Safety and Efficacy of Intrathecal Liposome-Encapsulated Cytarabine for Central Nervous System (CNS) Prophylaxis in Adult Patients with Burkitt and Atypical Burkitt Lymphoma Treated with the R-CODOX-M/R-IVAC (Magrath) Regimen: Results of a Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3716-3716
Author(s):  
Ferdinando Frigeri ◽  
Filippo Russo ◽  
Manuela Arcamone ◽  
Chiara Fraira ◽  
Gennaro Russo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Burkitt Lymphoma ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Single Agent ◽  
Primary Study ◽  
High Dose ◽  
Sustained Release Formulation ◽  
Cns Prophylaxis

Abstract Abstract 3716 Poster Board III-652 Introduction Intrathecal (IT) chemotherapy is an integral component of treatment for Burkitt lymphoma (BL), together with intensive systemic chemotherapy including blood brain barrier crossing agents such as high dose cytarabine (Ara-C) and methotrexate (MTX). However, the optimal IT treatment is yet to be established. Since cytotoxic concentrations of conventional IT agents (Ara-C and MTX), are maintained in the cerebrospinal fluid (CSF) for only a few hours, repeated lumbar punctures are necessary which may turn cumbersome for patients (pts) and pose technical difficulties in some instances. The availability of a sustained-release formulation of Ara-C (liposome-encapsulated Ara-C; Depocyte®) may offer the opportunity of reducing the total number of IT administrations by maintaining/enhancing, the efficacy of CNS prophylaxis. In this regard, a single 50 mg IT injection of Depocyte is able to achieve cytoxic concentrations of free-Ara-C in the CSF for 10-14 days. We report the results of a prospective phase II study aimed at evaluating the safety/activity profile of IT Depocyte in pts with BL and atypical (a)BL. Patients and Methods The study was designed to assess, in untreated pts with BL and aBL, the safety and feasibility of a 50% reduction (from 8 to 4) of the number of IT injections required by substituting IT Ara-C (4 doses) and MTX (4 doses) with 4 administrations (50 mg) of IT Depocyte. IT injections were planned on days (d) 1 or 2 of each rituximab (R)-CODOX-M courses and on d 8 of each R-IVAC course. Pts with aBL received 2 additional R-CODOX courses without any further IT therapy. Primary study endpoints were safety, Depocyte-related extra-hematologic adverse events ≥G3, and CNS failure, i.e. progression/relapse at leptomeningeal and/or parenchymal sites; secondary endpoints included event- and disease-free survival (EFS, DFS). Results A total of 30 HIV negative pts (15 BL and 15 aBL) were enrolled and treated with a dose-modified Magrath regimen (Lacasce, 2004). The median age of pts (M/F: 22/8) was 53 years (r, 25-78), 10 pts (33%) were considered as a low risk (LR) category by displaying ≥ 3 of the following factors: normal LDH, WHO PS 0-1, Ann Arbor stage I-II, and ≤ 1 extra nodal sites. All remaining cases (67%) were considered as high-risk (HR). At diagnosis, 3 pts (10%) had a positive CSF for lymphoma, 6 (20%) had bone marrow involvement and 12 (40%) bulky (>10 cm) disease. Each pt received a median of 4 (r, 1-6) IT injections of Depocyte at the a median day of 0.5 (r, -1 to 1) for R-CODOX-M1 (course1), 4.0 (r, -2 to 17) for R-IVAC1 (course 2), 1 (r, -1 to 1) for R-CODOX-M2 (course 3) and 6.5 (r, -3 to 14) for R-IVAC2 (course 4). On a total of 111 applications, the following IT injection-related adverse events (NCI-CTCAE v 3.0) of G1-G2 severity were recorded (pts experiencing toxicity): headache 26.6%, nausea 6.6%, vomiting 3.3%, fever 10%, lumbar pain 10%, fatigue 26.6%, somnolence 6.6% and sinus bradycardia 3.3%. A G3 headache episode, accompanied by a transient loss in visual acuity, led to refusal of further IT Depocyte by a single pt. At 51 mo.s, the EFS was 70% with a DFS of 90% at a median observation of 24 mo.s (r, 1-49). Among the 27 complete responders, no isolated leptomeningeal relapses occurred. In particular, none of the 3 responders with CSF involvement at presentation, displayed any form of CNS progression (leptomenigeal and/or parenchymal). In contrast, a parenchymal CNS involvement, with a negative CSF, was observed, at 4.0 mo.s, as a part of the systemic progression in a single pt (3.3%) with chemorefractory aBL. This pt presented with unfavorable features (hi-LDH, stage IVB, PS 2, bulky retroperitoneal adenopathy and 4 extra nodal sites including liver, pancreas, kidney and spleen) and skipped both the first IT and systemic MTX administrations. Conclusions Within the limits of a single arm study, our results show that substitution of 8 IT injections (Ara-C/MTX) with 4 IT administrations of Depocyte within the R-CODOX-M/IVAC regimen is feasible and devoid of severe and/or life-threatening/invalidating neurotoxicity. The CNS progression/recurrence rate was at least super imposable to historical results (CNS relapse rate: 6% to 11%) achieved by the Magrath regimen including double-agent IT treatment. Based on these results, it appears that Depocyte can be safely incorporated into the Magrath regimen to provide adequate single-agent CNS prophylaxis with a reduced burden of IT applications. Disclosures: Off Label Use: Liposome-encapsulated Ara-C for CNS prophylaxis. Vitolo:Mundipharma: Lecture fees. Pinto:Mundipharma: Lecture fees.

