A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by 24 Hour Infusion Every 2 Weeks to Patients with Myeloid Malignancies and Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2654-2654 ◽  
Author(s):  
Gautam Borthakur ◽  
Susan O’Brien ◽  
Farhad Ravandi-Kashani ◽  
Francis Giles ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Trial ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Ambulatory Setting ◽  
Clinical Activity ◽  
Qtc Prolongation ◽  
Grade 3

Obatoclax is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It activates apoptosis and has clinical activity in CLL (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. This Phase I trial was designed to evaluate the potential of prolonged infusions to minimize these toxicities while maintaining biological and clinical activity. We enrolled 14 patients at doses ranging from 7–40 mg/m2 over 24 hours every 2 weeks utilizing a modified accelerated titration design with 3–6 patients per cohort and doubling of the dose until 28 mg/m2. Cycle 1 was administered in a clinical research unit to accommodate PK sampling but subsequent cycles were administered in the ambulatory setting using portable infusion pumps. Median age was 62 (range 56–82) and 10 patients were male. The following diagnoses were included: myelodysplatic syndromes (MDS; 8, 4 secondary), refractory acute myelogenous leukemia (AML; 5) and CLL (1). A total of 51 infusions were administered. At doses ≤28 mg/m2, adverse events (AE) of Grade 1 dizziness (2/9), headache (2/9), euphoric mood (2/9) and Grade 2 somnolence (2/9) were of lesser frequency and intensity then at equivalent dose levels previously administered with a 3 hour infusion. At the 40 mg/m2 dose level, dose-limiting toxicities of Grade 3 QTc prolongation with no accompanying arrythmias were reported in 2/5 patients who both had QTc prolongation at baseline. Other toxicities included Grade 2 somnolence (4/5), Grade 1 euphoric mood (3/5), Grade 1 anxiety (2/5) and single reports of Grade 1 dizziness, dysarthria, dysphasia, confusion, hallucination and disorientation. The pharmacokinetics (PK) of obatoclax following a 24-hr IV infusion is dose proportional for both Cmax and AUC24h. Induction of apoptosis was monitored quantitatively with serial determinations of plasma concentration of histone-oligonucleosomal DNA (ODNA) complexes. An early release of ODNA greater than 4-fold occurred in 10/14 patients by the midpoint of the infusion and was sustained to the end of the infusion. The rapid elimination of the plasma obatoclax concentration immediately following the end of infusion was associated with a decline of the plasma oligonucleosomal DNA level; however multiple additional peaks of oligonucleosomal DNA concentrations occurring over days following the infusion were still detected in 9 of 14 patients. 3/8 patients with MDS showed hematological improvement with red blood cell or platelet transfusion independence. Bone marrow blasts were reduced from 14% to 4% in another patient with secondary MDS. Conclusions: Single agent obatoclax is well tolerated when administered as a 24 hour continuous infusion, with abrogation of previously noted infusional CNS toxicities. Biological and clinical activity are retained. Further prolongation of the infusion may lead to more robust activity and will be explored. Phase II single agent trials using 28 mg/m2 over 24 hours every 2 weeks have been initiated in patients with myelofibrosis and previously untreated MDS with anemia and/or thrombocytopenia to further evaluate the potential for hematological improvement in response to obatoclax.

A Phase I Trial of the Histone Deacetylase (HDAC) Inhibitor, Panobinostat, in Combination with Lenalidomide in Patients with Relapsed/Refractory Hodgkin's Lymphoma (HL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1644-1644 ◽  
Author(s):  
Beth Christian ◽  
Anne Kopko ◽  
Todd A. Fehniger ◽  
Nancy L. Bartlett ◽  
Kristie A. Blum
Keyword(s):  
Phase I ◽  
Hdac Inhibitor ◽  
Research Funding ◽  
Phase I Trial ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Phase 2 ◽  
Qtc Prolongation ◽  
Duration Of Response ◽  
Grade 3

