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NCT01578707
9
ASSESSMENT OF SAFETY
9. ASSESSMENT OF SAFETY
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NCT01578707
9.1
Safety Monitoring Plan
9.1. Safety Monitoring Plan The safety of this study will be assessed by an independent DMC. All enrolled patients will be evaluated clinically and using standard laboratory testing during their participation in this study. Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of protoc...
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NCT01578707
9.2
Definitions
9.2. Definitions
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NCT01578707
9.2.1
Adverse Events
9.2.1. Adverse Events An AE is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for...
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NCT01578707
9.2.2
Serious Adverse Event
9.2.2. Serious Adverse Event Note: The terms "severe" and "serious" are not synonymous. Severity (or intensity) refers to the grade of an AE (see below). "Serious" is a regulatory definition. A SAE (experience) or reaction is any untoward medical occurrence that at any dose: - Results in death (ie, the AE actually caus...
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NCT01578707
9.2.3
Severity
9.2.3. Severity Definitions found in the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) will be used for grading the severity (intensity) of nonhematologic AEs. Refer to [Appendix D](#page-99-0) for the grading of hematologic AEs. The CTCAE v4.0 displays Grades 1 through 5 with unique clinical ...
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NCT01578707
9.2.4
Causality
9.2.4. Causality The Investigator is to assess the causal relation (ie, whether there is a reasonable possibility that the study drug caused the event) using the following definitions: Not Related: Another cause of the AE is more plausible; a temporal sequence cannot be established with the onset of the AE and administ...
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NCT01578707
9.2.5
Unexpected Adverse Events
9.2.5. Unexpected Adverse Events An "unexpected" AE is an AE that is not listed in the Investigator's Brochure/package insert or is not listed at the specificity or severity that has been observed. For example, hepatic necrosis would be "unexpected" (by virtue of greater severity) if the Investigator's Brochure referre...
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NCT01578707
9.3
Documenting and Reporting of Adverse and Serious Adverse Events by Investigators
9.3. Documenting and Reporting of Adverse and Serious Adverse Events by Investigators The Investigator is responsible for ensuring that all AEs and SAEs that are observed or reported during the study, as outlined in the prior sections, are recorded on the CRF. All SAEs also must be reported on the SAE Worksheet (see [S...
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NCT01578707
9.3.1
Adverse Event Reporting Period
9.3.1. Adverse Event Reporting Period All adverse events will be reported from the time the patient signs the Informed Consent Form until 30 days following the last dose of study drug. If an SAE is present at the End-of-Treatment Visit, the SAE should be followed to resolution or until the Investigator assesses the pat...
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NCT01578707
9.3.2
Assessment of Adverse Events
9.3.2. Assessment of Adverse Events Investigators will assess the occurrence of AEs and SAEs at all patient evaluation timepoints during the study. All AEs and SAEs whether volunteered by the patient, discovered by study personnel during questioning, detected through physical examination, clinically significant laborat...
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NCT01578707
9.3.3
Expedited Reporting Requirements for Serious Adverse Events
9.3.3. Expedited Reporting Requirements for Serious Adverse Events All SAEs (initial and follow-up information) will be reported on the SAE Worksheet and faxed to Pharmacyclics Drug Safety, or designee, within 24 hours of the discovery of the event or information. Pharmacyclics may request follow-up and other additiona...
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NCT01578707
9.3.4
Events of Special Interest
9.3.4. Events of Special Interest Specific adverse events, or groups of adverse events, will be followed as part of standard safety monitoring activities by the Sponsor. These events will be reported to the Sponsor within 24 hours of awareness following the procedure described above for SAEs (Section 9.3.3) and will re...
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NCT01578707
9.3.4.1
Major Hemorrhage
9.3.4.1. Major Hemorrhage Defined as any hemorrhagic event that is Grade 3 or greater in severity, or that results in one of the following: intraocular bleeding causing loss of vision, the need for a transfusion of two or more units of red cells or an equivalent amount of whole blood, hospitalization or prolongation of...
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NCT01578707
9.3.4.2
Intracranial Hemorrhage
9.3.4.2. Intracranial Hemorrhage Any intracranial hemorrhage adverse event, including subdural hematoma/hemorrhage, epidural hematoma/hemorrhage and intracerebral hemorrhage, of any grade severity, will be captured as an event of special interest according to Section 9.3.4 above.
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NCT01578707
9.3.5
Other Malignancies
9.3.5. Other Malignancies In addition to all routine AE reporting, all new malignant tumors including solid tumors, skin malignancies and hematologic malignancies are to be reported for the duration of study treatment and during any protocol-specified follow-up periods including post-progression follow-up for overall s...
