A Phase II Study of Dasatinib in Relapsed and Refractory Chronic Lymphocytic Leukemia (CLL/SLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3126-3126 ◽  
Author(s):  
Philip C. Amrein ◽  
Eyal C. Attar ◽  
Tak Takvorian ◽  
Ephraim P. Hochberg ◽  
Karen Ballen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Lymphocytic Leukemia ◽  
Electrolyte Imbalance ◽  
Fish Analysis ◽  
Bone Marrow Biopsies ◽  
Lyn Kinase ◽  
Grade 3

Preclinical studies have shown that proliferation and survival of CLL cells are associated with overexpression of the Lyn kinase protein, and in vitro inhibition of Lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib inhibits Lyn kinase in CML cells at doses easily achievable in patients, we undertook this phase II study of dasatinib in patients with previously treated CLL/SLL. Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry/immunostains, and have failed at least 1 course of treatment with a fludarabine-containing regimen or at least 2 courses of non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for Lyn kinase activity. The design of the study provided for 2 phases such that if 3 responses were seen among the first 15 patients, the trial would expand to enroll another 20 patients. Among the first 9 patients enrolled there were 4 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 4 subjects, 1 in 3, and 2 in 2 subjects. All patients had previously received fludarabine: 1 subject had 1 prior treatment, 3 had 2 prior treatments, 3 had 3 prior treatments, and 2 had 4 prior treatments. By cytogenetic/FISH analysis there were 2 patients with del(17p) and another 4 patients with del(11q). All patients required treatment by NCI Working Group criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 7 subjects, grade 3 + 4 thrombocytopenia in 5 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. One subject developed a grade 2 pleural effusion. There was 1 patient with an electrolyte imbalance consisting of a transient serum K=6.8, and in 1 patient there was a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration of treatment on study was 9 weeks with a range of 4 to 23 weeks. The clinical response data of the first 15 patients will be presented along with the correlative studies of Lyn kinase inhibition by dasatinib.

Dasatinib Has Activity in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL/SLL), a Phase II Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3162-3162 ◽  
Author(s):  
Philip C. Amrein ◽  
Eyal Attar ◽  
Tak Takvorian ◽  
Ephraim Hochberg ◽  
Karen K. Ballen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Performance Status ◽  
Lymphocytic Leukemia ◽  
Ct Scans ◽  
Fish Analysis ◽  
Ecog Performance Status ◽  
Bone Marrow Biopsies ◽  
Lyn Kinase ◽  
Grade 3

Abstract Background: Preclinical studies have shown that CLL cells overexpress lyn kinase protein, and in vitro inhibition of lyn kinase leads to apoptosis of the CLL cells (Contri, J Clin Invest 2005). Because dasatinib has been shown to inhibit lyn kinase in CML cells at concentrations easily achievable in patients, we undertook this phase II study in patients with previously treated CLL/SLL. Methods: Patients were required to be over 18 years of age, have a diagnosis of CLL/SLL by flow cytometry or immunohistochemistry, and have failed either 1 course of treatment with a fludarabine-containing regimen or 2 non-fludarabine containing regimens. The starting dose of dasatinib was 140 mg daily by mouth. This dose could be reduced to 100 mg or 80 mg daily for toxicity. At baseline all patients had bone marrow biopsies and CT scans, and these were repeated at 2 months. Sequential blood and bone marrow samples were tested for lyn kinase activity. Results: Among the 15 patients enrolled there were 10 male and 5 female subjects with a median age of 59 years (40–78 years). ECOG performance status was 0 in 9 subjects, 1 in 3, and 2 in 3 subjects. All patients had previously received fludarabine, and 5 patients required treatment within 6 months of their last regimen. The median number of prior treatments was 3 (range: 1 to 7). By cytogenetic/FISH analysis there were 5 patients with del(17p) and 6 patients with del(11q). All patients required treatment by NCI–WG criteria. The major toxicity encountered was myelosuppression: grade 3 + 4 neutropenia in 10 subjects, grade 3 + 4 thrombocytopenia in 4 subjects. Gastrointestinal toxicity was minor with only 1 subject experiencing grade 3 diarrhea. Other toxicities: 1 patient had a grade 2 pleural effusion, 1 patient had a transient serum K=9.9 (likely an artifact of high white count and without clinical sequelae), and 1 patient had a transiently prolonged QTc of 516 ms. There were no fatal events, and all toxicities were reversible. The median duration on study was 10 weeks, but 5 responding or stable patients have remained on treatment for over 9 months. Partial responses (PR) by NCI-WG criteria were achieved in 2 of the 15 patients (13% with 90% CI 2%–36%). An additional 2 patients would have qualified for PR (lasting >2 months) except for myelosuppression. Among the remaining 11 patients, 6 had nodal responses (2 CR and 4 PR) by physical exam (PE) without a 50% reduction in lymphocytosis. CT scans confirmed nodal responses in 3 of the 10 patients with nodal responses by PE. The relationship between clinical response and lyn kinase, bcl-2, and mcl-1 expression will be presented at the meeting. Conclusions: Dasatinib has modest activity in CLL, and combinations with standard agents, perhaps in an intermittent schedule, should be considered in subsequent trials.

