protocol_id stringclasses 263
values | section_number stringlengths 1 12 | title stringlengths 1 1.88k | content stringlengths 0 866k | merged_titles listlengths 0 491 |
|---|---|---|---|---|
NCT02287233 | 1.1 | Protocol Amendment: Summary of Changes | 1.1 Protocol Amendment: Summary of Changes
Previous Protocol Versions | Protocol | Date | |-------------------------|------------------| | Original | 05 August 2014 | | Amendment 1 | 11 November 2015 | | Administrative Change 1 | 25 November 2015 | | Amendment 2 | 28 November 2016 | | Amendment 3 | 31 May 2017 | | Ame... | [
"Previous Protocol Versions",
"The purpose of this amendment is to:"
] |
NCT02287233 | 1.2 | Synopsis | 1.2 Synopsis | AbbVie Inc. | Protocol Number: M14-387 | |------------------------------------------------------|-----------------------------------------------| | Name of Study Drug: venetoclax(ABT-199/GDC-0199) | Phase of Development: 1/2 | | Name of Active Ingredient: ABT-199 | Date of Protocol Synopsis: 22October 20... | [
"Objectives:",
"Primary Objectives:",
"Secondary Objective:",
"Exploratory Objective:",
"Methodology:",
"Diagnosis and Main Criteria for Inclusion/Exclusion:",
"Main Inclusion:",
"Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):",
"Main Inclusion (Continued):",
"Main Exclusion:",
... |
NCT02287233 | 1.3 | List of Abbreviations and Definition of Terms | 1.3 List of Abbreviations and Definition of Terms
Abbreviations ABT-199 Study Drug Compound, "venetoclax" AE Adverse Event AESI Adverse Event of Special Interest ALL Acute Promyelocytic Leukemia ALT Alanine Aminotransferase (also called SGPT) AML Acute Myelogenous Leukemia ANC Absolute Neutrophil Count aPTT Activated ... | [
"Abbreviations",
"Pharmacokinetic and Statistical Abbreviations"
] |
NCT02287233 | 3.0 | Introduction | 3.0 Introduction
Venetoclax Activity and Preclinical Pharmacokinetic Profile Hematologic malignancies are highly dependent upon the anti-apoptotic protein Bcl-2 for survival. Over-expression of Bcl-2 is associated with tumor initiation, disease progression, and drug resistance, and is thus a compelling target for anti... | [
"Venetoclax Activity and Preclinical Pharmacokinetic Profile",
"Venetoclax Preclinical Toxicology",
"Venetoclax Clinical Data",
"Acute Myelogenous Leukemia"
] |
NCT02287233 | 3.1 | Study Rationale | 3.1 Study Rationale Currently, there is no consensus as to a single optimal therapy for older patients with AML who are not candidates for conventional induction treatment though subcutaneous low-dose cytarabine (LDC) is a common therapeutic approach. A common approach that hemato-oncologists utilize to determine fitne... | [
"1. Advanced age (over 75 years)"
] |
NCT02287233 | 3.2 | Differences Statement | 3.2 Differences Statement This is the first study of venetoclax in combination with LDC for subjects with AML. Venetoclax was tested in Phase 2 trial (Study M14-212) in subjects with relapsed, refractory AML or in a frontline setting in subjects who are unfit for intensive therapy to examine preliminary activity and sa... | [] |
NCT02287233 | 3.3 | Benefits and Risks | 3.3 Benefits and Risks Based on the venetoclax studies, the regimen is designed to escalate the dose of venetoclax rapidly and safely with a standard dose and schedule of LDC to optimize the opportunity for achieving a response and enable close subject monitoring. The dosing regimen will also enable interruptions and s... | [] |
NCT02287233 | 4.0 | Study Objective | 4.0 Study Objective The primary objectives of the Phase 1 portion are to assess the safety profile, characterize PK, determine the dose schedule, the maximum tolerated dose (MTD), and the recommended Phase 2 dose (RPTD) of venetoclax (ABT-199/GDC-0199) in combination with LDC in treatment-naïve subjects with AML who ar... | [] |
NCT02287233 | 5.0 | Investigational Plan | 5.0 Investigational Plan | [] |
NCT02287233 | 5.1 | Overall Study Design and Plan: Description | 5.1 Overall Study Design and Plan: Description This is a Phase 1/2, open-label, non-randomized, multicenter study that will evaluate the PK, safety and efficacy of orally administered venetoclax combined with LDC in treatment-naïve subjects with AML ≥ 60 years old and who are not eligible for standard induction therapy... | [
