Anlotinib plus TQB2450 in patients with advanced refractory biliary tract cancer (BTC): An open-label, dose-escalating, and dose-expansion cohort of phase Ib trial.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 292-292
Author(s):  
Jun Zhou ◽  
Jifang Gong ◽  
Yanshuo Cao ◽  
Zhi Peng ◽  
Jiajia Yuan ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Safety Profile ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Study Cohort ◽  
Open Label ◽  
Extrahepatic Cholangiocarcinoma ◽  
Cell Counts ◽  
Previously Treated ◽  
Dose Escalating

292 Background: Anti-angiogenic agents have been clinically investigated in combination with anti-PD-1/L1 mAbs due to their immuno-modulatory effects. Anlotinib (A), a potent oral multi-target tyrosine kinase inhibitor, has anti-angiogenic properties and anti-tumor efficacy with a favorable toxicity profile. The combination of A and TQB2450 (T), an anti-PD-L1 mAb, exhibited superior tumor growth suppression compared to either monotherapy in murine models. This ongoing phase 1b study cohort is aimed to assess the safety and efficacy of A+T in pts with advanced BTC. Methods: In this study cohort, patients (pts) with previously treated, advanced BTC were enrolled. A 3+3 dose escalation was used to determine the maximum tolerated dose (MTD) and a recommended phase 2 dose (RP2D) in a dose-escalating stage. Additional pts were enrolled in a dose-expansion stage to further establish the safety and determine the preliminary efficacy. Oral A of 10 and 12 mg was administered once daily for 14 days on / 7 days off with intravenous T of 1200 mg every 3 weeks. The primary endpoint was dose-limiting toxicity (DLT) during first cycle (first 3 weeks) to estimate the MTD, RP2D and overall response rate (ORR). Tumor response was assessed according to RECIST version 1.1 and iRECIST. The Secondary endpoints were progression-free survival (PFS), disease control rate (DCR) and safety. Results:25 pts were enrolled (8 with intrahepatic cholangiocarcinoma [IHCC]; 8 with extrahepatic cholangiocarcinoma [EHCC]; 9 with gall bladder cancer [GBC]) until August 2020. Median number of prior lines of therapy was 1 (range 1-5). During dose-escalation, no DLT was observed and 12 mg anlotinib was determined as RP2D for expansion. Among 24 evaluable pts (with at least once tumor assessment), 3 had achieved complete response (CR) and 7 had partial response (PR), which were all treated by 12 mg anlotinib plus TQB2450, 8 had stable disease (SD) and 6 had progression disease (PD). ORR was 41.67% and DCR was 75%. 10 pts were still on treatment. The median PFS was 240 days (95% CI, 83~NR).Treatment-related adverse events (TRAEs) occurred in 83.3% of pts (G3/4 in 16.7% [4/24], and leading to treatment discontinuation in 4.2% [1/24]). The most common TRAEs were hypertension (33.3%), decreased white blood cell counts (25.0%), increased TBIL (20.8%), decreased neutrophil counts (20.8%), increased DBIL (12.5%), and increased IBIL (12.5%). Conclusions: A+T had a manageable safety profile and encouraging antitumor efficacy in pts with previously treated, advanced BTC. No unexpected AEs were identified beyond the established safety profile for each agent. Clinical trial information: NCT03996408.

Open-label, multicenter, single-arm, phase I, dose-dscalation with efficacy tail extension study of vemurafenib in pediatric patients with surgically incurable and unresectable stage IIIc or IV melanoma harboring BRAFV600 mutations (NCT01519323).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS9104-TPS9104
Author(s):  
Fariba Navid ◽  
Julia C. Chisholm ◽  
Andrea Ferrari ◽  
Cynthia E. Herzog ◽  
Carlos Rodriguez-Galindo ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Pediatric Patients ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Stage Iiic ◽  
Unresectable Stage ◽  
The Usa ◽  
Previously Treated

