The Impact of GM-CSF on Arsenic Trioxide (As2O3, Trisenox) Therapy in Patients with Myelodysplastic Syndrome (MDS): Preliminary Results of a Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4856-4856 ◽  
Author(s):  
Blanche H. Mavromatis ◽  
Craig M. Kessler ◽  
Bruce D. Cheson ◽  
Aung Sein ◽  
Stewart A. Sharp
Keyword(s):  
Arsenic Trioxide ◽  
Phase Ii ◽  
Single Agent ◽  
Patient Characteristics ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Clinical Activity ◽  
Gm Csf ◽  
Pre Treatment ◽  
The Impact

Abstract Background: Arsenic trioxide(As2O3) has proven clinical efficacy in relapsed acute promyelocytic leukemia, and is currently being studied in the upfront setting. At micromolar doses, As2O3 induces apoptosis and cellular differentiation, promotes histone acetylation, and inhibits tumor angiogenesis. In preclinical MDS studies, As2O3 inhibits proliferation of malignant hematopoietic cells, and increases rates of apoptosis in short term cultures. Notably, pre-treatment with GM-CSF increases sensitivity of cells to the effect of As2O3. Single agent clinical activity has also been demonstrated in MDS and multiple myeloma. Methods: As2O3 was combined with GM-CSF in pts with MDS in a phase II trial. Eligible patients included those with Low/Int-1 and Int-2/High risk disease. Pts received treatment with As2O3 0.25 mg/Kg d1–d5 the first week, then twice a week for 9 weeks, then 2 weeks off. The cycle was repeated if a response was observed. GM-CSF was administered twice a week for the entire cycle. Pt characteristics are summarized in the table below. Toxicity: Grade 3 and 4 study related AEs included peripheral neuropathic pain (1/7), febrile neutropenia (2/7), infection (4/7), abdominal pain (2/7), thrombocytopenia (2/7), hypoxia (1/7), chills associated with infusion (1/7), VT despite normal electrolytes (1/7), AV block (1/7). Results. 7 pts were enrolled (5M/2F), RA (1), RARS (3) and RAEB (3). A minor hematologic response was seen in one patient with RARS. One patient with RAEB2 showed a reduction of marrow blast count from 15% to < 5% after one cycle. 3 pts completed less than one cycle and response could not be assessed. Conclusion: The data suggest that As2O3 with GM-CSF is active in MDS, however with significant side effects. The study of As2O3 with the newer approved agents such as 5-azacitidine or lenalidomide should be undertaken, but done sequentially in order to minimize any overlapping toxicities. Patient Characteristics and Results Patient Age MDS Subtype Cytogenetics IPSS Number of Cycles Response Overall Survival months) Nl: normal, RA: refractory anemia; RARS: refractory anemia with ringed sideroblasts; RAEB1: refractory anemia with excess blasts 1; Int risk: intermediate risk; IPSS: international prognostic scoring system 1 76 RARS Nl Int risk-1 3 Minor HI-E 28+ 2 75 RAEB1 Nl Int risk-2 2 PR 10 3 78 RA Nl Int risk-1 1 SD 7 4 69 RAEB1 Nl Int risk-1 <1 NA NA 5 58 RARS Nl Int risk-1 1 SD 25+ 6 65 RARS 7 del, 20 del Int risk-2 1 SD NA 7 62 RAEB1 Complex: 3q-, abn ch 12, 5q-, -7, 2 ring ch8, trisomy 22 Int risk-2 <1 NA NA

Capecitabine, an Oral Fluoropyrimidine Carbamate With Substantial Activity in Advanced Colorectal Cancer: Results of a Randomized Phase II Study

2000 ◽  
Vol 18 (6) ◽  
pp. 1337-1345 ◽  
Author(s):  
Eric Van Cutsem ◽  
Michael Findlay ◽  
Bruno Osterwalder ◽  
Walter Kocha ◽  
David Dalley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase Ii ◽  
Advanced Colorectal Cancer ◽  
Single Agent ◽  
Dose Intensity ◽  
Patient Characteristics ◽  
Complete Response ◽  
Phase Iii ◽  
Effective Treatment Option ◽  
Randomized Phase Ii

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m2/d bid continuously; arm B, 2,510 mg/m2/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m2/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.