"Dosing Schedule Overview – Venetoclax – Phase 1 Portion",
"Dosing Schemas for Phase 1",
"Low-Dose Cytarabine Dosing (Phase 1 and 2)",
"Dose Escalation and Modification Guidelines for Venetoclax – Phase 1",
"Dose Escalation Guidelines",
"Transition from Phase 1 to Phase 2",
"Dosing Schema for Initial Ph... |
NCT02287233 | 5.2 | Selection of Study Population | 5.2 Selection of Study Population Subjects will undergo screening procedures within 21 days prior to initial study drug administration. Adult male and female subjects who meet the inclusion criteria and who do not meet any of the exclusion criteria will be eligible for enrollment into the study. | [] |
NCT02287233 | 5.2.1 | Inclusion Criteria | 5.2.1 Inclusion Criteria A subject will be eligible for study participation if he/she meets the following criteria within 21 days prior to the first day of therapy: - 1. Subject must be ≥ 65 years of age in Phase 1 and initial Phase 2. Subjects enrolled in Phase 2 Cohort C must be either: - ≥ 75 years of age; OR - ≥ 60... | [
"Rationale for Inclusion Criteria"
] |
NCT02287233 | 5.2.2 | Exclusion Criteria | 5.2.2 Exclusion Criteria A subject will be eligible for study participation if he/she does not meet the following criteria within 21 days prior to the first day of therapy: - 1. Subject has received treatment with cytarabine for a pre-existing myeloid disorder. - 2. Subject has acute promyelocytic leukemia (French-Amer... | [
"Rationale for Exclusion Criteria"
] |
NCT02287233 | 5.2.3 | Prior and Concomitant Therapy | 5.2.3 Prior and Concomitant Therapy If a subject reports taking any over-the-counter or prescription medications, vitamins and/or herbal supplements or if administration of any medication becomes necessary, from the Screening Visit through the end of the study, the name of the medication, dosage information including d... | [
"Table 1. Excluded and Cautionary Medications and Dietary Restrictions (See Appendix C for Examples of the Medications)",
"Excluded Foods During Ramp-Up and Throughout Study",
"Excluded Medications During Venetoclax Ramp-Up Phase and Throughout Study:",
"Cautionary",
"Table 3. Study Activities (Phases 1 and... |
NCT02287233 | 5.3.1.1 | Study Procedures | 5.3.1.1 Study Procedures All study procedures outlined in [Table](#page-54-1) 3 are discussed in detail in this section, with the exception of adverse event information (discussed in Section [6.0\)](#page-96-2). All study data will be recorded on eCRFs. Study visits may be impacted due to the COVID-19 pandemic. This ma... | [
"Informed Consent",
"Medical and Oncologic History",
"Adverse Event and Prior/Concomitant Medication Assessment",
"Physical Examination",
"Vital Signs",
"COVID-19 Pandemic-Related Acceptable Protocol Modifications",
"ECOG Performance Status",
"12-Lead Electrocardiogram (ECG)",
"COVID-19 Pandemic-Rel... |
NCT02287233 | 5.3.1.2 | Confinement | 5.3.1.2 Confinement Subjects will be hospitalized during dose escalation of venetoclax. Confinement is recommended to begin by Study Day –1 and must occur by at least Day 1 through at least 24 hours after completion of the ramp-up period for subjects in both Phase 1 and Phase 2 including Cohort C. | [] |
NCT02287233 | 5.3.1.3 | Meals and Dietary Requirements | 5.3.1.3 Meals and Dietary Requirements Each dose of venetoclax will be taken with approximately 240 mL of water within 30 minutes after the completion of a meal, preferably breakfast.  Subjects may not consume grapefruit or grapefruit products, Seville oranges (including marmalade containing Sev... | [] |
NCT02287233 | 5.3.1.4 | Blood Samples for Pharmacogenetic Analysis | 5.3.1.4 Blood Samples for Pharmacogenetic Analysis A 4 mL whole blood sample for DNA isolation will be collected on Cycle 1 Day 1, Cycle 4 Day 1, and the Final Visit. The sample collection tubes will minimally be labeled with "PG-DNA," protocol number, visit, and subject number. Pharmacogenetic collection should occur ... | [] |
NCT02287233 | 5.3.1.5 | Pharmacodynamic and Predictive Biomarker Testing | 5.3.1.5 Pharmacodynamic and Predictive Biomarker Testing
Blood Collections Whole blood will be collected into appropriately labeled tubes and processed as outlined in the most current version of Study M14-387 Laboratory Manual.