Abstract Abstract 1644 Introduction: Previous phase 2 single agent trials with the immunomodulatory agent, lenalidomide, in patients with relapsed or refractory HL demonstrated overall response rates (ORR) of 14–29%, with a median duration of response of 6 months. Likewise, a single agent trial utilizing the orally available HDAC inhibitor, panobinostat, in 127 patients with relapsed/refractory HL after prior autologous stem cell transplant (ASCT) demonstrated an ORR of 27% with a median duration of response of 6.9 months. Based on the encouraging single agent activity of these agents and in vitro synergy of combined panobinostat and lenalidomide in myeloma cell lines, we are conducting a phase I/II trial to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and overall response rate (ORR) with this combination and results of the phase I study are presented. Methods: Patients with relapsed or refractory classical HL (cHL) or lymphocyte predominant HL (LP HL) after at least one prior therapy are eligibile. Measurable disease ≥1 cm in at least one dimension, ejection fraction ≥45%, ECOG PS 0–2, QTc on ECG ≤ 450 msec, ANC ≥1200/mm3, platelets ≥100,000/mm3, AST/ALT ≤ 2.5 × the upper limit of normal (ULN), bilirubin ≤ 1.5 × ULN, and creatinine clearance ≥60 ml/min are required at study entry. Prior ASCT, lenalidomide, and panobinostat are permitted. In the phase I trial, escalating doses of panobinostat (15 or 20 mg) days 1, 3, and 5 weekly are combined with lenalidomide 25 mg days 1–21 utilizing a cohorts of 3 design. DLT is defined during cycle 1 and includes grade 4 neutropenia or thrombocytopenia, grade 4 infection, grade 3 infection for > 7 days, treatment delays > 14 days, and other grade 3–4 non-hematologic toxicity. Six patients will be enrolled at the MTD to ensure patient safety prior to phase 2 enrollment. Twenty-eight days defines a cycle and patients may remain on therapy until disease progression or unacceptable toxicity. Response is assessed after cycles 2, 6, and every 4 cycles thereafter by International Harmonization Criteria (Cheson, JCO 2007). Results: Seven patients (6 males) with cHL (n=6) and LP HL (n=1) and a median age of 31 (range 24–72) have been enrolled. Patients received a median of 3 prior therapies (range 3–5), 1 patient received prior radiotherapy, 3 patients were refractory to their most recent therapy, 3 patients had prior ASCT, 6 patients had received prior brentuximab vedotin, and no patients had prior lenalidomide or panobinostat. Other characteristics included stage III-IV disease in 100% (57% stage IV), bulky adenopathy ≥5 cm in 14%, and bone marrow involvement in 14%. Seven patients have completed one or more cycles of therapy (median 3, range 1–4) with either 15 mg (n=3) or 20 mg (n=4) of panobinostat + 25 mg lenalidomide. Four patients discontinued therapy for progressive disease (PD) after 4 cycles (n=3) and 1 cycle (n=1), respectively. Three patients continue to receive protocol treatment, all receiving panobinostat 20 mg days 1, 3, and 5 weekly. No DLTs have been observed. Grade 3–4 events included neutropenia (43%), lymphopenia (29%), thrombocytopenia (29%), and hypophosphatemia (29%). No QTc prolongation has been observed. Dose reductions from 15 mg panobinostat days 1, 3, and 5 weekly + lenalidomide 25 mg to 15 mg panobinostat days 1, 3, and 5 weeks 1 and 3 only + 20 mg lenalidomide were required in 2 patients for grade 3–4 neutropenia during cycles 3 and 4. ORR is 33% in 6 evaluable patients with a complete response in 1 patient with cHL and partial response in 1 patient with LP HL. One patient has not yet undergone restaging scans. Conclusions: Combined panobinostat and lenalidomide appears to be well tolerated in patients with relapsed/refractory HL without dose limiting myelosuppression, cardiac toxicity, QTc prolongation, or other grade 3–4 non-hematologic toxicity. Study accrual continues, 2 additional patients will be added to the highest dose level (panobinostat 20 mg days 1, 3, and 5 weekly for 4 weeks + lenalidomide 25 mg days 1–21) to complete the phase I trial and will be followed by anticipated enrollment of a maximum of 25 patients to a two-stage phase 2 trial targeting an ORR of 30% or higher. Disclosures: Blum: Celgene: Research Funding; Novartis: Research Funding. Off Label Use: Panobinostat and lenalidomide are not approved for the treatment of HL.

Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase (HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myelogenous Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 444-444 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Allen S. Yang ◽  
Virginia Klimek ◽  
Jorge Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Response Rate ◽  
Single Agent ◽  
Substantial Reduction ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Flat Dose ◽  
Dose Levels

Abstract Epigenetic alterations are common in leukemia. MGCD0103 in an oral isotype-selective HDAC inhibitor that synergizes in vitro with the DNA methyltransferase inhibitor 5-azacitidine (Vidaza, Pharmion). Both agents have single-agent clinical activity in MDS and AML (Garcia-Manero, ASCO, 2006 & Silverman, JCO, 2002). We have developed a Phase I/II study of 5-azacitidine in combination with MGCD0103 in patients with AML and MDS. Patients with MDS (≥10% marrow blasts), relapsed/refractory AML, or untreated elderly patients with AML were eligible. Adequate performance status, renal and hepatic functions were required. 5-azacitidine was administered at its approved dose/schedule: 75 mg/m2 SC daily for the first 7 days of a 28 day cycle. MGCD0103 was administered as a flat dose orally three-times a week starting on the 5th day of 5-azacitidine administration. The phase I portion of the study design followed a classic “3+3” model and only MGCD0103 was dose escalated. The phase II portion targeted a 30% response rate. Final data from the Phase I and II portions of the study will be presented at the Meeting. Five dose levels of MGCD0103 have been evaluated: 35, 60, 90, 110 and 135 mg. At current data cut-off, 37 patients registered in the study were fully evaluable: median age was 67 (range 27–85); 31 patients had AML and 6 MDS. A total of 97 cycles were administered to date, mean = 2.6 (range 1–12). Dose limiting toxicities included nausea, vomiting, anorexia, diarrhea and dehydration which appear similar to dose limiting toxicities for MGCD0103 alone. The MTD of MGCD0103 was initially determined to be 110 mg, however, upon cohort expansion, this dose level was associated with excess toxicity and the starting dose was decreased to 90 mg. Eleven (30%) patients have achieved response: 4 CR, 5 CR-i, and 2 PR. Of these 11 patients, 6 continue on study with mean duration on study of 7 cycles. Of the 5 patients discontinued, 3 discontinued due to SAEs, 1 due to progressive disease and 1 to undergo transplantation. Of the 27 patients at the phase II dose levels of 90 and 110mg, 10 achieved a response (37%; same rate at both doses). Preliminary response data are available at the time of abstract preparation for 13 additional patients, revealing 4 with CR (one of which had 1% residual peripheral blast) and 3 with CR-I for a response rate of 53% in this subset. MGCD0103 pharmacokinetics were not affected by 5-azacitidine. Likewise, co-administration of MGCD0103 had no impact on the pharmacokinetics of 5-azacitidine. A majority of patients exhibited a substantial reduction in PBMC HDAC activity during treatment with the combination. Analysis of DNA methylation is ongoing. In conclusion, the combination of 5-azacitidine with MGCD0103 is safe in patients with advanced AML/MDS and has clinical activity potentially superior to that expected with 5-azacitidine alone in this patient population. These results form the bases of a planned randomized study of 5-azacitidine with or without MGCD0103 in AML and MDS.

Phase I Results of Combination Gemcitabine and Bortezomib (Velcade®) for Relapsed/Refractory Nodal T-Cell Non-Hodgkin Lymphoma (T-NHL) and Aggressive B-Cell NHL (B-NHL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2005-2005 ◽  
Author(s):  
Andrew M. Evens ◽  
Leo I. Gordon ◽  
David Patton ◽  
Steven T. Rosen ◽  
Jane N. Winter ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase I Study ◽  
Single Agent ◽  
Dose Intensity ◽  
Clinical Activity ◽  
Repeated Treatment ◽  
Treatment Schedule ◽  
Cell Transplant ◽  
Grade 3

