Oral (po) and Intravenous (iv) Clofarabine for Patients (pts) with Myelodysplastic Syndrome (MDS)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 222-222 ◽  
Author(s):  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
High Risk ◽  
Optimal Dose ◽  
Infectious Complications ◽  
Dose Finding ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Starting Dose ◽  
Grade 3 ◽  
Secondary Mds

Abstract Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in pts with acute myeloid leukemia (AML). Early reports also suggested activity in MDS, but the role of CLO in MDS has not been defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies of IV CLO and PO CLO, respectively. Pts were eligible with MDS and ≥5% blasts or IPSS intermediate-2 and high-risk, CMML, and RAEB-t by FAB. Hematopoietic growth factor support prior to and during the study was permitted. In the IV study pts were adaptively randomized (based on response) to receive CLO 15 or 30 mg/m2 IV over 1 hr. daily × 5 every 4–6 weeks. For the PO study, the starting dose of CLO was 40 mg/m2 orally daily × 5 every 4–6 weeks (oral bioavailability assumed ~ 50%, based on preclinical data), which was decreased to 30 mg/m2 orally daily × 5 after 6 pts had been treated on the higher dose. Sixty-one pts (6 RA/RARS/RCMD, 17 RAEB-1, 16 RAEB-2, 11 CMML, 11 RAEB-t) were treated. Forty-two pts (69%) had high- or intermediate-2 risk disease by IPSS. Thirty-six pts received IV CLO and 25 PO CLO. Median age was 67 yrs (range 25–89) (IV) and 70 yrs (54–86) (PO). Overall, > 80% of pts were older than 60 yrs. Approximately 1/3 of pts had secondary MDS: 13 (36%) (IV) and 8 (32%) (PO), respectively. Seventeen (47%) (IV) and 10 (40%) (PO) of pts had unfavorable cytogenetics (by IPSS definition). Thirty-nine (64%) pts failed prior hypomethylator therapy with either decitabine or azacitidine (22 [61%] pts on IV and 17 [68%] pts on PO CLO). Responses of 60 evaluable pts (one pt refused continuation of therapy on D4 of first course) are summarized in the Table: Response (%) Route Dose (mg/m2) N CR CRp HI PO 40/30 24 7 (29) 2 (8) 3 (13) IV 15 20 7 (35) 3 (15) - 30 16 4 (25) 2 (13) - Total - 60 18 (30) 7 (12) 3 (5) Six pts (10%) died on study (all IV CLO; most commonly related to infectious complications). All pts were evaluable for toxicities. Common AEs were nausea, vomiting, skin rash, hyperbilirubinemia and transaminase elevations. Toxicities ≥ grade 3 were rare. Acute renal failure occurred in 7 pts (2 IV [15 mg/m2], 3 IV [30 mg/m2], 2 PO). Myelosuppression and hospitalizations for neutropenic fever were common, but prolonged myelosuppression (> 42 days) was rare. In conclusion, CLO has activity in pts with higher-risk MDS. Optimal dose and schedule for PO and IV CLO remain to be defined. Lower doses of CLO are also associated with responses. Additional dose finding trials are underway to define the MTD and DLT of IV and PO CLO in high-risk MDS.

Results of an Exploratory Study of Oral (po) and Intravenous (iv) Clofarabine in Patients with Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1455-1455 ◽  
Author(s):  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Varsha Gandhi ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Optimal Dose ◽  
Risk Groups ◽  
Median Number ◽  
High Dose ◽  
Two Phase ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Febrile Episodes ◽  
Elevated Transaminases