scholarly journals A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

1987 ◽  
Vol 5 (6) ◽  
pp. 941-950 ◽  
Author(s):  
T Philip ◽  
R Ghalie ◽  
R Pinkerton ◽  
J M Zucker ◽  
J L Bernard ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Stage Iv ◽  
Observation Time ◽  
Phase Iii ◽  
High Dose ◽  
Initial Stage ◽  
Duration Of Response

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

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

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

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

Effectiveness and new safety profile of rasburicase (urate oxidase) in Japanese patients with malignant lymphoma and acute leukemia in phase II study (ARD5290)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8566-8566
Author(s):  
M. Ogura ◽  
K. Ishizawa ◽  
M. Hamaguchi ◽  
T. Hotta ◽  
K. Ohnishi ◽  
...  
Keyword(s):  
Uric Acid ◽  
Adverse Events ◽  
Phase Ii ◽  
Safety Profile ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Optimal Dose ◽  
Urate Oxidase ◽  
Application Site

8566 Background: Rasburicase (RAS) for the prevention of tumor lysis syndrome (TLS) populations at high risk, and for the treatment of hyperuricemia (HU) has obtained approvals in most countries in the world except in Japan. Thus, we conducted licensing phase II study of RAS with primary endpoint of overall efficacy response (ER) rate. We report efficacy and the new safety profile of only RAS administration prior to chemotherapy. Methods: Fifty patients (pts) with ML and/or AL, were administered RAS for 5 days using two dose-levels (0.15 mg/kg/day or 0.20 mg/kg/day). Chemotherapies were started from 4 to 24 hours after RAS treatment. ER was defined as keeping plasma uric acid level 7.5mg/dL by 48 hr after the start of first RAS infusion and lasting until 24 hr after the start of final (Day5) RAS infusion. Results: The overall ER rate was 98%. 49 pts (98%) completed 5 days of treatment. Both doses provided equally effective reduction of uric acid under the study conditions. Seven drug-related adverse events of grade 1 or 2 by NCI-CTC occurred in 6 pts during using only RAS (before first chemotherapy). ‘Hypersensitivity’ occurred in 3 pts, and ‘rash’, ‘anorexia’, ‘application site pain’, and ‘pyrexia’ occurred in 1 patient each. No grade 3 or 4 adverse events were reported. Only five pts (10%) had anti-RAS antibodies by Day29. Conclusions: RAS has proved to be highly effective with a good safety profile including the new safety one as single agent without chemotherapy. Although both two levels were effective, level of 0.20 mg/kg seems to be an optimal dose because RAS was effective against serious cases of HU in this level. The presence of anti-RAS antibodies was very low suggesting that the possibility for retreatment maybe possible. No significant financial relationships to disclose.