Abstract NF-κB is deregulated in several lymphoma subtypes, including aggressive B-NHL and T-NHL. The proteasome inhibitor, bortezomib, has the capacity to reverse some of the downstream consequences of NF-κB, but has only modest single-agent activity in aggressive NHL. Gemcitabine has a favorable toxicity profile and non-cross resistant mechanism of action with agents typically used in the first-line setting. Tumor cell lines and murine xenograft models demonstrate synergy between these two agents. Based on this data and the continued unmet clinical need for patients with relapsed/refractory aggressive NHL either ineligible for or relapsed after stem cell transplant (SCT), we conducted a phase I trial of the combination to determine a dosing regimen for phase II investigation. The phase I design was a 3+3 dose escalation of bortezomib (1.3 mg/m2 and 1.6 mg/m2, day (D) 1 and D8) with static gemcitabine dosing (800 mg/m2 D1 and D8) given on 21-day cycles. Following completion of bortezomib escalation, the phase II portion of the study was initiated. We report here the phase I study including toxicity and preliminary outcomes. 18 patients have enrolled, of whom 15 are evaluable for safety and preliminary efficacy. There were 8 women and 7 men, median age was 56 years (range 37–85 years), median prior therapies were 3 (range 2–5), and 67% had failed prior SCT. Histologies included diffuse large B-NHL (n=5) and T-NHL (1 hepatosplenic, 1 anaplastic, 2 angioimmunoblastic, 6 peripheral NOS). 11 pts accrued to the phase I portion. No dose limiting toxicity (DLT) was seen at bortezomib 1.3 mg/m2 (n=3 patients); 8 phase were tested at the next phase I dose level of bortezomib 1.6 mg/m2 since 2 patients experienced non-hematologic DLT (grade 3 hypertension and grade 3 liver function tests). The study continued to the phase II portion using bortezomib 1.6 mg/m2, in which 4 patients accrued. On planned analysis of the first 15 patients enrolled, it was noted that despite not meeting criteria for DLT, 10/15 patients experienced grade 3/4 neutropenia and/or thrombocytopenia resulting in repeated treatment delay(s). The median number of cycles delivered for all patients was 1 (range 1–3), while the median normalized dose-intensity was only 61%. Thus the trial was amended to institute a modified treatment schedule to administer gemcitabine and bortezomib on D1 and D15 on a 28-day schedule. Pre-planned analysis of the first 15 pts showed clinical activity/response allowing continuation of accrual onto the phase II portion (two partial remissions in T-NHL). In summary, our phase I study defined the safety/toxicity panel of combined bortezomib and gemcitabine dosing for patients with relapsed aggressive NHL. A planned analysis of the first 15 patients showed preliminary activity in heavily pre-treated patients allowing continuation to the 2nd stage, although repeated hematologic toxicities were seen leading to low dose intensity. Of note, data presented at ASCO 2008 (Luu et al. abstract #2563) studied the combination of bortezomib (D1, D4, D8, and D11) and gemcitabine (1,250 mg/m2 D1 and D8) in relapsed/ refractory advanced-stage solid tumors. The maximum tolerated dose of bortezomib there was 1.0 mg/m2 with gemcitabine. Furthermore, significant hematotoxicity was seen in that trial (grade 3/4 toxicity: 62% thrombocytopenia, 34% neutropenia, 17% anemia; with median of 2 cycles delivered). Accrual here continues to the phase II trial using a modified treatment schedule (gemcitabine 800 mg/m2 and bortezomib 1.6 mg/m2 both D1 and D15 on a 28-day schedule) in order allow more consistent delivery of the intended therapy.

A Phase I Trial of the Small Molecule Pan-Bcl-2 Family Inhibitor Obatoclax Mesylate (GX15-070) Administered by Continuous Infusion for up to Four Days to Patients with Hematological Malignancies.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 892-892 ◽  
Author(s):  
Aaron D. Schimmer ◽  
Joseph Brandwein ◽  
Susan M. O’Brien ◽  
Hagop Kantarjian ◽  
Bruce D. Cheson ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Dose Level ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Gait Disturbance ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Grade 3

