NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3033-3033 ◽  
Author(s):  
Dana Shelton Thompson ◽  
Glen J. Weiss ◽  
Suzanne Fields Jones ◽  
Howard A. Burris ◽  
Ramesh K. Ramanathan ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Multiple Tumor ◽  
Anti Cancer ◽  
Targeted Agent ◽  
Adequate Organ Function ◽  
Tumor Types ◽  
Post Therapy

3033 Background: NKP-1339 is a first-in-class small molecule anti-cancer compound that down-regulates GRP78, a key regulator of misfolded protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation occurs in many tumors, and is associated with intrinsic and chemotherapy-induced resistance. Preclinically, single agent NKP-1339 demonstrates activity against multiple tumor types, including chemoresistant lines. This phase I trial evaluates the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. Methods: Patients (pts) with advanced solid tumors, adequate organ function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then adjusted to standard 3+3 design. Doses from 20-780 mg/m2 are evaluated. PD samples for plasma GRP78 are collected. At MTD, an expanded cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 30 evaluable for dose determination; 4 replaced due to tumor progression in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, occurred at 780 mg/m2; MTD is 625 mg/m2. Gr 1 fever/chills is observed above 420 mg/m2, but is prevented by steroid premedication. The most common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 fatigue. No lab abnormalities were noted except reversible creatinine elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial response was in 1 pt (NET); stable disease in 7 pts, including NET (2), NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy duration 14+-88+ weeks. Soluble GRP78 is detected in the plasma of patients at baseline. Conclusions: NKP-1339is well tolerated with manageable side effects. Single agent activity is noted in multiple tumors including NET. Results from the expanded cohort and pre/post-therapy PD will be presented. Phase II single agent NKP-1339 and phase I NKP-1339 combination trials are planned.

Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12017-12017 ◽  
Author(s):  
F. Y. Lee ◽  
A. Camuso ◽  
S. Castenada ◽  
C. Flefleh ◽  
I. Ingio ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Lung Carcinoma ◽  
Therapeutic Potential ◽  
Single Agent ◽  
Human Colon ◽  
Maximum Tolerated Dose ◽  
Antitumor Efficacy ◽  
Efficacy Evaluation ◽  
Multiple Tumor ◽  
Tumor Types

12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]

First-in-human phase I clinical trial of QBI-139, a human ribonuclease variant, in solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3113-TPS3113 ◽  
Author(s):  
Laura E. Strong ◽  
John A. Kink ◽  
Baigen Mei ◽  
Mark N. Shahan ◽  
Ronald T. Raines
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Model Systems ◽  
In Vivo Models ◽  
Multiple Tumor ◽  
Naturally Occurring

TPS3113 Background: RNA has been recognized as a drug target for cancer therapy, as evidenced by the ongoing clinical trials of RNAi and antisense therapies. An alternative approach that circumvents the delivery and stability issues of RNAi and antisense is to harness the activity of naturally occurring enzymes that degrade RNA. Variants of human ribonucleases (RNase) have been generated with diminished binding to their natural inhibitor inside cells, which allows the new proteins to kill cancer cells. QBI-139, a variant that retains 95% sequence identity to a naturally occurring RNase, has demonstrated efficacy as both a single agent and in combination against multiple tumor types in in vivo models of human cancer. A first in human phase I trial was designed and initiated for QBI-139. Methods: Since QBI-139 showed efficacy against multiple cancers in model systems, a first in human phase I trial was designed for patients with advanced solid tumors (NCT00818831). Patients receive QBI-139 by intravenous infusion once weekly for a cycle of three weeks. In the absence of disease progression or unacceptable toxicity, treatment can continue on the twenty one day cycle. The trial is a standard 3+3 design with cohorts of three to six patients receiving escalating doses of QBI-139 until the maximum tolerated dose (MTD) and/or recommended phase II dose is determined. The inclusion/exclusion criteria are typical for the patient population. Forty three patients have been treated to date (January 2012) without identification of dose limiting toxicity. The starting dose in the clinical trial was 3 mg/m2 while the most recently completed cohort was treated with a dose of 50.4 mg/m2. Dose escalation is ongoing. The primary outcome is to evaluate the toxicity and tolerability of QBI-139 in patients with advanced refractory solid tumors. This information will allow for identification of the maximum tolerated dose. Clinical exposure levels are being monitored by measuring the pharmacokinetics of QBI-139. Tumor response to QBI-139 will be measured using RECIST criteria. Since QBI-139 demonstrated broad efficacy in model systems, another outcome of the phase I trial may be identification of the indications for the next stage of clinical development.