Combination of Ofatumumab and Lenalidomide In Patients with Relapsed Chronic Lymphocytic Leukemia: Initial Results of a Phase II Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2464-2464 ◽  
Author(s):  
Xavier Badoux ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
Stefan Faderl ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Research Funding ◽  
Performance Status ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Significant Activity ◽  
Superficial Vein Thrombosis ◽  
Grade 3

Abstract Abstract 2464 Frontline chemoimmunotherapies induce high response rates in patients with CLL. Once disease recurs, however, effective treatment options are limited and new therapeutic modalities and combinations are needed. Ofatumumab is a fully humanized anti-CD20 monoclonal antibody which produces an overall response rate (ORR) of 47%–58% in patients with fludarabine-refractory CLL (Wierda W. et al, 2010). Lenalidomide, an immunomodulatory agent, induces an ORR of 32–47% in patients with relapsed/refractory CLL, (Chanan-Khan A.A. et al. 2006; Ferrajoli A. et al. 2008). The rationale for combining ofatumumab and lenalidomide is based on their single agent efficacy, distinct and potentially complimentary mechanisms of action and non-overlapping toxicity profiles. Furthermore, the combination of lenalidomide and rituximab has shown significant activity in patients with relapsed disease (Ferrajoli et al. 2009). We, therefore, designed a phase II study to evaluate efficacy and tolerability of ofatumumab and lenalidomide given in combination in patients with relapsed CLL. Patients with active disease were eligible if they had received prior treatment with purine analog-based therapy, had an ECOG/WHO performance status of 0–2, adequate renal (creatinine clearance > 30ml/min) and hepatic function (total bilirubin < to 2 mg/dl and ALT < 2 × ULN). Patients with any neutrophil count were eligible, whereas patients with platelet counts < 30,000 mm3, positivity for HIV, active hepatitis B or C or recent history of tuberculosis were excluded from participation. In this trial ofatumumab is administered intravenously weekly for four consecutive weeks (300mg week 1, 1,000 mg week 2 and all subsequent doses), then monthly for months 2–6 and once every two months for months 7–24. Lenalidomide is given orally at the dose of 10 mg daily, starting on day 9 and continued daily. Allopurinol at the dose of 300mg daily is given during the first two weeks of treatment as tumor lysis prophylaxis. Treatment duration is 24 months, and responses are assessed after 3, 6, 12, 18 and 24 months of therapy. Thus far 26 of the 40 planned patients have been accrued to this study and we present an analysis of response and toxicity for the first 16 patients that have been on study for at least 3 months. The median age of the patients is 62 yrs (45–82). Eight patients (50%) had Rai stage III-IV disease. The median Beta-2M level was 4.4 mg/dL (2–6.1). The median number of prior treatments was 2 (1–8). Four patients (25%) were refractory to fludarabine and all pts had received prior rituximab. Nine patients (56%) had unmutated IGHV genes, 5 patients (31%) had chromosome 17p deletion and 3 patients (19%) had 11q deletion as detected by FISH analysis. Responses were evaluated according to the 2008 IWCLL criteria: 10 of the 16 evaluable patients achieved a response [2 CR (13%), 8 PR (50%)] for an ORR of 63%. Four patients with stable disease are continuing on treatment. One patient discontinued therapy and did not return for response assessment and another patient progressed. All patients are alive. The most common grade 3–4 treatment related adverse events observed were: neutropenia (8 pts, 50%) and anemia (2 pts, 13%). One patient (6%) developed grade 2 superficial vein thrombosis. Lenalidomide-associated tumor flare reaction was limited to grade 1 in 2 patients (13%) while a grade 3 infusion reaction was observed in 1 patient (6%) during the first ofatumumab administration. Three grade 3 infectious episodes occurred: 2 cases of pneumonia and 1 case of parotiditis. None of the patients received routine antibiotic prophylaxis. The median daily dose of lenalidomide tolerated was 5 mg/day (2.5–10 mg). In conclusion, our initial analysis indicates that the combination of ofatumumab and lenalidomide is therapeutically active in patients with relapsed CLL. This treatment is well tolerated. Neutropenia is the most common toxicity observed. Enrollment is ongoing, and updated results will be provided. Disclosures: Off Label Use: Ofatumumab and lenalidomide in patients with relapsed chronic lymphocytic leukemia. O'Brien: GlaxoSmithKline: Consultancy. Wierda: GlaxoSmithKline: Honoraria, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Estrov: Celgene Corporation: Consultancy. Keating: Celgene Corporation: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria. Ferrajoli: Celgene Corporation: Research Funding; GlaxoSmithKline: Research Funding.