Obatoclax antagonizes the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. It is active in chronic lymphocytic leukemia(CLL; O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 given over 3 h every 3 weeks with DLT of grade 3 infusional CNS toxicities. We evaluated prolonged infusions to minimize these toxicities while maintaining clinical activity. An initial trial established a Phase II dose of 28 mg/m2 over 24 h every 2 weeks with dose limiting toxicities (DLTs) at 40 mg/m2 and responses in 4/8 MDS patients (Borthakur et al., ASH 2006). We report on 21 patients who received obatoclax 20–28 mg/m2/24 h weekly (n=9) or 20 mg/m2/24 h for 2, 3 or 4 consecutive days every 2–3 weeks (n=12). The final dose level of 28 mg/m2/24 h for 4 days is now open. Median age was 61 (range 26–75) and 11 patients were male. Diagnoses included: acute myelogenous leukemia (AML; 13), myelodysplastic syndromes (MDS; 6), acute lymphocytic leukemia (ALL; 1) and CLL (1). A total of 180 infusions of 24 h were administered. The most common adverse events (AE) were euphoric mood (57%), fatigue (57%), febrile neutropenia (43%), gait disturbance (43%), chills (33%), diarrhea (33%), nausea (33%), somnolence (33%), dizziness (29%). All were of Grades 1–2 with the exception of 7 grade 3 AEs of febrile neutropenia (unrelated to obatoclax administration) and 1 each of diarrhea, fatigue and gait disturbance. There were no DLTs. Multiple day infusions were well tolerated; for the 20 mg/m2/24 h x 4days dose level, 4/6 patients received ≥ 4 cycles, with two ongoing at this time. Plasma concentrations of obatoclax reached a steady state before end of infusion. Mean Cmax values at 20 mg/m2/24 h during1x24, 2x24, 3x24,4x24 h, and 28 mg/m2/24 h during 1x24 h infusions was 15.3, 8.4, 10.1, 15.7 and 10.8 ng/mL, respectively. The mean AUC(0–tlast) values at 20 mg/m2/24 h associated with 1x24, 2x24, 3x24, 4x24 h, and 28 mg/m2/24 h associated with 1x24 h infusions were 264.3, 396.9, 624.3, 1109.3 and 211.1 ng · hr/mL, respectively, increasing as expected with the duration of the infusion. One patient with treatment-related AML with a t(9;11)(p22;q23) translocation achieved a cytogenetic complete response (CR) with complete hematological recovery and transfusion independence on Day 9 following the start of weekly 24 h infusions of obatoclax. This CR was sustained > 8 months while the patient received a total of 35 weekly infusions of 20 mg/m2 without cumulative toxicities. Conclusions: obatoclax can be administered by prolonged infusions without eliciting novel or cumulative toxicities. The dramatic response observed in a patient with AML with immediate recovery of peripheral blood counts supports that the cytotoxic effects of obatoclax are specific to malignant cells while sparing normal bone marrow, as did our earlier reports of improvement in cytopenias in patients with MDS and CLL. The infusional schedules described here will be attractive to combine with standard chemotherapy regimens for AML and other indications to improve treatment outcomes where they may be limited by overexpression of Bcl-2 family members.

Phase I to II Multicenter Study of Oblimersen Sodium, a Bcl-2 Antisense Oligonucleotide, in Patients With Advanced Chronic Lymphocytic Leukemia

2005 ◽  
Vol 23 (30) ◽  
pp. 7697-7702 ◽  
Author(s):  
Susan M. O'Brien ◽  
Charles C. Cunningham ◽  
Anatoliy K. Golenkov ◽  
Anna G. Turkina ◽  
Steven C. Novick ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Phase Ii ◽  
Intravenous Infusion ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Parent Drug ◽  
Lymphocytic Leukemia ◽  
Complete Disappearance ◽  
Continuous Intravenous Infusion

Purpose To determine the maximum-tolerated dose (MTD), efficacy, safety, and pharmacokinetics of oblimersen sodium in patients with advanced chronic lymphocytic leukemia (CLL). Patients and Methods Eligible patients had relapsed or refractory CLL after treatment with fludarabine. Oblimersen was administered at doses ranging from 3 to 7 mg/kg/d as a 5-day continuous intravenous infusion in cycle 1 and as a 7-day continuous intravenous infusion in subsequent cycles every 3 weeks in stable or responding patients. Results Forty patients were enrolled and treated (14 patients in phase I and 26 patients in phase II). Dose-limiting reactions in phase I included hypotension and fever, and the MTD for phase II dosing was established at 3 mg/kg/d. Two (8%) of 26 assessable patients achieved a partial response. Other evidence of antitumor activity included ≥ 50% reduction in splenomegaly (seven of 17 patients; 41%), complete disappearance of hepatomegaly (two of seven patients; 29%), ≥ 50% reduction of lymphadenopathy (seven of 22 patients; 32%), and ≥ 50% reduction in circulating lymphocyte counts (11 of 22 patients; 50%). Adverse events included transient hypotension, fever, fatigue, night sweats, diarrhea, nausea, vomiting, hypokalemia, and cough. Plasma concentrations of oblimersen (parent drug) and its major metabolites were variable. Renal clearance represented only a small portion of total parent drug clearance. Conclusion Dosing with oblimersen sodium in patients with CLL is limited by development of a cytokine release syndrome that is characterized by fever, hypotension, and back pain. Oblimersen sodium has modest single-agent activity in heavily pretreated patients with advanced CLL, and further evaluation of its activity in combination with cytotoxic drugs is warranted.

