Phase I/II Clinical Trial of Erwinia Asparaginase (ErwinaseR) in Combination with Prednisolone, Vincristine and Pirarubicin in Children and Young Adults with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3657-3657
Author(s):  
Chitose Ogawa ◽  
Atsushi Manabe ◽  
Hiroaki Goto ◽  
Katsuyoshi Koh ◽  
Daisuke Tomizawa ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase I ◽  
Phase Ii ◽  
Safety And Efficacy ◽  
E Coli ◽  
Asparaginase Activity ◽  
Erwinia Asparaginase ◽  
Children And Young Adults ◽  
Level 1 ◽  
Grade 3

Abstract Introduction: L-asparaginase is an important component of multi-agent chemotherapy for children and young adults with ALL. In Japan, only one asparaginase preparation, native-E-coli-asparaginase (LeunaseR), has been approved so far by the Health, Labour and Welfare Ministry. The incidence of clinical allergy to native-E-coli -asparaginase can be more than 30% with repeated administration. To continue treatment with asparaginase, Erwinia asparaginase (ErwinaseR), deriving from Erwinia chrysanthemi, is recommended for patients who develop clinical allergy to native-E-coli-asparaginase, because the drug has no cross reactivity. We planned phase I/II trial OP-01-001 to investigate the safety and efficacy of Erwinase in combination chemotherapy consist of prednisolone, vincristine and pirarubicin. Patients and Methods: Eligible patients on this study were children and young adults with ALL/ LBL in remission, >=1 to =<25 years of age, and had developed allergy to E-coli-asparaginase. Patients with a history of pancreatitis or previous administration of Erwinase were excluded. The study was approved by IRB at each institution and patients/guardians provided informed consent/assent. In this trial regimen OP-01-001, level 1 (25,000) or level 0 (20,000 IU/m2) x 6 doses of Erwinase were planned to administer intramuscularly (IM) on day 2, 5, 7, 9, 11 and 13 with 40 mg/m2/day x15 days of prednisolone, 1.5mg/m2 x 3 doses of vincristine and 20 mg/m2x 2 doses of pirarubicin. In phase I, we determined the maximum tolerated dose, dose limiting toxicity (DLT), and the recommended phase II dose (RP2D) of Erwinase. Safety, efficacy and pharmacokinetic/dynamic study were evaluated in all patients. Blood samples were obtained at scheduled time points during Erwinase therapy and assayed for asparaginase activity and asparagine concentration in plasma. Primary endpoint was asparaginase activity in plasma at 48h after the first dosing. Results: A total of 24 eligible patients were enrolled to phase I/II study from February 2012 to January 2014. In phase I study, 6 eligible/evaluable patients were enrolled to level 1, starting at 25,000 IU/m2. Since all patients completed the scheduled treatments without DLT in level 1, RP2D was determined 25,000 IU/m2and 18 patients were enrolled in phase II study. PK, PD, safety and efficacy were evaluated as phase I/II study. The median age of 24 evaluated patients was 7.5 years (range 2-16) and 15 patients (62.5%) were male. In PK/PD study, one patient was excluded because essential clinical dataset was not obtained. After the first dosing, serum asparaginase activity exceeded 0.1 IU/mL in 23/23 patients (100%) at 48 hours and it did in 18/23 patients (78.3%) at 72 hours. After the sixth dosing, the activity at 72 hours was higher than 0.1 IU/mL in 19/23 (82.6%). Plasma asparagine was significantly depleted (<1.0 μM) in 22/23 (95.7%) 48 hours after the first dosing and it was also depleted in 22/23 (95.7%) 72 hours after the last dosing in all but one patients. All patients maintained remission status during the trial. No allergic reaction related to Erwinase was reported. Hypertriglyceridemia or blood triglycerides increased was reported in 12/24 (50%), 4 cases in grade 3 and 1 in grade 4. Increase in blood sugar was observed in 3 patients (12.5%), 2 in grade 1 and 1 in grade 2. In addition, 23 (95.8%) and 1 (4.2%) developed decrease in fibrinogen and increase in ammonia at grade 2-4. Grade 3 febrile neutropenia and bacteremia were reported in 8 patients (33.3%) and in 1 patient (4.2%), respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion: Erwinase as administered using the OP-01-001 regimen was well tolerated without unexpected toxicities and achieved good serum asparaginase activity at both 48 and 72 hours after dosing. In previous reports, a much lower dose of Erwinase at 10,000 IU/m2/dose was used in the study of EORTC (Duval M. Blood 2002;99:2734), which was subsequently assessed as suboptimal and the identical dose of erwinase at 25,000 IU/m2/dose was used in the study of COG (Salzer WL. Blood 2013;122:507). We herein showed that following allergy to E-coli native-asparaginase, erwinase 25,000 IU/m2 x 6 doses IM in 2 or 3 days interval in 2 weeks was effective and safe in children and young adults in Japan. Disclosures Ogawa: OHARA Pharmaceutical Co., Ltd.: Honoraria. Manabe:OHARA Pharmaceutical Co., Ltd.: Honoraria. Fukushima:OHARA Pharmaceutical Co., Ltd.: Honoraria. Horibe:OHARA Pharmaceutical Co., Ltd.: Honoraria. Hamada:OHARA Pharmaceutical Co., Ltd.: Employment. Ohara:OHARA Pharmaceutical Co., Ltd.: Honoraria.

