Papers by Heidi Gillenwater
Blood, Nov 13, 2019
Background Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, genetically ... more Background Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, genetically modified, autologous cellular immunotherapy administered as a defined composition of CD8+ and CD4+ components to deliver target doses of viable chimeric antigen receptor (CAR) T cells from both components. The CAR comprises a CD19-specific scFv and 4-1BB-CD3ζ endodomain. Liso-cel is being developed for the treatment of multiple B cell malignancies, including relapsed/refractory large B cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The liso-cel manufacturing process design includes controls that enable robustness across heterogeneous patient populations and disease indications, minimizing between-lot variability. This is highlighted by consistency in process duration, reduction of terminally differentiated T cells present in the T cell starting material, and consistency in T cell purity across B cell NHL and CLL/SLL indications. Methods The liso-cel manufacturing process involves selection of CD8+ and CD4+ T cells from leukapheresis, followed by independent CD8+ and CD4+ activation, transduction, expansion, formulation, and cryopreservation. Liso-cel was manufactured in support of the TRANSCEND NHL 001 (NCT02631044) and TRANSCEND CLL 004 (NCT03331198) clinical trials. Phenotypic analysis of T cell and B cell composition from leukapheresis, T cell starting material, and CAR T cell product was performed by flow cytometry. Molecular characterization of T cell receptor (TCR) clonality was estimated from the T cell starting material and CAR T cell product through transcriptional profiling. Results Liso-cel manufacturing process optimizations have been implemented in advance of commercialization. These optimizations have significantly improved process duration consistency (Figure 1; F test P=4.1×10−36). Both phenotypic and molecular TCR clonality analyses demonstrated a significant reduction in terminally differentiated CD8+ T cells across the manufacturing process. Frequencies of CD45RA+ CCR7− populations were measured by flow cytometry in CD8+ T cell starting material (median=35.1%) and CAR T cell product (median=11.7%; Wilcoxon rank sum P=3.1×10−25). Characterization of TCR clonality showed a significant decrease in clonality in the CAR T cell product compared with T cell starting material (Wilcoxon rank sum P=5.6×10−6), suggesting selective expansion of clonally diverse, less differentiated T cell populations. These findings are supported by the predominant memory T cell composition observed in liso-cel. Manufacturing process robustness enabled by in-process T cell selection is further demonstrated by the capability to produce highly pure T cell products across heterogeneous patient populations and different disease indications. T cell and B cell composition were characterized in the leukapheresis, selected T cell material, and CAR T cell product, demonstrating consistent clearance of non-T cells, including CD19+ B cells in both B- cell NHL and CLL/SLL patient cohorts. Although the CD19+ B cell composition is significantly higher in leukapheresis from patients with CLL/SLL (median=10.0% of leukocytes) compared with B cell NHL patients (median=0.0% of leukocytes, Wilcoxon rank sum P=1.6×10−9), CAR T cell products manufactured from both CLL/SLL and B cell NHL patient populations consistently demonstrated clearance of non-T cells, including CD19+ cells, to below levels of quantitation. Conclusion Despite variation between B cell NHL and CLL/SLL patient leukapheresis, T cell enrichment before activation and transduction enables consistent downstream process performance and T cell purity, and a substantially reduced risk of transducing residual tumor cells. In addition, the reduction of terminally differentiated effector T cells and capacity to retain T cell diversity further improved consistency in product quality. Taken together, process modifications have enabled consistent manufacturing duration and quality of liso-cel product, which support operational efficiency and scalability for commercial production. Disclosures Teoh: Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Johnstone:Juno Therapeutics, a Celgene Company: Employment, Patents & Royalties: Author on a number of patent applications and invention disclosures relating to cell therapy and immunosequencing. Christin:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Yost:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Haig:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Mallaney:Juno Therapeutics, a Celgene Company: Employment. Radhakrishnan:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Gillenwater:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Albertson:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Guptill:Juno Therapeutics, a Celgene Company: Employment.…