Abstract Clofarabine (CLO) is an adenosine nucleoside analog with activity in adult acute myeloid leukemia (AML). Its activity in MDS is less well defined. To evaluate the activity and safety of CLO in MDS we designed two phase II studies with iv CLO and po CLO, respectively. Pts were eligible if they had MDS with ≥ 5% blasts, fell into IPSS intermediate-2 and high-risk groups, or had CMML. No prior intensive chemotherapy or high-dose cytarabine was allowed. Hematopoietic growth factor support was permitted. In the iv study pts were adaptively randomized to receive CLO 15 or 30 mg/m2 iv daily x 5 every 4–6 weeks. The second study used a starting dose of CLO 40 mg/m2 orally daily x 5 every 4–6 weeks (assuming oral bioavailability about 50%), which was then decreased to 30 mg/m2 orally daily x 5. Thirty pts (18 RAEB, 6 RAEB-T, 6 CMML) have been treated. Assignment by IPSS for RAEB and RAEB-T pts: 10 high-risk, 10 intermediate-2, and 4 intermediate-1. Fifteen pts received iv CLO and 15 po CLO. Median age was 68 yrs (range 57–86). Median number of prior therapies was 1 (0–4). Twenty (67%) pts received prior decitabine or azacitidine. Karyotype was abnormal in 24 (80%) pts, including 10 pts with −5/−7 abnormalities. Responses were determined according to International Working Group criteria (IWG). Twenty-seven pts were evaluable for response (2 pts too early, one refused further treatment on day 4 of first course). Eleven (41%) pts responded [7 (26%) CR, 2 (7%) HI, 2 (7%) clinical benefit (CB)] (see table). Response (%) Route Dose (mg/m2) N CR HI CB po 40 6 - - 1 (17) 30 6 1(17) 2 (33) 1 (17) iv 30 6 2 (33) - - 15 9 4 (44) - - Response by IPSS: 67% intermediate-1, 44% intermediate-2, 40% high. Twenty-seven pts are evaluable for toxicities. Grade ≥ 3 toxicities occurred in 8 of 13 pts on iv CLO (rash, hyperbilirubinemia, elevated transaminases, elevations of creatinine, acute renal failure) and 4 of 14 pts with po CLO (rash, hyperbilirubinemia, elevated transaminases). Myelosuppression resulting in febrile episodes and hospitalizations with both iv and po CLO was ubiquitous, but prolonged myelosuppression (> 42 days) was rare. In summary, CLO has activity in pts with higher-risk MDS. The optimal dose and schedule for po and iv CLO have not been defined yet. Lower doses of CLO are associated with responses. Correlative PK studies may help to provide further support for optimal dose and route of administration of CLO in pts with MDS.

The role of UGT1A1 polymorphisms (*28 and *6) in Japanese cancer patients.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 570-570
Author(s):  
S. Morimoto ◽  
M. Shimada ◽  
N. Kurita ◽  
T. Iwata ◽  
M. Nishioka ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Prospective Trial ◽  
Optimal Dose ◽  
Japanese Patients ◽  
Dose Finding ◽  
Severe Toxicity ◽  
Severe Diarrhea ◽  
First Line Therapy ◽  
Grade 3

570 Background: Combination protocol using FU-LV with irinotecan (FOLFIRI) is currently regarded as standard first-line therapy in advanced colorectal cancer (CRC). Although irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Here we present the result of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC. Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 23 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. Results: On the 23 patients, the genotypes of UGT1A1 *28 were homozygous in 1 (0.5%) and heterozygous in 5 (28%), *6 were homozygous in 0 and heterozygous in 6 (26%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (33%), but in *28 heterozygous patients were not (0%). There was no decrease of irinotecan doses in each group. In Japanese people, UGT1A1 *6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). Conclusions: When the dosage of irinotecan is decided, it is necessary to consider the UGT1A1 *6 heterozygous in Japanese cancer patients. [Table: see text]

Combination of Oxaliplatin Plus Irinotecan in Patients With Gastrointestinal Tumors: Results of Two Independent Phase I Studies With Pharmacokinetics

1999 ◽  
Vol 17 (6) ◽  
pp. 1751-1751 ◽  
Author(s):  
Ernesto Wasserman ◽  
Caroline Cuvier ◽  
François Lokiec ◽  
François Goldwasser ◽  
Salima Kalla ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Two Phase ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Minute Period ◽  
Grade 3 ◽  
Febrile Episodes