L-Asparaginase Monotherapy in Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma, Nasal Type: Results of A Phase II Study.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2730-2730
Author(s):  
Ye Guo ◽  
Xuejun Ma ◽  
Zuguang Xia ◽  
Kai Xue ◽  
Qunling Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Hematopoietic Stem ◽  
Nasal Type ◽  
Nk T Cell

Abstract Abstract 2730 Introduction: Recently, L-asparaginase-based combination chemotherapy was found to be effective in salvage treatment in patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type. To explore the single-agent activity of L-asparaginase, we conducted a single-institute, prospective phase II study. Methods: Patients with relapsed or refractory extranodal NK/T-cell lymphoma, nasal type were eligible for enrollment regardless of prior treatment. L-asparaginase monotherapy (6000 U/m2 on days 1 to 7) was administered as the protocol treatment and repeated every 3 weeks for at most 8 cycles. For responding patients, the decision to proceed with hematopoietic stem-cell transplantation was made at the discretion of treating physicians. The primary endpoint was the best objective response after L-asparaginase. Results: A total of 40 patients were enrolled and treated with L-asparaginase for a median of 5 cycles (range, 1 – 8). The patient characteristics were shown in Table 1. Half of the patients had stage IV disease at enrollment and the vast majority (18 patients) presented with disseminated cutaneous and soft-tissue involvement. Thirty-seven patients (92.5%) had prior exposure to systemic chemotherapy and 14 of them (37.8%) received more than 1 line. The overall response rate was 82.5%. The complete response (CR) and partial response (PR) rates were 40% and 42.5%, respectively. The incidence of adverse events was shown in Table 2. In short, anemia, neutropenia, hypoalbuminemia, nausea and liver-related disorders were common toxicities, which were usually mild and manageable. No grade 4 adverse events and treatment-related mortality were observed. Five patients (12.5%) developed allergic reaction to L-asparaginase and 3 of them had to withdraw from the study since L-asparaginase re-challenge with prophylactic antiallergic agents was unsuccessful. After a median follow-up time of 31.6 months (range, 21.9 – 41.3), the median progression-free survival (PFS) was 12.8 months and median overall survival (OS) was not reached. Response status (CR, PR or no response) after L-asparaginase had a significant impact on either PFS (Figure 1) or OS (Figure 2). Moreover, its prognostic value was confirmed in the multivariate analysis. Conclusions: L-asparaginase demonstrated a high single-agent activity in salvage setting for patients with extranodal NK/T-cell lymphoma, nasal type. The first-line L-asparaginase-containing chemotherapy regimen warrants urgent investigation. Disclosures: Off Label Use: L-asparaginase, which was used in our study for NK/T-cell lymphoma, is approved to treat acute lymphocytic leukemia by US and Chinese FDA.

A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7625-7625 ◽  
Author(s):  
H. J. Groen ◽  
E. F. Smit ◽  
A. Dingemans
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Smoking Status ◽  
Single Agent ◽  
Stage Iiib ◽  
Correlative Imaging ◽  
Unknown Reason ◽  
Grade 3