Trisenox® (arsenic trioxide) in Patients with Myelodysplastic Syndromes (MDS): Preliminary Results of a Phase I/II Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1433-1433
Author(s):  
Norbert Vey ◽  
Francois Dreyfus ◽  
Agnes Guerci ◽  
Pierre Fenaux ◽  
Herve Dombret ◽  
...  
Keyword(s):  
Phase I ◽  
Arsenic Trioxide ◽  
Lower Risk ◽  
Single Agent ◽  
Clinical Activity ◽  
Molecular Response ◽  
Improvement Rate ◽  
Preliminary Results ◽  
Duration Of Response ◽  
Grade 3

Abstract Introduction: Single-agent Trisenox® (arsenic trioxide) induces high hematologic and molecular response rates leading to prolonged survival in patients with relapsed/refractory acute promyelocytic leukemia. Arsenic trioxide exhibits multifaceted mechanisms of action, including induction of tumor cell differentiation, apoptosis, and angiogenesis inhibition. Recent reports have documented the clinical activity of arsenic trioxide in MDS patients, leading to improvements in hematologic parameters and to transfusion independence or reduction. We report preliminary results of an ongoing European multicenter phase I/II study of arsenic trioxide in MDS patients. Patient eligibility includes all FAB categories with <30% blasts. Final results of the study will be reported. Methods: Arsenic trioxide is given as a 1-hr IV infusion, loading dose of 0.30 mg/kg/day for 5 days, and maintenance with 0.25 mg/kg/day 2X a week for >15 weeks. Disease assessments are every 8 weeks, by modified IWG response criteria. Patients: 105 patients have been enrolled: median age is 67 years (range 31–89), median time from diagnosis to 1st dose is 10.9 months (range 0.2–117.6). 101 patients have received drug and have been evaluated (78M/23F). 39 patients have IPSS lower-risk (LR: low and Int-1) and 62 have higher-risk (HR: high and Int-2) MDS. FAB categories are RA (9 patients), RARS (11), RAEB (62), RAEB-t (13), and CMML (6). 86 patients were transfusion dependent at baseline. Results: Responses were observed in 27 evaluable patients (27%). They include 1 CR (1%), 20 major Hematologic Improvements (HI: 20%) and 6 minor HI (6%). Responses were seen across the 3 lineages: major HI-Erythroid: 11; major HI-Neutrophil: 8 (including 2 also HI-E); and major HI-Platelet: 6 (including 3 also HI-E). The hematologic improvement rate among LR patients was 9/39 (23%) and among HR patients, 18/62 (29%, including the CR). 14 patients became transfusion independent and an additional 7 patients had transfusions reduced by ≥50%. Responses were seen after 1–3 months of treatment, and median duration of response is 4+ months at this time. The true duration of response is not yet known, as 20 patients were still responding at their most recent assessments. Arsenic trioxide toxicity was manageable and mostly mild; 4 patients had treatment-related grade 3 febrile neutropenia and 1 patient each experienced grade 3 and grade 4 thrombocytopenia. One had grade 4 neutropenia; the only other grade 4 toxicity was 1 pulmonary edema. An additional 14 patients each had a different grade 3 event. QTc prolongation was reported in only 1 patient, who had 2 isolated episodes that were considered clinically insignificant and did not result in treatment delay. No patient had alopecia or severe nausea or vomiting. Summary and Conclusions: These preliminary results indicate that arsenic trioxide is generally well tolerated, even by elderly patients, and that it induces responses in all three hematopoietic lineages, in similar proportions of patients with higher risk and with lower risk MDS. 14 of 86 transfusion-dependent patients became transfusion independent. Final results of the study will be presented.

Phase II Window Study of the Farnesyltransferase Inhibitor R115777 (Zarnestra®) in Untreated Juvenile Myelomonocytic Leukemia (JMML): A Children’s Oncology Group Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2587-2587 ◽  
Author(s):  
Robert P. Castleberry ◽  
Mignon L. Loh ◽  
Nalini Jayaprakash ◽  
April Peterson ◽  
Vicky Casey ◽  
...  
Keyword(s):  
Phase Ii ◽  
Initial Dosage ◽  
Colony Growth ◽  
Juvenile Myelomonocytic Leukemia ◽  
Cell Transplant ◽  
Monocyte Count ◽  
Similar Frequency ◽  
Gm Csf ◽  
The Impact