Phase II Study of Dasatinib In Patients with Relapsed Chronic Lymphocytic Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4488-4488 ◽  
Author(s):  
Ali M Al-Ameri ◽  
Xavier Badoux ◽  
Alessandra Ferrajoli ◽  
William G. Wierda ◽  
Luis Fayad ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Lymphocytic Leukemia ◽  
Hematological Toxicity ◽  
Abl Kinase ◽  
Grade 3

Abstract Abstract 4488 Src-family kinases (SFK) are described to be over expressed in CLL resulting in increased BCR signaling. Aberrant activation of the SFK, Lyn, leads to defective apoptosis of CLL cells in-vitro. C-Abl kinase is also overexpressed in CLL cells compared to normal B-lymphocytes. Since dasatinib is a dual Src and c-abl kinase inhibitor with in-vitro pro-apoptotic properties in CLL cells, we investigated the activity of dasatinib in patients (pts) with CLL. We designed a phase II study of dasatinib in pts with relapsed CLL/SLL and T-PLL. Pts were eligible if they were previously treated and had indication for therapy according to NCI-working group criteria. All pts had adequate performance status, renal and liver function prior to therapy. Treatment consisted of dasatinib 50mg given orally twice daily. In case of suboptimal response the dose of dasatinib could be increased up to a maximum dose of 70mg twice daily. Dose reductions to 20mg twice daily were permitted for toxicity. Pts were assessed for treatment response according to 1996 NCI-WG criteria. Seventeen pts have been enrolled in this study. The median age was 67 years (42-83 years), 9 (52%) had Rai stage III-IV, median beta-2 microglobulin levels was 5.9 (3.0 – 11.8) mg/L. The median number of prior treatments was 4 (1 – 8). An objective response (PR) was observed in 1 patient, 13 pts had no objective response and 3 pts were not evaluable for response due to early discontinuation of therapy (0-3 days). Fourteen pts remained on therapy for a median of 2 (0-19) months with 4 pts discontinuing due to disease progression and 9 pts discontinuing due to adverse events and lack of response. Hematological toxicities consisted of grade 3–4 neutropenia in 76% of the pts, grade 3–4 thrombocytopenia in 44% of pts and grade 1–2 anemia in 80%. Non-hematological toxicity consisted of grade 3–4 fatigue in 1 patient and grade 3 pleural effusions in another patient. Grade 1 and 2, toxicities included flushing 38%, headache 38%, fatigue 46% anorexia and nausea 46%, and diarrhea 23%. Several pts showed evidence of biological activity. Treatment with dasatinib lacks efficacy in pts with heavily pretreated CLL. Responses occurred in only 6% of pts and dasatinib administration was associated with a high incidence of neutropenia. Disclosures: O'Brien: Bristol-Myers Squibb: Research Funding.