Blood Collection for Mutational Profiling: Approximately 2.5 mL for blood will be collecte... | [
"Blood Collections",
"Blood Collection for Mutational Profiling:",
"Blood Collection for Plasma",
"Blood Collection for Serum",
"Blood Collection for Ex Vivo Sensitivity and Translational Research (e.g., mutational analysis, BH3 profiling):",
"Blood Collection for Bcl-2 Family Protein Analysis",
"Bone M... |
NCT02287233 | 5.3.2 | Drug Concentration Measurements | 5.3.2 Drug Concentration Measurements | [] |
NCT02287233 | 5.3.2.1 | Collection of Samples for Analysis | 5.3.2.1 Collection of Samples for Analysis The timing of PK blood collections will take priority over all other scheduled study activities except for dosing. The order of blood collections will be maintained to the minute such that the time intervals relative to the preceding dosing will be the same for all ![](page79P... | [
"Blood Samples for Venetoclax Assay",
"Phase 1 Cohorts",
"Initial Phase 2 Cohort",
"Phase 2 Cohort C",
"Blood Samples for Cytarabine Assay"
] |
NCT02287233 | 5.3.2.2 | Handling/Processing of Samples | 5.3.2.2 Handling/Processing of Samples
Blood Samples for Venetoclax PK Assay Detailed sample collection and processing instructions for the venetoclax PK samples will be provided in the lab manual for this study.
Blood Samples for Cytarabine PK Assay Detailed sample collection and processing instructions for the cyta... | [
"Blood Samples for Venetoclax PK Assay",
"Blood Samples for Cytarabine PK Assay"
] |
NCT02287233 | 5.3.2.3 | Disposition of Samples | 5.3.2.3 Disposition of Samples The frozen plasma PK samples for venetoclax and cytarabine will be packed in dry ice sufficient to last during transport and shipped from the study site to the central lab according to instructions in the laboratory manual. An inventory of the samples included will accompany the package. ... | [] |
NCT02287233 | 5.3.2.4 | Measurement Methods | 5.3.2.4 Measurement Methods Plasma concentrations of venetoclax will be determined by the Drug Analysis Department at AbbVie using a validated method. Plasma concentrations of possible venetoclax metabolite(s) may be determined with either validated or non-validated methods. Plasma concentrations of cytarabine will be ... | [] |
NCT02287233 | 5.3.3 | Efficacy Variables | 5.3.3 Efficacy Variables
Efficacy Assessments Responses will be evaluated based on the revised guidelines by the International Working Group (IWG) for AML.[38](#page-136-0) As a significant number of the subjects in this study might have antecedent hematologic illnesses, hematologic response will also be evaluated. Tr... | [
"Efficacy Assessments",
"Reporting of Results"
] |
NCT02287233 | 5.3.4 | Safety Variables | 5.3.4 Safety Variables The following safety evaluations will be performed during the study: adverse event monitoring and vital signs, physical examination, ECG and laboratory tests assessments.  | [] |
NCT02287233 | 5.3.5 | Pharmacokinetic Variables | 5.3.5 Pharmacokinetic Variables For the intensive PK days of venetoclax, values for the PK parameters including the maximum observed plasma concentration (Cmax), the time to Cmax (peak time, Tmax), the area under the plasma concentration-time curve (AUC) from 0 to the time of the last measurable concentration (AUCt) an... | [] |
NCT02287233 | 5.3.6 | Pharmacogenetic Variables | 5.3.6 Pharmacogenetic Variables DNA samples may be sequenced, and data analyzed for genetic factors contributing to the disease or to the subject's response to venetoclax (or other study treatment) in terms of PK, efficacy, tolerability, and safety. Such genetic factors may include genes for drug metabolizing enzymes, ... | [] |
NCT02287233 | 5.3.7 | Pharmacodynamic Variables | 5.3.7 Pharmacodynamic Variables Several putative biomarkers of efficacy and response may be evaluated in this protocol with the goal of defining the relationship between drug concentration and disease status. Samples taken may be used for the assessment of specific biologic markers, including proteins and/or nucleic ac... | [] |
NCT02287233 | 5.4 | Removal of Subjects from Therapy or Assessment | 5.4 Removal of Subjects from Therapy or Assessment | [] |
NCT02287233 | 5.4.1 | Discontinuation of Individual Subjects | 5.4.1 Discontinuation of Individual Subjects Each subject has the right to withdraw from the study at any time. In addition, the investigator will discontinue a subject from the study at any time if the investigator considers it necessary for any reason including: - The investigator believes it is in the best interest ... | [
"COVID-19 Pandemic-Related Acceptable Protocol Modification"
] |