Administration of Erwinia Asparaginase (Erwinase®) Following Allergy to PEG-Asparaginase In Children and Young Adults with Acute Lymphoblastic Leukemia Treated on AALL07P2 Achieves Therapeutic Nadir Serum Asparaginase Activity: A Report From the Children's Oncology Group (COG)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2134-2134
Author(s):  
Wanda Salzer ◽  
Barbara Asselin ◽  
Jeffrey Supko ◽  
Meenakshi Devidas ◽  
Nicole Kaiser ◽  
...  
Keyword(s):  
United States ◽  
Young Adults ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
The United States ◽  
E Coli ◽  
Clinical Allergy ◽  
Asparaginase Activity ◽  
Erwinia Asparaginase ◽  
Children And Young Adults

Abstract Abstract 2134 Introduction: L-asparaginase is a vital component of multi-agent chemotherapy for children and young adults with acute lymphoblastic leukemia (ALL). In the United States, there are 2 asparaginase preparations approved by the Food and Drug Administration, native E. coli (Elspar®) and PEG-asparaginase (Oncaspar®). PEG-asparaginase is the most commonly utilized asparaginase product due to its longer half-life and decreased immunogenicity. However, the incidence of clinical allergy to PEG-asparaginase approaches 20%, with repeated administration. Due to cross reactivity with native E. coli asparaginase, there is no FDA-approved preparation available for patients who develop clinical allergy to PEG-asparaginase. A third preparation, Erwinia asparaginase (Erwinase®), derived from Erwinia chrysanthemi, is not commercially available in the United States. The optimal dosing of Erwinase® necessary to obtain nadir asparaginase activity > 0.1 IU/mL similar to that obtained after conventional dosing of PEG-asparaginase is unknown. Patients and Methods: We hypothesized that substitution of Erwinase® 25,000 IU/m2 × 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule in children and young adults with ALL would provide a 48 hour nadir serum asparaginase activity ≥ 0.1 IU/mL, and effectively deplete plasma asparagine, a surrogate marker of asparaginase activity. Eligible patients on COG study AALL07P2 were >1 to <30 years of age, concurrently enrolled on a frontline COG ALL treatment study, and had documented ≥ grade 2 allergy (NCI Common Terminology Criteria 3.0) to PEG-asparaginase. Results: A total of 55 eligible/evaluable patients were enrolled from February 2008 to April 2010. Blood samples were obtained at scheduled time points during Erwinase® therapy and assayed for serum asparaginase activity and asparagine concentration in plasma. Nadir serum asparaginase activity ≥ 0.1 IU/mL was achieved in 49/53 patients (92.5%) at 48 hours after dosing and in 46/52 patients (88.5%) at 72 hours after dosing. Plasma asparagine was significantly depleted (<1.0 μM) in all 49 patients for whom samples were satisfactorily obtained. Grade 2–3 allergic reaction and grade 1–2 hyperglycemia related to Erwinase® were reported in 5 and 3 patients, respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion: Erwinase® as administered using the AALL07P2 regimen was well tolerated and achieved nadir serum asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with PEG-asparaginase. We conclude that following allergy to PEG-asparaginase, Erwinase® 25,000 IU/m2 × 6 doses IM on a Monday/Wednesday/Friday schedule can be substituted for a single dose of PEG-asparaginase. Disclosures: Supko: EUSA Pharma: Research Funding. Plourde: EUSA Pharma: Employment. Winick: EUSA Pharma: EUSA Advisory Board.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