7625 Background: In advanced NSCLC, E and B either as a single agent (E) or in combination with chemotherapy (B) show improved survival. Combinations of targeted agents may prove to be effective and better tolerated than chemotherapy. Methods: This is a multi-center 2-stage phase II study (Simon's optimal design; p0=40%, p1=60%, a=0.05, β=0.20). Primary endpoint is non-progression (NPR) at 6 weeks defined by CT and FDG-PET. If 7 or less of the first 16 pts had NPR, the study would close. If 24/46 pts had NPR at 6 wks treatment would be declared to have sufficient activity for further testing. Pts (PS 0–2) with advanced non- squamous NSCLC who had received no prior chemotherapy were treated with E (150 mg/day) plus B (15 mg/kg every 21 days) until PD or unacceptable toxicity. Results: Between 30/01/06 and 08/12/06, 38 pts were included; 33 pts are evaluable for safety, 32 for efficacy. M/F 17/16; median age 59 (range 34–80); stage IIIB/IV 8/25; PS 0/1/2: 16/13/4; smoking status: current/former/never 12/17/4. Treatment-related adverse events (all grades) were: rash (32%); diarrhea (18%); hemorrhage (2.6%); hypertension (2.7%); and thrombosis (2.7%). Grade 3/4 events were rash (9.9%); thrombosis (1.8%); diarrhea (0.9%); and hypertension (0.9%). Six pts withdrew early from the study: 2 due to toxicity (trombosis and mucositis); 2 due to death (1 death for unknown reason, 1 due to pneumonia); 2 for treatment unrelated reasons. Six pts had E dose reductions due to toxicity. Five pts had delays of less than 2 wks before receiving B. Percentage of NPR at 6 weeks is 75% (24/32). The median follow-up: 6.3 months (95% CI 3.5–9.2). Median TTP: 5.5 months (95% CI 1.9 - 9.2), At time of analysis 22/33 patients are alive, 17 patients are without PD. Conclusions: E + B regimen is well tolerated, with a low rate of grade 3/4 adverse events and no unexpected toxicities. The primary endpoint has already been met. Updated results including correlative imaging studies will be presented. No significant financial relationships to disclose.

Assessment of two dosing schedules of GSK1363089 (GSK089), a dual MET/VEGFR2 inhibitor, in metastatic gastric cancer (GC): Interim results of a multicenter phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4502-4502 ◽  
Author(s):  
M. Jhawer ◽  
H. L. Kindler ◽  
Z. Wainberg ◽  
J. Ford ◽  
P. Kunz ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase Ii ◽  
Drug Targets ◽  
Phase Ii Study ◽  
Single Agent ◽  
Metastatic Gastric Cancer ◽  
Study Endpoint ◽  
Primary Study ◽  
Best Response ◽  
Ecog Ps

4502 Background: GSK089 is an oral, small-molecule inhibitor of cMET and VEGFR2/KDR, and has potent antitumor activity in cMET-amplified cell lines and xenografts. cMET is reportedly amplified, overexpressed and/or activated in GC, making it an attractive therapeutic target. This phase II study examines the safety and efficacy of 2 dosing schedules of GSK089 as a single agent in patients (pts) with metastatic GC. Methods: Pts with distal esophagus, GE junction or stomach adenocarcinoma, 0–2 prior chemotherapy regimens, adequate organ function, measurable disease, and ECOG PS 0–2 are sequentially enrolled in 2 cohorts: 1) Intermittent 5 days on/9 off - GSK089 240 mg/d on D1–5 repeated every 14 days, and 2) Daily - 80 mg/d. Primary study endpoint (response) is assessed every 8 weeks. cMET amplification by FISH (≥2 copies of cMET per copy of chromosome 7) is not an entry criterion, but is determined on archival tissue for all pts. Pre- and on-treatment tumor biopsies in select pts and plasma samples in all pts are analyzed for GSK089 effects on direct and downstream drug targets. GSK089 pharmacokinetics (PK) are also evaluated. Results: As of 12/19/08, enrollment to the 5 on/9 off cohort is complete with 41 evaluable pts, and 14 evaluable pts have enrolled on the daily cohort. cMET amplification was seen in 3/43 (7%) pts tested; all 3 were in 5 on/9 off cohort. Best response of stable disease (SD), was noted in 6/41 (15%) pts in the 5 on/9 off cohort (none were cMET-amplified), with 2 pts SD >6 months, 1 ongoing; and in 3/14 (21%) pts in the daily cohort. Among all-enrolled pts (48 pts in 5 on/9 off, 16 pts in daily cohort), LFT abnormalities (9%), fatigue (5%), and venous thromboembolism (3%) were the most common GSK089 related grade 3- 4 adverse events (AE). Only 1 possibly related grade 5 AE, death due to unknown cause, was noted. Conclusions: GSK089 is well tolerated on both dosing schedules. cMET amplification in metastatic GC is rare. Single agent GSK089 demonstrates minimal antitumor activity in a cMET-unselected gastric population on the 5 on/9 off schedule. Enrollment on the daily dosing schedule continues, now with mandatory pre- and on-treatment biopsies to better define cMET pathway and target inhibition with GSK089. No significant financial relationships to disclose.

