Dose-escalation Trial In Patients Research Articles

Pharmacokinetics (PK) of PF-562271, a focal adhesion kinase (FAK) inhibitor, and its effect on CYP3A in patients with advanced nonhematologic malignancies.

2553 Background: FAK transduces signaling from integrins and growth factors to modulate tumor cell invasion, proliferation, and survival. PF-562271, a potent FAK inhibitor, is under development as an anticancer agent. Preclinical studies demonstrated that PF-562271 is an inhibitor of its primary metabolizing enzyme, CYP3A. PF-562271 PK and its effect on CYP3A were investigated in a dose-escalation trial in patients with nonhematologic malignancies. Methods: Escalating doses of PF-562271 were administered orally to a total of 67 patients twice a day (BID) or once a day (QD), with or without food. Serial serum samples were collected after the first dose and at steady state to determine PK of PF-562271. To evaluate the effect of PF-562271 on CYP3A activity, plasma PK of orally administered midazolam were determined prior to PF-562271 administration and after repeated PF-562271 dosing to steady state in 8 patients who received the recommended phase 2 dose of 125 mg BID. Serum PF-562271 and plasma midazolam concentrations were determined using validated HPLC-MS/MS methods. The concentration-time data for PF-562271 and midazolam were analyzed by noncompartmental methods. Results: After a single oral dose, PF-562271 was readily absorbed with the maximum serum concentration achieved in 0.5 to 6 hours. The increases in systemic exposure (AUCinf) were dose proportional over the 5 to 25 mg range, but greater than dose proportional from 35 to 225 mg. After multiple oral doses, PF-562271 demonstrated nonlinear accumulation in exposure; the mean ratio of steady state AUC during a dose interval to AUCinf after the first dose ranged from 1.3 to 5.3, indicating time-dependent PK. Similar PK parameters for PF-562271 were observed at comparable doses given with or without food. When co-administered, PF-562271 (125 mg BID) increased total midazolam plasma exposure approximately 5.9-fold. Conclusions: PF-562271 displayed time- and dose-dependent nonlinear PK, and is a potent CYP3A inhibitor. The nonlinear PK of PF-562271 likely resulted from auto-inhibition of CYP3A. In the limited number of subjects evaluated, food did not substantially alter the PK of PF-562271. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer

Phase 1 Clinical Trial of the Novel Structure Proteasome Inhibitor NPI-0052 in Patients with Relapsed and Relapsed/Refractory Multiple Myeloma (MM).