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

scholarly journals Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

2013 ◽  
Vol 31 (5) ◽  
pp. 584-591 ◽  
Author(s):  
Xavier C. Badoux ◽  
Michael J. Keating ◽  
Sijin Wen ◽  
William G. Wierda ◽  
Susan M. O'Brien ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Salvage Therapy ◽  
Phase Ii Study ◽  
Venous Thromboembolic Event ◽  
Febrile Episode ◽  
Lymphocytic Leukemia ◽  
Common Grade ◽  
Venous Thromboembolic ◽  
Grade 3

Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation.

A Phase II Study of Denileukin Diftitox (ONTAKR) in Patients with Fludarabine Refractory B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4824-4824 ◽  
Author(s):  
Philip Kuriakose ◽  
Francesco Turturro ◽  
Jesus G. Berdeja ◽  
Robert Kerr ◽  
Asha Surendranathan ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Left Ventricular ◽  
Lymphocytic Leukemia ◽  
Electrolyte Imbalance ◽  
Close Monitoring ◽  
Denileukin Diftitox ◽  
Duration Of Response ◽  
Transient Elevation

Abstract Therapeutic options for chronic lymphocytic leukemia (CLL) at relapse are limited because of myelosuppressive toxicity. Denileukin diftitox (ONTAK®, Ligand Pharmaceuticals) is a genetically engineered fusion protein comprising the enzymatically active domain of diphtheria toxin and the full length sequence of interleukin-2 (IL-2) targeting malignancies expressing the medium and high affinity IL-2 receptors. We designed a phase II study to evaluate the efficacy of ONTAK® in patients with fludarabine-refractory CLL, which is a follow-up to the previously published study (Frankel, et al, Clin. Cancer Res.2003; 9:3555). Denileukin diftitox was administered at a dose of 18μg/kg IV daily for 5 days every 3 weeks, for a maximum of 8 cycles. Thirteen patients have been treated so far, with 10 patients being evaluable for response (completed ≥ 3 cycles). Median age was 59 years (range 44–84), and 62% (8/13) were Rai stage III-IV, with a median of 3 prior therapies (range 1–6). The overall response was 40%, with 1 CR (10%, duration of response 5+ months) and 3 PR (30%, duration of response 3+, 3+ and 4+ months). Two responding patients (both PR) are still on study, while two (1 CR, 1 PR) were removed from study because of toxicities after 7 and 5 cycles, respectively. Four patients (40%) had progressive disease after cycles 3, 4, 4, and 7, respectively. One patient has completed four cycles and restaging studies are pending. Of the 3 patients not evaluable for response, two are still on study (having not completed 3 cycles), while one refused further treatment after 4 doses of cycle one. The grade 3/4 toxicities encountered were: neutropenia 4/13, thrombocytopenia 4/13, vascular leak syndrome 3/13, left ventricular cardiac dysfunction 1/13, hypotension 2/13, tachyarrhythmia 3/13, elevated PT 1/13, fatigue 1/13, rash 1/13, SIADH 1/13, constipation 1/13, vomiting 2/13, petechiae 1/13, transient elevation of GGT 1/13, transient elevation of AST/ALT 7/13, hyperglycemia 4/13, electrolyte imbalance 8/13, infection and/or febrile neutropenia 4/13, insomnia 1/13, visual disturbance 1/13, dyspnea 2/13, hypoxia 2/13. We conclude that denileukin diftitox has activity in CLL, with toxicities that can be managed with adequate premedication and close monitoring.