Abstract JMML is a rare and often fatal leukemia of young children exhibiting unique clinical, hematopoietic and genetic features including GM-CSF hypersensitivity, and mutations of NF1, RAS, and PTPN11. Ras proteins control a number of cell signaling events becoming activated in part by the addition of a farnesyl moiety via farnesyl protein transferase (FTPase). Given that hyperactive Ras is central to JMML pathogenesis, it is intuitive that an FTPase is an appropriate therapeutic target in JMML. One FTPase inhibitor, L739,749, has previously been shown to abrogate spontaneous in vitro colony growth in 9 JMML samples (Blood 95:639, 2000). R115777 is a potent in vitro and in vivo inhibitor of FTPase, abrogating the growth of H-ras, K-ras and N-ras transformed tumors. In humans, it is well tolerated with the dose-limiting toxicities being myelosuppression and diarrhea. To assess the efficacy and toxicity of R115777 in JMML, a phase II window study was conducted as a part of COG study AAML0122 in newly diagnosed patients who were given the option of receiving this agent prior to cytosine arabinoside, fludarabine and 13-cis retinoic acid followed by stem cell transplant. R115777 was administered PO BID for 21 days with a 7 day rest for two courses in the absence of disease progression or excessive toxicity. The starting dosage in the first 11 patients was 200mg/m2 with escalation in subsequent patients to 300mg/m2 if the initial dosage was tolerated. Overall response was based upon changes in WBC and organomegaly. The impact of R115777 upon in vitro spontaneous colony growth, GM-CSF hypersensitivity and farnesylation was monitored. A total of 47 patients were accrued: M:F=30:17, median (med) age 15 mos. (1–76); med WBC 30X109/L (4–151); med monocyte count 18X109/L (1–55); med platelet count 58X109/L (2–587); elevated fetal hemoglobin 30 (65%). RAS and PTPN11 mutations were tested in 42 cases and inhibition of prenylation in 33. R115777 was well tolerated at both dosages with the most common grade 3/4 toxicities being thrombocytopenia (40%), anemia (40%), neutropenia (15%), and diarrhea (6%). There were no deaths during the trial. The table details the responses in patients receiving one course (N=47) and 2 courses (N=38) of R115777. The 9 patients not receiving two courses were removed from study due to lack of response or progressive disease. WBC ONLY 0VERALL (WBC & organomegaly) COURSE #1 CR CR PR MR SD PD Total     200mg/m2 6 0 4 4 2 1 11     300mg/m2 18 1 17 9 4 5 36 COURSE #2     200mg/m2 6 0 6 1 2 1 10     300mg/m2 17 2 14 7 2 3 28 FTPase activity was inhibited in 13/15 cases (med 71%; range 38–91%) with similar frequency and degree of inhibition at both dosages of R115777. There was no relationship between FTPase inhibition or response and the presence of RAS/PTPN11 mutations or inhibition of prenylation in an HJ2 assay. In conclusion, R115777 provides an overall CR/PR rate of 58% with no significant differences between the two dosages (p=0.7). This agent should be considered in the future management of JMML.

Phase II Trial of Combination of the Histone Deacetylase Inhibitor ITF2357 and Meclorethamine Demonstrates Clinical Activity and Safety in Heavily Pretreated Patients with Relapsed/Refractory Hodgkin Lymphoma (HL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2586-2586 ◽  
Author(s):  
Carmelo Carlo-Stella ◽  
Anna Guidetti ◽  
Simonetta Viviani ◽  
Valeria Bonfante ◽  
Pinuccia Valagussa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Response To Therapy ◽  
Prior Treatment ◽  
Study Entry ◽  
Clinical Activity ◽  
Synergistic Activity ◽  
Heavily Pretreated ◽  
Ongoing Phase