Abstract 431 Background:NPI-0052 has a novel, non-peptide based, bicyclic structure resulting in a unique proteasome inhibition and safety profile. In contrast to other proteasome inhibitors, NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities. Preclinical data subsequently suggested improvements in toxicology and efficacy, including activity MM resistant to bortezomib (BZ) and other agents (Chauhan et al, Cancer Cell 2005), thus this Phase 1 dose escalation trial in patients (pts) with relapsed/refractory MM was initiated. Materials and Methods:Patients (pts) were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. Measurable disease by EBMT criteria was not required. The dose of NPI-0052 was escalated using a combination of accelerated titration and 3+3 design. PK and proteasome inhibition (blood and PBMCs) were assayed after the first and third doses. Preliminary Results:27 pts have been treated at doses ranging from 0.025 to 0.7 mg/m2; median age is 62; 18 males/9 females; IgG/IgA/light chain/non-secretory 14/4/2/6; median of 4 prior regimens and 27% refractory to prior bortezomib. Reversible DLT was observed in two out of eight patients treated at 0.7 mg/m2 (Grade 3 fatigue; Grade 3 mental status changes and loss of balance), with 2 additional pts undergoing dose reductions in Cycle 1 (nausea and vomiting; vertigo and confusion/word-finding difficulties). Prophylactic anti-emetics have been instituted with a decrease in infusion-related nausea; similarly, pts with dizziness/vertigo have been administered meclizine with symptomatic improvement. Other drug-related adverse events have consisted principally of mild-to-moderate fatigue, nausea, vomiting, dizziness, headache and diarrhea; interestingly, myelosuppression, neuropathy and thrombosis do not appear to be elicited by NPI-0052. PK assessment demonstrates a rapid elimination half-life (<20 minutes) and relatively large Vz. NPI-0052 produces dose dependent proteasome inhibitions. At 0.7 mg/m2, Day 1/Day 15 inhibition of chymotrypsin-like activity in whole blood is 73% and 99%, respectively (the value for bortezomib at 1.3 mg/m2 is 65%). One patient with IgA MM (4 prior regimens plus ASCT; relapsed after prior BZ, not refractory) had a 71% decrease in M-protein (unconfirmed PR; off study after 3 cycles). A second pt with non-secretory disease (4 prior regimens;relapsed after prior BZ, not refractory) had a nearly 50% reduction in involved light chain; this pt remains active on study at 5+ months. In addition, 8 pts with relapsed/refractory MM remained on study for between 6-15 months (3 pts were on-study for over one year) with stable disease and no significant toxicity; 2 of these pts were BZ-refractory. Conclusions:Tolerability of 0.7 mg/m2 continues to be investigated in pts with MM, with prophylactic antiemetics and meclizine to reduce common drug-related toxicities of nausea and dizziness. The safety profile of NPI-0052 is importantly different from bortezomib in spite of higher and more durable proteasome inhibition; peripheral neuropathy and thrombocytopenia were not seen. Accrual continues to expand upon these results and assess the new lyophile formulation of NPI-0052. Disclosures:Richardson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees; Gentium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Jakubowiak:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria; Bristol-Myers-Squibb: Consultancy, Honoraria. Spear:Nereus Pharmaceuticals: Employment, Equity Ownership. Palladino:Nereus Pharmaceuticals: Employment, Equity Ownership. Longenecker:Nereus Pharmaceuticals: Employment, Equity Ownership. Neuteboom:Nereus Pharmaceuticals: Employment, Equity Ownership. Cropp:Nereus Pharmaceuticals: Consultancy. Lloyd:Nereus Pharmaceuticals: Employment, Equity Ownership. Hannah:Nereus Pharmaceuticals: Consultancy. Anderson:Nereus Pharmaceuticals: Consultancy, Research Funding.

A Dose-Escalation Study of Aerosolized Sargramostim in the Treatment of Metastatic Melanoma

Early testing of aerosolized sargramostim therapy demonstrated anecdotal clinical responses in patients with metastatic melanoma associated with emergence of systemic antitumor immunity. To improve the clinical and immunologic efficacy of therapy without compromising patient safety, we performed a further dose escalation trial in patients with metastatic melanoma. We conducted a dose-escalation clinical trial of HLA-A2 patients with metastatic melanoma to the lung treated with aerosolized granulocyte macrophage colony stimulating factor (GM-CSF) (500-2000 microg/dose, with increments of 250 microg/dose/cohort) twice/d on days 1 to 7 and 15 to 21 every 28 days until progression or severe toxicity to find a dose where a majority of patients develop antitumor immunity. Five patients were treated per each dose level. Clinical, immune, and safety parameters were examined. The study accrued 40 patients. Toxicity was acceptable. All doses levels were exhausted without identifying a dose of GM-CSF at which a majority of patients (> or =3 of 5) demonstrated significant up-regulation of antitumor immunity. Three of 16 patients who were tetramer positive for at least one melanoma antigen (eg, MART-1) pretreatment developed an immune response (IR) to different tumor antigens. Two of 9 patients who were tetramer negative to all melanoma antigens pretreatment developed an IR against gp100. The greatest changes in antitumor immunity occurred at the highest dose levels. A dose of aerosolized GM-CSF capable of inducing antitumor immunity in the majority of patients was not reached. All tested doses were well tolerated. The greatest increase in antitumor T cell IRs was achieved at the highest doses of GM-CSF.