scholarly journals Phase II Study of Venetoclax in Combination with Obinutuzumab and Bendamustine in Patients with High Tumor Burden Follicular Lymphoma As Front Line Therapy (PrECOG 0403)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 814-814
Author(s):  
Craig A. Portell ◽  
Opeyemi Jegede ◽  
Nina D. Wagner-Johnston ◽  
Grzegorz S. Nowakowski ◽  
Christopher D. Fletcher ◽  
...  
Keyword(s):  
Adverse Events ◽  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumor Burden ◽  
Type I ◽  
High Tumor Burden ◽  
Grade 3

Abstract Background: Chemoimmunotherapy is considered standard initial therapy for follicular lymphoma (FL) with high tumor burden (HTB). Obinutuzumab and Bendamustine (OB) with maintenance Obinutuzumab (mO) is considered a standard therapy for the frontline treatment of HTB FL (GALLIUM, Marcus et al, NEJM 2017). Venetoclax (VEN), an oral BCL2 inhibitor, is an attractive target in FL given the high BCL2 expression; though single agent activity has been disappointing (Davids et al. JCO 2017). BCL2 inhibition is thought to be synergistic with chemotherapy. Thus, the PrE0403 study evaluated the OB-VEN combination in frontline HTB FL. Here we present end of induction (EOI) outcomes. Methods: The primary objective of this Phase II study was to estimate the complete remission (CR) rate at EOI. Potential participants must have had a histologically confirmed diagnosis of FL grade 1, 2, or 3a with HTB defined by GELF or high risk defined by FLIPI-1 criteria. They must have had adequate performance status and organ function. Notably, creatinine clearance must have been ≥50 mL/min. Participants must have not had prior treatment for FL. Eligible participants were treated with Bendamustine IV 90 mg/m2 Day (D) 1 & 2, Obinutuzumab IV 100 mg D1, 900 mg D2, 1000 mg D8 and D15 of Cycle (C) 1 then D1 of each cycle, and VEN 800 mg orally daily D1-10 every 28 days for 6 total cycles. Due to a high rate of laboratory tumor lysis syndrome (TLS) during C1 in the first 21 patients, VEN was removed from C1 and given in C2-6 only. Participants with a CR at EOI were treated with mO IV 1000 mg D1 every 8 weeks for 2 years. Those with a partial response (PR) or stable disease (SD) were treated with mO as well as VEN 800 mg orally daily for 2 years. Pneumocystis jiroveci Pneumonia (PJP) and antiviral prophylaxis was required as was G-CSF support. Response was assessed via Lugano Criteria at EOI including PET/CT and bone marrow assessment. Adverse Events (AEs) were evaluated using CTCAE v5.0. To be considered promising, OB-VEN should improve the null hypothesis CR rate of 50% (OB) to 65%. With an 85% power and a one sided 15% type I error, 56 participants would be needed with an estimated 51 eligible. Support for the study was from Genentech, Member of the Roche Group. Results A total of 56 participants were enrolled and treated between 12/2017 and 11/2020; baseline characteristics are listed in Table 1. TLS was closely monitored in C1 and 8/21 participants developed TLS when VEN was administered in C1; 0/35 when it was not. However, monitoring for TLS in C1 became less stringent when VEN was not administered. Treatment related Grade ≥3 toxicities occurred in 47/56 participants (83.9%) with serious