NCT02287233 | 5.4.2 | Discontinuation of Entire Study | 5.4.2 Discontinuation of Entire Study AbbVie may terminate this study prematurely, either in its entirety or at any study site, for reasonable cause provided that written notice is submitted in advance of the intended termination. The investigator may also terminate the study at his/her site for reasonable cause, after... | [
"Interruption/Discontinuation of Study Drug Due to COVID-19 Infection"
] |
NCT02287233 | 5.5 | Treatments | 5.5 Treatments | [] |
NCT02287233 | 5.5.1 | Treatments Administered | 5.5.1 Treatments Administered Study drug will be administered daily as follows: Each dose of venetoclax will be taken with approximately 240 mL of water. Subjects will be trained to self-administer venetoclax orally QD within 30 minutes after the completion of a meal, preferably breakfast. If vomiting occurs within 15 ... | [
"COVID-19 Pandemic-Related Acceptable Protocol Modifications"
] |
NCT02287233 | 5.5.2 | Identity of Investigational Products | 5.5.2 Identity of Investigational Products Information about the venetoclax and cytarabine formulations to be used in this study is presented in [Table](#page-91-4) 11. Table 11. Identity of Investigational Products | Study Drug | Trademark | Formulation | Route ofAdministration | Manufacturer | |------------|---------... | [] |
NCT02287233 | 5.5.2.1 | Packaging and Labeling | 5.5.2.1 Packaging and Labeling The venetoclax tablets will be packaged in high density polyethylene (HDPE) plastic bottles. Each bottle will be labeled per local regulatory requirements. Cytarabine will be provided as one vial per carton. Each vial and carton will be labeled per local regulatory requirements. | [] |
NCT02287233 | 5.5.2.2 | Storage and Disposition of Study Drug | 5.5.2.2 Storage and Disposition of Study Drug The venetoclax study drug must be stored at 15° to 25°C (59° to 77°F). Cytarabine must be stored at 15° to 25°C (59° to 77°F). The investigational products are for investigational use only and are to be used only within the context of this study. The study drug supplied for... | [] |
NCT02287233 | 5.5.3 | Method of Assigning Subjects to Treatment Groups | 5.5.3 Method of Assigning Subjects to Treatment Groups There is no randomization schedule for this study. Subjects will be assigned at screening a unique subject number via IRT system beginning with 30101 for the Phase 1 portion of the study. For the Phase 2 portions of the study, subjects will be assigned at screening... | [] |
NCT02287233 | 5.5.4 | Selection and Timing of Dose for Each Subject | 5.5.4 Selection and Timing of Dose for Each Subject Selection of the dose for this study is discussed in Section [5.6.4.](#page-94-2) Venetoclax will be administered orally once daily (QD) on Days 2 through Day 28 of Cycle 1 (28-day cycle) for subjects enrolled into Phase 1 and the initial Phase 2 portion. Venetoclax w... | [] |
NCT02287233 | 5.5.5 | Blinding | 5.5.5 Blinding This is an open-label study. | [] |
NCT02287233 | 5.5.6 | Treatment Compliance | 5.5.6 Treatment Compliance The investigator or his/her designated and qualified representatives will dispense study drug only to subjects enrolled in the study in accordance with the protocol. The study drug must not be used for reasons other than that described in the protocol. An interactive response system (IRT) wil... | [] |
NCT02287233 | 5.5.7 | Drug Accountability | 5.5.7 Drug Accountability The investigator or his/her representative will verify that study drug supplies are received intact and in the correct amounts. This will be documented by signing and dating the Proof of Receipt or similar document. The investigator or his/her designated representatives will administer study d... | [] |
NCT02287233 | 5.6 | Discussion and Justification of Study Design | 5.6 Discussion and Justification of Study Design | [] |
NCT02287233 | 5.6.1 | Discussion of Study Design and Choice of Control Groups | 5.6.1 Discussion of Study Design and Choice of Control Groups Low-dose cytarabine is a commonly prescribed treatment within the United States for subjects who fulfill the entry criteria of this study. Venetoclax is undergoing testing in other clinical trials as a single-agent treatment for AML and in combination with o... | [] |
NCT02287233 | 5.6.2 | Appropriateness of Measurements | 5.6.2 Appropriateness of Measurements Standard PK, statistical, clinical and laboratory procedures will be utilized in this study. The efficacy measurements in this study are standard and validated. | [] |
NCT02287233 | 5.6.3 | Suitability of Subject Population | 5.6.3 Suitability of Subject Population Subjects who have histological confirmation of acute myelogenous leukemia who are treatment-naïve, greater than or equal to 60 years of age, and who are not eligible for standard induction therapy due to co-morbidity or other factors will be selected to participate in this study. | [] |