TPS9104 Background: Although rare, melanoma is the most common form of skin cancer in children and the incidence is rising in the adolescent population. Similar to adults, the outcome for pediatric patients with advanced or recurrent melanoma is poor. Many adult studies of melanoma exclude patients under the age of 18 years. Approximately 50% of melanomas carry a mutation in the BRAF gene and the oral BRAF inhibitor vemurafenib (VEM) has demonstrated improved rates of overall and progression-free survival in adult melanoma patients who carry this mutation (Chapman et al; NEJM 2011). The current study is designed to determine the maximum tolerated dose (MTD)/recommended dose (RD), pharmacokinetics, safety, tolerability, and efficacy of VEM in pediatric patients with surgically incurable and unresectable stage IIIC/IV melanoma harboring BRAFV600mutations. Methods: Patients aged 12 through 17 years with newly diagnosed or previously treated measurable disease are eligible. Patients with radiographically stable, asymptomatic previously treated central nervous system lesions are also eligible. In the dose-escalation phase, patients will be enrolled sequentially to increasing dose cohorts of VEM following a 3+3 design. Dose-limiting toxicity will be assessed during the first cycle (defined as the first 28 days). The initial dose will be 720 mg BID (patients ≥45 kg) or 480 mg BID (patients <45 kg). Once the MTD/RD for the extension phase is defined based on the dose-escalation window, all patients will be eligible to receive the MTD/RD. The efficacy tail of the trial will enroll additional pediatric patients at the MTD/RD. Patients will receive VEM until disease progression, death, unacceptable tolerability, discontinuation from the study, or other protocol-specified criteria. The study aims to treat approximately 20 patients at the RD with 3-15 additional patients treated at other dose levels during the dose-escalation phase. This study is currently open at 18 sites in the USA, UK, Germany, Italy, and Australia. As of January 24, 2013, one patient has been enrolled. Clinical trial information: NCT01519323.

scholarly journals Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma

2014 ◽  
Vol 4 (2) ◽  
pp. e182-e182 ◽  
Author(s):  
D S Siegel ◽  
P Richardson ◽  
M Dimopoulos ◽  
P Moreau ◽  
C Mitsiades ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Adverse Events ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Laboratory Studies ◽  
Open Label ◽  
Adverse Experiences ◽  
Previously Treated ◽  
Dose Escalating

Abstract The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), informed by laboratory studies suggesting synergy. This was a phase I, multicenter, open-label, non-randomized, dose-escalating study in patients with relapsed or relapsed and refractory MM. Clinical evaluation, electrocardiogram, laboratory studies and adverse events were obtained and assessed. The maximum-tolerated dose was not reached owing to a non-occurrence of two dose-limiting toxicities per six patients tested at any of the dosing levels. Patients tolerated the highest dose tested (Level 5) and this was considered the maximum administered dose: at 400 mg vorinostat on days 1–7 and 15–21, 25 mg lenalidomide on days 1–21 and 40 mg dexamethasone on days 1, 8, 15 and 22, per 28-day cycle. Drug-related adverse events were reported in 90% of patients serious adverse experiences were reported in 45% of the patients and 22% of all patients had adverse experiences considered, possibly related to study drug by the investigators. A confirmed partial response or better was reported for 14/30 patients (47%) evaluable for efficacy, including 31% of patients previously treated with lenalidomide. Vorinostat in combination with lenalidomide and dexamethasone proved tolerable with appropriate supportive care, with encouraging activity observed.

Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7027-7027 ◽  
Author(s):  
Harry Paul Erba ◽  
Pamela S. Becker ◽  
Paul J. Shami ◽  
Michael Richard Grunwald ◽  
Donna L. Flesher ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Biological Effects ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Median Response ◽  
Puma Expression ◽  
Phase 1B ◽  
Mdm2 Inhibitor

7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.

