Bevacizumab in combination with TMZ in patients with recurrent GBM: Final OS and PFS analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2087-2087
Author(s):  
Juan Manuel Sepulveda ◽  
Cristobal Belda-Iniesta ◽  
Miquel Gil ◽  
Pedro Pérez Segura ◽  
Alfonso Berrocal ◽  
...  
Keyword(s):  
Median Number ◽  
Medical Decision ◽  
Subtotal Resection ◽  
Toxicity Profile ◽  
Open Label ◽  
Macdonald Criteria ◽  
Baseline Characteristics ◽  
Dose Dense ◽  
Ecog Ps ◽  
Recurrent Gbm

2087 Background: BEV provides a consistent clinical benefit in the treatment of relapsing GBM in terms of a delayed progression and increased median overall survival compared to historical controls. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of BEV with dose dense TMZ, reporting the final results of PFS, OS and the toxicity experienced. Methods: A phase II multicenter, national, open-label study in pts diagnosed of recurrent GBM treated with BEV 10 mg/kg day q2w and TMZ 150 mg/m2 days 1-7 and 15-21 q28d d until disease progression or unacceptable toxicity or medical decision, as first line of treatment all pts received radiotherapy and at least 3 cycles of adjuvant TMZ. This study evaluates efficacy by PFS as primary endpoint and as secondary endpoints: OS, RR based on the adapted MacDonald criteria and toxicity profile (NCI CTC v3.0). Results: From June 10 to July 11, 32 evaluable pts were recruited in 8 sites. The baseline characteristics were as follows: 17 males and 15 females, median age 57.5 y (29-74), ECOG PS 0: 25%, PS 1: 50% and PS 2: 25%, 44% patients had gross total resection, 50% had subtotal resection and 6% biopsy only, MGMT promotor was methylated in 12 pts, unmeth in 6 pts and missing in 14 pts. The median number of TMZ or BEV cycles administered across all patients was 4 (TMZ range 1-9 and BEV range 1-25) The median PFS was 4.4 m [IC 95% (3.7 – 5.6)]. The 6m-PFS probability was 29.25%. The median OS (75% events) was 7.5 m[IC 95% (5.98 – 9.11)]. No significant association with MGMT status was found in terms of OS or PFS. BEV related AEs have been reported in 56.2% of the population being most of them mild or moderate. Grade 3-4 most frequent toxicity: lymphopenia 31% and fatigue 12.5%. Six of 32 pts were long term survivors, in this population the median PFS was 9.8 m [IC 95% (8.2 – 24.4)] and median OS (50% events) was 15.9 m [IC 95 %( 9.2 – NA)], no differences in baseline characteristics were identified in comparison with total population. The median number of TMZ cycles administered was 4 and median BEV cycles were 9. Conclusions: Although the combination don’t met the previous reported activity of BEV, 19% of patients had longer survivals which suggest the need to identify patients that benefit for this treatment. Clinical trial information: NCT01115491.

Randomized open label phase II study of pegilated liposomal doxorubicine (PLD) four or six-week scheduled in metastatic breast cancer (MBC) patients (p)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10751-10751 ◽  
Author(s):  
M. Ruiz ◽  
J. L. Bayo ◽  
J. A. Moreno Nogueira ◽  
J. Dorta ◽  
A. M. Casas ◽  
...  
Keyword(s):  
Median Time ◽  
Ductal Carcinoma ◽  
Metastatic Breast ◽  
Stage Iv ◽  
Dose Intensity ◽  
Primary Objective ◽  
Comparable Efficacy ◽  
Toxicity Profile ◽  
Open Label ◽  
Ecog Ps

