ABSTRACT
BACKGROUND: Zolbetuximab, a monoclonal antibody targeting claudin-18 isoform 2 (CLDN18.2), has shown efficacy in patients with CLDN18.2-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. We report the results of the SPOTLIGHT trial, which investigated the efficacy and safety of first-line zolbetuximab plus mFOLFOX6 (modified folinic acid [or levofolinate], fluorouracil, and oxaliplatin regimen) versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. METHODS: SPOTLIGHT is a global, randomised, placebo-controlled, double-blind, phase 3 trial that enrolled patients from 215 centres in 20 countries. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥75% of tumour cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, with radiologically evaluable disease (measurable or non-measurable) according to Response Evaluation Criteria in Solid Tumors version 1.1; an Eastern Cooperative Oncology Group performance status score of 0 or 1; and adequate organ function. Patients were randomly assigned (1:1) via interactive response technology and stratified according to region, number of organs with metastases, and previous gastrectomy. Patients received zolbetuximab (800 mg/m2 loading dose followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 (every 2 weeks) or placebo plus mFOLFOX6. The primary endpoint was progression-free survival assessed by independent review committee in all randomly assigned patients. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03504397, and is closed to new participants. FINDINGS: Between June 21, 2018, and April 1, 2022, 565 patients were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (283 patients; the zolbetuximab group) or placebo plus mFOLFOX6 (282 patients; the placebo group). At least one dose of treatment was administered to 279 (99%) of 283 patients in the zolbetuximab group and 278 (99%) of 282 patients in the placebo group. In the zolbetuximab group, 176 (62%) patients were male and 107 (38%) were female. In the placebo group, 175 (62%) patients were male and 107 (38%) were female. The median follow-up duration for progression-free survival was 12·94 months in the zolbetuximab group versus 12·65 months in the placebo group. Zolbetuximab treatment showed a significant reduction in the risk of disease progression or death compared with placebo (hazard ratio [HR] 0·75, 95% CI 0·60-0·94; p=0·0066). The median progression-free survival was 10·61 months (95% CI 8·90-12·48) in the zolbetuximab group versus 8·67 months (8·21-10·28) in the placebo group. Zolbetuximab treatment also showed a significant reduction in the risk of death versus placebo (HR 0·75, 95% CI 0·60-0·94; p=0·0053). Treatment-emergent grade 3 or worse adverse events occurred in 242 (87%) of 279 patients in the zolbetuximab group versus 216 (78%) of 278 patients in the placebo group. The most common grade 3 or worse adverse events were nausea, vomiting, and decreased appetite. Treatment-related deaths occurred in five (2%) patients in the zolbetuximab group versus four (1%) patients in the placebo group. No new safety signals were identified. INTERPRETATION: Targeting CLDN18.2 with zolbetuximab significantly prolonged progression-free survival and overall survival when combined with mFOLFOX6 versus placebo plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma. Zolbetuximab plus mFOLFOX6 might represent a new first-line treatment in these patients. FUNDING: Astellas Pharma, Inc.
Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , Male , Female , Antibodies, Monoclonal, Humanized/adverse effects , Stomach Neoplasms/pathology , Esophagogastric Junction/pathology , Antibodies, Monoclonal/adverse effects , Adenocarcinoma/pathology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Double-Blind Method , Claudins/therapeutic useABSTRACT
Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).
Subject(s)
Aniline Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Docetaxel/adverse effects , Neoplasms/drug therapy , Sulfonamides/adverse effects , Administration, Oral , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Docetaxel/administration & dosage , Docetaxel/pharmacokinetics , Drug Administration Schedule , Fatigue/chemically induced , Fatigue/epidemiology , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Nausea/epidemiology , Neutropenia/chemically induced , Neutropenia/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiologyABSTRACT
The oral BCL2 inhibitor navitoclax has moderate single-agent efficacy in chronic lymphocytic leukaemia (CLL) and minor activity in lymphoma in Phase 1 trials. Navitoclax synergizes with rituximab in preclinical models of B-cell lymphoid cancers. We report the safety, pharmacokinetics and clinical activity of this combination. Patients received navitoclax (200-325 mg) daily and four standard weekly doses of rituximab. Twenty-nine patients were enrolled across three dose-escalation cohorts and a safety expansion cohort (250 mg/d navitoclax). The combination was well tolerated. Common toxicities were mild diarrhoea (79%) and nausea (72%). Grade 4 thrombocytopenia occurred in 17% of patients (dose limiting at 325 mg/d). CD19(+) counts were severely reduced, while CD3(+) cells (~ 20%) and serum immunoglobulin M levels (~ 33%) were also reduced during the first year. The maximum tolerated dose for navitoclax in combination was 250 mg/d. Pharmacokinetic analyses revealed no apparent interactions between the drugs. The response rate in patients with follicular lymphoma was 9/12, including five complete responses. All five patients with CLL/small lymphocytic leukaemia achieved partial responses. One of nine patients with aggressive lymphoma responded. The addition of rituximab to navitoclax 250 mg/d is safe; the combination demonstrates higher response rates for low-grade lymphoid cancers than observed for either agent alone in previous Phase 1 trials.