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of ≤2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m2 for oxaliplatin and 150 to 250 mg/m2 for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m2 plus irinotecan 200 mg/m2 in one study and oxaliplatin 110 mg/m2 plus irinotecan 250 mg/m2 in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2. At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU–resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Oral Clofarabine in the Treatment of Patients with Higher-Risk Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 118-118 ◽  
Author(s):  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Zeev Estrov ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Research Funding ◽  
Optimal Dose ◽  
Oral Formulation ◽  
Median Number ◽  
Infectious Complications ◽  
Molecular Characteristics ◽  
Number Of Cycles ◽  
Almost All

Abstract Abstract 118 Clofarabine (CLO) is a second generation deoxyadenosine nucleoside analog with activity in patients (pts) with acute myeloid leukemia (AML). Early reports also suggestedactivity of iv CLO in myelodysplastic syndrome (MDS), but the role of CLO in MDS therapy remains largely undefined. Due to the molecular characteristics of CLO it can also be administered as an oral formulation with a bioavailability of around 50%. As an oral agent has obvious advantages over parenteral administrations, we designed a phase 2 study to evaluate the activity and safety of oral CLO in patients with MDS. Pts were eligible if they had MDS and ≥ 5% blasts (including RAEB-t by FAB) or IPSS intermediate-2 and high-risk, and CMML. Hematopoietic growth factor support prior to and during the study was permitted. Thirty-two pts (2 RA, 11 RAEB-1, 11 RAEB-2, 2 RAEB-t, 5 CMML-1, 1 CMML-2) were treated. Twenty-two pts (69%) had intermediate-2 or high-risk disease by IPSS. Median age was 70 yrs (range 53–86). Overall, ≥ 27 pts (84%) were older than 60 yrs. Thirteen pts (41%) had a history of a prior malignancy and 20 pts (66%) failed prior hypomethylator therapy (6 pts azacitidine, 12 pts decitabine, 2 pts both). Cytogenetics were intermediate and poor in 9 (28%) and 10 (31%) pts, respectively. The starting dose of CLO was 40 mg/m2 orally daily × 5 days every 4–6 weeks (6 pts), which was decreased due to toxicities to 30 mg/m2 orally daily × 5 days (19 pts), and eventually 20 mg/m2 orally daily × 5 days (7 pts). Twenty-eight pts (88%) received treatment in an outpatient facility and almost all pts (94%) received anti-infectious prophylaxis. Responses of 31 evaluable pts are summarized in the Table: Among 20 pts who failed prior hypomethylator therapy responses were CR in 2 (10%), HI in 2 (10%), and CB in 2 (10%). The median number of cycles to response was 1 (range 1–3). Of 10 pts who received further consolidation cycles, the median number was 1 (range 1–8+). No pts died within 6 wks of induction. Acute renal failure occurred in 4 pts (1 pt 40 mg/m2, 3 pts 30 mg/m2) in the context of myelosuppresssion-associated infectious complications; 4 pts died. Common adverse events were nausea/vomiting, rashes, reversible transaminase elevations and hyperbilirubinemia, and fatigue and were mainly ≤ grade 2. The most frequent ≥ grade 3 toxicity were reversible elevations of transaminases. Myelosuppression was ubiquitous, but prolonged myelosuppression (> 42 days) was rare in responding pts. Infectious episodes occurred in 16 pts and were more frequent in pts receiving CLO at 40 or 30 mg/m2. Oral CLO has an ORR of 46% in pts with higher-risk MDS. Responses are lower in pts failing prior hypomethylator therapy. The optimal dose and schedule to balance activity and toxicity remain to be defined. Disclosures: Faderl: Genzyme: Consultancy, Research Funding. Off Label Use: Clofarabine in MDS. Kantarjian:Genzyme: Consultancy, Research Funding.