10751 Background: PLD has the advantage of delivering the active anthracycline directly to the tumour site, provide comparable efficacy to conventional doxorubicin with a more favourable toxicity profile and significantly less cardiotoxicity. The most frequent dosing schedule is 50 mg/m2 every 4 weeks. Recent studies have shown that PLD 60 mg/m2 every 6 weeks is an active and well tolerated treatment, and could be more convenient for the p. The primary objective was to evaluate response rate in six- and four-week schedule (arms A and B). Secondary objective was toxicity profile. Methods: P histologically confirmed of MBC, age 18–75 years old, ECOG PS ≤ 2, at least one measurable lesion and adequate bone marrow, renal, hepatic and cardiac function, were eligible. Prior chemotherapy with anthracyclines for MBC or adjuvant anthracycline-based regimen in the previous 12 months was not allowed. P were randomly assigned to receive PLD 60 mg/m2 i.v. in 1 hour every 6 weeks (arm A) or PLD 50 mg/m2 i.v. in 1 hour every 4 weeks (arm B). Results: Ten p have been included in the interim analysis over 11 enrolled, with median age of 50 years, ECOG PS 0–1 70% and stage IV 50%. Median time from diagnosis of metastatic disease was 9.2 months. Histology: 80% of p had ductal carcinoma, 10% lobular and 10% undifferentiated. Main tumour locations were lung (60%), liver (60%) and bone (40%). Two p had positive hormonal receptor status in arm A and 4 in arm B. Previous treatment included chemotherapy (80%), hormonotherapy (80%) and radiotherapy (40%). Up to date, a total of 15/17 cycles (median 3/3, range 1–6/1–5) were administered. Absolute dose intensity was 2.2 mg/day in arm A and 3.0 mg/day in arm B. Two p were not evaluated and over 8 evaluable p for efficacy (4 A and 4 B), 2 achieved partial response in arm A and 1 in arm B. Median time to progression was 168 days in arm A and 104 in arm B. The only grade III/IV toxicity was mucositis and stomatitis in 4 p. The most common grade I/II toxicities were palmar-plantar erythrodysesthesia (5p), anorexia (4p) and alopecia (4p). Conclusions: PLD at 50 mg/m2 every 4 weeks and 60 mg/m2 every 6 weeks are effective and well tolerated regimens in MBC p. The most relevant adverse events were mucositis and palmar-plantar erythrodysesthesia. No significant financial relationships to disclose.

AVALUZ study: First line with bevacizumab in combination with paclitaxel (P) and gemcitabine (G) in patients with HER2-negative or recurrent mBC: OS analysis.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11535-e11535
Author(s):  
Javier Salvador ◽  
Eva M. Ciruelos ◽  
Manuel Codes ◽  
Ana Jaen ◽  
Miquel Gil ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Response Rate ◽  
Dose Intensity ◽  
Response Assessment ◽  
High Response Rate ◽  
Medical Decision ◽  
Published Data ◽  
Toxicity Profile ◽  
First Line ◽  
Open Label

e11535 Background: The combination of bevacizumab (B) with taxanes, capecitabine or anthracyclines has shown increased PFS in pts with mBC. The combination with G and P has been evaluated and has demonstrated high response rate and good toxicity profile. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of B with G and P, providing the final result of PFS, update of OS and the toxicity experienced in all pts treated. Methods: A phase II multicenter, national, open-label study in pts diagnosed of recurrent or metastatic HER-2 negative BC, treated with first line B 10 mg/kg, P 150 mg/m2 and G 2000 mg/m2 day 1 and 15 c/28 d until progression disease, unacceptable toxicity or medical decision. This abstract evaluates efficacy by PFS as primary endpoint and as secondary endpoints: OS, response rate and toxicity profile (NCI CTC v3.0 criteria). Results: From January 2009 to December 2009, 82 evaluable pts were recruited in 23 sites. The characteristic of the all of pts included (90) are: median age 51.5 (26-81), ER + 68%, PR + 59%, triple negative pts 19%, previous chemotherapy (neoadj or adj) 64.4% and > 3 metastatic sites 21% of patients (19). The median cycles administered per pts was 7 (1-28) and the relative median dose intensity was 0.93 for B, 0.89 for P and 0.91 for G. Of the 76 pts with response assessment, the overall response rate obtained was 72% with a clinical benefit of 89.5% (80.3-95.34%). Of the 82 pts with a median follow up of 20.21m (0.23- 30.07), median PFS (50% events) for these pts was 11.51 m (9.01-17.6), the median duration of first response (MDR) was 12.4 m (7.6-15.2) and the median OS (42% events) was 27.4 m (21.9- NA). The one year OS % was 84.15 (74.27 – 90.47). Toxicity was generally manageable. Related AEs have been reported in 69/82 pts which were mostly mild or moderate. Safety analysis revealed 24 SAEs in 21 pts Conclusions: Bevacizumab in combination with paclitaxel and gemcitabine showed significant OS compared with the published data with paclitaxel and gemcitabine and high clinical benefit with manageable safety profile.