A phase I/II study of cetuximab (cet) in combination with S-1 and oxaliplatin (SOX) in first-line treatment for metastatic colorectal cancer (mCRC) (JACCRO CC-06).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 571-571 ◽  
Author(s):  
Akihito Tsuji ◽  
Yu Sunakawa ◽  
Tadamichi Denda ◽  
Yasutaka Takinishi ◽  
Masahito Kotaka ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Maximum Tolerated Dose ◽  
Safety And Efficacy ◽  
Dose Adaptation ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Early Tumor ◽  
Ecog Ps ◽  
Level 2

571 Background: Both SOX and cet are effective treatments each other in patients (pts) with mCRC. COIN trial indicated that the use of cet in combination with capacitabine and oxaliplatin should not be recommended. However, the safety and efficacy of cet plus SOX are not clear. To evaluate the safety and clinical efficacy of the combination, we conducted a multi-center phase I/II study. Methods: In this trial, we assigned pts with KRAS wild type (wt), EGFR-expressing tumor and no prior chemotherapy to receive cet (initial dose 400, and 250 mg/m2 weekly) followed by SOX (oxaliplatin on day 1 and S-1 40 mg/m2 twice daily on days 1-14). The treatment was repeated every 3 weeks. The phase I part was designed to determine the maximum tolerated dose (MTD) and recommended dose (RD) according to the dose adaptation schedule of oxaliplatin (100 mg/m2 for level 1 and 130 mg/m2 for level 2). In the following phase II part, the enrolled pts were treated with the RD. The primary endpoint was response rate (RR) evaluated by the external review board according to RECIST criteria v1.1. Secondary endpoints included PFS, OS, and safety. In addition, we prospectively evaluated early tumor shrinkage (ETS). Results: A total of 67 pts were enrolled from January 2012 to February 2013. In the phase I part, level 2 was determined to be the RD. The MTD was not determined because dose limiting toxicity was not confirmed in level 2. In the phase II part, 59 pts including 6 pts of phase I cohort were assessable for the efficacy. The median age was 64 years, 51% of pts were male, and ECOG PS 0 was observed in 85% of pts. The median course of treatment was 5 (range 1-14). The RR was 62.7% (95%CI, 50.4 to 75.1) and ETS was observed in 72% of pts. In safety analysis, grade 3 or worse adverse events were platelet count decreased (13.1%), neutropenia (8.2%), anorexia (11.7%), rash acneform (6.7%) and peripheral neuropathy (3.3%). Conclusions: We determined the RD of cet plus SOX treatment in pts with mCRC. This combination is tolerable at full doses of cet and SOX, with manageable toxicities, and demonstrates advantages in RR for pts with KRAS wt tumor. Updated safety and efficacy data will be presented. Clinical trial information: UMIN000007022.

Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2032-2032 ◽  
Author(s):  
Nadia N. Laack ◽  
Evanthia Galanis ◽  
Clinton Leinweber ◽  
Jan C. Buckner ◽  
Caterina Giannini ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Progressive Disease ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Entire Study ◽  
Randomized Phase Ii ◽  
Level 1 ◽  
Grade 3

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.