Proceedings of the Society for Experimental Biology and Medicine, Dec 1, 1999
Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this... more Estrogens are widely regarded as beneficial to arterial wall health. Among the mechanisms of this benefit are antioxidant effects on LDL and the arterial wall. Because progestins oppose the effect of estrogen in several systems, we asked if progestins oppose the antioxidant effect of estrogen. To study this question, LDL and various female sex hormones were incubated alone and combined in the absence or presence of bovine aortic endothelial cells, placental trophoblast, or macrophages, and LDL oxidation and cytotoxicity were quantitated. In the absence of cells, LDL incubated with copper in phosphate-buffered saline enhanced the oxidation of LDL. When 17-estradiol was added to this system, an antioxidant effect was observed. Progestins inhibited this protective estrogenic effect. In endothelial cell culture, progestins also opposed the antioxidant effect of estrogen, with the strongest antiestrogenic effect seen with the synthetic progestins, levonorgestrel and medroxyprogesterone acetate (MPA). Endothelial cell cytotoxicity was proportional to the enhanced lipid peroxide formation observed with progestins or estrogen. Similar opposing effects were seen when estrogen and progesterone were added to primary cultures of placental trophoblast or macrophages. Thus, three cell culture systems modeling circulating arterial blood contact with cell surfaces demonstrated opposing effects of estrogens and progestins on LDL oxidation and cell cytotoxicity. These studies are in keeping with published reports that female sex steroids influence LDL oxidation in vivo and consequent arterial wall injury.
Cancer, Sep 17, 2002
BACKGROUND. This Phase II multicenter, open-label, single-arm study evaluated the efficacy and sa... more BACKGROUND. This Phase II multicenter, open-label, single-arm study evaluated the efficacy and safety of a three-drug combination of irinotecan (CPT-11), paclitaxel, and carboplatin in advanced nonsmall cell lung carcinoma (NSCLC). METHODS. Patients received repeated 21-day cycles at starting doses of paclitaxel 175 mg/m 2 administered over 3 hours, followed by carboplatin AUC of 5 over 30 minutes and CPT-11 at a starting dose level of 100 mg/m 2 over 90 minutes, all given on the first day of each cycle. Patients were evaluated for objective tumor response, time to tumor progression (TTP), survival, and safety. RESULTS. Forty patients were enrolled. Baseline patient characteristics included: median age 58 years (range, 32-79); 23 males and 17 females; performance status of 0 (21 patients), 1 (18 patients), or 2 (1 patient); and Stage IIIB (10 patients) and Stage IV (30 patients) disease. A median of six cycles (range, one to eight) were administered. Grade 3-4 toxicities observed in Ն 10% of the patients included neutropenia (78%), asthenia (20%), diarrhea (20%), nausea (18%), vomiting (13%), anemia (10%), and dyspnea (10%). Febrile neutropenia occurred in eight patients (20%), with one death due to neutropenic sepsis. Twelve of 38 evaluable patients had confirmed tumor responses (32%), while 21 (55%) had stable disease (including 12 patients [32%] with minor responses). Only 13% had disease progression at their initial tumor assessment. The median TTP and survival were 5.3 months (range, 0.03-6.2 months) and 12.5 months (range 0.3-28.6ϩ months), respectively. The one and two year survival probabilities were 0.50 (95% confidence interval [CI], 0.28-0.73) and 0.21 (95% CI, 0.0-0.67), respectively. CONCLUSIONS. The combination of CPT-11, paclitaxel, and carboplatin can be safely administered and is active in the treatment of advanced NSCLC. Based on the favorable survival outcome, this regimen is undergoing evaluation in prospective randomized trials.
Journal of Clinical Oncology, May 20, 2012
e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavail... more e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.