Phase II study of talabostat and rituximab in fludarabine/rituximab-resistant or refractory patients with CLL

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6598-6598 ◽  
Author(s):  
K. D. Khan ◽  
S. O’Brien ◽  
K. R. Rai ◽  
J. R. Brown ◽  
C. Abboud ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Stage Iv ◽  
Response Duration ◽  
Median Number ◽  
Open Label ◽  
Eligibility Criteria ◽  
Primary Resistance ◽  
Molecule Inhibitor ◽  
Grade 3 ◽  
Ecog Ps

6598 Background: Talabostat (TAL) is an orally administered small molecule inhibitor of dipeptidyl peptidases such as CD26 and fibroblast activation protein (FAP) in bone marrow, lymph nodes, and stroma of solid tumors, and TAL induces cytokine and chemokines in lymph nodes and spleen. TAL enhances the activity of rituximab (RTX) in a mouse model of lymphoma. This study evaluates the efficacy of TAL + RTX in patients with advanced CLL who failed fludarabine (FLU) and/or RTX. Methods: Single-arm, open-label study of RTX 375mg/m2 weekly × 4 weeks, and TAL-300mcg BID for 6 days following each RTX infusion for a tx course of 28 days. Additional courses permitted depending on tolerability. Eligibility criteria include ECOG PS 0–2, CD20+ B-CLL, Rai Stage III/IV or Rai I/II with marked lymphadenopathy, no CNS metastases, and primary resistance or PD following FLU and/or RTX. Primary endpoint is response rate per NCI-WG criteria. Secondary endpoints include response duration, PFS, and survival. Results: 40 patients (32 men, 8 women), median age 64.0 (range 42–83) have entered the study. Most (85%) are caucasian, and 78% of patients are Rai Stage IV. Mean serum B2 microglobulin is 6.5mg/L. The median number of prior regimens is 4 (range 1 to 10); 78% of patients received prior RTX and 33% prior alemtuzumab. Partial response (PR) has been reported in 8/36 evaluable patients (22%), 6 of whom had failed RTX; 3 of these patients had also failed alemtuzumab. Response duration currently ranges from 2 to 10 months (median 5.0 months). Most toxicities are Grade 1 or 2, and include nausea, fever (28% each), and edema (25%). Fever with associated Grade 3 or 4 neutropenia is reported in 2 and 1 patient, respectively. Other Grade 3 AEs include dyspnea (n=3), fatigue (n=2), and aspergillus pneumonia and a dermal fungal infection in 1 patient each. Grade 4 AEs are thrombocytopenia, hypoglycemia, and pulmonary embolism in 1 patient each. 4 patients died due to CLL (2 due to PD) or related complications (PE or MRSA pneumonia, 1 each). Conclusions: TAL + RTX shows promising activity in CLL patients with advanced disease who failed FLU and/or RTX. AEs are similar to those seen with RTX, with the exception of edema in 25% of patients. Updated results, including median PFS and survival will be presented at the annual meeting. [Table: see text]