Ibrutinib In Combination With Rituximab (iR) Is Well Tolerated and Induces a High Rate Of Durable Remissions In Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 675-675 ◽  
Author(s):  
Jan A. Burger ◽  
Michael J. Keating ◽  
William G. Wierda ◽  
Julia Hoellenriegel ◽  
Ghayathri Jeyakumar ◽  
...  
Keyword(s):  
High Risk ◽  
Subdural Hematoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Single Agent ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
High Rate ◽  
Grade 3

Abstract The Bruton tyrosine kinase (BTK) inhibitor ibrutinib is a promising new targeted therapy for patients with mature B cell malignancies, especially CLL and mantle cell lymphoma (MCL). Single agent ibrutinib induces an overall response rate (ORR) of 71% in relapsed CLL, based on the Phase 1/2 experience. To accelerate and improve responses to ibrutinib in high-risk CLL, ibrutinib was combined with rituximab; we update this Phase 2 single-center clinical trial with a median follow-up of 14 months. Methods Patients were treated with ibrutinib 420 mg PO daily continuously throughout the study Rituximab (375 mg/m2) was administered weekly for the first four weeks (cycle 1), then monthly until cycle 6.at which point patients continued on ibrutinib monotherapy. Study inclusion required high-risk disease (del17p or TP53 mutation [treated or untreated]), PFS < 36 months after frontline chemo-immunotherapy, or relapsed CLL with del11q. Results Characteristics of the 40 patients enrolled included median age of 65 (range 35–82) with a median of 2 prior therapies. There were14 female and 26 male patients. 20 patients had del17p or TP53 mutation (4 without prior therapy), and 13 patients had del11q. 32 patients had unmutated IGHV, only one patient mutated IGHV, the remaining patients had inconclusive IGHV results. The median β2 microglobulin was 4.2 mg/L (2.2 – 12.3), At a median follow up of 14 months, 32 of 40 patients continue on therapy (16 out of 20 with del17p or TP53 mutation) without disease progression. 39 patients were evaluable for response assessment per 2008 IWCLL guidelines; 34 (87%) achieved partial remission (PR), and three (8%) complete remission (CR), accounting for an ORR of 95%. One CR was negative for MRD by flow cytometry, The ORR in the 20 patients with del17p or TP53 mutation was 90% (16 PR, 2 CR). Among the 8 patients that came off study, 3 patient died from unrelated infectious complications (2 cases of sepsis, 1 case of pneumonia), and 1 died from unrelated respiratory and cardiovascular failure. Two patients came off study because of possibly ibrutinib-related toxicity (one subdural hematoma, one grade 3 mucositis), one patient had progressive disease, and one proceeded to stem cell transplantation. Treatment generally was well tolerated, with infectious complications (6 cases of pneumonia and 3 cases of upper respiratory infections) being the most common complication. There were two Grade 3, possibly related AEs: mucositis (n=1), and peripheral neuropathy (n=1). Milder toxicities included Grade 1-2 bruising (n=7), Grade 1 subdural hematoma (n=1), fatigue (n=2), bone pain, myalgias, and arthralgia (n=5), or diarrhea (n=1). Questionnaires revealed significantly improved overall health and quality of life (QOL) after 6 months, based on the EORTC-QOL-v.3 questionnaire, which coincided with a significant weight gain at 3 and 6 months. Conclusion Ibrutinib in combination with rituximab is a safe, well tolerated regimen for high-risk CLL patients, which induces high rates of durable responses. Responses were associated with significant improvements in QOL. Compared to ibrutinib monotherapy, the redistribution lymphocytosis resolves more rapidly and completely (see Figure), and consequently the ORR is higher. Whether the addition of rituximab to ibrutinib therapy translates into longer progression-free and overall survival will be addressed in an upcoming larger, randomized trial of ibrutinib versus iR in relapsed/refractory CLL. Disclosures: Burger: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Ibrutinib (PCI-32765) for treatment of high-risk CLL patients. O'Brien:Pharmacyclics: Research Funding.