Blood, Mar 24, 2022
Liso-cel was associated with manageable toxicities and rapid and deep responses in patients with ... more Liso-cel was associated with manageable toxicities and rapid and deep responses in patients with relapsed/ refractory CLL/SLL. With successful manufacturing of lisocel for patients with CLL/SLL and the encouraging phase 1 results, a phase 2 study is underway. Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard-or high-risk features treated with 3 or 2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 3 10 6 or 100 3 10 6 CAR 1 T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 3 10 6 CAR 1 T cells. This trial was registered at clinicaltrials.gov as NCT03331198.
Blood, Nov 5, 2020
Background: Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, defined com... more Background: Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Liso-cel is being studied in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the ongoing, open-label, phase 1/2 TRANSCEND CLL 004 study (NCT03331198). Here, we report outcomes of patients in the phase 1 monotherapy cohort after a median follow-up of 18 months (mo). Methods: Eligible patients had received ≥3 (standard-risk disease) or ≥2 (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) lines of prior therapy, including a Bruton tyrosine kinase inhibitor (BTKi) unless contraindicated. Patients with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter transformation were excluded. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received liso-cel infusion at 1 of 2 dose levels (DLs): 50 × 106 (DL1) or 100 × 106 (DL2) CAR+ T cells. Dose-limiting toxicities were evaluated for 28 days postinfusion. Responses were assessed using 2018 International Workshop on CLL criteria. Minimal residual disease (MRD) was assessed in blood by flow cytometry and/or in bone marrow (BM) by next-generation sequencing (both with a sensitivity of ≤10-4). Persistence of liso-cel was monitored by quantitative polymerase chain reaction. Results: Overall, 23 and 22 patients were evaluable for safety and efficacy, respectively. Median age was 66 (range, 49‒79) years, median number of prior therapies was 6 (range, 3‒13), and 83% of patients (n=19/23) had high-risk disease. All patients (N=23) had received prior ibrutinib, with 91% (n=21) refractory to, or who relapsed on, ibrutinib and 9% (n=2) who were intolerant to ibrutinib; overall, 48% (n=11) were refractory to both a prior BTKi and venetoclax. The safety profile was similar to that previously reported; no late or delayed adverse events of concern have emerged with the longer follow-up (Table). Among the 22 efficacy-evaluable patients, overall response rate (ORR; complete response [CR]/CR with incomplete blood count recovery [CRi] + partial response) was 82% (n=18); the CR/CRi rate was 45% (n=10). By Day 30, 68% of patients (n=15) achieved an overall response. At 15 mo and 18 mo, 53% (n=10/19; 6 CRs) and 50% (n=7/14; 5 CRs) of patients maintained their responses, respectively. At a median follow-up of 18 mo, the median duration of response was not reached (NR) in patients who had achieved a response to liso-cel (n=18), and median progression-free survival was 18 mo (95% CI, 3.0-NR) in all efficacy-evaluable patients. Two patients who completed the study maintained their response through 24 mo on study and have enrolled in a long-term follow-up study. Five of 8 patients who progressed had Richter transformation. The subgroup of patients refractory to both a prior BTKi and venetoclax had a similar ORR compared with the total evaluable population, with a CR rate of 60% (n=6/10; Table). Of 20 MRD-evaluable patients, 15 (75%) had undetectable MRD (uMRD) in the blood, 13 (87%) of whom also had uMRD in the BM, with most (60%) achieving uMRD in the BM by Day 30. Preliminary data show that liso-cel was detectable in the blood for up to 18 mo postinfusion in 4 (36%) of 11 patients. Conclusions: Liso-cel treatment resulted in a high rate of uMRD in this heavily pretreated, high-risk population of patients with R/R CLL/SLL, including those refractory to both a BTKi and venetoclax. Responses were rapid and durable, with liso-cel detectable for up to 18 mo postinfusion. No late or delayed adverse events of concern emerged with longer follow-up. The phase 2 monotherapy expansion of the study is currently enrolling at DL2. Disclosures Siddiqi: AstraZeneca: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; PCYC: Membership on an entity's Board of Directors or advisory committees; Astrazenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy. Soumerai:Genentech/Roche: Research Funding; BostonGene: Research Funding; Beigene: Consultancy, Research Funding; GlaxoSmithKine: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy;…