Subject(s)
Antigens, CD20 , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Lymphoma, Follicular/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antibodies, Monoclonal, Murine-Derived/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/blood , Lymphoma, Follicular/blood , Male , Middle Aged , Rituximab , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/pharmacokineticsABSTRACT
Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, potent, orally bioavailable, small molecule Bcl-2 inhibitor. Primary endpoints assessed the safety and pharmacokinetic (PK) interactions between navitoclax in combination with carboplatin/paclitaxel or paclitaxel alone in patients with solid tumors The study comprised two arms, one a combination of navitoclax with paclitaxel and carboplatin, the second with navitoclax and paclitaxel alone. Nineteen patients were enrolled in this study. The most frequently reported treatment-emergent AEs were alopecia (57.9 %), anemia (52.6 %), nausea (52.6 %), constipation (42.1 %), diarrhea (42.1 %), fatigue (42.1 %), neutropenia (36.8 %), thrombocytopenia (36.8 %), vomiting (31.6 %), decreased appetite (31.6 %), dehydration (26.3 %), and hypomagnesaemia (26.3 %). In the light of significant hematological and non-hematological toxicity the study was ended before de-escalation of navitoclax. Only one partial response was obtained at any dose tested, thus lowering doses could not have increased efficacy. It is the combination of toxicity with modest efficacy that led to discontinuation. No apparent PK interaction was observed between navitoclax and carboplatin or paclitaxel and the combination of navitoclax and paclitaxel had modest anti-tumor activity.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Aniline Compounds/administration & dosage , Aniline Compounds/blood , Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/blood , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carboplatin/administration & dosage , Carboplatin/blood , Carboplatin/pharmacokinetics , Female , Humans , Male , Middle Aged , Neoplasms/blood , Paclitaxel/administration & dosage , Paclitaxel/blood , Paclitaxel/pharmacokinetics , Sulfonamides/administration & dosage , Sulfonamides/blood , Sulfonamides/pharmacokinetics , Treatment OutcomeABSTRACT
PURPOSE: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. EXPERIMENTAL DESIGN: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: navitoclax administered orally on days 1-3 and 8-10,; and gemcitabine 1,000 mg/m(2) on days 1 and 8; 28-day dosing schedule: navitoclax administrated orally on days 1-3, 8-10, and 15-17; and gemcitabine 1,000 mg/m(2) on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of navitoclax. RESULTS: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m(2) for the 21-day schedule. No clinically significant pharmacokinetic drug-drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). CONCLUSIONS: The combination of navitoclax 325 mg with gemcitabine 1,000 mg/m(2) was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Aniline Compounds/blood , Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/blood , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/analogs & derivatives , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/blood , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sulfonamides/blood , Sulfonamides/pharmacokinetics , Treatment Outcome , GemcitabineABSTRACT
A recent industry perspective published in this journal describes the benefits received by drug companies from participation in the MIDD Pilot Program. Along with the primary objectives of supporting good decision-making in drug development, there were substantial savings in time and development costs. Furthermore, many sponsors reported qualitative benefits such as new learnings and clarity on MIDD strategies and methodology that could be applied to other development programs. Based on the success of the Pilot Program, the FDA recently announced the continuation of the MIDD Paired Meeting Program as part of the Prescription Drug User Fee Act (PDUFA VII). In this report, we describe the collective experiences of industry participants in the MIDD Program to date, including all aspects of the process from meeting request submission to follow-up actions. The purpose is to provide future participants with information to optimize the value of the MIDD Program.