NCT02287233 | 5.6.4 | Selection of Doses in the Study | 5.6.4 Selection of Doses in the Study In the initial Phase 1 trial (Study M12-175) evaluating venetoclax monotherapy in subjects with CLL and NHL, the most significant toxicity was TLS in CLL subjects  during the initiation of dosing. Reductions in circulating CLL cells and electrolyte changes c... | [] |
NCT02287233 | 6.0 | Complaints | 6.0 Complaints A Complaint is any written, electronic, or oral communication that alleges deficiencies related to the physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or performance of a product/device after it is released for distribution. Complaints associa... | [] |
NCT02287233 | 6.1 | Medical Complaints | 6.1 Medical Complaints The investigator will monitor each subject for clinical and laboratory evidence of adverse events on a routine basis throughout the study. The investigator will assess and record any adverse event in detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, time co... | [] |
NCT02287233 | 6.1.1 | Definitions | 6.1.1 Definitions | [] |
NCT02287233 | 6.1.1.1 | Adverse Event | 6.1.1.1 Adverse Event An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (... | [] |
NCT02287233 | 6.1.1.2 | Serious Adverse Events | 6.1.1.2 Serious Adverse Events If an adverse event meets any of the following criteria, it is to be reported to AbbVie as a serious adverse event within 24 hours of the site being made aware of the serious adverse event: Death of Subject An event that results in the death of a subject. Life-Threatening An event that, i... | [] |
NCT02287233 | 6.1.1.3 | Adverse Events Commonly Associated with Acute Myelogenous Leukemia Study Population and/or Progression of Acute Myelogenous Leukemia | 6.1.1.3 Adverse Events Commonly Associated with Acute Myelogenous Leukemia Study Population and/or Progression of Acute Myelogenous Leukemia Certain adverse events are anticipated to occur in the study population (AML) at some frequency independent of drug exposure. Such events include known consequences of the underly... | [] |
NCT02287233 | 6.1.2 | Adverse Event Severity | 6.1.2 Adverse Event Severity The investigator will rate the severity of each adverse event according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE Version 4.0).[40](#page-136-2) If a reported adverse event increases in severity, the initial adverse event should be given fina... | [] |
NCT02287233 | 6.1.3 | Adverse Events Expected Due to Study Related Endpoints | 6.1.3 Adverse Events Expected Due to Study Related Endpoints | [] |
NCT02287233 | 6.1.3.1 | Deaths | 6.1.3.1 Deaths For this protocol, overall survival is an efficacy endpoint. Deaths that occur during the protocol-specified adverse event reporting period (see Section [6.1.5\)](#page-102-1) that are attributed by the investigator solely to progression of AML should be recorded only on the Study Completion and Death eC... | [] |
NCT02287233 | 6.1.3.2 | Lack of Efficacy or Worsening of Disease | 6.1.3.2 Lack of Efficacy or Worsening of Disease Events that are clearly consistent with the expected pattern of progression of the underlying disease are also considered an expected outcome for this study and will not be subject to expedited reporting. | [] |
NCT02287233 | 6.1.4 | Relationship to Study Drug | 6.1.4 Relationship to Study Drug The investigator will use the following definitions to assess the relationship of the adverse event to the use of study drug:  Reasonable Possibility After consideration of factors including timing of the event, biologic plausibility, clinical judgment, and pote... | [] |
NCT02287233 | 6.1.5 | Adverse Event Collection Period | 6.1.5 Adverse Event Collection Period All protocol-related serious adverse events and nonserious adverse events must be collected from the signing of the study specific informed consent until study drug administration. Serious and nonserious adverse events occurring after the study-specific informed consent is signed b... | [] |
NCT02287233 | 6.1.6 | Adverse Event Reporting | 6.1.6 Adverse Event Reporting In the event of a serious adverse event, whether associated with study drug or not, the investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made aware of the serious adverse event by entering the serious adverse event data into the electronic data capture ... | [
"COVID-19 Pandemic-Related Acceptable Protocol Modifications"
] |
NCT02287233 | 6.1.7 | Pregnancy | 6.1.7 Pregnancy Pregnancy in a study subject must be reported to an AbbVie representative (Section [6.1.6](#page-103-2) or Section [7.0\)](#page-113-0) within 1 working day of the site becoming aware of the pregnancy. Subjects who become pregnant during the study must be discontinued (Section [5.4.1](#page-86-2)). All ... | [] |