adverse events in 31 of 56 (55.5%). Atypical infections were seen; there was one treatment related death on study due to cytomegalovirus (CMV) encephalitis as well as PJP pneumonia which occurred after induction C6. Enrollment was temporarily suspended and CMV monitoring was implemented with no further occurrences. Another participant receiving mO later developed BK virus nephropathy following mO C6 and now requires ongoing hemodialysis. Another was diagnosed with Respiratory Syncytial Virus pneumonia 30 days after C6 and later PJP pneumonia after C2 of mO. Common (incidence >10%) AEs during induction are listed in Table 2. 45 of 56 (80.4%) participants were able to receive all 6 cycles of OB-VEN. CR was seen in 41 of 56 participants (73.2%, 2 sided 95% Confidence Interval (CI) 59.7-84.2%) at the EOI. 30 participants (53.5%) went onto maintenance. With a median follow up of 20.9 months, estimated 2 year Overall Survival (OS) and Progression-Free Survival (PFS) (90% CI) is 94.4% (82.4-98.3%) and 85.8% (68.8-93.9%) respectively. Conclusions This Phase II study of OB-VEN in untreated HTB FL showed high CR rate and met its primary endpoint with early signs of prolonged PFS. Laboratory TLS was identified but it was unclear if attributed solely to VEN, as baseline laboratory TLS rate for OB is unknown. The rate of Grade ≥3 AE of 83.9% (compared to 69% for OB in GALLIUM, Hiddeman JCO 2018) and the observation of opportunistic infections including CMV encephalitis, PJP pneumonia and BK nephropathy, suggests the combination is highly immunosuppressive. Therefore, while the study met its primary outcome, the combination of OB-VEN at 800 mg for 10 days, plus mO, does not have an acceptable risk/benefit profile. Participants will continue to be followed for efficacy and safety during the maintenance phase. Figure 1 Figure 1. Disclosures Portell: Acerta/AstraZeneca: Research Funding; SeaGen: Research Funding; Pharmacyclics: Honoraria; Xencor: Research Funding; Aptitude Health: Honoraria; BeiGene: Honoraria, Research Funding; Abbvie: Research Funding; TG Therapeutics: Honoraria, Research Funding; Kite: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Morphosys: Honoraria; Targeted Oncology: Honoraria; Genentech: Research Funding; VelosBio: Research Funding. Nowakowski: MorphoSys: Consultancy; Incyte: Consultancy; Kymera Therapeutics: Consultancy; TG Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Nanostrings: Research Funding; Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene/Bristol Myers Squibb: Consultancy, Research Funding; Zai Labolatory: Consultancy; Daiichi Sankyo: Consultancy; Bantham Pharmaceutical: Consultancy; Curis: Consultancy; Karyopharm Therapeutics: Consultancy; Selvita: Consultancy; Ryvu Therapeutics: Consultancy; Kyte Pharma: Consultancy. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Kahl: AbbVie, Acerta, ADCT, AstraZeneca, BeiGene, Genentech: Research Funding; AbbVie, Adaptive, ADCT, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Genentech, Incyte, Janssen, Karyopharm, Kite, MEI, Pharmacyclics, Roche, TG Therapeutics, and Teva: Consultancy. OffLabel Disclosure: Venetoclax is not approved for follicular lymphoma or in combination with bendamustine and obinutuzumab