Subject(s)
Drug Development , Drug Industry , United States Food and Drug Administration , United States , Drug Development/legislation & jurisprudence , Drug Development/methods , Humans , Drug Industry/legislation & jurisprudence , Pilot Projects , Drug ApprovalABSTRACT
PURPOSE: Zolbetuximab, an IgG1 monoclonal antibody, binds to claudin 18.2 (CLDN18.2) and mediates tumor cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. We sought to examine zolbetuximab combinations in CLDN18.2-positive HER2-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. PATIENTS AND METHODS: This phase II study assessed efficacy and safety of zolbetuximab, alone or with modified FOLFOX6 (mFOLFOX6) or pembrolizumab, in CLDN18.2-positive advanced/metastatic G/GEJ adenocarcinoma. Patients received zolbetuximab as monotherapy in third/later-line (Cohort 1A, n = 30), with mFOLFOX6 in first-line (Cohort 2, n = 21), or with pembrolizumab in third/later-line (Cohort 3A, n = 3) treatment. The primary endpoint for Cohort 1A was objective response rate (ORR). Key secondary endpoints were ORR (Cohorts 2 and 3A), overall survival (OS; Cohort 1A), and progression-free survival (PFS) and safety (all cohorts). RESULTS: ORR was 0% in Cohorts 1A and 3A, and 71.4% [95% confidence interval (CI), 47.82-88.72] in Cohort 2. Median PFS was 1.54 months (95% CI, 1.31-2.56) in Cohort 1A, 2.96 months (95% CI, 1.48-4.44) in Cohort 3A, and 17.8 months (95% CI, 8.05-25.69) in Cohort 2. Median OS in Cohort 1A was 5.62 months (95% CI, 2.27-11.53). Gastrointestinal adverse events occurred across cohorts [nausea, 63%-90% (grade ≥ 3, 4.8%-6.7%) and vomiting, 33%-67% (grade ≥ 3, 6.7%-9.5%)]. CONCLUSIONS: Zolbetuximab plus mFOLFOX6 demonstrated promising efficacy in previously untreated patients with CLDN18.2-positive G/GEJ adenocarcinoma. These data support the first-line development of zolbetuximab in patients whose tumors are CLDN18.2-positive. Across cohorts, zolbetuximab treatment was tolerable with no new safety signals.
Subject(s)
Adenocarcinoma , Antibodies, Monoclonal , Claudins , Esophageal Neoplasms , Stomach Neoplasms , Humans , Adenocarcinoma/pathology , Adenocarcinoma/therapy , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Claudins/metabolism , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophagogastric Junction/pathology , Stomach Neoplasms/pathology , Stomach Neoplasms/therapyABSTRACT
We have done a research on mathematical morphology filter in order to eliminate baseline drift in the wave of electrocardiograph (ECG). Marago morphology filter type was chosen and flat structuring element filtering was found to be the best morphology filter modality for eliminating baseline drift, and the ratio of "signal numerical frequency to length of structuring element" determined the attenuation magnitude of the signal eliminated. We have come to the conclusion that the length of flat structuring element ought to be greater than or equal to the width of the signal component to be eliminated. The arithmetical algorithm was simulated with Matlab software, and was transplanted to DSP hardware platform. The result of experiment has shown that the arithmetic operation is simple and the method spends a short time (less than 1 ms) in eliminating the baseline drift of ECG effectively and instantly.
Subject(s)
Algorithms , Artifacts , Electrocardiography/instrumentation , Signal Processing, Computer-Assisted , Electrocardiography/methods , Equipment Design , HumansABSTRACT
The paper is to report the establishment of an HPLC method for determination of the components of bitespiramycin and its products, and to evaluate the components profile of bitespiramycin and its related products. Liquid chromatography combined with mass spectrometry (LC-MS) was used to identify the nine major components of the reference substance of bitespiramycins. The nine components of bitespiramycins and its products have been quantified by HPLC with gradients elution methods. The content of the component of 4"-O-isovalerylspiramycin III was not less than 35%, the content of the components of 4"-O-isovalerylspiramycin (I + II + III) was not less than 60%, and the contents of the nine components of bitespiramycin were not less than 80%, separately. In addition to the components mentioned above, there also exists some other impurities, however, with lower contents. This gradient elution HPLC method reported by this paper is considered to be suitable for the quality control of bitespiramycin.