Phase I trial of vorinostat (V) in combination with pemetrexed (Pem) and cisplatin (CDDP) in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18088-18088 ◽  
Author(s):  
L. Chen ◽  
N. J. Vogelzang ◽  
G. Blumenschein ◽  
F. Robert ◽  
J. M. Pluda ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
First Line Therapy ◽  
Solid Malignancies ◽  
Deacetylase Inhibitor ◽  
Adequate Organ Function ◽  
Ecog Ps ◽  
Tumor Types

18088 Background: Pem and CDDP are active agents in many tumor types, and the combination is approved as first line therapy in malignant pleural mesothelioma (meso). Vorinostat (V), an orally active histone deacetylase inhibitor, was shown to induce PR in 2 meso patients (pts) (Krug 2006, Kelly 2005). A Phase I trial was undertaken to determine the safety and maximum tolerated dose (MTD) of Pem+CDDP+V. Methods: Pts with advanced solid malignancies, adequate organ function, ECOG PS = 2, = 1 prior chemotherapy, >18 yrs of age, and at least 6 months from prior treatment with Pem+CDDP were eligible. Patients were treated on 21 day cycles. V was started 2 days before standard doses of CDDP (75 mg/m2) and Pem (500 mg/m2) and was given on 4 schedules: dose levels were: I-200 mg BID for 14/21 d, II- 300 mg BID for 3/7 d wk1, 2 wk rest, III-300 mg QD for 7/21 d, and IV- 400 mg QD for 7/21 d. Results: Twenty-two pts were treated: median age was 60 (range 31–81); 13M: 9F. Tumor types were NSCLC 8, meso 5, bladder 3, colorectal 2, other 4. Nineteen of 22 patients were evaluable for investigator determined response: 1 CR (5.3%), 1 PR (5.3%), 11 SD (57.9%), 6 PD (31.6%). Conclusions: Dehydration and fatigue were common DLTs on different schedules of Pem+CDDP+V. V 300 mg x 7 days was tolerable in this combination. Hints of clinical activity were observed in bladder cancer and sarcoma patients, and stable disease was seen in three mesothelioma patients. Alternative dose schedules of Pem + V are under investigation. [Table: see text] No significant financial relationships to disclose.

A Phase I Study of OMN54 (Aneustat™) in Patients with Advanced Malignancies

2020 ◽  
Vol 7 (2) ◽  
pp. 125-132
Author(s):  
Karen A. Gelmon ◽  
Christian Kollmannsberger ◽  
Stephen Chia ◽  
Anna V. Tinker ◽  
Teresa Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Salvia Miltiorrhiza ◽  
Performance Status ◽  
Parent Drug ◽  
Maximum Tolerated Dose ◽  
Ecog Performance Status ◽  
Advanced Malignancies ◽  
Gi Toxicity ◽  
Adequate Organ Function ◽  
Recommended Phase Ii Dose

Background/Objective: With the increasing interest in natural products, a phase I openlabel study of OMN54 (Aneustat™) in patients with advanced malignancies was initiated to determine toxicity, maximum tolerated dose (MTD), dose limiting toxicities (DLT), and pharmacokinetics (PK). OMN54 is a multitargeted agent, combining three Chinese botanicals; Ganoderma lucidium, Salvia miltiorrhiza and Scutellaria barbata. Methods: Eligible patients (pts) were >18 years of age with advanced solid tumors, able to swallow oral capsules, ECOG performance status < 2, measurable disease as defined by RECIST 1.1 and adequate organ function. Results: Twenty-two patients were enrolled in 6 dose levels, 2 with daily dosing and 4 with twicedaily dosing ranging from 1 to 5 grams daily. All were evaluated for toxicity and 20 for response. No treatment-related dose-limiting toxicities (DLTs) were reported and the recommended phase II dose (RP2D) was determined to be 2.5 g twice daily. Seven adverse events in 5 patients were reported as possibly drug-related; 6 were GI toxicity and 1 was a skin disorder. All were grade 1 except one grade 2 vomiting. No RECIST responses were seen. Six pts were treated with > 2 cycles; one for 8 cycles. Four patients had reductions in TGF –β and EGF, exploratory biomarkers possibly suggestive of a drug effect. Plasma half-lives of 1 -2 hours were noted for all parent drug chemical markers with no accumulation over time. Conclusion: OMN54 was well tolerated, with no DLTs observed. Further studies at the RP2D will assess the biological activity.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