Pharmacokinetic Results Of a Feasibility and Phase II Study (ITCC 021) On Bortezomib (BTZ) In Pediatric Relapsed ALL: Lack Of Significant Penetration Of BTZ In The Cerebrospinal Fluid

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1439-1439
Author(s):  
Gertjan Kaspers ◽  
Ron Mathot ◽  
Satianand Ramnarain ◽  
Denise Niewerth ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Peak Plasma ◽  
Bone Marrow Involvement ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Interindividual Variation ◽  
Leptomeningeal Involvement ◽  
Fourth Dose

Abstract Prognosis of refractory and relapsed ALL is poor and improvement requires the introduction of agents with a new mechanism of action. Bortezomib (BTZ) as a proteasome inhibitor is such an agent, and was safe as single agent in phase I studies in children (Blaney 2004; Horton 2007). Messinger et al. (2012) reported a single-arm study that BTZ can be combined safely with conventional drugs; the combination was remarkably effective. BTZ results in sensitization of malignant cells to anticancer agents, both in vitro for leukemias as well as for multiple myeloma patients. In patients with ALL, this effect regarding glucocorticoids has not been addressed yet. It also has not been studied whether BTZ reaches the cerebrospinal fluid (CSF), which is relevant in pediatric leukemias in view of the frequent leptomeningeal involvement. In the setting of the lack of clinical experience with BTZ in children in Europe, we developed a European multicentre feasibility/phase II study in refractory or relapsed ALL, in which all patients get BTZ (NTR 1881, EUDRaCT 2009-014037-25, ITCC 021). A randomisation is done for BTZ to start “early”, on day 1 of treatment, or “late”, on day 8 of treatment. Bortezomib is given as iv push for 4 doses at 1.3 mg/m2/dose, thus in group “early” on days 1, 4, 8 and 11 and in group “late” on days 8, 11, 15 and 18. In addition, all patients receive dexamethasone (10 mg/m2/day in 3 doses for 2 weeks, orally or iv) and vincristine (1.5 mg/m2/dose with a maximum of 2 mg as 1-hour infusion on days 8 and 15), and one intrathecal administration of methotrexate (dose age-adjusted) on day 1. Eligible patients have 2nd or greater relapsed ALL, 1st relapsed ALL after allogeneic stem cell transplantation (allo-SCT) in 1st complete remission (CR1), or refractory 1st relapsed ALL, bone marrow involvement and at least 100 leukemic cells per ul blood. Exclusion criteria includes symptomatic CNS leukemia, among other factors. It is planned to have 24 fully evaluable patients. This interim analysis is limited to a description of pharmacokinetic (PK) data, especially concerning the CSF. As per June 1, 2013 a total of 14 patients has been enrolled, 9 boys and 5 girls, median 8.7 years of age (range, 1.6-16.2). Most had 2nd relapsed ALL (n=9), others 1st relapsed ALL following allo-SCT in CR1 (n=3) or refractory 1st relapsed ALL (n=2). Regarding PK in the peripheral blood, there was remarkable intra- and inter-individual variability in peak plasma concentrations, between patients ranging from 4.7 to 2920 ng/ml 15 minutes after the first administration of BTZ, median 12.4 ng/ml (18.7 ng/ml in the group with BTZ “early”, 12.1 ng/ml in the group with BTZ “late”). Peak levels after the fourth administration were higher, median 41.1 ng/ml (29.5 ng/ml in the group with BTZ “early” and 158.9 ng/ml in the group with BTZ “late”). There was a 10-fold interindividual variation in the area-under the concentration versus time curve until 72 h (AUC[0-72h]) after administration. Median ratio of AUC[0-72h] fourth dose / AUC[0-72h] first dose was 2.7 (range 0.9 – 9.3), which is indicative of accumulation. In all patients, PK of BTZ was studied in the CSF 15 minutes after administration of the first and third dose (group “early” only) of BTZ, as well as 4 days (group “late”) or one week (group “early”) after the last administration. In general, no BTZ was detected with a lower detection limit of 0.1 ng/ml. In 4 patients some BTZ was detected in CSF, at 0.2 – 0.4 – 1.7 - 5.2 ng/ml. Of potential interest, the latter patient also had the highest peak plasma level of BTZ (2920 ng/ml) and the highest AUC. Future analyses in the complete cohort of 24 randomised patients will focus on more extensive population PK and pharmacodynamic analyses, as well as on efficacy of BTZ. The higher peak plasma levels after the fourth dose suggest decreased clearance (especially in the group which received bortezomib “late”), which indeed has been reported in adults and which requires careful monitoring of toxicity over time. Mean peak plasma concentrations in adults were reported to be 173 ng/ml, and thus seem higher. Meanwhile, BTZ does not or hardly penetrate the cerebrospinal fluid and is unlikely to be a drug that significantly adds to the treatment of leptomeningeal involvement in leukemia. Financially supported by the Dutch Foundation Children Cancer-free. Disclosures: Off Label Use: bortezomib in pediatric relapsed acute lymphoblastic leukemia.