A phase I, open-label, first-time-in-patient dose escalation and expansion study to assess the safety, tolerability, and pharmacokinetics of nanoparticle encapsulated Aurora B kinase inhibitor AZD2811 in patients with advanced solid tumours.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2608-TPS2608 ◽  
Author(s):  
Howard A. Burris ◽  
Judy Sing-Zan Wang ◽  
Melissa Lynne Johnson ◽  
Gerald Steven Falchook ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Subsequent Development ◽  
Aurora Kinase ◽  
Maximum Tolerated Dose ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Open Label ◽  
Aurora Kinase B ◽  
Chemotherapy Study

TPS2608 Background: Aurora kinase B performs key roles in the regulation of the cell cycle and represents a potential target for anticancer therapy. AZD2811, formerly designated AZD1152 hydroxy-quinazoline pyrazole anilide (AZD1152 hQPA), is a potent and selective inhibitor of Aurora B kinase activity and has been incorporated into a polymer nanoparticle carrier for intravenous (IV) administration. The phosphate pro-drug of AZD2811, known as AZD1152 (barasertib), reached Phase II of clinical development as a continuous IV infusion. While promising efficacy was seen with barasertib in elderly acute myeloid leukaemia (AML) patients ( Kantarjian HG et al., Cancer 2013;119:2611-19), continuous intravenous drug delivery precluded subsequent development in this disease setting and there were limited clinical responses in solid tumour patients due to dose-limiting myelotoxicity. AZD2811 nanoparticle has been designed to overcome these issues. Methods: Patients with relapsed advanced solid malignancies with no standard treatments are eligible for the part A dose escalation. Primary endpoint is to determine the maximum tolerated dose of AZD2811 nanoparticle using a 3+3 design. Patients with refractory/relapsed small cell lung cancer (SCLC) will be eligible for the part B expansion, where the safety, PK and anti-tumour activity of AZD2811 nanoparticle will be assessed as monotherapy and in combination with chemotherapy. Study enrolment is ongoing. Clinical trial information: NCT02579226.

scholarly journals A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

2021 ◽  
Author(s):  
Noboru Yamamoto ◽  
Toshio Shimizu ◽  
Kan Yonemori ◽  
Shigehisa Kitano ◽  
Shunsuke Kondo ◽  
...  
Keyword(s):  
Liver Function ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Enzyme Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Open Label ◽  
Phase 1 Study ◽  
Open Label Phase

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the gastric cancer cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4030-4030
Author(s):  
Hyun Cheol Cheol Chung ◽  
Zarnie Lwin ◽  
Carlos A. Gomez-Roca ◽  
Federico Longo ◽  
Eduardo Yanez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Advanced Gastric Cancer ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Phase 2 ◽  
Open Label ◽  
Previously Treated

4030 Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients. Clinical trial information: NCT03797326.

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

scholarly journals A Phase I Study to Evaluate the Safety of the Herbal Medicine SH003 in Patients With Solid Cancer

2020 ◽  
Vol 19 ◽  
pp. 153473542091144 ◽  
Author(s):  
Chunhoo Cheon ◽  
Seong-Gyu Ko
Keyword(s):  
Herbal Medicine ◽  
Adverse Events ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Solid Cancer ◽  
Open Label ◽  
Major Health Problem ◽  
Study Results ◽  
Label Dose ◽  
Grade 3

Background: Cancer is a major health problem worldwide and the leading cause of death in many countries. Preclinical studies have shown the therapeutic anticancer effects of SH003, a novel herbal medicine containing Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii. The present study investigated the maximum tolerated dose of SH003 in patients with solid cancers. Methods: This open-label, dose-escalation trial used the traditional 3 + 3 dose-escalation design. Patients with solid cancers were recruited and administered 1 to 4 tablets of SH003 thrice daily for 3 weeks according to the dose level. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE). Dose-limiting toxicities (DLTs) were defined as Grade 3 or higher adverse events based on CTCAE. The maximum tolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced DLT. Results: The present study enrolled 11 patients. A total of 31 adverse events occurred. According to the CTCAE, all the observed adverse events were grade 2 or less and no adverse events of grade 3 or more corresponding to DLT occurred. Conclusion: The study results indicated that the maximum tolerated dose of SH003 was 4800 mg/day. A Phase 2 study is required to determine the efficacy of SH003 in patients with cancer at a dose of 4800 mg/day or less.