Abstract Introduction: HL patients with refractory disease or relapsing after autologous stem cell transplantation (SCT) have very poor prognosis with currently available salvage chemotherapy. ITF2357 (Italfarmaco S.p.A., Milano, Italy) is an orally bioavailable hydroxamate inhibitor of class I and II histone deacetylases (HDACs) with preclinical and clinical activity as single agent in hematopoietic cancers. Our preclinical data demonstrating a synergistic activity of ITF2357 with the alkylating agent Meclorethamine in HL cell lines, established the rationale for this currently ongoing phase II study aimed to determine activity and safety of the sequential ITF2357 and Meclorethamine treatment. Methods: Patients with relapsed/refractory HL who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled. Eligibility criteria included prior treatment with autologous and/or allogeneic SCT, prior treatment with single agent Meclorethamine, at least one target lesion ≥2 cm, ECOG performance status of 0–1, and platelet ≥75,000/μL. ITF2357 (50 mg QID, per os, days 1–3) followed by Meclorethamine (6 mg/sqm, intravenously, day 4) was dosed in 3-week cycles until disease progression or appearance of clinical significant toxicity, but for a maximum of 12 cycles. Tumor responses were determined after cycles 2, 6, 9 and 12 by computed tomography (CT) and positron emission tomography (PET) scan. Serum levels of thymus- and activation-regulated chemokine (TARC) were assessed by ELISA prior to each cycle of therapy. Results: To date, 19 patients have been enrolled (16 males and 3 females; median age, 33 years; range, 21–61 years), including 8 patients enrolled in a preliminary compassionate use trial, and 11 patients of a planned 23 enrolled in this ongoing phase II trial. Prior to study entry, patients received a median of 5 (range 2–7) lines of treatment with autologous SCT performed in 15 (79%) and an additional allogeneic SCT in 5 (26%) patients. At study entry, 6 patients had relapsed and 13 refractory HL. Seventeen of 19 patients received a median of 3 cycles (range, 1–10) of ITF2357/Meclorethamine and are evaluable for response by CT and PET scans. Best response to therapy included 2 (12%) complete remissions (CR) and 3 (18%) partial remissions (PR), for an overall response rate (ORR) of 30%. In addition, 5 (29%) patients had stable disease (SD) with 4 (23%) patients achieving SD for ≥4 months, while 7 (41%) patients progressed. After the first cycle of therapy, serum TARC levels were decreased by 70±16% (mean±SEM, P ≤0.05) in 5 patients who achieved major clinical responses (PR+CR), and by 16±14% (P = ns) in patients who achieved SD. Overall, therapy was well tolerated without significant adverse events, and no patient required dose reductions for management of toxicities. The most common drug-related non-hematological toxicities were grade 1–2 nausea (12/17) and fatigue (14/17). Four patients experienced infections [pneumonia (n = 1), oral herpes simplex (n = 2), oral candidiasis (n = 1)]. No prolongation of QT/QTc interval has been detected over 70 therapy cycles. Hematological toxicities included grade 1–2 anemia (13/17), neutropenia (7/17), and thrombocytopenia (12/17). Grade 3–4 neutropenia and thrombocytopenia were observed in 7 and 8 patients, respectively. RBC and platelet transfusions were required by 4 and 5 patients, respectively. Conclusions: Preliminary results from this ongoing trial suggest that ITF2357, in combination with Meclorethamine, demonstrates significant anti-tumor activity in heavily pretreated relapsed/refractory HL and is well tolerated. Preliminary data also suggest that early decrease in serum TARC levels may predict response to therapy.

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.

Combination of Sorafenib, Idarubicin, and Cytarabine Has a High Response Rate in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Younger Than 65 Years

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 768-768 ◽  
Author(s):  
Farhad Ravandi ◽  
Jorge Cortes ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Susan O’Brien ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
High Response Rate ◽  
Clinical Activity ◽  
Mutation Burden