A phase II study of mammalian target of rapamycin (mTOR) inhibitor RAD001 plus imatinib mesylate (IM) in patients with previously treated advanced renal carcinoma (RCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15600-15600 ◽  
Author(s):  
J. S. Chan ◽  
J. Vuky ◽  
L. A. Besaw ◽  
T. M. Beer ◽  
C. W. Ryan
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
High Dose ◽  
Grade 3 ◽  
Asco 2006 ◽  
Free Rate

15600 Background: The serine-threonine kinase mTOR is a valid target for RCC therapy with temsirolimus treatment resulting in improved overall survival in poor-risk patients (Hudes G et al., ASCO 2006). RAD001 is an oral inhibitor of mTOR which has demonstrated activity in RCC at 10mg/day (Amato R et al., ASCO 2006). IM is a tyrosine kinase inhibitor (TKI) of platelet-derived growth factor receptor (PDGFR), a target that may promote angiogenesis and growth of RCC. Combined mTOR and PDGFR inhibition with RAD001 and IM may achieve vertical blockade through the PI3K/AKT pathway. Methods: Eligibility: metastatic clear cell RCC, performance status (PS) 0–2, adequate organ function, and prior treatment with = 1 systemic therapy. Doses were based on a phase I study of the combination in GIST (Van Oosterom AT et al., ASCO 2005): RAD001 2.5 mg p.o. daily and IM 600 mg p.o. daily. Patients were reimaged every 6 weeks. This is a 2-stage phase II study to determine the 3-month progression-free rate. Results: 14 pts have been enrolled. Median age 66 years (51–79). 6 pts PS 0 and 8 pts PS 1. Median number of prior therapies 1.5 (1–4). 12 of 14 patients had prior TKI therapy. Prior therapies included sorafenib (11 pts), interferon (7), sunitinib (3), bevacizumab (2), erlotinib (1), panitumumab (1), high-dose IL-2 (1). Of 10 pts evaluable for the primary endpoint, 3 are progression-free = 3 months. Best response for 9 pts evaluable by RECIST: PR/CR 0, SD 7, PD 2. Most common adverse events in 11 evaluable patients include nausea (8), edema (7), increased creatinine (7), fatigue (7), transaminase elevation (6), thrombocytopenia (5), leukopenia (5), cough (5), diarrhea (5). Grade 3 adverse events include fatigue (3), LE edema, rash, pleural effusion, increased creatinine, abdominal pain, and thrombocytopenia (1 each). There were no grade 4 toxicities. Unique suspected RAD001 toxicities include grade 3 pneumonitis (1) and angioedema (1). Conclusions: The combination of RAD001 and IM has moderate toxicity. This is one of the first studies in RCC patients predominantly pretreated with a TKI. 3 month progression-free rate appears to be a clinically relevant endpoint in this population. [Table: see text]

A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8521-8521 ◽  
Author(s):  
Jinhyun Cho ◽  
Myung-Ju Ahn ◽  
Kwai Han Yoo ◽  
Hansang Lee ◽  
Hee Kyung Kim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Immunosuppressive Agents ◽  
Rapidly Progressive Glomerulonephritis ◽  
Progression Free Survival ◽  
Median Number ◽  
High Dose ◽  
Epithelial Tumor ◽  
Thymic Epithelial Tumor

8521 Background: No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate the efficacy and safety. Methods: Between March 2016 and December 2016, patients with histologically confirmed TET who progressed after platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The trial was registered with ClinicalTrials.gov, number NCT02607631. Results: 33 patients were enrolled, 26 with thymic carcinoma (TC) and 7 with thymoma (T). 19 (57.3%) patients received ≥ 2 prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-13) and median follow up was 6.3 months (ranges, 1.4-9.9). Of 33 patients, 8 (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was not reached for 7 T and 6.2 months for 26 TC. The most common adverse events of any grade include dyspnea (33.3%), chest wall pain (30.3%), anorexia (21.2%) and fatigue (21.2%). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (12.1%), myocarditis (9.1%), myasthenia gravis (6.1%), thyroiditis (3.0%), ANCA-associated rapidly progressive glomerulonephritis (3.0%), colitis (3.0%), and subacute myoclonus (3.0%) except anemia (3.0%). 8 (24.2%) patients (5 T, 3 TC) discontinued study treatment due to irAE, which were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (87.5%). Conclusions: Pembrolizumab showed promising antitumor activity in refractory or relapsed TET. Given the relatively high incidence of irAEs, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET. Clinical trial information: NCT02607631.

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