Preliminary Results From A Phase I Dose Escalation Study to Determine the Maximum Tolerated Dose of Plerixafor In Combination with Rituximab In Patients with Relapsed Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2450-2450 ◽  
Author(s):  
Leslie Andritsos ◽  
John C. Byrd ◽  
Jeffrey A. Jones ◽  
Becker Hewes ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Peripheral Blood ◽  
Research Funding ◽  
Single Agent ◽  
Autologous Transplantation ◽  
Fold Increase ◽  
Maximum Tolerated Dose ◽  
Hematopoietic Stem ◽  
Genzyme Corporation ◽  
Previously Treated

Abstract Abstract 2450 Background: Dose intense rituximab in previously-treated patients (pts) with CLL has demonstrated modest activity. Preclinical data indicate that the CXCR4/CXCL12 axis plays a key role in CLL cell homing and retention in tissue microenvironments, such as the bone marrow. Disruption of this axis using the small-molecule CXCR4-antagonist, plerixafor, may abrogate stroma-mediated drug resistance, and enhance sensitivity of CLL cells to rituximab. To test this hypothesis, we initiated a phase 1 trial of plerixafor + rituximab in previously-treated pts with CLL. Aims: The primary objective was to determine the maximum tolerated dose (MTD) and safety of plerixafor when combined with rituximab. Methods: Adult pts with WBC≤ 50×109/L, intermediate/high risk CLL not refractory to rituximab, and with active disease by NCI criteria were eligible in this ongoing study. Pts were treated with 3x/week rituximab, as a 100mg flat dose on Day 1, and subsequently 375mg/m2 IV for 12 total doses (i.e. for 4 weeks). Plerixafor was given SC prior to rituximab starting at the 4th rituximab dose (Day 8) for 9 total doses. Cohorts of pts were treated at 1 of 4 dose levels with plerixafor (0.08mg/kg, 0.16mg/kg, 0.24mg/kg and 0.32mg/kg). Pts were observed for dose-limiting toxicities (DLT) from the first plerixafor dose (Day 8) through Day 29 and cohort advancement followed dose escalation rules using a 3+3 design. Peripheral blood (PB) CD34+ and CLL cells were enumerated on Days 8 and 26 by flow cytometry; PB samples were obtained at baseline pre-plerixafor treatment and at 2, 4, 6, 10, and 24 hours post-plerixafor. Responses were assessed as defined by Cheson et al (Blood, 1996). Results: 17 pts (median age 64 years; 88% male; Rai Stage IV: 53%) were enrolled, 3 pts each in the 0.08 and 0.24 mg/kg cohorts, 4 pts in the 0.16mg/kg cohort and 7 pts in the 0.32mg/kg cohort (Table 1). No DLTs were reported. Of 14 evaluable pts, 5 (36%) had partial response, 3 (21%) had stable disease for ≥2 months and 6 (43%) had progressive disease. Treatment-emergent, plerixafor-related adverse events (AEs) were seen in 5 pts and included diarrhea, vomiting, nausea, appetite loss, headache, hypoaesthesia and paraesthesia. All AEs were grade 1 except nausea (n=1) that was grade 2. Treatment-emergent serious AEs were seen in 2 pts (0.16mg/kg dose; grade 3 EBV infection, grade 2 gastrointestinal reflux disease and grade 2 dyspnea); all unrelated to plerixafor. On Day 8, there was a median 3.8-fold increase in PB CLL cells (range: 1.2 –15.0-fold), indicating CLL cell mobilization. On Day 26 fewer PB CLL cells were detected with a median fold increase of 1.5 (range, 0.9–8.0). Conclusions: The combination of plerixafor + rituximab in CLL pts with WBC < 50×109/L was well tolerated. CLL cells were mobilized following plerixafor, and partial remissions were seen in a proportion of pts. In some cases, maximum responses were seen several months after completion of rituximab, consistent with single agent therapy. This suggests that continued follow up may show additional responses in recently treated pts. Disclosures: Andritsos: Genzyme Corporation: Research Funding. Off Label Use: Plerixafor (Mozobil®), a hematopoietic stem cell mobilizer, is approved by the US FDA in combination with granulocyte-colony stimulating factor (G-CSF) to mobilize hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. Byrd: Genzyme Corporation: Research Funding. Jones: Genzyme Corporation: Research Funding. Hewes: Genzyme Corporation: Employment. Kipps: Genzyme Corporation: Research Funding. Hsu: Genzyme Corporation: Employment, Equity Ownership. Burger: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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