A Phase I Study of the Kinesin Spindle Protein Inhibitor Ispinesib (SB-715992) in Relapsed/Refractory Acute Leukemia

Background. Ispinesib is a novel polycylic, nitrogen-containing heterocycle small molecule that acts by inhibition of the mitotic kinesin spindle protein (KSP) HsEg5. Pre-clinical studies demonstrate activity against both murine and human solid tumor and leukemia cell lines by inhibition of adenosine diphosphate release from KSP, causing monopolar spindle formation and programmed cell death.Methods. This was a single agent, phase I dose-escalation trial in patients with relapsed/refractory acute myeloid (AML) or lymphoid leukemia (ALL) or advanced myelodysplastic syndrome (MDS). Intravenous ispinesib was given for 3 consecutive days every 21 days. Doses were escalated from 1.5 mg/m2/day to 13.3 mg/m2/day in cohorts of 3 patients. Clinical and peripheral blood responses were monitored on at least a weekly basis and bone marrow evaluations were done every three weeks. Grade 3 or greater non-hematologic toxicities were considered dose limiting toxicities (DLT) with the exception of infectious complications, electrolyte abnormalities or self-limited gastrointestinal toxicities.Results. Thirty-six adults (14 women, 22 men) with a median age of 66.5 years (range 28–82 years) were enrolled. The median number of previous induction treatments was 3, with a range from 0 to 8. Two patients had MDS, 5 had ALL and 29 had AML. Patients received a median number of 1.5 cycles of ispinesib, with a range from 1 to 5. The maximum tolerated dose (MTD) was determined to be 10 mg/m2/day given on 3 consecutive days. DLTs related to the study drug were grade 3 transaminitis and hyperbilirubinemia, and these developed in a total of 6 patients; one at dose level 3 mg/m2/day, 2 at dose level 7.5 mg/m2/day and 3 at dose level 13.3 mg/m2/day. Five patients developed self-limited grade 3 mucositis at dose level 13.3 mg/m2/day. Three patients died on study. One died due to disease progression, and two died both due to infection and hepatic dysfunction. None of the patients had normalization of their blood counts. Three patients with very high peripheral blast counts had rapid clearing of the blasts during treatment. Two patients had late bone marrow responses with less than 5% blasts at dose level 10 mg/m2/day after cycle 2 and cycle 3, respectively; both subsequently died of infection without count recovery. An additional three patients had a decrease in bone marrow cellularity with persistence of leukemic blasts.Conclusions. The MTD of ispinesib in this patient population and on this schedule was higher than that observed in prior trials of non-hematologic malignancies (30 mg/m2versus 18 mg/m2). The toxicity profile was different with DLT of hepatic toxicity in this trial and DLT of neutropenia in the solid tumor trials. Ispinesib appeared to provide myelosuppression in some patients at higher dose levels; however, there appeared to be minimal effect on the leukemic marrow component. Even in the majority of patients with myelosuppression, the leukemic clone persisted and proliferated following treatment. Ispinesib was effective at clearing the peripheral blood of blasts in a minority of patients. Ispinesib, given as a single agent in this trial on this schedule, is not an effective anti-leukemic therapy.

Safety and Clinical Activity of the Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) in Combination with Rituximab in Follicular Lymphoma or Diffuse Large B-Cell Lymphoma: Preliminary Report of a Phase 1/2 Study

Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Inotuzumab ozogamicin targets B-cell malignancies since they often express CD22. In a previously reported phase 1 dose-escalation trial in patients with CD22-positive B-cell non-Hodgkin's lymphoma (NHL), the maximum tolerated dose (MTD) was determined to be 1.8 mg/m2 every 4 weeks. Responses were seen in patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). This ongoing study consisted of a limited dose escalation (DE) portion to confirm the MTD of inotuzumab ozogamicin when combined with rituximab, followed by an expanded MTD cohort to further define safety and efficacy. Patients with FL and DLBCL who relapsed or progressed after 1 or 2 prior therapies were eligible. Prior rituximab treatment was required and prior autologous transplant allowed if >6 months from enrollment. Rituximab refractory patients, as defined by progression within 6 months of the first dose of rituximab, were excluded. Patients received rituximab 375 mg/m2 on day 1 of each 28-day cycle and inotuzumab ozogamicin on day 2 at doses of 0.8 mg/m2 (n=5), 1.3 mg/m2 (n=3), and 1.8 mg/m2 (n=7) for a maximum of 8 cycles. After confirmation of the MTD dose at 1.8 mg/m2 ditional patients were enrolled in an expanded MTD cohort. Safety data and preliminary efficacy data were collected. As of June 2008, the DE portion was completed and the study is enrolling in the MTD portion. To date, 61 patients have been treated: median age 63 yr (range 33–85 yr), 62% men. All 61 patients were evaluable for safety and currently 30 patients (16 FL, 14 DLBCL) in the expanded MTD cohort were evaluable for tumor response based on available data. 20% of patients discontinued treatment due to an adverse event (AE), which included hematologic AEs (8 patients) or elevation of ³1 liver function test (5 patients). The overall safety profile was characterized by AEs that were manageable; the most common drug-related AEs (all grades) were thrombocytopenia (41%), nausea (38%), fatigue (36%), AST increased (26%), and neutropenia (25%). Grade 3/4 AEs that occurred in 5% of patients included thrombocytopenia (21%), neutropenia (15%), and lymphopenia (7%). Tumor responses were seen in all DE cohorts and the MTD cohort, and the response rates in evaluable patients are shown in the Table. The 6-month progressionfree survival rate was 100% for FL and 66% DLBCL for all patients in the MTD cohort. The safety profile of inotuzumab ozogamicin plus rituximab exhibits a similar profile seen in the previous inotuzumab ozogamicin monotherapy study. The main toxicity was clinically manageable, self-limited thrombocytopenia. The preliminary efficacy in recurrent/refractory FL and DLBCL is promising and may indicate a durable response. These data support the continuing development of inotuzumab ozogamicin in combination with rituximab in the management of NHL.Table: Best Overall Response, Evaluable* Patients in the Dose Escalation (DE) and MTD CohortsFL, n (%)DLBCL, n (%)DEMTDDEMTDResponse0.8 (n=1)1.3 (n=2)1.8 (n=3)Total (n=6)1.8 (n=16)0.8 (n=3)1.3 (n=1)1.8 (n=2)Total (n=6)1.8 (n=14)CR/CRu1 (100)1 (50)1 (33)3 (50)7 (44)1 (33)01 (50)2 (33)6 (43)ORR1 (100)2 (100)2 (67)5 (83)14 (88)1 (33)1 (100)2 (100)4 (67)10 (71)CR=complete response; CRu=CR unconfirmed;ORR=objective response rate (CR/CRu+partial response)*Best response during treatment and follow up.Evaluable patients had 32 doses inotuzumab ozogamicin and a response assessment

An Initial Report of a Radiation Dose-Escalation Trial in Patients with One to Five Sites of Metastatic Disease

Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy. Patients with one to five sites of metastatic cancer with a life expectancy of >3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade > or =3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients. Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.

Genetic and Biochemical Biomarkers of IMPDH Inhibition in Phase I Dose Escalation of AVN-944 for Hematologic Malignancies.

AVN-944 is an orally bioavailable inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH). IMPDH2 is highly upregulated and required for the de novo production of guanine nucleotides in many malignancies, including hematologic cancers. AVN-944 is currently in a repeat-dose, dose escalation trial in patients with advanced hematologic cancers including AML, CLL, Multiple Myeloma, and lymphomas. In addition to the objective of defining the maximum tolerated dose and repeat dose pharmacology of AVN-944 (given bid for 21 days on a 28 day cycle), we have examined a comprehensive set of pharmacodynamic biomarkers. We have isolated peripheral blood samples from all patients in this trial both before and after receiving AVN-944. These samples are being used to determine the effects of the drug on GTP pools and IMPDH enzyme activity, and to correlate these changes to the genetic response of the circulating cells using gene expression detection technologies. We previously identified a set of 32 genes that respond to AVN-944 exposure in a multitude of laboratory settings including different cell types, different concentrations and timepoints. These genes relate directly to cellular pathways and functions dependent upon, or required for, guanine nucleotide biosynthesis, including purine and pyrimidine biosynthesis, mitochondrial functions, metabolic pathways and energy production, cell proliferation and the apoptotic cascade. Examination of the behavior of these genes in patient samples from this phase I trial show a dynamic response of subsets of these genes depending onthe type of malignancy,the predominant cell type in the peripheral blood, andthe dose of AVN-944 received.One set of 9 disease-related genes show changes in expression following drug administration in leukemia patients, while another set of 6 genes designed to report pharmacodynamic effects in normal cells consistently shows changes in expression in the peripheral blood lymphocytes of multiple myeloma patients. In total, 27 of 34 selected genes examined by qPCR showed changes following dosing of AVN-944 at the starting dose of 25 mg p.o. Increasing doses resulted in increases in the number of genes changing per individual, and/or an increase in the magnitude of change in a gene-dependent manner. These genetic markers, correlated with biochemical effects of the drug on protein function and guanine nucleotide levels, can be used as important biomarkers in selecting the optimal dose with which to initiate phase II studies with this drug.