Phase I Trial of Escalating-Dose Irinotecan Given Weekly With Cisplatin and Concurrent Radiotherapy in Locally Advanced Esophageal Cancer

2003 ◽  
Vol 21 (15) ◽  
pp. 2926-2932 ◽  
Author(s):  
David H. Ilson ◽  
Manjit Bains ◽  
David P. Kelsen ◽  
Eileen O’Reilly ◽  
Martin Karpeh ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Phase I ◽  
Induction Chemotherapy ◽  
Phase Ii ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Phase Iii ◽  
Concurrent Radiotherapy ◽  
Minimal Toxicity ◽  
Grade 3

Purpose: To identify the maximum-tolerated dose and dose-limiting toxicity (DLT) of weekly irinotecan combined with cisplatin and radiation in esophageal cancer. Patients and Methods: Nineteen patients with clinical stage II to III esophageal squamous cell or adenocarcinoma were treated on this phase I trial. Induction chemotherapy with weekly cisplatin 30 mg/m2 and irinotecan 65 mg/m2 was administered for four treatments during weeks 1 to 5. Radiotherapy was delivered weeks 8 to 13 in 1.8-Gy daily fractions to a dose of 50.4 Gy. Cisplatin 30 mg/m2 and escalating-dose irinotecan (40, 50, 65, and 80 mg/m2) were administered on days 1, 8, 22, and 29 of radiotherapy. DLT was defined as a 2-week delay in radiotherapy for grade 3 to 4 toxicity. Results: Minimal toxicity was observed during chemoradiotherapy, with no grade 3 or 4 esophagitis, diarrhea, or stomatitis. DLT caused by myelosuppression was seen in two of six patients treated at the 80-mg/m2 dose level, thus irinotecan 65 mg/m2 was defined as the recommended phase II dose. Dysphagia improved or resolved after induction chemotherapy in 13 (81%) of 16 patients who reported dysphagia before therapy. Only one patient (5%) required a feeding tube. Six complete responses (32%) were observed, including four pathologic complete responses in 15 patients selected to undergo surgery (27%). Conclusion: Cisplatin, irinotecan, and concurrent radiotherapy can be administered on a convenient schedule with relatively minimal toxicity and an acceptable rate of complete response in esophageal cancer. Further phase II evaluation of this regimen is ongoing. A phase III comparison to fluorouracil or taxane-containing chemoradiotherapy should be considered.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

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.

A Phase II Study of the TNF-α Inhibitor Etanercept and Thrice Weekly Rituximab: Evidence of Clinical Activity in the Absence of del(17p13.1) Genomic Abnormalities.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3469-3469 ◽  
Author(s):  
Thomas S. Lin ◽  
Nyla A. Heerema ◽  
Jennifer Swenor ◽  
Margaret S. Lucas ◽  
Mollie E. Moran ◽  
...  
Keyword(s):  
Phase Ii ◽  
Antibody Therapy ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Tnf Α ◽  
Grade 3 ◽  
Induced Apoptosis ◽  
Anti Cd20 ◽  
Necrosis Factor