Cancer Chemotherapy and Pharmacology, May 14, 2001
Carboplatin is frequently dosed to achieve a desired area under the plasma concentrationtime curv... more Carboplatin is frequently dosed to achieve a desired area under the plasma concentrationtime curve (AUC) by using the Calvert or Chatelut equations to estimate carboplatin clearance. Accurate determination of glomerular ®ltration rate (GFR) is necessary to correctly calculate carboplatin clearance using the Calvert equation. In clinical practice, the Cockcroft-Gault formula is frequently used to estimate GFR, but this practice has been reported to under-and overestimate carboplatin clearance. The purpose of this trial was to compare determinations of carboplatin clearance using the Chatelut equation and four separate GFR determinations, including 99m Tc-DTPA, the Cockcroft-Gault formula, a 24-h urine collection and a 2-h urine collection. Methods: Carboplatin clearance was estimated in 21 previously untreated extensive-stage small-cell lung cancer patients. GFR was determined using 99m Tc-DTPA, the Cockcroft-Gault formula, 24-h urine collection and 2-h urine collection. Serum and urine creatinine concentrations were measured using enzymatic assays. The carboplatin clearance was then calculated by individually adding 25 to the four GFR determinations based on the Calvert equation, which states that carboplatin clearance equals GFR+25 (nonrenal clearance). The carboplatin clearance was also estimated using the Chatelut equation. The ®ve determinations of carboplatin clearance were compared using Friedman's test and post-hoc Wilcoxon signed rank tests. Precision and bias for each carboplatin clearance determination were calculated assuming that 99m Tc-DTPA provided the most accurate measure of GFR. Results: A statistically signi®cant dierence was found between the ®ve methods of estimating carboplatin clearance (P<0.001). No dierence was found between carboplatin clearance calculated using 99m Tc-DTPA and the Chatelut equation, the Cockcroft-Gault formula or the 2-h urine collection. The Chatelut equation provided more precision and less bias than the 2-h urine collection (median precision 20% and 30%, median bias ±1% and ±18%, respectively). Conclusion: Compared to 99m Tc-DTPA, the Chatelut equation more accurately estimates carboplatin clearance than the Cockcroft-Gault formula, the 2-h urine collection and the 24-h urine collection. The greater negative bias found for the latter three estimates of carboplatin clearance could result in underdosing of carboplatin.
Investigational New Drugs, Feb 29, 2016
Purpose To determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, a... more Purpose To determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, and pharmacokinetic and pharmacodynamic profiles of the tripeptide epoxyketone proteasome inhibitor oprozomib in patients with advanced refractory or recurrent solid tumors. Methods Patients received escalating once daily (QD) or split doses of oprozomib on days 1-5 of 14-day cycles (C). The split-dose arm was implemented and compared in fasted (C1) and fed (C2) states. Pharmacokinetic samples were collected during C1 and C2. Proteasome inhibition was evaluated in red blood cells and peripheral blood mononuclear cells. Results Forty-four patients (QD, n = 25; split dose, n = 19) were enrolled. The most common primary tumor types were non-small cell lung cancer (18 %) and colorectal cancer (16 %). In the 180-mg QD cohort, two patients experienced DLTs: grade 3 vomiting and dehydration; grade 3 hypophosphatemia (n = 1 each). In the split-dose group, three DLTs were observed (180-mg cohort: grade 3 hypophosphatemia; 210-mg cohort: grade 5 gastrointestinal hemorrhage and grade 3 hallucinations (n = 1 each). In the QD and split-dose groups, the MTD was 150 and 180 mg, respectively. Common adverse events (all grades) included nausea (91 %), vomiting (86 %), and diarrhea (61 %). Peak concentrations and total exposure of oprozomib generally increased with the increasing dose. Oprozomib induced dose-dependent proteasome inhibition. Best response was stable disease. Conclusions While generally low-grade, clinically relevant gastrointestinal toxicities occurred frequently with this oprozomib formulation. Despite dose-dependent increases in pharmacokinetics and pharmacodynamics, single-agent oprozomib had minimal antitumor activity in this patient population with advanced solid tumors.