A Phase I/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 428-428 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Magdalini Migkou ◽  
Konstantinos Pamboukas ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Low Dose ◽  
Alkylating Agents ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 428 Lenalidomide (R) has significant activity in patients with multiple myeloma (MM). R has also shown activity in patients with AL amyloidosis, especially in combination with dexamethasone (D). However, AL patients are usually frail and R at the standard dose of 25 mg/day has been associated with significant toxicity. In MM patients, R with low dose D (Rd) has a better toxicity profile than the combination of R with high dose D. Alkylating agents, such as cyclophosphamide (C), are active in patients with AL and combinations of R with alkylating agents have given promising results in patients with MM. Thus, we designed a phase I/II trial of R, with low dose D and low dose C (RdC) in patients with AL. Primary objective of the study was to determine the maximum tolerated dose (MTD) for RdC and to assess hematologic response. Patients receive D 20 mg on days 1-4 (total 80 mg per cycle) , C on days 1-10, R on days 1-21 every 28 days, according to dose level (level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg). In the phase I part of the study, patients were observed for 2 cycles for determination of Dose Limiting Toxicity (DLT) according to a standard 3+3 design. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function were enrolled. All patients receive low-dose aspirin or LMWH if indicated. So far 23 patients have been enrolled in the study (16 in phase I, 7 in phase II). In the phase I study, 3 patients were enrolled in dose level 0, 7 in dose level 1 and 6 in dose level 2. Dose level 2, (R 15 mg, C 100 mg) is being further explored; 7 patients have been enrolled in phase II and accrual is ongoing. So far, 132 cycles of therapy have been administered; 8 patients have receive ≥6 cycles of RdC and 3 have completed 12 cycles of treatment. According to consensus criteria, heart was involved in 65%, kidneys in 61%, liver in 9% and 17% had AL-related peripheral neuropathy; 95% of the patients were Mayo stage II or III. Most patients (70%) were previously untreated. Among 7 pretreated patients, 2 had refractory disease, 2 had prior thalidomide and 5 had prior bortezomib. Hematologic response rates for patients who received at least 2 cycles of treatment, among all cohorts, was 64% and for the patients treated at dose level 2 was 75%. Median time to hematologic response was 2.5 months (range 0.9-4.8 months) for all patients and 1 month (range 0.9-2.9) for those treated at dose level 2. Organ responses have been recorded in 5 patients so far (3 cardiac and 3 renal responses, 1 patient had both cardiac and renal response). After a median follow-up of 7 months, 7 patients have died; 5 due to progressive heart amyloid, one patient had an acute MI followed by acute stent thrombosis and one died due to sepsis. The most common hematologic toxicities were anemia (grade 3/4 in 17%) and neutropenia (grade 3/4 in 17%). Most common non-hematologic toxicities were infection (grade ≥3 in 22%), fatigue (grade ≥3 in 9%), and rash (in 22%, grade 3 in 4%); also one patient suffered a stroke and one had DVT while on treatment with RdC. In parallel, and on a compassionate basis, AL patients with creatinine >2.5 mg/dL or on dialysis, were offered RdC with R dose adjusted according to CrCl. Initially R was given 15 mg every other day for CrCl <30 ml/min, or 15 mg thrice per week on the day after dialysis but due to toxicity R dose was reduced to 10 mg. So far, 13 patients have been treated with attenuated-dose RdC: 3 patients achieved a CR, one achieved a cardiac and one patient a liver response. However, the non-hematologic toxicity of the combination in patients with renal impairment was significant including fatigue (53%), infections (38%), rash (31%), diarrhea (15%), hyponatriemia (15%). Three patients discontinued treatment due to toxicity after the 1st cycle (including one early death due to non-neutropenic infection). In conclusion, RdC is an effective oral regimen for patients with AL amyloidosis, inducing significant rates of hematologic and organ responses. The recommended dose for RdC was R at dose of 15 mg, C at a dose of 100 mg and 20 mg of D and is further evaluated in the phase II of the study. Toxicity is manageable for patients with serum creatinine <2.5 mg/dL but can be significant for AL patients with more severe renal impairment. Lower doses of R, at 10 mg or less every other day or thrice per week should be used in these patients. Accrual in the phase II study is ongoing and updated results will be presented at the meeting. Disclosures: Dimopoulos: Celgene: Honoraria, Research Funding.