Abstract The monoclonal anti-CD20 antibody rituximab (Rituxan) induces the death of chronic lymphocytic leukemia (CLL) cells in part through apoptosis. Tumor necrosis factor (TNF)-α and other cytokines up-regulate bcl-2 and other anti-apoptotic proteins, thereby inhibiting apoptosis. In addition, TNF-α may play a role in the cytokine release syndrome and infusion toxicity associated with monoclonal antibody therapy. Therefore, antagonists of TNF-α represent potential therapeutic agents that may be able to decrease infusion toxicity and enhance rituximab-induced apoptosis. We initiated a phase II trial of etanercept in combination with rituximab in patients (pts) with relapsed CLL or small lymphocytic lymphoma (SLL), with the goals of increasing clinical activity of rituximab and reducing infusion toxicity through neutralization of TNF-α. Pts received etanercept 25 mg subcutaneously (SC) twice weekly during weeks 1–5 and rituximab 375 mg/m2 intravenously (IV) three times weekly during weeks 2–5. Stepped up dosing of rituximab was used with the first two rituximab treatments. From 12/02 to 10/03, 19 pts (14 male) with a median of 2 prior therapies (range 1–8) were enrolled. Therapy was generally well tolerated, although 5 pts developed grade 4 neutropenia and 5 pts developed grade 3–4 infection or neutropenic fever. Four of 19 pts achieved an NCI 96 partial response, with no responses in 8 pts with del(17p13.1), corresponding to loss of the p53 gene. In contrast, 4 of 11 pts without del(17p13.1) achieved a PR, including 1 pt with a complex karyotype. This study was stopped for interim analysis and has reopened, with the exclusion of patients with a del(17p13.1) based upon the response outcome above and a previous preliminary report by our group demonstrating that rituximab was ineffective for del(17p13.1) CLL (Cancer Res63:36, 2003). We conclude that the combination of rituximab and etanercept has clinical activity in heavily treated, relapsed CLL pts without del(17p13.1), irrespective of prior rituximab treatment. Accrual to this study continues, and the results will be updated at the 2004 ASH meeting.

Sequential Phase II Studies of Flavopiridol by 72-Hour Continuous Infusion and 1-Hour Intravenous Bolus for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia: Results from CALGB Study 19805.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3485-3485
Author(s):  
John C. Byrd ◽  
Bercedis L. Peterson ◽  
Janice L. Gabrilove ◽  
Olatoyosi M. Odenike ◽  
Michael R. Grever ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Phase Ii ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Intravenous Bolus ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Flavopiridol has in vitro activity in CLL and promotes apoptosis independent of p53 function or prior fludarabine exposure. We sought to determine if flavopiridol administered using two different schedules has activity in CLL. Patients with previously treated CLL were enrolled on two sequentially performed phase II studies. Patients in the first trial received flavopiridol (50 mg/m2 daily) as a continuous infusion (CI) over 72-hours every 2 weeks. Patients in the second trial received flavopiridol 50 mg/m2 as a 1-hour intravenous bolus (IVB) daily for three days repeated every 3 weeks. Patients received up to 6 (CI cohort) or 8 (IVB cohort) cycles of therapy. Fifteen patients enrolled in the 72-hour CI phase II trial; 6 (40%) had intermediate (Rai stage I or II) and 9 (60%) high (Rai stage III and IV) risk stages. No responses were noted in this group with 27% having stable disease (SD) and 73% progressive disease (PD). Thirty-six patients enrolled in the IVB study, with 13 (36%) having intermediate and 23 (64%) having high-risk disease. Four patients (11%) had partial responses, 19 (53%) SD, and 13 (36%) PD. The progression-free survivals for responders in the IVB study were 2.9, 3.2, 8.7, and 19.3 months. The median progression-free survival was 2.1 months (95% confidence interval [CI] 1.8 – 3.8) for patients in the CI study and 3.2 months (95% CI [2.5 – 7.4]) for the IVB study. The median overall survival was 27 months (95% CI [20–42]) for the CI study and 24 months (95% CI [18–31]) for the IVB study. Toxicity was manageable and included mainly myelosuppression (granulocytopenia and thrombocytopenia), infections, diarrhea and fatigue. Grade 3 and 4 toxicities were 20% and 27%, respectively, on the CI study and 39% and 33% on the IVB study. One patient on the IVB study had tumor lysis syndrome that was managed medically and did not require dialysis. There was one on-study death following a myocardial infarction on the IVB study. We conclude that flavopiridol has modest, schedule-dependent clinical activity in relapsed CLL and warrants future investigation utilizing alternative schedules of administration.

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