Journal of Clinical Oncology, Feb 1, 2008
Purpose-Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PD... more Purpose-Aberrant vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) signaling have been shown to play a role in non-small-cell lung cancer (NSCLC) pathogenesis and are associated with decreased survival. We evaluated the clinical activity and
Lancet Oncology, 2016
Background Bortezomib with dexamethasone is a standard treatment option for relapsed or refractor... more Background Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfi lzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfi lzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Methods In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfi lzomib with dexamethasone (carfi lzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratifi ed by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfi lzomib (20 mg/m² on days 1 and 2 of cycle 1; 56 mg/m² thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1•3 mg/m²; intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866.
Lung Cancer, Jun 1, 2006
Phase III trials in elderly patients with advanced (stage IIIB/IV) non-small cell lung cancer (NS... more Phase III trials in elderly patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) reveal treatment with single agent chemotherapy improves survival. The role of double agent therapy in this patient population is an area of investigation.
Seminars in Radiation Oncology, 2002
For limited-stage small cell lung cancer, twice-daily radiation with concurrent chemotherapy impr... more For limited-stage small cell lung cancer, twice-daily radiation with concurrent chemotherapy improves survival rate, but has dose-limiting esophageal toxicity. The authors studied 34 patients treated with amifostine in an attempt to decrease the incidence and grade of esophagitis. The results indicate that there was no reduction in toxicity, but the authors were able to maintain the high complete response rate that had been reported previously. These results differ from the use of amifostine in non-small cell lung cancer in which there is the observation of esophageal protection.
Cancer Chemotherapy and Pharmacology, Mar 13, 2003
Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve ... more Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors. A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1. Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05). Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.
Cancer Investigation, 1999
Advanced metastatic non-small cell lung cancer (NSCLC) that has progressed on initial cisplatin-b... more Advanced metastatic non-small cell lung cancer (NSCLC) that has progressed on initial cisplatin-based chemotherapy has a poor prognosis. Although paclitaxel is an active agent in the first-line therapy of NSCLC, 24-hr infusion of paclitaxel in patients with NSCLC failing first-line cisplatin-based regimens has shown minimal activity. Prolonged infusions of paclitaxel have shown activity in breast cancer patients who have failed short infusions of paclitaxel. In this study, 13 patients with refractory NSCLC who progressed on or after initial chemotherapy were treated with 96-hr paclitaxel (140 mg/m2 over 96 hr every 3 weeks) infusions as outpatients using a CADD infusion pump via a central catheter. Nine patients received only one or two cycles of treatment because of disease progression and had a median survival of 3 months (range, 1-5 months). Four patients had stabilization of disease for two to six cycles of treatment and had a median survival of 8 months (range, 8-12+ months). Grade 3-4 hematologic and nonhematologic toxicity occurred in &lt; 10% of cycles, and no treatment-related hospitalizations occurred. Quality of life (QOL) assessments using the Functional Assessment of Cancer Therapy-Lung questionnaire were performed at baseline and with each treatment cycle. In conclusion, although no objective responses were seen, disease stabilization occurred in 31% of patients. Overall toxicity was tolerable with no major negative impact on QOL in those patients receiving two or more cycles of treatment.