Phase I Trial of Intravenous Administration of PV701, an Oncolytic Virus, in Patients With Advanced Solid Cancers

2002 ◽  
Vol 20 (9) ◽  
pp. 2251-2266 ◽  
Author(s):  
Andrew L. Pecora ◽  
Naiyer Rizvi ◽  
Gary I. Cohen ◽  
Neal J. Meropol ◽  
Daniel Sterman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Intravenous Administration ◽  
Single Agent ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Repeat Dose ◽  
Tumor Cell Membrane ◽  
Dosing Regimens ◽  
Higher Doses

PURPOSE: PV701, a replication-competent strain of Newcastle disease virus, causes regression of tumor xenografts after intravenous administration. This phase I study was designed to define the maximum-tolerated dose (MTD) and safety of single and multiple intravenous doses of PV701 as a single agent in patients with cancer. PATIENTS AND METHODS: Seventy-nine patients with advanced solid cancers that were unresponsive to standard therapy were enrolled. Four PV701 intravenous dosing regimens were evaluated: (1) single dose: one dose every 28 days; (2) repeat dose: three doses in 1 week every 28 days; (3) desensitizing: one lower dose followed by two higher doses in 1 week every 28 days; and (4) two week: one lower dose followed by five higher doses over 2 weeks every 21 days. RESULTS: A 100-fold dose intensification was achieved over 195 cycles. A first-dose MTD of 12 × 109 plaque-forming units (PFU)/m2 was established for outpatient dosing. After an initial dose of 12 × 109 PFU/m2, patients tolerated an MTD for subsequent doses of 120 × 109 PFU/m2. The most common adverse events were flu-like symptoms that occurred principally after the first dose and were decreased in number and severity with each subsequent dose. Tumor site–specific adverse events and acute dosing reactions were also observed but not cumulative toxicity. Objective responses occurred at higher dose levels, and progression-free survival ranged from 4 to 31 months. Tumor tissue from one patient was obtained after 11 months of therapy and showed evidence of PV701 particles budding from the tumor cell membrane by electron microscopy and a pronounced lymphoplasmacytic infiltrate by histologic examination. CONCLUSION: PV701 warrants further study as a novel therapeutic agent for cancer patients.

Sequences of topotecan and cisplatin: phase I, pharmacologic, and in vitro studies to examine sequence dependence.

1996 ◽  
Vol 14 (12) ◽  
pp. 3074-3084 ◽  
Author(s):  
E K Rowinsky ◽  
S H Kaufmann ◽  
S D Baker ◽  
L B Grochow ◽  
T L Chen ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
In Vitro Studies ◽  
Pharmacokinetic Studies ◽  
Sequence Dependence ◽  
Renal Tubular