Phase I/II trial of vorinostat combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (N0874-ABTC0902, Alliance): Final results of the phase I trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2046-2046
Author(s):  
Evanthia Galanis ◽  
Jann Nagina Sarkaria ◽  
S. Keith Anderson ◽  
Wenting Wu ◽  
Kurt A. Jaeckle ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Single Agent ◽  
Wound Dehiscence ◽  
Newly Diagnosed ◽  
Level 1 ◽  
Rna Expression Profiling ◽  
Grade 3 ◽  
Experienced Grade

2046 Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its single-agent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.

A phase I study of pegylated doxorubicin (DOX) and weekly topotecan (TOP) in patients (pts) with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12018-12018
Author(s):  
G. A. Masters ◽  
M. Guarino ◽  
C. Schneider ◽  
D. Biggs ◽  
S. Grubbs
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Level 1 ◽  
Grade 3 ◽  
Ecog Ps

12018 Background: The primary endpoint of this prospective phase I study of DOX-TOP in pts with advanced solid tumors was to identify the maximum tolerated dose and dose-limiting toxicities (DLT) of this combination. Other objectives included a description of additional toxicities and efficacy in this patient population with refractory cancers. Pharmacokinetic sampling of TOP plasma levels will be reported separately. Methods: Eligible pts had advanced solid tumors and had either failed standard chemotherapy (chemo) or were pts for whom no standard therapy existed. They had ECOG PS = 0–2, adequate organ function, and gave written, informed consent. Initial doses included DOX 40 mg/m2 day 1 and TOP 2 mg/m2 days 1, 8 and 15 q 28 days. TOP was to be escalated in cohorts of pts. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, any grade 3 non-hematologic toxicity, or the inability to receive subsequent treatment due to ongoing toxicity. Treatment was held for ANC < 1000 or platelets < 75,000. Results: Fourteen pts have been enrolled on this phase I study, all of whom were evaluable for toxicity. There were 12 males and 2 females, and the median age was 57 years (range 25–86). Four had ECOG PS = 0, 9 had PS = 1, and 1 had PS = 2. Cancer types included head and neck (3), renal (2), and breast, pancreas, liver, esophagus, germ cell tumor, sarcoma, and others (one each). In the 6 pts treated at dose level 1, toxicities included grade 3 anemia (1) and neutropenia (2), and grade 4 neutropenia (1). DLT consisted of grade 4 thrombocytopenia (1) and inability to deliver day 15 TOP in 3/6 pts at this dose. Thus, TOP was reduced to 1.5 mg/m2 weekly for dose level -1, and 8 pts have been treated. Toxicities included grade 3 anemia (1)and neutropenia (2), and grade 4 neutropenia (1) and thrombocytopenia (1). Enrollment continues at this dose level to confirm tolerability. No patient achieved an objective response to therapy, but 2 pts have stable disease for up to 4 cycles. Conclusions: DOX-TOP can be safely combined in pts with advanced solid tumors, with hematologic toxicity as the DLT. The preliminary recommended phase II dose is DOX 40 mg/m2 and TOP 1.5 mg/m2. We plan to explore an additional dose level of DOX 30 mg/m2 and TOP 2 mg/m2. Phase II evaluation is contemplated in selected tumor types. [Table: see text]

Phase I trial of TS-1 plus carboplatin in patients with advanced non-small cell lung cancer: A Central Japan Lung Study Group Trial-CJLSG0402

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17065-17065
Author(s):  
H. Saka ◽  
C. Kitagawa ◽  
M. Ichikawa ◽  
Y. Yamada ◽  
H. Saito ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Small Cell ◽  
Small Cell Lung ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