Assessing the Safety and Efficacy of Ruxolitinib in a Multicenter, Open-Label, Expanded-Access Study in Japanese Patients with Myelofibrosis (MF)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1625-1625
Author(s):  
Keita Kirito ◽  
Norio Komatsu ◽  
Kazuya Shimoda ◽  
Hikaru Okada ◽  
Taro Amagasaki ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Spleen Size ◽  
Phase 2 ◽  
Spleen Volume ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Starting Dose ◽  
Grade 3 ◽  
Eortc Qlq

Abstract BACKGROUND: Ruxolitinib is a potent and selective JAK1/JAK2 inhibitor that has demonstrated durable improvements in splenomegaly and MF-related symptoms, and has been associated with improved overall survival in patients (pts) with MF in randomized clinical trials. Results from the phase 2 Asian multinational study (NCT01392443) supported these findings in Asian pts, including 30 Japanese pts. The current study was initiated to collect further data on the safety and efficacy of ruxolitinib in pts with MF and included intermediate (Int)-1-risk pts and those with a platelet (PLT) count of 50 to < 100 × 109/L, 2 pt populations not included in the phase 3 COMFORT studies or the phase 2 Asian study. METHODS: Pts with primary MF (PMF), post-polycythemia vera (PPV) MF, or post-essential thrombocythemia (PET) MF classified as high-risk, Int-2 risk, or Int-1 risk with a palpable spleen (≥ 5 cm from costal margin) were included. The primary objective was to assess safety of ruxolitinib. Efficacy endpoints included changes in spleen size and patient-reported outcomes (EORTC QLQ-C30 symptoms and functional scales and the 7-day modified MFSAF v2.0). All pts were to receive ruxolitinib for 24 wk with the starting dose based on PLT count at baseline (50 to ˂ 100 × 109/L, 5 mg twice daily [bid]; 100 to 200 × 109/L, 15 mg bid; ˃ 200 × 109/L, 20 mg bid) and adjusted for each pt to maximize safety and efficacy (minimum, 5 mg bid; maximum, 25 mg bid). The primary analysis occurred when all pts completed 24 wk or discontinued. RESULTS: Overall, 51 pts (PMF, n = 23; PPV-MF, n = 14; PET-MF, n = 14) were treated. Most pts were Int-2 (33.3%) or high risk (54.9%); 11.8% were classified as Int-1. The median age was 65 years (range, 44-85 years), and 52.9% (n = 27) were male. The median palpable spleen length was 16.5 cm (range, 2-30 cm), and the median spleen volume was 2028.7 cm3 (range, 480-4682 cm3). Median hemoglobin at baseline was 99.0 g/L (range, 62-141 g/L), and median PLT count was 247 × 109/L (range, 57-1265 × 109/L); 13.7% of pts had a baseline PLT count of 50 to < 100 × 109/L. Most pts received a starting dose of 20 mg bid (62.7%; n = 32) or 15 mg bid (23.5%; n = 12); the rest started treatment at 5 mg bid. Most pts completed treatment as per protocol (86.3%; n = 44); 9.8% (n = 5) discontinued due to adverse events (AEs). Other reasons for discontinuation included disease progression and loss to follow-up (2.0% each). The most common hematologic AEs were anemia (62.7%; grade 3/4, 47.1%) and thrombocytopenia (29.4%; grade 3/4, 7.8%). Nonhematologic AEs in ≥ 10% of pts included constipation (13.7%; grade 3/4, 0%), abnormal hepatic function (11.8%; grade 3/4, 3.9%), and nasopharyngitis (11.8%; grade 3/4, 0%). No deaths occurred on study. At wk 24, 30.0% of evaluable pts (15/50) experienced ≥ 50% reduction in palpable spleen length from baseline; 26.0% (13/50) had a ≥ 35% reduction in spleen volume. The majority of pts (52.0%; 26/50) had a ≥ 50% reduction in palpable spleen length from baseline at any time by wk 24; 38.0% (19/50) had a ≥ 35% reduction in spleen volume by wk 24. Ruxolitinib treatment led to clinically significant improvements in symptoms, with 75.0% of evaluable pts (30/40) achieving a ≥ 50% reduction from baseline in MFSAF total symptom score at wk 24. Improvements were also observed in quality of life and role functioning (as assessed by the EORTC-QLQ), with pts reporting reductions in MF-related symptoms, including fatigue, pain, and appetite loss. Overall, IgM, CD3, CD4, and CD8 levels remained stable during treatment; IgG levels decreased slightly in the first 4 wk but then increased to near baseline levels (Figure). CONCLUSIONS: As observed in other studies of ruxolitinib, most pts in this study experienced spleen size reductions and improvement in symptoms. The most common AEs were anemia and thrombocytopenia, consistent with previous reports. Additionally, this study evaluated the effect of ruxolitinib on the levels of different immune markers, an analysis not conducted in previous studies with ruxolitinib, and identified no negative effects on the levels of these markers during the course of treatment. The safety and efficacy of ruxolitinib here is consistent with the phase 3 COMFORT studies and the phase 2 Asian study. These findings indicate that ruxolitinib is a safe and effective therapy in Japanese pts with MF, including Int-1-risk pts and those with PLT counts 50 to < 100 × 109/L. Disclosures Kirito: Novartis Pharma KK: Honoraria. Shimoda:Novartis: Consultancy, Honoraria. Okada:Novartis Pharma K.K.: Employment. Amagasaki:Novartis Pharma K.K.: Employment. Yonezu:Novartis Pharma K.K.: Employment. Akashi:Asahi Kasei: Research Funding, Speakers Bureau; Shionogi: Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Consultancy, Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau.