Phase II prospective study of dose-dense doxorubucin and ifosfamide in high-grade, locally advanced or metastatic soft tissue sarcoma (STS) patients

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 20509-20509 ◽  
Author(s):  
G. F. Almeida ◽  
G. Castro ◽  
I. Snitcovsky ◽  
S. A. Siqueira ◽  
C. R. Oliveira ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Dose Intensity ◽  
Hepatic Function ◽  
Median Number ◽  
High Dose ◽  
High Grade ◽  
Curative Intent ◽  
Dose Dense ◽  
Number Of Cycles ◽  
Ecog Ps

20509 Background: High grade STS is expected to benefit from dose-dense doxorubicin/ifosfamide (doxo/ifo) sequential chemotherapy. This trial was designed using the two-stage Minimax design, in which 6 responses were needed among the first 19 pts to proceed to the second stage of the trial (a=0.05, β=0.20) to detect a 20% difference in RR as compared to expected 30%. Preliminary results of the first 20 pts are presented. Patients and Methods: Eligible pts had untreated, metastatic or locally advanced, high-grade STS, > 5 cm; age 18- 60 y; ECOG-PS 0–2; normal cardiac, renal and hepatic function; and signed informed consent. Pts were treated with doxo 30 mg/m2/d, D1–3, every 14 d, 3 cycles, followed by ifo 2.5 g/m2/d, D1–5, every 21 d, 3 cycles, with mesna and G-CSF support. Results: 20 pts were enrolled (7 in the neo-adjuvant setting with curative intent, 13 palliative). Median age: 39y (23–60); 5 synovial, 5 leiomyo, 4 sarcoma NOS, 2 MFH, 4 others. Primary site: 11 lower extremity; mean tumor size 13 cm. Median number of cycles was 3 for both drugs. 12 pts completed all planned chemotherapy cycles, and the mean relative dose intensity was 92±15% and 89±16% for doxo and ifo, respectively. Anemia was the most frequent toxicity (18 pts). 75 cycles were administered and grade 3/4 toxicities (CTC NCI 2.0) were observed in 27. G3 neutropenia was observed in 4 pts, none fatal. Thromboembolic events occurred in 4 pts (2 DVT, 2 PE). One pt presented a LVEF drop from 60% to 34% and developed symptomatic cardiac failure. Among 10 evaluable pts who completed chemotherapy, no response (CR or PR) was observed; eight pts had stable and 2 progressive disease. Surgery was performed in 6 pts, 4 of them limb-sparing, without changing the previous surgical plan. None of these pts presented complete pathologic response, with rate of necrosis ranging from 0–60%. At a median follow-up of 6 mo (1–16), 6 pts had died: 4 of disease progression, one sudden death (unknown cause) after 2 wks from the last chemotherapy cycle, and one patient died from pulmonary embolism. Conclusion: Sequential high-dose doxorubicin followed by ifosfamide failed in demonstrating any response in high grade STS, in addition to an unacceptable toxicity profile. Results of overall survival are pending. No significant financial relationships to disclose.

Randomized phase II trial of maintenance sunitinib versus placebo following response to chemotherapy (CT) for patients (pts) with advanced urothelial carcinoma (UC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 265-265 ◽  
Author(s):  
Petros Grivas ◽  
David M. Nanus ◽  
Walter Michael Stadler ◽  
Stephanie Daignault ◽  
Robert Dreicer ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Placebo Response ◽  
Complete Response ◽  
Median Number ◽  
Progression Rate ◽  
Open Label ◽  
Best Response ◽  
Response To Chemotherapy ◽  
Ecog Ps