Analysis of Peripheral Blood CD4+/CD25high Treg Cells and FOXP3 mRNA Expression in Patients Treated with Ipilimumab (Monoclonal Human Anti-CTLA4, MDX-010) for Relapse of Malignancy Following Allogeneic Hematopoietic Transplantation.

CTLA-4 is expressed upon activation of T-cells,and serves as an important negative regulator of their effector function. It is also expressed constitutively on CD4+/CD25+ regulatory T cells (Treg), where its function is not clear. Following allogeneic hematopoietic stem cell transplantation (allo-HCT), CTLA-4 function may be involved in suppression of alloreactive T cells that mediate the graft-versus malignancy effect and GVHD. We have studied the administration of a single dose of Ipilimumab (MDX-010), a fully human monoclonal anti-CTLA-4 antibody, in a dose escalation trial in patients with relapse/progression of malignancy following allo-HCT. Here we report effects of ipilimumab on peripheral CD4+/CD25+ cell levels and FOXP3 mRNA expression in these patients. Seventeen patients with a variety of malignancies were enrolled in this study. Ipilimumab was given intravenously at a dose level of 0.1, 0.33, 0.66, 1, and 3mg/kg. The blood samples were obtained prior and after infusion at day 7, 14 and 30. The immunophynotyping of peripheral blood mononuclear cells (PBMC) was analyzed by flow cytometry. CD4+/CD25+ cells from nine patients at day 0, 7, and five normal donors were separated using a Dynal CD4+/CD25+ Treg kit. FOXP3 mRNA expression on CD4+/CD25+ cells were analyzed by a quantitative RT-PCR. Expression level of FOXP3 was normalized to 18S rRNA. Within CD4+ cell population, the percentage of CD4+/CD25high cells was significantly higher in patients at day 0 (11.6±6.7%, n=17), compared with normal donors (3.8±1.6%, n=12; P<0.001). There was no significant change in CD4+/CD25high Treg cells in 17 patients after infusion. However, there was a transient 55±24% decrease of CD4+/CD25high Treg cells in 6 patients at day 7. FOXP3 mRNA expression in CD4+/CD25+ cells was significantly higher in patients at day 0 (2451±1731, n=9) compared with normal donors (918±348, n=5; P<0.001). After ipilimumab infusion, 3/9 patients showed a greater than 50% decrease, 4/9 patients showed no significant change, and 2/9 patients showed a 3–10 fold increase of FOXP3 mRNA expression at day 7. There was no correlation between the dose of ipilimumab and the percentage of CD4+/CD25high cells, or the FOXP3 mRNA expression. We did not observe a correlation of CD4+/CD25high Treg cells and FOXP3 mRNA expression in patients who had a clinical response or immune breakthrough adverse events in response to ipilimumab. These data suggest that in-vivo CTLA-4 blockade does not consistently impact the number of CD4+ CD25high Treg cells and that the clinical effects observed are probably related to the effects of ipilimumab upon activated effector T-cells.

Combination of Motexafin Gadolinium (MGd) with 90Y Ibritumomab Tiuxetan (Zevalin®; 90Yttrium-Zevalin) Radioimmunotherapy (RIT) Produces High Complete Remission Rates in Relapsed Rituximab-Refractory Follicular Non- Hodgkin's Lymphoma (NHL).