NCT02287233 | 6.1.8 | Toxicity Management | 6.1.8 Toxicity Management | [] |
NCT02287233 | 6.1.8.1 | Definition – Dose Limiting Toxicity | 6.1.8.1 Definition – Dose Limiting Toxicity Dose limiting toxicities (DLTs) for dose-escalation purposes will be determined during Cycle 1 (4 weeks) of study treatment. Adverse events that occur after the first cycle will also be evaluated by the investigator and the AbbVie medical monitor and may be considered as dose... | [] |
NCT02287233 | 6.1.8.2 | Prophylaxis and Management of Tumor Lysis Syndrome (TLS) | 6.1.8.2 Prophylaxis and Management of Tumor Lysis Syndrome (TLS) There is a potential for TLS for patients with AML receiving induction therapy, especially for those with elevated pretreatment LDH levels, elevated leukocyte count, renal dysfunction, and dehydration. To mitigate the risk for TLS,[36](#page-135-5) subjec... | [
"Tumor Lysis Syndrome Prophylaxis and Management for Subjects Dose Escalated in Protocol Version 1 and Amendment 1",
"Tumor Lysis Syndrome Prophylaxis and Management in Phase 2 Cohort C – Applies to Subjects Enrolled in Amendment 2"
] |
NCT02287233 | 6.1.8.3 | Management of Myelosuppresion (Cytopenias) | 6.1.8.3 Management of Myelosuppresion (Cytopenias)
Venetoclax Myelosuppression and the related adverse events (thrombocytopenia, anemia, neutropenia, and febrile neutropenia) are common in both treated and untreated subjects with AML. Subjects with baseline neutropenia or have significant bone marrow involvement may b... | [
"Venetoclax",
"Standard Therapy: Low – Dose Cytarabine"
] |
NCT02287233 | 6.1.8.4 | Management of Decreased Spermatogenesis | 6.1.8.4 Management of Decreased Spermatogenesis Based on findings in a preclinical study of venetoclax, there is a potential for decreased spermatogenesis. Male subjects should consider sperm banking before treatment with venetoclax if they are considering preservation of fertility. | [] |
NCT02287233 | 6.1.8.5 | Management of Other Toxicities | 6.1.8.5 Management of Other Toxicities If other events occur that are related to venetoclax or LDC the investigator, in consultation with the AbbVie medical monitor, may interrupt or dose reduce venetoclax and/or reference therapy, as appropriate. Grade 3 or greater nonhematologic toxicity (e.g., nausea, vomiting, and ... | [] |
NCT02287233 | 6.1.8.6 | Determination of the MTD | 6.1.8.6 Determination of the MTD If a single subject within a cohort experiences a DLT, a total of 6 subjects will be enrolled and dosed at the same dose level. If these additional subjects do not exhibit a DLT, dose escalation may proceed. If any of the additional subjects exhibits a DLT, then dose de-escalation may o... | [] |
NCT02287233 | 6.1.8.7 | Determination of the RPTD | 6.1.8.7 Determination of the RPTD If an MTD is reached, the RPTD will not be a dose higher than the MTD and will be selected by the sponsor based on the types of DLTs which occur and the MTD identified. If an MTD is not reached, then the RPTD will be defined based on the safety and PK data. | [] |
NCT02287233 | 7.0 | Protocol Deviations | 7.0 Protocol Deviations AbbVie does not allow intentional/prospective deviations from the protocol. The principal investigator is responsible for complying with all protocol requirements, and applicable global and local laws regarding protocol deviations. If a protocol deviation occurs (or is identified, including thos... | [
"Size"
] |
NCT02287233 | 8.1.1 | Baseline Characteristics | 8.1.1 Baseline Characteristics All baseline summary statistics and analyses will be based on characteristics obtained prior to the initiation of study drug. Unless otherwise stated, baseline for a given variable will be defined as the last value for that variable obtained prior to the first dose of study drug. | [] |
NCT02287233 | 8.1.1.1 | Demographics | 8.1.1.1 Demographics Age, height, weight and gender will be summarized with means, standard deviation and range. Frequencies and percentages will be computed for the following parameters: race, smoking history, and performance status. | [] |
NCT02287233 | 8.1.1.2 | Medical History | 8.1.1.2 Medical History Frequencies and percentages will be computed for each medical history parameter. | [] |
NCT02287233 | 8.1.2 | Pharmacokinetics | 8.1.2 Pharmacokinetics | [] |
NCT02287233 | 8.1.2.1 | Tabulations and Summary Statistics | 8.1.2.1 Tabulations and Summary Statistics Plasma concentrations and PK parameter values of venetoclax and cytarabine will be tabulated for each subject, visit, and dose regimen, and summary statistics will be computed for each sampling time and each parameter. | [] |
NCT02287233 | 8.1.2.2 | Model and Tests | 8.1.2.2 Model and Tests All analyses will be performed on the Phase 1 portion subjects only.