265 Background: UC response to CT is not durable. Angiogenesis may play a role in the progression of UC. We evaluated whether maintenance sunitinib delays progression after response to CT. Methods: Pts with ECOG PS 0-2, adequate organ function, stable disease, partial or complete response (SD, PR, CR) after 4-6 cycles of CT for advanced UC were randomized to oral sunitinib 50 mg/day, 28 days on, 14 days off (6-week cycle) or placebo. Disease was assessed every 12 wks. At progression, placebo pts were offered open label sunitinib. Primary endpoint: progression rate at 6 months (ms); secondary endpoints: safety, objective response rate, survival, VEGF/sVEGFR2 serum level changes. Using a randomized selection design 42 pts/arm has 90% probability of selecting sunitinib if true reduction in 6-ms progression rate is 15% (from 50% to 35%). Results: Study was closed early due to slow accrual. 54 pts with median age 69 years, median ECOG PS 1, 70% with bladder primary, 26 with SD, 23 with PR, 5 with CR to CT were randomized to sunitinib (26) or placebo (28). The median number of cycles was 2/arm (sunitinib 0-15, placebo 0-13). The 6-ms progression rate was 81% (95%CI 61-93%), median time-to-progression (TTP) 5 ms (0.3-22.2, 95%CI 2.4-6.3) for sunitinib and 75% (95%CI 55-89%), 2.7 ms (0.8-19.6, 95%CI 2.5-7.4) for placebo. Response rate in pts with SD at enrollment was 9% for sunitinib and 7% for placebo. Most common G3/4 AEs on sunitinib were diarrhea (15.4%/0%), fatigue (15.4%/3.8%), thrombocytopenia (15.4%/7.7%), hypertension (11.5%/0%). 16 placebo pts received sunitinib with best response 1 PR (6.25%), 6 SD (37.5%), 5 PD (31.25%); 4 not response evaluable. Median TTP was 3.4 ms (0.1-22, 95%CI 1.6-5.5). 11 pts had G3/4 AEs, 5 pts discontinued sunitinib due to AEs (4 related, 1 unrelated). Placebo pts had no change in VEGF/sVEGFR2 over time. Sunitinib pts had no change in VEGF but sVEGFR2 significantly decreased after 1 cycle (p<0.0001) and at progression (p=0.0002). VEGF/sVEGFR2 did not correlate with TTP. Conclusions: Maintenance sunitinib was feasible but did not improve 6-ms progression rate; open label sunitinib had limited activity. sVEGFR-2 decreased on sunitinib.

Phase IIa trial of cilengitide (EMD121974) single-agent therapy in patients (pts) with recurrent glioblastoma (GBM): EMD 121974-009

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2002-2002 ◽  
Author(s):  
D. Reardon ◽  
K. Fink ◽  
B. Nabors ◽  
T. Cloughesy ◽  
S. Plotkin ◽  
...  
Keyword(s):  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Recurrent Glioblastoma ◽  
Tumor Control ◽  
Clinical Activity ◽  
Open Label ◽  
Recurrent Gbm

2002 Background: Our phase IIa study evaluated the safety, toxicity, and clinical activity of the cyclic RGD pentapeptide cilengitide (EMD121974), an inhibitor of integrins avβ3 and avβ5, as a single agent at doses of 500 and 2000 mg in pts with recurrent GBM. Methods: In this multicenter, open-label, randomized, uncontrolled study, pts with GBM and measurable disease that had relapsed after previous temozolomide and radiotherapy were randomized to receive cilengitide at either 500 mg or 2000 mg i.v., 2x/week, until progression. Neurologic exams were performed after every cycle (4 weeks) and MRIs were performed every other cycle. Central, blinded pathology and radiology reviews were performed. The primary endpoint was Progression Free Survival (PFS) at 6 months (6-mth PFS). Secondary endpoints included response, survival, time to disease progression, safety, tolerability and pharmacokinetics (PK). Results: 81 pts accrued (median Karnofsky Performance Status 80%; median age 57 yrs) at 15 sites including 41 at the 500 mg and 40 at the 2000 mg dose levels. Demographic and pretreatment variables were comparable between dose level cohorts. The median number of infusions was 16 [range, 4–179]. PK studies revealed significantly greater exposures among the 2000 mg cohort. Treatment related NCI CTC grade 3 adverse events (AEs) included elevated transaminases (at 500 mg), arthralgia/ myalgia (at 500 mg), and weight increase/ edema (at 2000 mg) in 1 patient, respectively. No grade 4 therapy related AEs were reported. One CTC grade 2 cerebral hemorrhage was reported in a pt at progression. The 6- mth PFS was 16.1% (n=13/81 pts). 10 pts (12.3 %, n=4 with 500 mg, n=6 with 2000 mg) received 12 or more cycles. Six pts (7.4%) remain progression-free and on treatment. Median Overall Survival (mOS) was 6.5 mths [95% CI: 5.2–9.3 mths] in the 500 mg arm and 9.9 mths [95% CI, 6.3–15.7 mths] in the 2000 mg arm. Although not statistically significant, there was a trend towards better tumor control in pts receiving 2000 mg 2x/week. Conclusions: Cilengitide was well tolerated and demonstrated single agent activity in recurrent GBM, with long term disease stabilization in a subset of pts. [Table: see text]