Lung Cancer, Mar 1, 2005
Gemcitabine and paclitaxel both have significant single agent activity in non-small cell lung can... more Gemcitabine and paclitaxel both have significant single agent activity in non-small cell lung cancer (NSCLC). Because both are cell cycle and phase specific in their mechanism of action, frequent exposure should optimize activity. Phase I data support that gemcitabine is maximally converted to the active metabolite when it is infused at a rate of 10 mg/(m2 min). Based on this, we designed a phase II trial to examine gemcitabine 800 mg/m2 infused over 80 min with paclitaxel 110 mg/m2 infused over 3 h both on days 1, 8 and 15 every 28 days as first line therapy in patients with advanced NSCLC. The primary objectives were to assess the response rate, toxicity and survival of the combination in advanced NSCLC. Secondary objectives were to determine the effect of paclitaxel on the pharmacokinetic (PK) distribution of gemcitabine, the ability to achieve a concentration of 10-20 microM when gemcitabine was infused at a rate of 10 mg/(m2 min), as well as to assess the quality of life (QOL) with the functional assessment of cancer therapy-lung (FACT-L) questionnaire. Patients with NSCLC, no prior treatment, ECOG performance status (PS) 0-1, adequate bone marrow, renal, and hepatic function were eligible for this trial. Paclitaxel 110 mg/m2 was infused over 3 h, followed by gemcitabine 800 mg/m2 infused over 80 min on days 1, 8, and 15 every 28 days for the first 2 patients, and then amended to days 1 and 8 every 21 days after the first 2 patients required day 15 dose omissions due to myelosupression. Thirty-nine patients were treated. Nine PS = 0; 28 PS = 1; Stage IIIB = 3, Stage IV = 36; median age 62 (range: 39-77). A median of six cycles (range: 0-10) was delivered. Grade 3-4 toxicities observed in &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =10% of patients included leucopenia in 26%, neutropenia in 28%, dyspnea in 13%, febrile neutropenia in 3% (1 patient). Fourteen of 39 (35%, 95% CI: 21-53%) patients had a partial response (PR), 14 of 39 (35%, 95% CI: 21-53%) had stable disease (SD) and 5 patients (13%, 95% CI: 4-27%) had progressive (PD). Median survival was 10.4 months (95% CI: 5.3-13.6). One-and two-year survival rates were 35% (95% CI: 21-53%) and 5% (95% CI: 0.6-17%), respectively. QOL as measured by the FACT-L and the trial outcome index (TOI) did not change significantly from baseline over the course of therapy. Paclitaxel and gemcitabine is an active and well-tolerated combination in advanced NSCLC. Patients on this trial had no significant change in their QOL as assessed by the FACT-L questionnaire.
Cancer Investigation, 2005
Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carbop... more Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.
Blood, Nov 16, 2012
Abstract 203 Background: Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (... more Abstract 203 Background: Oprozomib (OPZ, formerly ONX 0912), a structural analog of carfilzomib (CFZ), is an orally bioavailable, next-generation proteasome inhibitor being evaluated in hematologic malignancies and solid tumors. Similar to CFZ, OPZ is a potent, selective, and irreversible proteasome inhibitor. In an earlier dose-escalation study of once-daily (QD) OPZ in patients with advanced refractory solid tumors, the maximum tolerated dose (MTD) was 150 mg QD, leading to exploration of a split-dose schedule with the drug administered twice daily (BID). The present phase 1 study (NCT01416428) is evaluating OPZ administered using the split-dose schedule in patients with hematologic malignancies. Methods: This is an ongoing, phase 1b, open-label, dose-escalation study of OPZ in patients with hematologic malignancies. The primary objectives are to evaluate safety and tolerability and to determine the MTD. Secondary objectives of the study include pharmacokinetic and pharmacodynamic analyses. OPZ is administered PO on days 1–5 of a 14-day cycle using a standard 3 + 3 dose-escalation scheme. Treatment was initiated at 120 mg (60 mg BID), with an interval of 4–6 h between