenic agents administered in such pts. The accrual is now completed, and a longer follow-up is necessary to better analyze the clinical benefit and the prognostic factors. [Table: see text]

A randomized phase II trial comparing two doses of lenalidomide for the treatment of stage IV ocular melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20012-e20012 ◽  
Author(s):  
J. B. Zeldis ◽  
C. Heller ◽  
G. Seidel ◽  
N. Yuldasheva ◽  
D. Stirling ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Stage Iv ◽  
Ocular Melanoma ◽  
Eligibility Criteria ◽  
Randomized Phase Ii ◽  
Animal Data ◽  
Disease Stabilization ◽  
Grade 3

e20012 Background: Ocular melanoma is the most common primary intraocular malignancy in adults with an incidence of 4.3 new cases per million. Approximately 50% of patients will develop metastases and the mean survival of those with liver metastases is 8–10 months. There are no effective systemic therapies. Pre-clinical studies of the antiangiogenic and immunomodulatory agent, lenalidomide, have shown promise in animal models of human ocular melanoma. We therefore conducted a phase II trial comparing two doses of oral lenalidomide. Methods: Patients with stage IV ocular melanoma, who met eligibility criteria and demonstrated disease progression, were enrolled on an IRB approved prospective random assignment trial comparing 5 mg and 25 mg of lenalidomide administered once a day orally for 21 days with a 7 day recovery (one cycle). Lesions were measured at baseline and every 3 months and scored for response by RECIST criteria. Patients who completed 3 cycles were eligible for response evaluation. Patients with responding lesions or with stable disease could continue receiving the agent. Toxicity was assessed using the NCI Common Toxicity Criteria. Results: Seventeen patients (13 female, 4 male; mean age 53) met eligibility criteria and were randomized to 5 mg (9 patients) or 25 mg (8 patients) of lenalidomide. The agent was well tolerated at both doses with only three grade 3 toxicities (two decreased ANC and one rash/puritis) requiring dose adjustments. Sixteen patients were eligible for response assessments. Nine patients had progressive disease by RECIST criteria following 3 cycles of therapy. Seven patients (44%) had stable disease for a mean of 7 months (range 6–12 months). There were no RECIST defined responders. There were no differences between the two dose groups with respect to toxicity or disease stabilization. Conclusions: Lenalidomide is well tolerated at doses of 5 mg and 25 mg orally for a 21 day cycle by patients with stage IV ocular melanoma. While no responses were seen, disease stabilization for a mean of 7 months was seen in 44% of patients. This effect was consistent with the pre-clinical animal data. Based on these results, further development of lenalidomide in combination with other agents should be considered for the treatment of metastatic ocular melanoma. [Table: see text]

FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3516-3516 ◽  
Author(s):  
Hiroshi Tamagawa ◽  
Shigeyoshi Iwamoto ◽  
Takao Takahashi ◽  
Masato Nakamura ◽  
Yoshinori Munemoto ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Primary Endpoint ◽  
Therapy Response ◽  
Progression Free Survival ◽  
Optimal Dose ◽  
Phase Iii ◽  
Eligibility Criteria ◽  
Significance Level ◽  
Line Therapy ◽  
Grade 3

3516 Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ≥20 years, mCRC, ECOG PS ≤1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (≥4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p=0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p=0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p=0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.

Phase II study of alternate-day oral therapy with S-1 for unresectable advanced pancreatic cancer: An updated report.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 252-252
Author(s):  
Sohei Satoi ◽  
Motoki Miyazawa ◽  
Masaji Tani ◽  
Manabu Kawai ◽  
Seiko Hirono ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adverse Effects ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Current Data ◽  
Standard Regimen ◽  
Grade 3

252 Background: Based on the results of GEST, S-1 was confirmed to be non-inferior to gemcitabine. However, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effect. Grade3/4 toxicities (%) in S-1 were neutropenia 8.8, anorexia 11.4, diarrhea 5.5. On the other hand, we experienced in clinical practice that the alternate-day administration of S-1 reduced adverse effects and was tolerable for unresectable advanced pancreatic cancer patients unwilling to continue the standard daily administration. We therefore conducted a multi-center cooperative prospective study to compare daily with alternate-day administration of S-1 for unresectable advanced pancreatic cancer. Methods: Patients with unresectable advanced pancreatic cancer (PS, 0 to 1; age, 20 to 80 years; no other therapy) were eligible for enrollment in this trial. S-1 was administered a dose of 40 to 60 mg twice daily, assigned according to body-surface area, on Monday, Wednesday, Friday, and Sunday (specified days). Each treatment cycle will be 42 days (6 weeks). The primary endpoint was overall survival (OS). Secondary endpoints were safety, response rate (RR), progression free survival (PFS), time to treatment failure (TTF). Results: A total of 50 patients were enrolled from Sep 2009 to Feb 2011. 48 patients were evaluable for response. Male/Female was 21/27, PS: 0/1 was 40/8. With a median follow-up time of 28.2 months, OS as primary endpoint was 8.4 months (95% CI, 5.4-10.8) with the 1 year survival rate 29.2%. PFS was 5.5 months, and TTF was 3.9 months. RR was 10.4% (95% CI: 3.5-19.1), and Disease Control rate was 79.2%. Grade 3/4 hematological and non-hematological toxicities were minor. All of those adverse reactions were tolerable and reversible. Conclusions: We will report the data from the final analysis at this meeting. The current data show mitigation of adverse effects with alternate-day administration of S-1, and it appears to be a more sustainable option for unresectable advanced pancreatic cancer. A randomized phase II trial comparing this regimen of S-1 with standard regimen of S-1 is ongoing. Clinical trial information: 000003453.

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