Efficacy and safety of bevacizumab combined with capecitabine in progressive, metastatic well-differentiated digestive endocrine tumors (BETTER study).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4071-4071 ◽  
Author(s):  
Emmanuel Mitry ◽  
Thomas Walter ◽  
Eric Baudin ◽  
Jean-Emmanuel Kurtz ◽  
Philippe Ruszniewski ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Median Number ◽  
Tumor Control ◽  
Endocrine Tumors ◽  
Open Label ◽  
Ki 67 ◽  
Primary Tumor Site ◽  
Ecog Ps

4071 Background: Neuroendocrine digestive tumors are highly vascularized neoplasms known to express the vascular endothelial growth factor (VEGF). We assessed the activity of bevacizumab (Bv), a monoclonal antibody directed against VEGF combined with capecitabine (CAP). Methods: In this multicenter, open-label, non-randomized, two-group phase II trial, one group assessed Bv (7.5 mg/m² on d1/3 weeks) combined with CAP (1,000 mg/m2 twice daily, orally d1-14, resumed on day 22). Eligible patients (pts) had progressive, metastatic well-differentiateddigestive tract endocrine tumors (WHO 2000 classification), ECOG-PS ≤2, Ki 67 index < 15%, no prior systemic chemotherapy and acceptable organ functions. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival, response rate, safety and quality of life. Pts were treated for a minimum of 6 months and study duration was 24 months. Results: From Jun 2007 to Oct 2009, 49 pts were enrolled, 26 (53.1%) were men; median age 60.3 years (41.2-82.3); ECOG-PS was 0/1 in 46 (93.9%) pts. Primary tumor site was: small intestine 40 (81.6%) pts, caecum 3 (6.1%), rectum 4 (8.2%) and stomach 2 (4.1%). Ki-67 proliferative index was 0-2% in 17 (35.4%) pts, 3-4% in 14 (29.2%), 5-9% in 13 (27.1%), 10-14% in 4 (8.3%) Metastatic sites were liver: 46 (93.9%) pts, lymph nodes: 24 (49.0%), peritoneum 23 (46.9%). Median treatment duration was 13.8 months; median number of cycles was 19. At 24 months, median PFS was 23.4 months [95%CI: 13.2; not reached] based on 26 events. PFS rate at 18 months was 55%. Tumor control rate was 87.8% (n=43) including partial response in 9 (18.4%) pts and stable disease in 34 (69.4%) pts. Survival rate at 24 months was 85%, median overall survival was not reached, 8 patients died. CTC grade 3/4 Adverse Events (AEs) occurred in 41 (83.7%) pts, mainly digestive 14 (28.6%) pts. Main G3/4 Bv targeted AE was hypertension in 15 (30.6%) pts. Conclusions: In this chemotherapy resistant tumor, the combination of capecitabine and bevacizumab, assessed in a phase II study, shows such encouraging results that this combination may become a reference in the medical treatment of ileal NET.