doses, with escalation in 30-mg increments in successive cohorts until MTD is determined. Tumor response is assessed by investigator. Results: As of June 15, 2012, 9 patients have been enrolled in the study, 3 in each of the 120-mg, 150-mg, and 180-mg dosing cohorts. No dose-limiting toxicities have been observed. Enrollment is ongoing at 210 mg/day. The median age of all patients is 67 years (range 53−81) and prior therapies included a median of 4 chemotherapy regimens (range 2−8). Patients have received a median of 5 cycles of treatment with OPZ, including 4 patients who have received ≥6 cycles. Dose reduction was required by only 1 patient in the 180-mg (90 mg BID) group for Grade 3 diarrhea and abdominal pain. Gastrointestinal (GI) AEs predominantly of Grade 1/2 in severity were the most common, with diarrhea and nausea each occurring in 7 patients, and vomiting occurring in 6 patients. The majority of GI AEs improved or resolved with concomitant medications. Thrombocytopenia was the only Grade 3/4 AE reported in more than 1 patient, occurring in 3 patients (1 at each dose level). Notably, no events of peripheral neuropathy were noted in patients in the first 3 dosing cohorts. AEs led to discontinuation in 2 patients at the 180-mg dose level, and no deaths have been reported. OPZ showed dose-dependent exposure across the 120- to 180-mg dose levels. Patients receiving split dosing had similar total exposure and lower Cmax than patients receiving QD dosing of the same total daily dose, although there was high inter-patient variability. Dose-dependent proteasome inhibition was observed in whole blood and increased from the first to the second of the split daily doses. Proteasome inhibition levels were similar to those achieved with single-dose equivalents and were &gt;80% at the 180-mg dose level. Eight of 9 patients are evaluable for efficacy. There was preliminary evidence of anti-tumor activity of ≥SD across all doses, including 1 patient with chronic lymphocytic leukemia who attained a PR after prior exposure to 3 lines of therapy, and 1 PR and 1 MR in patients with multiple myeloma. Conclusions: Oral OPZ was generally well tolerated using a split-dose schedule in this phase 1 trial in patients with hematologic malignancies. AEs were generally mild and manageable. An MTD has not been reached at cumulative doses up to 180 mg/d (90 mg BID). Dose-dependent proteasome inhibition was observed, with &gt;80% inhibition at the highest dose tested. OPZ also demonstrated encouraging clinical activity across the first 3 dose levels in heavily pretreated patients. Dose escalation will continue until the MTD is reached, with planned phase 2 expansion at the MTD in patients with hematologic malignancies. Disclosures: Off Label Use: Oprozomib is in Phase 1 clinical trials for hematologic malignancies and is not approved by the FDA for any use. Lee:Onyx Pharmaceuticals: Employment. Wong:Onyx Pharmaceuticals: Employment. Lee:Onyx Pharmaceuticals: Employment. Gillenwater:Onyx Pharmaceuticals: Employment. Siegel:Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau.
Blood, Dec 3, 2015
This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication... more This is a PDF file of an unedited peer-reviewed manuscript that has been accepted for publication. NPG are providing this early version of the manuscript as a service to our customers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
Blood, Dec 3, 2015
Introduction: Single-agent carfilzomib has previously shown activity in patients with relapsed an... more Introduction: Single-agent carfilzomib has previously shown activity in patients with relapsed and refractory multiple myeloma (MM) who have high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). In the randomized phase 3 study ENDEAVOR (NCT01568866; N=929), carfilzomib plus dexamethasone (Kd) demonstrated a clinically meaningful and statistically significant 2-fold improvement in median progression-free survival (PFS) compared with bortezomib plus dexamethasone (Vd; 18.7 vs 9.4 months; hazard ratio [HR]: 0.53; 95% confidence interval [CI]: 0.44-0.65; P&lt;.0001) (Dimopoulos