Preliminary results from two phase II studies of lenalidomide monotherapy in relapsed/refractory non-Hodgkin’s Lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17569-17569 ◽  
Author(s):  
P. H. Wiernik ◽  
I. S. Lossos ◽  
G. Justice ◽  
J. B. Zeldis ◽  
K. Takeshita ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Phase Ii ◽  
Prior Treatment ◽  
Hodgkin's Lymphoma ◽  
Two Phase ◽  
Preliminary Results ◽  
Phase Ii Studies ◽  
Non Hodgkin's Lymphoma ◽  
Grade 3

17569 Background: Lenalidomide is an immunomodulatory drug of the IMiD class that has activity in multiple myeloma, myelodysplastic syndromes and chronic lymphocytic leukemia. We report preliminary results of two Phase II studies assessing the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent or aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with indolent (study NHL-001) or aggressive (study NHL-002) relapsed/refractory NHL following ≥ 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated until disease progression. Response and progression are evaluated using cross sectional imaging by the NCI criteria. Results: 10 subjects (2 indolent (I), 8 aggressive (A)) of a planned 80 (40 in each study) have enrolled thus far. Median age is 66 (45–80) and 7 subjects are female. Indolent histology is follicular center lymphoma grade 1, 2 (n = 2) and aggressive histology diffuse large cell lymphoma (n = 7) and follicular center lymphoma grade 3 (n = 1). Median time from diagnosis to lenalidomide monotherapy is 2.9 years (1.1–10) and median number of prior treatment regimens per subject is 3 (1–6). Median duration of follow-up is 2 months. Of eight subjects (2 I, 6 A) evaluable for response at two months, three demonstrated a decrease in their tumor burden by 72% (I), 68% (A) and 52% (A), two subjects (2 A) exhibited stable disease and three subjects (1 I, 2 A) had disease progression. Six of the ten subjects (2 I, 4 A) demonstrated no Grade 3 or 4 adverse events. Grade 3 or 4 hematological adverse events (neutropenia, thrombocytopenia) occurred in four subjects including one febrile neutropenia and one of these four subjects also exhibited Grade 3 cellulitis. No tumor flare or tumor lysis has been observed to date. Conclusions: Preliminary data of lenalidomide monotherapy in relapsed and refractory NHL are encouraging. [Table: see text]