Phase Ib study of NGR-hTNF, a selective vascular targeting agent (VTA), in combination with cisplatin in patients with refractory solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3570-3570
Author(s):  
G. Citterio ◽  
F. G. De Braud ◽  
V. Gregorc ◽  
T. M. De Pas ◽  
R. Scalamogna ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Low Dose ◽  
Dose Range ◽  
Progression Free Survival ◽  
Median Number ◽  
Infusion Reaction ◽  
Toxicity Profile ◽  
Lung Cancer Patients ◽  
Dose Scheme ◽  
Ecog Ps

3570 Background: NGR-hTNF is a VTA exploiting a tumor-homing-peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed on tumor blood vessels. In preclinical models, significant synergy between low-dose NGR-hTNF and cisplatin was shown. Methods: Patients with resistant/refractory solid tumors were treated with NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A 3+3 escalation/de-escalation design was followed. PK sampling was performed after the first 3 cycles. DLT definition: any G3–4 toxicity related to NGR-hTNF. Results: 22 patients (median age: 60 years, range, 47–75; 14M/8F; ECOG PS 0/1 12/10) with different tumor types were evaluated over 77 cycles (range, 1–10). Median number of prior regimens was 3 (range, 1–6) and 12 patients (55%) were previously treated with platinum-based regimens. Both NGR-hTNF Cmax and AUC increased proportionally with dose. The combination was safe without PK interaction or exacerbation of platinum-associated toxicity profile. No shedding of soluble TNF receptors was observed up to 0.8 μg/m2. As expected for the low-dose range explored, MTD was not reached and no DLTs were registered at 0.2 μg/m2 (n = 4), 0.4 μg/m2 (n = 3) and 1.6 μg/m2 (n = 3). At 0.8 μg/m2, a patient had a G3 transient acute infusion reaction. This cohort was expanded up to 6 patients for safety reasons, with no DLTs registered, and up to 12 patients, for preliminary activity evaluation. At this dose level of 0.8 μg/m2, two lung cancer patients, both pre-treated with platinum, achieved a partial response (-79%) and a significant tumor shrinkage (-28%) lasting 7.2 and 6.7 months, respectively, and an additional 4 patients experienced stable disease for a median duration of 6.4 months. The median progression-free survival for all patients (n = 22), for patients enrolled at 0.8 μg/m2 (n = 12), and for patients pre-treated with platinum (n = 9) was 2.7, 4.7, and 4.3 months, respectively. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 shows a favourable toxicity profile and promising antitumor activity. [Table: see text]

Phase II study of biweekly cetuximab (C) and irinotecan (I) as a second-line regimen for metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15088-e15088
Author(s):  
B. A. Carneiro ◽  
N. Bahary ◽  
B. Lembersky ◽  
M. Fakih ◽  
S. S. Krishnamurthi ◽  
...  
Keyword(s):  
Sample Size ◽  
Phase Ii ◽  
Small Sample Size ◽  
Median Number ◽  
Small Sample ◽  
Second Line ◽  
Braf Mutations ◽  
Open Label ◽  
Prior Therapy ◽  
Ecog Ps