et al, J Clin Oncol 2015;33:abstr 8509; Dimopoulos et al, Haematologica 2015;100[s1]:abstr LB2071). Herein we present results of a preplanned subgroup analysis of the efficacy and safety of Kd vs Vd in the ENDEAVOR study based on baseline cytogenetic risk status. Methods: Adult patients with relapsed MM (RMM; 1-3 prior lines of therapy) were eligible. Patients in the Kd arm received carfilzomib (30-minute intravenous [IV] infusion) on days 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle. Patients in the Vd arm received bortezomib 1.3 mg/m2 (IV bolus or subcutaneous injection) on days 1, 4, 8, and 11 and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of a 21-day cycle. Cycles were repeated until disease progression, withdrawal of consent, or unacceptable toxicity. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), rate of grade ≥2 peripheral neuropathy (PN), and safety. Fluorescence in situ hybridization was used to assess cytogenetic risk status. The high-risk group was defined as those patients with the genetic subtypes t(4;14) or t(14;16) in ≥10% of screened plasma cells, or deletion 17p in ≥20% of screened plasma cells based on central review of bone marrow samples obtained at study entry; the standard-risk group consisted of patients without these genetic subtypes. Results: A total of 929 patients were randomized (Kd: 464; Vd: 465). Baseline cytogenetic risk status was well-balanced between the treatment arms (high-risk: Kd, 20.9%; Vd, 24.3%; standard-risk: Kd, 61.2%; Vd, 62.6%; unknown: Kd, 17.9%; Vd, 13.1%). Efficacy end points by baseline cytogenetic risk status are presented in the Table; Kaplan-Meier PFS curves by baseline cytogenetic risk status are shown in the Figure. Median PFS in the high-risk group (n=210) was 8.8 months (95% CI: 6.9-11.3) for Kd vs 6.0 months (95% CI: 4.9-8.1) for Vd (HR: 0.646; 95% CI: 0.453-0.921). Median PFS in the standard-risk group (n=575) was not estimable for Kd (95% CI: 18.7-not estimable) vs 10.2 months (95% CI: 9.3-12.2) for Vd (HR: 0.439; 95% CI: 0.333-0.578). ORRs (≥partial response) were 72.2% (Kd) vs 58.4% (Vd) in the high-risk group and 79.2% (Kd) vs 66.0% (Vd) in the standard-risk group. In the high-risk group, 15.5% (Kd) vs 4.4% (Vd) achieved a complete response (CR) or better. In the standard-risk group, 13.0% (Kd) vs 7.9% (Vd) achieved ≥CR. Median DOR in the high-risk group was 10.2 months for Kd vs 8.3 months for Vd. Median DOR in the standard-risk group was not estimable for Kd vs 11.7 months for Vd. Grade ≥3 adverse events (AEs) were reported at higher rates with Kd vs Vd in the high- and standard-risk groups (70.1% vs 63.1% and 73.9% vs 68.3%). Rates of grade ≥3 AEs of interest by baseline cytogenetic risk status are shown in the Table. Grade ≥2 PN was reported at lower rates with Kd vs Vd in the high-risk group (3.1% vs 35.1%; odds ratio: 0.059; 95% CI: 0.018-0.198) and also in the standard-risk group (6.4% vs 33.4%; odds ratio: 0.135; 95% CI: 0.079-0.231). Conclusion: As expected, median PFS for patients with high-risk cytogenetics was lower compared with the overall population; however, patients treated with Kd had a clinically meaningful improvement in PFS compared with Vd in patients with high- or standard-risk cytogenetics. Higher response rates, a greater depth of response, and longer DOR were also observed with Kd vs Vd across cytogenetic subgroups. Kd had a favorable benefit-risk profile in patients with high-risk relapsed MM, and was superior to Vd, regardless of baseline cytogenetic risk status. Disclosures Goldschmidt: BMS: Consultancy, Research Funding; Amgen, Takeda: Consultancy; Onyx: Consultancy, Honoraria; Janssen, Celgene, Novartis: Consultancy, Honoraria, Research Funding; Chugai, Millennium: Honoraria, Research Funding. Dimopoulos:Onyx: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Genesis: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Moreau:Novartis, Janssen, Celgene, Millennium, Onyx Pharmaceuticals: Consultancy, Honoraria. Joshua:Celgene: Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals,…
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