A Multicentre Phase II Study of the Aminopeptidase Inhibitor, CHR- 2797, in the Treatment of Elderly and/or Previously Treated patients with Acute Myeloid Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 961-961 ◽  
Author(s):  
B. Lowenberg ◽  
F. Davies ◽  
C. Müller-Tidow ◽  
Ulrich Dührsen ◽  
A. Burnett ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Clinical Activity ◽  
Open Label ◽  
Elderly Aml ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Tosedostat (TSD, CHR-2797) is an aminopeptidase inhibitor that selectively depletes amino acid pools in malignant cells, resulting in anti-proliferative, pro-apoptotic and antiangiogenic effects. In a phase I study, treatment with TSD resulted in complete remission in a number of refractory AML patients. The primary objective of this phase II study was to determine whether TSD was a sufficiently effective therapy to warrant pivotal studies. Methods. This was an open label, single agent, phase II study to assess clinical activity of TSD in elderly and/or previously treated patients with AML/MDS. Patients were treated with once daily oral doses of the maximum acceptable dose (130 mg) of TSD for up to 84 days. Further treatment was allowed if, in the opinion of the investigator, this was considered to be beneficial. Clinical responses were assessed by monthly bone marrow aspirates and weekly hematological assessments. Results. Of the 41 TSD-treated patients with AML (n=38) or MDS (n=3), who were enrolled between March and October 2007, 27 were male, 14 female, with a mean age of 67 years (range 34–82). The median performance status (ECOG) at baseline was 1 (range 0–2). Twelve (31.6%) AML patients and 2 (66.7%) MDS patients were chemotherapy naïve, and 9 (23.7%) AML patients had either secondary disease or adverse cytogenetics. For 16 (39%) patients, treatment with TSD was a second or later salvage attempt. Thirty two patients (30 AML, 2 MDS-RAEB1 and 2) received ≥28 days treatment, and 21 (51.2%) patients completed the formal 84-day study period (19 AML, 2 MDS). Nine (22%) of the patients (7 AML, 2 MDS) continued treatment with TSD after 84 days, and 6 (15%) patients were on TSD in total for more than 6 months (4 AML, 2 MDS). Ten (26.3%) of the AML patients responded to treatment; amongst these, 2 patients received TSD as 2nd/3rd salvage therapy, and a further 2 patients did not show a complete response (CR) after 2 previous induction courses of chemotherapy. Three AML patients achieved a CR (< 5% blasts in bone marrow), of whom 2 were in durable remission (232 days, continuing*; 171 days), and 7 had a partial response (PR, 5–15% blasts) lasting approximately 1–3 months. Two (66.7%) of the MDS patients also responded to treatment with TSD; these patients maintained stable disease for more than 6 months. All responders (CR, PR and SD) were >60 years at the time of the first dose. Median overall survival in AML patients was 130 days (range 8 – 478 days*). The most frequently reported adverse events were: fatigue (61%), thrombocytopenia (49%), pyrexia (39%), peripheral edema (39%) and diarrhea (34%); 9 (22%) patients withdrew due to drug related toxicity. TSD had no effect on hemoglobin or neutrophils. Conclusions. This study in patients with advanced AML/MDS with adverse prognosis demonstrates the anti-leukemic activity of TSD in elderly AML patients, as measured by CR and decreases in leukemic blasts. In addition, 2 relapsed high risk MDS patients achieved disease stabilization. TSD at 130mg qd is also very well tolerated over a long period of exposure (6–10 months). These results support further pivotal studies with TSD in elderly AML and MDS patients.

Phase II study of TS-1 (S) plus cisplatin (P) with concurrent thoracic radiotherapy for unresectable stage III non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18070-18070
Author(s):  
F. Ohyanagi ◽  
N. Yamamoto ◽  
A. Horiike ◽  
T. Horai ◽  
K. Gomi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Progression Free Survival ◽  
Stage Iii ◽  
Fourth Generation ◽  
Unresectable Stage ◽  
Stage Iii Nsclc ◽  
Grade 3

18070 Background: Although combined chemoradiotherapy is the standard of care in stage III NSCLC, the optimal chemotherapy regimen is not established. S-1, a fourth-generation oral fluoropyrimidine is an active new agent for NSCLC and the combination with cisplatin has a favorable toxicity profile. The objective of this study was to evaluate feasibility and efficacy of S plus P with concurrent radiation for unresectable stage III NSCLC. Methods: Patients with histologically or cytologically confirmed NSCLC, 20 to 75 years in age, performance status 0–1, with no prior chemotherapy were eligible for the study. Patients were treated with P (60 mg/m2 on day 1) and S (orally at 40 mg/m2/dose bid (80 mg/m2/d), on days 1 to 14) repeated every 3–4 weeks for 4 cycles and TRT (60 Gy/30 fr over 6 weeks starting on day 2). The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 28 patients (Simon’s two-stage minimax design, P0=70%, P1=90%, a =0.1, β = 0.1). Results: Of 28 patients enrolled between August 2005 and October 2006, 28 were evaluable. There were 24 males and 4 females, median age of 63 (range 40–74) and 11 IIIA and 17 IIIB. Chemoradiotherapy was well tolerated; 2 cycles of SP and 60 Gy of TRT were administered in all patients and 24 (86%) patients received 4 cycles of SP. During concurrent chemoradiotherapy, grade 3 toxicities were neutropenia (8 pts), leukopenia (6 pts), fatigue (6 pts), anorexia (5 pts), febrile neutropenia (4 pts) and, esophagitis (4 pts). Only one grade 4 leukopenia were observed. During consolidation therapy, grade 3–4 neutropenia, anemia, esophagitis, and pneumonitis were developed in 4, 1, 1 and 2 patients, respectively. No toxic deaths have occurred. Overall RR was 85.7% (95% CI: 79.1- 98.7%) with 4 SDs and 24 PRs. The median progression-free survival and median survival is not mature enough to estimate as only 4 progression and no deaths have occurred. Conclusions: This chemoradiotherapy regimen produced promising response rate in patients with stage III NSCLC and it seems to be well-tolerated. No significant financial relationships to disclose.