PURPOSE A phase I and pharmacologic study was performed to evaluate the feasibility of administering the topoisomerase I (topo I) inhibitor topotecan (TPT) in combination with cisplatin (CDDP) in minimally pretreated adults with solid tumors. The study was designed to evaluate the magnitude of the toxicologic and pharmacologic differences between the two sequences of drug administration. MATERIALS AND METHODS TPT was administered as a 30-minute infusion daily for 5 days and CDDP was given either before TPT on day 1 or after TPT on day 5. Each patient was treated with both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or CDDP resulted in three dosage permutation of TPT/CDDP (mg/m2): 0.75/50, 1/50, and 0.75/75. After the maximum-tolerated dose (MTD) level was achieved, the feasibility of using granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was studied. To examine the interaction of TPT and CDDP in vitro, human A549 lung cancer cells were exposed to these agents concurrently and sequentially. RESULTS Dose-limiting neutropenia and thrombocytopenia resulted after the doses of TPT or CDDP were increased to greater than 0.75 and 50 mg/m2, respectively, without and with G-CSF. The sequence of CDDP before TPT induced significantly worse neutropenia and thrombocytopenia than the alternate sequence. In vitro studies failed to provide any evidence for the differences in the cytotoxicity of these two sequences. Instead, pharmacokinetic studies suggested that the differences in toxicity were due, in part, to lower TPT clearance and exposure when CDDP preceeds TPT, possibly due to subclinical renal tubular toxicity induced by CDDP. CONCLUSION The sequence of CDDP before TPT at doses of 50 and 0.75 mg/m2, respectively, is recommended for subsequent clinical trials in tumor types in which both agents have significant single-agent activity. The potential for sequence-dependent cytotoxic, toxicologic, and pharmacologic effects should be evaluated in concurrent clinical and laboratory studies in the course of developing combination chemotherapy regimens that consist of topo I-targeting agents and other antineoplastic agents, particularly DNA-damaging agents.

Phase I and Pharmacokinetic Study of Novel l-Nucleoside Analog Troxacitabine Given as a 30-Minute Infusion Every 21 Days

2002 ◽  
Vol 20 (10) ◽  
pp. 2567-2574 ◽  
Author(s):  
Karl Belanger ◽  
Malcolm Moore ◽  
Sharyn D. Baker ◽  
Jeanne Dionne ◽  
Martha Maclean ◽  
...  
Keyword(s):  
Phase I ◽  
Skin Rash ◽  
Maximum Tolerated Dose ◽  
Nucleoside Analog ◽  
Unknown Primary ◽  
Bone Lesions ◽  
Phase Ii Studies ◽  
Best Response ◽  
Metastatic Lung ◽  
Hand Foot Syndrome

PURPOSE: Troxacitabine (Troxatyl, BCH-4556; BioChem Pharma Inc, Basingstoke, United Kingdom) is a novel synthetic l-nucleoside analog with activity against a broad range of human tumors in preclinical models. Preclinical toxicity suggested a predictable toxicity profile consistent with an agent of this class, with evidence of interspecies differences. We conducted a phase I study of troxacitabine given as a 30-minute infusion once every 21 days. PATIENTS AND METHODS: The starting dose of troxacitabine was 0.025 mg/m2, based on toxicology data from the most sensitive species studied (cynomolgus monkey). Doses were doubled until grade 1 skin or mucosal or grade 2 other toxicity was encountered. A modified Fibonacci scale was used. RESULTS: A total of 45 patients were enrolled at 13 dose levels. Most common nonhematologic side effects were skin rash (44%), lethargy (29%), nausea (24%), alopecia, dry skin (18%), anorexia (13%), neurosensory symptoms (13%), and hand-foot syndrome (13%). In patients treated with prednisone 25 mg/d orally for 5 days, starting on day 1, skin rash was less problematic. Two patients at 12.5 mg/m2 experienced dose-limiting (grade 4) granulocytopenia. Confirmed partial responses were documented in one patient with previously untreated renal cell carcinoma with metastatic lung and bone lesions and in one patient with an unknown primary tumor. Eighteen patients had a best response of stable disease with a median duration of 5.1 months (range, 2.1 to 18.7 months). CONCLUSION: When given in this schedule, the maximum-tolerated dose of troxacitabine is 12.5 mg/m2, and the recommended dose for additional phase II studies is 10 mg/m2 once every 21 days with steroid premedication.

Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4528-4528
Author(s):  
Richard Sposto ◽  
Elizabeth A. Raetz ◽  
Charles P. Reynolds ◽  
Paul S. Gaynon
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a &gt; 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4765-4765
Author(s):  
John L. Reagan ◽  
James N. Butera ◽  
Alan G. Rosmarin ◽  
Ahmed Nadeem ◽  
Fred J. Schiffman ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Chop Chemotherapy ◽  
Intermediate Grade ◽  
Chemotherapeutic Regimen ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

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