Subject(s)
Anti-Bacterial Agents/chemistry , Chromatography, High Pressure Liquid/methods , Spiramycin/analogs & derivatives , Chromatography, Liquid/methods , Quality Control , Spiramycin/analysis , Spiramycin/chemistry , Tandem Mass Spectrometry/methodsABSTRACT
PURPOSE: The oral Bcl-2 inhibitor navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of navitoclax plus irinotecan. METHODS: In this multicenter, open-label, phase 1 dose escalation study, adults with advanced solid tumors received navitoclax (starting dose 150 mg/day) in combination with 1 of 2 irinotecan schedules during a 21-day cycle: a once-every-3-week regimen (Q3W 180, 250, or 350 mg/m(2)) or a once-weekly regimen (QW 75 or 100 mg/m(2)). Enrollment occurred until a maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD) was reached. RESULTS: All patients (Q3W, n = 14; QW, n = 17) were evaluable for safety, PK, and efficacy. The most common adverse event in both groups was diarrhea (Q3W 92.9 %; QW 76.5 %), which was the most frequent grade 3/grade 4 adverse event (Q3W 42.9 %; QW 29.4 %). The study was amended to exclude 4 UGT1A1*28 7/7 homozygous patients due to frequent irinotecan-related grade 3/grade 4 diarrhea and/or febrile neutropenia. No apparent PK interactions between navitoclax and irinotecan were observed. The MTD of the combination was exceeded in the Q3W group at the lowest dose administered. In the QW group, the MTD and RPTD for navitoclax were 150 mg when combined with irinotecan 75 mg/m(2). One patient in each group achieved a partial response. CONCLUSION: The RPTD of navitoclax in combination with irinotecan 75 mg/m(2) QW during a 21-day cycle was 150 mg in these heavily pretreated patients.
Subject(s)
Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , Camptothecin/analogs & derivatives , Neoplasm Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Sulfonamides/pharmacokinetics , Adenocarcinoma/drug therapy , Adult , Aged , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/pharmacokinetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Diarrhea/chemically induced , Disease Progression , Dose-Response Relationship, Drug , Febrile Neutropenia/chemically induced , Female , Hematologic Diseases/chemically induced , Humans , Irinotecan , Male , Middle Aged , Neoplasms/pathology , Salvage Therapy , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Treatment OutcomeABSTRACT
OBJECTIVE: Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of navitoclax as well as the time course of the platelet counts in cancer patients receiving navitoclax. METHODS: Data from 256 patients who received oral navitoclax (dose range 10-475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell "pool", which describes a large pool of platelet progenitor cells at the beginning of navitoclax treatment. RESULTS: The PD model was able to describe a slight downward trend of platelet counts over the long-term navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies. CONCLUSIONS: We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial navitoclax administration and long-term decline of platelets after continuous administration of navitoclax.
Subject(s)
Aniline Compounds/adverse effects , Aniline Compounds/pharmacokinetics , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Thrombocytopenia/chemically induced , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Bone Marrow/drug effects , Humans , Models, Theoretical , Platelet CountABSTRACT
BACKGROUND AND AIM: Navitoclax is a targeted B-cell lymphoma-2 (Bcl-2) family protein inhibitor. The present study evaluated the effect of ketoconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor, on the pharmacokinetics of navitoclax in patients with cancer. PATIENTS AND METHODS: Eleven patients with cancer were enrolled in this Phase I study. Single doses of navitoclax at 60 mg were administered orally on days 1 and 8. Ketoconazole at 400 mg was given once daily from days 7 through 10. Blood samples were collected pre-dose through 72 h after each navitoclax dose. RESULTS: Ten patients had evaluable pharmacokinetic data and were, therefore, included in pharmacokinetic statistical analyses. The maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinite time (AUC∞) of navitoclax in the presence of ketoconazole was 94% (90% confidence interval (CI)=53165%) and 155% (90% CI=91264%), respectively of those observed with navitoclax when administered alone. The increase in navitoclax AUC∞ was primarily driven by two patients, who had 5-fold and 11-fold increases, respectively, in navitoclax AUC∞ in the presence of ketoconazole. These two participants had unusually low plasma drug exposure when navitoclax was administered alone, and their navitoclax exposure in the presence of ketoconazole increased to be within the range of the other 8 patients. There were no adverse events related to navitoclax exposure reported in these 2 patients. CONCLUSION: Co-administration of navitoclax with ketoconazole did not increase navitoclax exposure above that observed with navitoclax monotherapy and did not appear to affect its safety profile. Results suggest CYP3A does not play a major role in elimination of navitoclax.