e15088 Background: I + C is a standard second line mCRC regimen. Our study investigated the efficacy and safety of a biweekly I + C combination in patients (pts) with mCRC. Methods: mCRC pts who failed 1st line fluoropyrimidine/oxaliplatin regimens and had not received I or C, were eligible for this open label phase II trial with response rate (RR) as the primary end-point and planned sample size of 31 patients to achieve a 25% RR with 80% power. C 500 mg/m2 IV was administered on d1 followed by I 180 mg/m2 IV over 60 minutes biweekly. Results: Pt. characteristics (n=32): Male (n=17), female (n=15), Median age 59.9; ECOG PS ≤1 (31 pt), PS=2 (1). Median number of cycles 3 (range 1–21), 17pts received ≤ 3 cycles. Chemotherapy doses were reduced/delayed in 20 pts. Initial I dose was reduced to 150mg/m2 in 12 pts due to previous radiation (6 pts), age ≥ 70 years (5 pts), or PS 2 (1 pt). Grade 3 or 4 adverse events: acneiform rash (n=6), diarrhea (n=5), and neutropenia (n=4); possible grade 5 (respiratory failure). One PR was seen, 12 pts had stable and 13 pts PD; 6 pts were not evaluable for response. Median OS 11.1 mos (95% CI 6.0–15.1) and TTP 2.4 mos (95% CI 1.4-NA). Among the 23 pts tested, 9 pts had KRAS, and 2 pts BRAF mutations. There was a trend towards higher OS and TTP among pts with wild type (wt) KRAS (OS 11.9 vs 9.96mo, p=0.66; TTP 5.97 vs 3.11mo, p=0.288) and BRAF (OS 12 vs 4.6mo, p=0.17; TTP 4.56 vs 1.86mo, p=0.239). Conclusions: The lower RR than previously reported was likely caused by the small sample size and possibly those factors leading to initial I dose reductions. In addition 90% of patients had prior therapy with FOLFOX/bevacizumab. The OS and TTP are consistent with those reported previously (Martin et al Brit J Cancer 2008, Pfeiffer P et al Ann Oncol 2008), supporting biweekly I + C as a convenient second-line regimen in mCRC. [Table: see text]

Final results of NKTR-102, a topoisomerase I inhibitor-polymer conjugate, in patients (Pts) with pretreated metastatic breast cancer (MBC) demonstrating significant antitumor activity.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 269-269 ◽  
Author(s):  
A. Garcia ◽  
A. Awada ◽  
S. Chan ◽  
G. H. M. Jerusalem ◽  
R. E. Coleman ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Metastatic Breast ◽  
Study Drug ◽  
Median Number ◽  
Phase Iii ◽  
Open Label ◽  
Topoisomerase I Inhibitor ◽  
Polymer Conjugate ◽  
Open Label Phase ◽  
Ecog Ps

269 Background: NKTR-102 is a topoisomerase I inhibitor-polymer conjugate with reduced peak concentration and a continuous concentration profile. Methods: This was an open-label phase II study in MBC pts following PD on a taxane (T). Pts were randomized to NKTR-102 given IV at 145 mg/m2 over 90-min every 14 or 21 days. Efficacy endpoints included ORR by RECIST v1.0; PFS and OS. Results: 70 pts (35 per schedule) randomized from Feb 2009 to May 2010 (median follow-up: 10 mo). Median age: 55 (range 33–83). ECOG PS 0/1: 40%/60%. Neoadjuvant and/or adjuvant: 74%. Median number of prior cytotoxic regimens for metastatic disease: 2. All pts had received prior T: 7% (adjuvant); 93% (metastatic). 89% had received prior anthracyclines (A): 63% (adjuvant); 26% (metastatic). 63% had received prior AT only (23% in MBC); an additional 26% had received prior AT/capecitabine (ATC). 61% were ER/PR+; 30% had TNBC; 86% had visceral metastases. Median PFS for q14d, q21d and overall were 3.5 mo, 5.3 mo and 4.6 mo. Median OS for q14d, q21d and overall were 8.8 mo, 13.1 mo and 10.3 mo. Toxicity was manageable, with diarrhea as the most common grade 3+ toxicity, with median time to onset ∼3 mo. Discontinuation from study drug due to AEs: 20%/14% for q14d/q21d. Neuropathy was absent; alopecia was minimal (20%/11% grade 1–2 for q14d/q21d). Conclusions: NKTR-102 demonstrates significant anti-tumor activity in pts with advanced MBC, including poor prognosis pts with TNBC and having received prior ATC. A phase III study is being planned in patients with MBC previously treated with taxanes. [Table: see text]

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