Background: MGd is a novel anti-cancer agent that selectively accumulates in tumor cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd induces apoptosis in lymphoma cells and is additive or synergistic with radiation, chemotherapy and rituximab in pre-clinical studies. In solid tumor clinical trials, there has been no evidence of hematopoietic toxicity with MGd at doses of 5 mg/kg x 10 days. In rituximab-refractory follicular NHL, single-agent Zevalin® produces a response rate (RR) of 74% (15% complete response [CR]). We reasoned that MGd and Zevalin® would be synergistic and provide higher response rates that are more durable.Method: To test this hypothesis, we are conducting a phase I/II dose escalation trial for patients with relapsed/refractory NHL using fixed dose 90Yttrium-Zevalin (0.4 mCi/kg) with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg and 5.0 mg/kg) based on a modified Fibonacci scheme. Patients receive MGd days 1 to 4 (with 111Indium-Zevalin given day 1) and days 8 to 11 (with 90Yttrium-Zevalin given day 8). Since MGd contains the paramagnetic metal ion, gadolinium, the molecule is detectable by MRI, which may be used to visualize tumor selective localization.Results: Seven of 10 treated patients are evaluable (3 female, 4 male) at 2.5 mg/kg and 3.5 mg/kg MGd dose levels. Median age is 57 (range, 37 to 80). The histologies include: 5 follicular, 1 transformed (follicular to diffuse large B-cell [DLBCL]), 1 mantle-cell. Median number of prior therapies is 3 (range, 2–4), and 7/7 patients were refractory to rituximab (defined as no response or time to treatment progression of less than 6 months). No dose limiting toxicity (grade 3 or 4 non-hematologic or grade 4 hematologic) has been seen. Response has been seen in 6/7 patients. Response by histology is shown in the table.Response According to HistologyHistologyNumberOverall RRCRfollicular55/54/5transformed11/11/1mantle-cell10/10/1Of the 6 responders, response (by CT scan) was documented at 4 weeks in all patients (5 CR/Cru and 1 partial remission). One patient relapsed at 8 months (at dose level 1), while the other patients remain in remission at 13, 12, 7, 7, 6 and 2 months. In one patient, where MRI data were obtained, the day 4 non-contrast MRI of a superficial scalp mass showed 30% increase in MRI signal intensity (compared with a pre-MGd scan) indicating tumor-selective uptake of MGd.Conclusion: We found that MGd at doses of 2.5 and 3.5 mg/kg x 8, when given with Zevalin®, is safe and does not appear to increase hematologic or other toxicity. Moreover, we have observed prompt tumor responses and complete remission in a very high proportion of rituximab-refractory follicular lymphoma patients (overall RR for these histologies was 100%, CR 80%). These data suggest possible synergistic effects of MGd and Zevalin® RIT.

626 Pharmacokinetics and pharmacodynamics of valopicitabine (NM283), a new nucleoside HCV polymerase inhibitor: Results from a phase I/II dose-escalation trial in patients with HCV-1 infection

626 Pharmacokinetics and pharmacodynamics of valopicitabine (NM283), a new nucleoside HCV polymerase inhibitor: Results from a phase I/II dose-escalation trial in patients with HCV-1 infection

Safety, tolerability, and pharmacokinetics of idebenone in a dose-escalation trial in patients with Friedreich's ataxia

Friedreich's ataxia is a progressive neurodegenerative disorder caused by a GAA trinucleotide expansion within the fraxatin gene. This mutation results in a loss of the frataxin protein within mitochondria leading to reduced activity of key enzymes, excess production of free radicals, and defective oxidative phosphorylation. Recent studies suggest that the antioxidant, idebenone, may prevent disease progression and greater efficacy may be seen with higher doses. In order to explore the full dose range, 81 patients divided evenly among adults, adolescents, and children participated in an unblinded, 1 day dose-escalation trial of oral idebeonone divided TID. No dose limiting toxicity was observed, and the maximum allowed dose of 75 mg/kg was achieved in all cohorts. Analysis of serum levels of total idebenone revealed a large variation in absorption of the drug. This variation precluded complete analysis of plasma concentration obtained during repetitive dosing; however, the terminal half-life following the last dose was consistent across the dose levels, indicating dose proportionality. A follow-up study in 15 patients revealed that a dose of 60 mg/kg/day was safe and well tolerated for 1 month. These findings indicate that higher doses of this drug should be explored for efficacy in Friedreich's ataxia and other diseases associated with oxidative stress. Clinical Pharmacology & Therapeutics (2005) 77, P68–P68; doi: 10.1016/j.clpt.2004.12.150