Abstract Background: Sorafenib is an orally active multi-kinase inhibitor with potent activity against the Raf/ERK/MEK pathway, VEGFR, PDGFR-β, and c-KIT. In vitro, it has growth-inhibitory effects in several AML cell lines with or without constitutive activation of ERK signaling. Sorafenib selectively induces cell growth arrest and apoptosis in FLT3-mutant human AML cell lines at nM concentrations. In a phase I study of single agent sorafenib in patients (pts) with AML escalating doses were well tolerated with no myelosuppression and with significant clinical activity predominantly (but not exclusively) in FLT3 mutated pts. Methods: This study was conducted to determine the tolerability and efficacy of combination of sorafenib with cytarabine 1.5 g/m2 iv over 24 hours daily × 4 (× 3 for pts over 60) and idarubicin 12 mg/m2 iv daily × 3. In the phase I portion of study, pts with relapsed AML were treated with escalating doses of sorafenib po (400 mg qod, 400 mg daily and 400 mg bid) for 7 days during induction, and 400 mg bid was established as a safe dose for phase II evaluation. Pts achieving CR receive up to 5 courses of consolidation with idarubicin 8 mg/m2 iv daily × 2 and cytarabine 0.75 g/m2 iv daily × 3 in addition to continuous sorafenib 400 mg po bid for up to 28 days per cycle. Maintenance with sorafenib 400 mg bid would continue for up to a year after consolidation. Results: Ten pts (median age 34 years, range 21–58) with relapsed AML (median prior therapy 2, range 1–6) were treated on the phase I portion. Seven had FLT3-ITD mutation (5 with high mutation burden, 2 with low), and 3 were negative. Four achieved CR, and 6 failed. In the phase II portion, 30 pts (including 8 with FLT3-ITD and 2 with FLT3-TKD) have been treated. Median age is 53 years (range 18 – 65) Cytogenetics were diploid in 13, +8 in 3, −5/−7 in 3, t(9;11) in 1, miscellaneous in 6, and unavailable in 4. The median presentation WBC was 4.6 × 109/L (range 1.5 –122.7 × 109/L). FLT3 mutation burden was low in blasts from 4 pts, and high in 6). Five pts were FLT3-ITD+/NPM1-. Among 25 evaluable pts, 22 (88%) have achieved CR (n=19), or CRi (n=3); 1 achieved PR, 1 died at induction from pneumonia, 1 was resistant; 5 pts are too early. The regimen is well tolerated and grade 3 adverse events thought to be possibly related to the study combination have included elevation of transaminases (3), hyperbilirubinemia (4), small bowel obstruction (1), diarrhea (2), rash (2), pericarditis (1), elevated creatinine (1), and atrial fibrillation (1). Median follow-up is 8 weeks (range, 1 – 28) with the probability of survival at 6 months of 87%; 2 pts have relapsed with CR durations of 2 and 3 months. Samples from 8 pts were studied prior to and 24–48 hours post sorafenib administration, and prior to chemotherapy. In six pts (75%), sorafenib alone induced apoptosis in peripheral blood blasts and in CD33/CD34 positive leukemia progenitor cells as determined by flow cytometry. Expression of phospho-ERK (pERK) was detectable by flow cytometry in 5 out of 7 samples tested at baseline; 24-hour exposure to sorafenib resulted in >50% downregulation of pERK in 3 of the 5 samples. Plasma inhibitory assay was performed using day 7 samples from 10 pts; mutant FLT3 was suppressed by all samples with 5-fold more potent suppression against mutant versus wildtype FLT3. Conclusions: Combination of sorafenib with idarubicin and cytarabine is safe and has a high CR rate in frontline therapy of younger pts with AML. Correlative studies confirm potent activity of sorafenib against ERK and FLT3 signaling.

Phase II Study of the Histone Deacetylase Inhibitor Panabinostat (LBH589) in Patients with Low or Intermediate-1 Risk Myelodysplastic syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1731-1731
Author(s):  
Sophie Dimicoli ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Tapan Kadia ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Median Duration ◽  
Lower Risk ◽  
Response Rate ◽  
Phase Ii Study ◽  
Single Agent ◽  
Clinical Activity ◽  
Number Of Patients ◽  
Deacetylase Inhibitor