A phase II study of DJ-927 as second-line therapy in patients (pts) with advanced gastric cancer (GC) who have failed a 5-FU non taxane based regimen

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4081-4081 ◽  
Author(s):  
T. Evans ◽  
R. Dobrila ◽  
R. Berardi ◽  
K. A. Sumpter ◽  
L. R. Wall ◽  
...  
Keyword(s):  
Objective Response ◽  
Optimal Dose ◽  
Primary Objective ◽  
Neutropenic Sepsis ◽  
Line Therapy ◽  
Starting Dose ◽  
Measurable Disease ◽  
Complete Treatment ◽  
Grade 3

4081 Background: Most 1st-line combination chemotherapy regimens in pts with advanced GC include 5-FU. Taxanes are also active agents in GC, either alone or in combination. However, there is no recognized 2nd-line regimen for use in pts with advanced GC. DJ-927 is a semi-synthetic novel taxane with in vitro activity against GC cells lines. It is administered orally, with hematologic dose-limiting toxicity (DLT) in Phase I studies. The primary objective of this study was to determine the objective response rate of DJ-927 as 2nd-line therapy in pts with advanced GC. Methods: Eligible pts had confirmed advanced GC with no more than 1 prior systemic 5-FU-containing regimen for advanced disease, with adequate hematologic, renal and liver function, and with measurable disease. The starting dose in the 1st cohort of 6 pts was 27 mg/m2 orally, every 3 weeks. If < 2 DLTs occurred at this dose, the next cohort of 6 pts would start at a dose of 35 mg/m2, every 3 weeks, and all subsequent pts would be treated at the optimal dose level. Measurable disease was assessed after every 2 courses. Pharmacokinetic sampling was performed during course 1 only. Sample size based on a 3-outcome 1-stage design was calculated to be 27 pts evaluable for response, with ≥ 4 responses of 27 pts indicating that DJ-927 has activity in advanced GC. Results: 36 pts (male=25; female = 11), KPS ≥ 60%, with GC (n = 23) or OG junction cancer (n = 13), received 104 courses (median = 2; range 1–9) of DJ-927. 2 DLTs (febrile neutropenia; Grade 4 neutropenia > 5 days) occurred at 35 mg/m2, and the optimal starting dose was confirmed as 27 mg/m2. 6 of 36 pts were not evaluable for response (< 1 complete treatment course) due to early disease progression (3), toxicity (2), and drug not given (1). Response data is available for 26 of 30 evaluable pts with confirmed PR (n = 5), SD (15), and PD (6). Toxicity, ≥ grade 3, in evaluable pts (n = 33) included neutropenia (17), anemia (5), thrombocytopenia (4), diarrhoea (7), fatigue (5), lethargy (4), neutropenic sepsis (5). Conclusions: DJ-927 has modest activity in pts with GC who have failed a 5-FU non-taxane based regimen. Toxicities include neutropenia ± sepsis, diarrhoea and lethargy. Further studies of DJ-927 in combination with other active agents are warranted in pts with GC. [Table: see text]

Pilot study of fixed-dose bevacizumab (200 mg) for solid malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14600-e14600
Author(s):  
S. K. Reddy ◽  
M. Curti ◽  
M. Janis ◽  
R. Minow
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Optimal Dose ◽  
Median Number ◽  
Fixed Dose ◽  
Phase I Studies ◽  
Phase Ii Studies ◽  
Prospective Phase ◽  
Grade 3 ◽  
Grade Iii