Phase II study of bortezomib with cisplatin as first-line treatment of malignant pleural mesothelioma (MPM): EORTC 08052.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7081-7081 ◽  
Author(s):  
Mary O'Brien ◽  
Rabab Mohamed Gaafar ◽  
Sanjaykumar Popat ◽  
Francesco Grossi ◽  
Allan Price ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Dose Intensity ◽  
Line Treatment ◽  
First Line ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
First Line Treatment

7081 Background: Cisplatin is one of the most active drugs available in MPM while bortezomib has shown some activity in single agent phase II studies against MPM. This was a prospective phase II study of cisplatin and bortezomib (CB) in the first line treatment of MPM. Methods: Patients with histological proven MPM, with performance status (PS) 0/1, were eligible. The doses were cisplatin 75mg/m2 /3 wks and bortezomib 1.3mg/m2 day 1, 4, 8, 11 every 3 wks. The primary end-point was progression free survival rate at 18 wks (PFSR=18). The 2-stage Simon design (a=0.1; b = 0.05, P0=0.50 and P1=0.675) was used. In the first step of the study 37 eligible patients were planned. If more than 19 patients were alive and free of progression at 18 wks the total sample size was increased to 76 eligible patients. Results: Between 2007 and 2010 82 patients were entered. The median follow-up time is 32.3 months The median age was 55 years (range: 22-77yrs), male/female: 55/27 , PS 0/1: 9/73, Stage T1: 10%; T2: 42%, T3: 25%; T4: 23% and N0: 57%; N1: 4%; N2: 33%; N3: 6%. The median number of cycles received was 4 and 38% received 6 cycles. Cisplatin/ bortezomib dose intensity was 98/ 80%. Toxicity (grade 3/4): neutropenia 10%, thrombocytopenia 11%, anaemia 1%. Grade 3-4 hyponatraemia/ hypokalaemia occurred in 46/ and 17%. Grade 2 tinnitus, grade 3 fatigue occurred in 16%, and 12%, of patients. Motor/sensory/other neurotoxicity was grade 1: 6/28/7%, grade 2: 2/26/2% and grade 3: 1/7/2% respectively. There were 2 toxic deaths at 32 and 74 days due to acute pneumonitis and cardiac arrest. The PFRS-18 (including symptomatic progression) was 53% (80% confidence intervals, CI, 42-64%). The overall survival was 13.5 months (95% CI 10.5-15) with 56% (95% CI 44-66%) alive at 1 year. The PFS was 5.1 months (95% CI 3.3-6.5). Conclusions: On the basis of the PFRS-18, the null hypothesis could not be rejected, although CB gave predictable toxicity and was as active as other reported regimens in MPM.

Phase II study of PX-866 in recurrent glioblastoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2053-2053 ◽  
Author(s):  
Marshall W. Pitz ◽  
Elizabeth A. Eisenhauer ◽  
Mary Valeria MacNeil ◽  
Brian Thiessen ◽  
David R. Macdonald ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Recurrent Glioblastoma ◽  
Pik3ca Mutations ◽  
Overall Response ◽  
Grade 3

2053 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (< 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ≥ 10 early progressions would stop accrual; after full accrual, ≥ 4 responses OR ≤ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.

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