A randomized radiation dose escalation trial in patients with recurrent or incompletely resected benign meningiomas treated with proton-photon irradiation

A randomized radiation dose escalation trial in patients with recurrent or incompletely resected benign meningiomas treated with proton-photon irradiation

L-dT: An ongoing phase I/IIa dose-escalation trial in patients with chronic HBV infection (NV-02B-001)

L-dT: An ongoing phase I/IIa dose-escalation trial in patients with chronic HBV infection (NV-02B-001)

L-dT: An ongoing phase I/IIa dose-escalation trial in patients with chronic HBV infection (NV-02B-001)

L-dT: An ongoing phase I/IIa dose-escalation trial in patients with chronic HBV infection (NV-02B-001)

A Phase-I Study of an Anti-CD25 Ricin A-Chain Immunotoxin (RFT5-SMPT-dgA) in Patients With Refractory Hodgkin's Lymphoma

AbstractThe anti-CD25 immunotoxin (IT), RFT5-SMPT-dgA, was used in a phase I dose escalation trial in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody RFT5 via a sterically hindered disulfide linker to deglycosylated ricin-A. All patients in this trial were heavily pretreated with a mean of 5 (range, 2 to 8) different prior therapies, including autologous bone marrow transplantation in 8 of 15. The mean age was 29 years (range, 19 to 34 years). Thirteen of 15 patients had advanced disease (stage IV) with massive tumor burdens and 6 of 15 had B symptoms. The IT was administered intravenously over 4 hours on days 1, 3, 5, and 7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Patients received one to four cycles of treatment. The peak serum concentration of intact IT varied from 0.2 to 9.7 μg/mL. The serum half life (T1/2 ) of the IT ranged from 4.0 to 10.5 hours (mean, 6.1 hours). Side effects were related to vascular leak syndrome (VLS), ie, decreases in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. Two patients had a National Cancer Institute (NCI) grade 2 allergic reaction with generalized urticaria and mild bronchospasm. At 15 mg/m2, 1 patient experienced a grade 3 myalgia. All 3 patients receiving 20 mg/m2 experienced NCI grade 3 toxicities (edema, nausea, dyspnea or tachycardia) and 1 patient had NCI grade 4 myalgia. Thus, the maximal tolerated dose was 15 mg/m2. Seven of 15 patients made human antiricin antibodies (≥1.0 μg/mL) and 6 of 15 developed human antimouse antibodies (≥1.0 μg/mL). Clinical response included 2 partial remissions, 1 minor response, 3 stable diseases, and 9 progressive diseases. As has been predicted from the preclinical tests, these data seem to indicate clinical effecicacy of this new IT in heavily pretreated Hodgkin's patients, thus warranting further clinical investigation.

Phase I study of safety and pharmacokinetics of a human anticytomegalovirus monoclonal antibody in allogeneic bone marrow transplant recipients.

This study examined the safety and pharmacokinetic profile of a potentially therapeutic and fully human anti-CMV monoclonal antibody (SDZ MSL-109) in a phase I dose escalation trial in patients receiving allogeneic bone marrow transplants. Fifteen adult marrow transplant patients, twelve with chronic myelogenous leukemia and three with acute nonlymphocytic leukemia, in cohorts of five patients each, were administered monoclonal antibody intravenously at doses of 50, 250, and 500 micrograms/kg at approximately three-week intervals for six months. Administration of the monoclonal antibody was associated with minimal side effects and no dose-related toxicity. Antibody elimination curves in all dose groups were consistent with a two-compartment model with an alpha half-life at the low, middle, and high dose groups of 1.03, 0.82, and 0.79 days, and a beta half life of 13.9, 14.0, and 16.5 days, respectively. The volume of distribution decreased with repetitive dosing to approximate the plasma volume in each patient and the pharmacokinetic profile was comparable to that of human IgG. There was no host antiidiotypic or antiallotypic antibody formation, indicating that MSL-109 was not immunogenic. Further studies are warranted to assess the potential efficacy of human monoclonal anti-CMV disease in marrow transplant recipients and other patients with immunodeficiency disorders.