e14600 Background: We report our initial experience with fixed dose bevacizumab at 200mg (approximately 3mg/kg). Phase I studies suggested that an optimal dose for phase II studies with bevacizumab is 3mg/kg and that circulating VEGF was undetectable at 0.3mg/kg. (Gordon et al. JCO 2001) We proposed a fixed-dose regimen of bevacizumab which we hypothesized would yield equivalent response rates with reduced toxicities and cost versus higher-dose regimens. Patients with advanced malignancies for whom bevacizumab would be indicated were analyzed. Methods: 15 patients were treated with 200mg bevacizumab in combination with antineoplastic therapy. 6 patients had NSCLCa, 8 patients had Colorectal cancer, and 1 patient had BRCA. Results: 15 patients are evaulable for response and have completed a total of 234 doses of bevacizumab (median number of doses =13) with no grade III/IV toxicity, or bevacizumab associated toxicities seen. No grade III or greater hypertension was observed. Proteinuria was not formally assessed, but no grade 3 or greater proteinuria was reported. All patients are evaluable for response with overall response rate of 33% (5/15). With a median follow-up (from the start of bevacizumab) of 452 days (222–1,699 days), median survival has not been reached with only 2 deaths. Conclusions: Fixed dose bevacizumab appears to be effective, less toxic, significantly less expensive and supported by biologic rationale and prior phase I studies and warrants further investigation. Additional patients will be accrued in a prospective phase II trial. [Table: see text]

Feasibility study of irinotecan based on UGT1A1 polymorphisms for metastatic colorectal cancer: Interim report.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
Hideya Kashihara ◽  
Mitsuo Shimada ◽  
Nobuhiro Kurita ◽  
Masanori Nishioka ◽  
Takashi Iwata ◽  
...  
Keyword(s):  
Response Rate ◽  
Prospective Trial ◽  
Optimal Dose ◽  
Japanese Patients ◽  
Dose Finding ◽  
Severe Toxicity ◽  
Interim Report ◽  
Severe Diarrhea ◽  
Gene Type ◽  
Grade 3

505 Background: Although Irinotecan prolongs survival, it causes severe diarrhea and neutropenia. Recent pharmacogenetic studies on irinotecan have revealed significant associations of UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms *28 and *6, the latter being specifically detected in East Asians resulting in severe toxicity. It is necessary that the dose-finding trial that decided the optimal dose according to the gene polymorphism to draw out the maximum therapeutic effect while evading the side effect. Previously, we showed UGT1A1 polymorphisms in Japanese patients (2011 ASCO-GI). Here, we present the interim report of prospective trial of the safety about FOLFIRI therapy according to each gene type of UGT1A1 for Japanese patients with advanced CRC. Methods: From 2008, 250 Japanese patients in TOKUSHIMA University were enrolled in this study. Homo group (*6/*6 and *28/*28 or a both hetero types), hetero group (It was *28 and either *6 was hetero type), and wild group (*28 and *6 were wild types) were defined. On the 30 patients with advanced CRC treated with FOLFIRI after standard chemotherapy, wild and homo groups were administered 150mg/m2 irinotecan, and homo group was 100mg/m2. The incidences of severe toxicities in each gene type of UGT1A1 and the response rate in FOLFIRI therapy were investigated. Results: In Japanese people, UGT1A1*6 polymorphisms were higher than *28 (*6 homo 3%, hetero 27% vs *28 homo 0.5%, hetero 13%). On the 30 patients with advanced CRC treated with FOLFIRI, the genotypes of UGT1A1*28 were homozygous in 1 (3%) and heterozygous in 6 (20%), *6 were homozygous in 0 and heterozygous in 8 (27%). In *6 heterozygous patients, severe toxicities (grade 3 or more) were found (38%). In *28 heterozygous patients, 1 patient (17%) showed severe toxicities. There was no decrease of irinotecan doses in each group. The number of course to PD was 7.6 (1-23). Regarding the response rate, PR, SD, PD was observed in 2 (7%), 6 (20%) and 18 patients (60%), respectively. Conclusions: In our interim report, the dosages of irinotecan based on UGT1A1 polymorphisms are safety in FOLFIRI therapy.

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