Abstract Abstract 1731 Panabinostat is a very potent panhistone deacetylase inhibitor (HDACi) with activity in acute myelogenous leukemia (CCR 2006;12: 4628). We hypothesized that single agent panabinostat could be active in patients with low and intermediate-1 risk MDS. Oral route of administration and safety profile further increased interest in this approach. To test this concept we designed a phase II study of panabinostat for patients above 18 years of age with lower risk disease. Patients could have received prior therapy or be treatment naïve. Appropriate renal, hepatic and cardiac functions were required. Patients were excluded if they had previous HDACi treatment. Patients with history of cardiac pathology such as rhythm alterations were excluded from the study. Use of drugs that could induce QT prolongation and CYP3A4 inhibitors were not allowed. Panabinostat was used at dose of 20 mg orally three times a week for consecutive 3 weeks with cycles repeated every 4 weeks. The primary objective of the study was overall response rate defined by IWG. A maximum of 40 patients could be enrolled. The study was to stop early if the expected response rate was less than 15%. Stopping rules were as follows: Stop if the number of patients with hematologic improvement/the number of patients evaluated was 0/15 or 1/32. The study also contained a stopping rule for non-hematological toxicity. Thirteen patients were enrolled between August 2009 and December 2010. Median age was 70 years (range 47 to 84, 84% of patients older than 60), 70% were transfusion dependent, 70% had intermediate-1 risk MDS, most patients were diploid but one patient with del(5q), one with trisomy 8, one with complex cytogenetics and 2 with deletion of 20q were included. Median percent of marrow blasts was 1% (range 1 to 6%). At start of therapy, median hemoglobin was 9.5 (range 7.5–11.2 G/dL), median platelet count was 56 (range 6–431 k/uL) and median white blood cell count was 4.6 (range 0.8–20.3 k/uL). Approximately 40% had previous therapy for MDS including hypomethylating agents, lenalidomide and investigational agent. Median number of prior therapies for treated patients was 2 (range 1 to 4). Median duration of disease at time of enrollment was 10 months (range 1–50). Patients received a median of 4 cycles of panabinostat (range 1–9). Of 13 patients, 1(8%) achieved a hematological improvement including both an erythroid and platelet response that lasted for 3 months. No complete remissions or partial responses were documented. Six patients (46%) had stable disease for a median duration of 6 months (range 2–13.6). Median overall survival was 15 months (1–31 months). Two patients died because progression to AML. Therapy was well tolerated: no major adverse events were documented except for one patient that developed significant QTc prolongation. Adverse events included mild fatigue and gastrointestinal toxicity. As a biomarker of molecular activity, histone H3 acetylation was measured in 5 patients with variable results. Induction of acetylation was documented in 2. Despite the fact that the stopping rule for activity was not officially met, because of the very modest clinical activity observed, the study was closed to new patient entry. In conclusion, panabinostat given as a single agent orally at a dose of 20 mg thee times a week for 3 weeks followed by one week of rest has limited clinical activity in patients with lower risk MDS. Disclosures: No relevant conflicts of interest to declare.

Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3001-3001 ◽  
Author(s):  
L. Amler ◽  
M. S. Gordon ◽  
A. Strauss ◽  
N. Rabbee ◽  
M. K. Derynck ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Advanced Ovarian Cancer ◽  
Ca 125 ◽  
Clinical Activity ◽  
Fresh Tissue ◽  
Formalin Fixed Paraffin ◽  
Heavily Pretreated ◽  
Dimerization Inhibitor

3001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P. [Table: see text]

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin lymphoma (NHL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10000-10000 ◽  
Author(s):  
A. Reiter ◽  
A. Meinhardt ◽  
B. Burkhardt ◽  
M. Zimmermann ◽  
A. Borkhardt ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Single Agent ◽  
Newly Diagnosed ◽  
Response Evaluation ◽  
Non Hodgkin Lymphoma ◽  
Pre Treatment ◽  
Study Plan ◽  
Measurable Lesion ◽  
Performance Scale

10000 Background: Pediatric mature B-cell NHL differ from aggressive B-NHL of adults in terms of biology and treatment outcome. In contrast to adults, rituximab (Rx) is not established in the treatment of pediatric B-NHL has not be determined yet. Even the activity of Rx in pediatric B-NHL is not determined. We conducted a phase II window study to examine the activity of Rx in newly diagnosed pediatric B-NHL. Methods: Eligibility: age < 19 y, CD20 + B-NHL, ≥ 1 measurable lesion/s, informed consent. Exclusion: Lansky performance scale 5, pre-treatment, impaired renal-, heart-, liver-function, hepatitis B, pre-existing disease, pregnancy. Treatment: Rx 375 mg/m2 IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS+ pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts. Results: One hundred thirty-six pts were enrolled from 04/04–08/08. NTC °3/4 toxicities: general condition 16%, fatigue 13%, anaphylaxis (chill/fever/bronchospasm) 6 (1/2/4)%, infection 3%, S-GOT/GPT 10%, acute tumor lysis (ATL) 7%, capillary leakage (0), toxic death (0). Forty-nine pts were not evaluable for response: Withdrawal (anaphylaxis 8, ATL 2, suspected progression, not verified 4, other 2), IT therapy in CNS- pts (8), corticosteroids (3), technical inadequacy of response evaluation (21), no index lesion (1). Of the 87 evaluable pts 37 were RPs (42.5%, 95%-CI 32% - 54%). RR by histology: BL/B-ALL 29/68, DLBCL 6/14, juvenile follicular lymphoma 1/2, PMBCL 1/1, B-NHL nfs 0/2. Fifty pts were non-RPs. Conclusions: Although the RR was lower than requested Rx as single agent is active in pediatric B-NHL. No significant financial relationships to disclose.

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