17065 Background: TS-1, a novel oral antimetabolite, is active against advanced non-small cell lung cancer (NSCLC). A response rate of 21.3% was reported in a monotherapy trial. In combination with cisplatin, TS-1 demonstrated a response rate of 47.3% in NSCLC. To develop a clinically relevant combination, we investigated TS-1 plus carboplatin in patients (pts) with advanced NSCLC. This is a report of the phase I section of a phase I/ II trial. In the phase I section, primary endpoints were to determine the maximum tolerated dose (MTD), the recommended dose for the phase II section, and to evaluate the toxic profile. Methods: Pts were enrolled who were chemo-naïve, in stages IIIB and IV, with ages between 20 and 74, PS (ECOG) of 0 or 1, and with adequate bone marrow and major organ functions. Post-surgical relapses and asymptomatic brain metastases were accepted. Pts received a fixed dose of carboplatin (6 mg/mL min) via IV infusion on day 1, once every 3 weeks. TS-1 was given at the initial dose of 60 mg/m2 (level 1) with dose escalation in 10 mg/m2 increments from day 1 to day 14, repeated every 3 weeks. Severe toxicities occurring in cycle 1 were considered dose-limiting toxicities (DLTs). Results: Sixteen pts were enrolled in 3 cohorts receiving 60 (n = 3), 70 (n = 7), and 80 (n = 6) mg/m2. Median age was 65 years (range, 37 to 74 years) and median performance status was 1. Ten pts had stage IV, and 4 pts had stage IIIB disease. Two pts had post-surgical relapses. Adenocarcinoma (n = 11) was the dominant histology. DLT was observed in 1 pt in level 1, 2 pts in level 2 (TS-1, 70 mg/m2), and 3 pts in level 3 (TS-1, 80 mg/m2). DLTs were grade-4 thrombocytopenia (n = 3), grade-4 neutropenia (n = 1), grade-3 liver dysfunction (n = 1), and grade-3 anorexia (n = 1). Conclusions: The MTD was level 3 (TS-1 80 mg/m2, carboplatin 6 mg/mL min). According to the total delivered doses, the recommended dose for phase II study was determined to level 2 (TS-1 70 mg/m2, carboplatin 6 mg/mL min). The phase II study is currently underway. [Table: see text] No significant financial relationships to disclose.

A phase II trial of docetaxel and irinotecan (DI) in children and young adults with recurrent or refractory Ewing sarcoma family of tumor (ESFT).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9579-9579
Author(s):  
Jong Hyung Yoon ◽  
Hyeon Jin Park ◽  
Byung-Kiu Park
Keyword(s):  
Young Adults ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Median Number ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Children And Young Adults ◽  
Grade 3

9579 Background: Patients with ESFT resistant to second-line therapy, such as topotecan plus cyclophosphamide, have a dismal prognosis and few therapeutic options. Docetaxel (D), a microtubule inhibitor, demonstrated activity in patients with ESFT (Zwerdling T et al. Cancer 2006:106:1821-1828). Irinotecan (I), a toposiomerase I inhibitor, is being evaluated in clinical trials for ESFT. Despite the different mechanisms of action of D and I, and their activities as a single-agent against ESFT, DI combination has not been previously evaluated in ESFT. Thus, we prospectively performed a single-arm, phase II trial of DI in a single center in Korea. Methods: Patients <30 years with ESFT, who failed second-line therapy, were eligible for the study. D was administered IV over 60 minutes at a dose of 100 mg/m2 on Day 1, and I at a dose of 80 mg/m2 over 90 minutes on Days 1 and 8 of a 21-day cycle until disease progression. The primary end-point was objective response assessed by RECIST; the secondary end-point was safety. All toxicities were graded according to the National Cancer Institute’s Common Toxicity Criteria (version 4.0). Results: Of seven eligible patients (4 males; median age, 17 years (range 5-21)), 4 were recurrent/refractory cases, and 3 refractory cases. Median number of previous regimens was 6 (range 3-6). One CR, 1 PR, and 5 PD were obtained by DI combination (median number of cycles, 2 (range 1-15)), with objective response (CR+PR) rate of 2/7 (28.6%). One patient with PR achieved CR with subsequent surgery. CR of these two patients lasted 8.9 months and 10.6 months. Of all seven patients fully evaluable for toxicity, grade 4 neutropenia occurred in 7 (100%); grade 3 and 4 thrombocytopenia in 1 (14%) and 6 (86%), respectively; grade 3 pericardial effusion, paresthesia, motor weakness, oral mucositis, each in one (14%). Two patients required ≥1 dose delay; 2 required ≥1 dose reduction due to adverse events, but no one experienced treatment-related mortality. Conclusions: DI combination demonstrated activity in children and young adults with ESFT who were heavily pre-treated, and was feasible.

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