Dose Proportionality and Covariate Selection of Venetoclax The following analysis will be performed separately on Cycle 1 Day 10 and Cycle 1 Day 18 venetoclax PK parameters. An analysis will be performed for dose-normalized Cm... | [
"Dose Proportionality and Covariate Selection of Venetoclax",
"Venetoclax Effect on Cytarabine Pharmacokinetics Parameters",
"Cytarabine Effect on Venetoclax Pharmacokinetics Parameters"
] |
NCT02287233 | 8.1.2.3 | Missing Values and Model Violations | 8.1.2.3 Missing Values and Model Violations All available data will be included the mixed effect analyses. Data exclusion, if any, will be documented and justification provided. Normally distributed values of PK variables (Cmax, AUC, etc.) will be determined without replacing missing individual concentration values, si... | [] |
NCT02287233 | 8.1.3 | Efficacy Summaries | 8.1.3 Efficacy Summaries Efficacy will include analyses of ORR as defined by CR + CRi + PR, CR rate, CRi rate, CRh rate, CR + CRi rate, CR + CRh rate, DOR, EFS, OS, the exploratory analysis of the proportion of for all subjects who achieve MRD negativity, the proportion of subjects who are transfusion independent post ... | [] |
NCT02287233 | 8.1.3.1.1 | Overall Response Rates | 8.1.3.1.1 Overall Response Rates CRh (Complete remission with partial hematologic recovery) is a derived response based on bone marrow blast count and hematology lab values. A response of CRh is achieved when the following criteria are met: - Bone marrow with 3 /µL\ and - peripheral blood platelet count ≥ 0.5 × 105 /µL... | [] |
NCT02287233 | 8.1.3.1.2 | Duration of Response | 8.1.3.1.2 Duration of Response Duration of response will be defined as the number of days from the date of first response (CR, CRi, or PR) per the IWG criteria for AML to the earliest recurrence or PD. If a subject is still responding, then the subject's data will be censored at the date of the subject's last available... | [] |
NCT02287233 | 8.1.3.1.3 | Event-Free Survival | 8.1.3.1.3 Event-Free Survival Event-free survival (EFS) will be defined as the number of days from the date of first dose to the date of earliest evidence of progression or relapse, subsequent treatment other than stem cell transplant while in composite complete response (CR + CRi), or death. If the specified event (re... | [] |
NCT02287233 | 8.1.3.1.4 | Overall Survival | 8.1.3.1.4 Overall Survival Overall survival will be defined as number of days from the date of first dose to the date of death. For subjects who did not die, their data will be censored at the date of last study visit or the last known date to be alive, whichever is later. Overall survival will be analyzed by Kaplan-Me... | [] |
NCT02287233 | 8.1.3.1.5 | MRD Negativity Rate | 8.1.3.1.5 MRD Negativity Rate The proportion of subjects who reach MRD negativity in this exploratory measurement and the duration of this status will be summarized. | [] |
NCT02287233 | 8.1.3.1.6 | Proportion of Subjects Who Undergo Transplant | 8.1.3.1.6 Proportion of Subjects Who Undergo Transplant The proportion of subjects who undergo a subsequent transplant will be summarized. | [] |
NCT02287233 | 8.1.3.1.7 | Post Baseline Transfusion Independence (RBC/Platelet) | 8.1.3.1.7 Post Baseline Transfusion Independence (RBC/Platelet) Post baseline transfusion independence is defined as a period of at least 56 days with no RBC or platelet transfusion between the first dose of study drug and the last dose of study drug + 30 days. Post baseline transfusion independence rate will be estima... | [] |
NCT02287233 | 8.1.4 | Safety | 8.1.4 Safety The safety of Venetoclax and cytarabine will be assessed by evaluation study drug exposure, adverse events, serious adverse events, all deaths, as well as changes in laboratory determinations and vital sign parameters. Safety analyses will be performed for all subjects who take at least one dose of study d... | [] |
NCT02287233 | 8.1.4.1 | Adverse Events | 8.1.4.1 Adverse Events Analyses of adverse events will include only "treatment-emergent" events, i.e., those that have an onset on or after the day of the first dose of study drug.  Analyses of adverse events will not include those that have an onset greater than 30 days after the last dose of ... | [] |
NCT02287233 | 8.1.4.2 | Serious Adverse Events | 8.1.4.2 Serious Adverse Events Serious adverse events will be summarized using the same methods as adverse events described above. | [] |
NCT02287233 | 8.1.4.3 | Deaths | 8.1.4.3 Deaths The number of subject deaths will be summarized (1) for deaths occurring within 30 days of the last dose of study drug, (2) for deaths occurring more than 30 days of the last dose of study drug and (3) for all deaths in this study regardless of the number of days after the last dose of study drug. | [] |
NCT02287233 | 8.1.4.4 | Longitudinal Analyses of Laboratory and Vital Signs Data | 8.1.4.4 Longitudinal Analyses of Laboratory and Vital Signs Data Changes from baseline will be analyzed for each scheduled post-baseline visit and for the final visit for blood chemistry and hematology parameters, as well as urinalysis and vital sign parameters. If more than one measurement exists for a subject on a pa... | [] |
NCT02287233 | 8.1.4.5 | Analyses of Laboratory Data Using NCI CTCAE | 8.1.4.5 Analyses of Laboratory Data Using NCI CTCAE Where applicable, blood chemistry, hematology and lymphocyte enumeration determinations will be categorized according to NCI CTCAE Version 4.0[40](#page-136-2) grades, and  shifts from baseline NCI CTCAE[40](#page-136-2) grades to maximum and ... | [] |
NCT02287233 | 8.2 | Determination of Sample Size | 8.2 Determination of Sample Size This is a Phase 1/2 study where the Phase 1 portion is a dose escalation study and the Phase 2 portion is a dose expansion study. For the Phase 1 portion of the study, the sample size is dependent upon the dose levels utilized and whether toxicities require and allow enrollment of 3 or ... | [] |
NCT02287233 | 9.0 | Ethics | 9.0 Ethics | [] |
NCT02287233 | 9.1 | Independent Ethics Committee (IEC) or Institutional Review Board (IRB) | 9.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, the Investigator's Brochure, the informed consent and all other forms of subject information related to the study (e.g., advertisements used to recruit su... | [] |
NCT02287233 | 9.2 | Ethical Conduct of the Study | 9.2 Ethical Conduct of the Study The study will be conducted in accordance with the protocol, International Conference on Harmonization (ICH) GCP guidelines, applicable regulations and guidelines governing clinical study conduct and ethical principles that have their origin in the Declaration of Helsinki. In the event ... | [] |
NCT02287233 | 9.3 | Subject Information and Consent | 9.3 Subject Information and Consent The investigator or his/her representative will explain the nature of the study to the subject, and answer all questions regarding this study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement will be reviewed and signed an... | [] |
NCT02287233 | 10.0 | Source Documents and Case Report Form Completion | 10.0 Source Documents and Case Report Form Completion | [] |
NCT02287233 | 10.1 | Source Documents | 10.1 Source Documents Source documents are defined as original documents, data, and records. These may include hospital records, clinical and office charts, laboratory data/information, subject diaries or evaluation checklists, pharmacy dispensing and other records, recorded data from automated instruments, microfiches... | [] |
NCT02287233 | 10.2 | Case Report Forms | 10.2 Case Report Forms Case report forms (CRF) must be completed for each subject screened/enrolled in this study. These forms will be used to transmit information collected during the study to AbbVie and regulatory authorities, as applicable. The CRF data for this study are being collected with an electronic data capt... | [] |
NCT02287233 | 11.0 | Data Quality Assurance | 11.0 Data Quality Assurance Prior to enrolling any subject in the study, an initiation meeting will be held with AbbVie personnel, the investigator(s), and the study coordinators/project manager(s). This meeting will include a detailed discussion and review of the protocol and essential documents, performance of study ... | [] |
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