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NCT01578707
9.3.6
Pregnancy
9.3.6. Pregnancy Before study enrollment, patients must agree to take appropriate measures to avoid pregnancy. However, should a pregnancy occur in a female study patient, consent to provide follow-up information regarding the outcome of the pregnancy and the health of the infant until 30 days old will be requested. A ...
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NCT01578707
9.3.7
Eye-Related Adverse Events
9.3.7. Eye-Related Adverse Events New or worsening eye-related symptoms that are Grade ≥2 should be evaluated by an ophthalmologist whose findings should be reported on the ophthalmic CRF.
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NCT01578707
9.4
Reporting of Serious Adverse Events by Sponsor
9.4. Reporting of Serious Adverse Events by Sponsor Regulatory Authorities, IRBs/REBs/IECs, and Investigators will be notified of SAEs in accordance with applicable requirements (eg, Good Clinical Practices [GCPs], ICH guidelines, national regulations, and local requirements). The Pharmacyclics Pharmacovigilance Commit...
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NCT01578707
10
WITHDRAWAL OF PATIENT FROM TREATMENT OR STUDY
10. WITHDRAWAL OF PATIENT FROM TREATMENT OR STUDY Investigators are encouraged to keep a patient experiencing clinical benefit on study treatment unless significant toxicity puts the patient at risk or routine noncompliance puts the study outcomes at risk.
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NCT01578707
10.1
Discontinuation of Treatment
10.1. Discontinuation of Treatment If the patient meets any of the following criteria then discontinuation from treatment is mandatory: - Progressive disease as determined by protocol defined criteria - Toxicity as defined in dose discontinuation portions of the protocol - Death - Withdrawal from treatment by patient i...
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NCT01578707
10.2
Withdrawal from the Study
10.2. Withdrawal from the Study A patient may be withdrawn from the study for any of the following reasons including: - Death - Lost to follow-up - Study terminated by Sponsor - Withdrawal of consent - o Withdrawal of consent is the primary reason for study termination only if a patient refuses any further contact or f...
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NCT01578707
10.3
Extension Study
10.3. Extension Study Patients who were on study drug and did not progress at the time of study closure may enroll into a long-term extension study and continue to receive ibrutinib when access to commercial ibrutinib is not feasible.
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NCT01578707
11
ENDPOINTS
11. ENDPOINTS
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NCT01578707
11.1
Primary
11.1. Primary The primary endpoint of the study is PFS, as assessed by IRC review per IWCLL 2008 criteria [\(Section 8.4\)](#page-65-2).
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NCT01578707
11.2
Secondary
11.2. Secondary Efficacy To compare between the two treatment groups in terms of: - OS - Overall response rate (ORR) is defined as the proportion of patients who achieve complete response (CR), complete response with incomplete bone marrow recovery (CRi), nodular partial response (nPR), or partial response (PR) per IW...
[ "Efficacy", "Safety" ]
NCT01578707
11.3
Exploratory
11.3. Exploratory - Investigator-assessed PFS per IWCLL 2008 criteria - Investigator-assessed ORR per IWCLL 2008 criteria - Improvement of disease-related symptoms (weight loss, fatigue, fever, night sweats, abdominal pain due to splenomegaly, or anorexia). - Patient reported outcomes (PRO) as measured by EORTC QLQ-C30...
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NCT01578707
12
STATISTICAL CONSIDERATIONS
12. STATISTICAL CONSIDERATIONS This section outlines statistical analysis approaches and methods for the study. Specific details for efficacy and safety analyses will be described in the Statistical Analysis Plan (SAP).
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NCT01578707
12.1
General Considerations
12.1. General Considerations
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NCT01578707
12.1.1
Independent Review Committee (IRC)
12.1.1. Independent Review Committee (IRC) The IRC will be chaired by a physician with expertise in CLL and SLL and will conduct response evaluations in accordance with the IRC charter.
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NCT01578707
12.1.2
Data Monitoring Committee (DMC)
12.1.2. Data Monitoring Committee (DMC) The safety of this study will be monitored by an independent DMC. An early safety analysis will be performed after approximately 50 patients have been treated for approximately 8 weeks. This analysis will focus on deaths, treatment discontinuations, SAEs, and grade 3/4 AEs as wel...
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NCT01578707
12.2
Randomization
12.2. Randomization Two randomization schemes will be generated: one for each geographic region (North America versus Rest of World). Under each scheme, randomization will be stratified using the following two stratification factors and patients will be randomized in a 1:1 ratio to receive either ofatumumab or ibrutini...
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NCT01578707
12.3
Sample Size considerations
12.3. Sample Size considerations This study is designed to evaluate PFS and is powered based on this endpoint. Therefore, the desired operating characteristics for the PFS endpoint are used to determine the study's total sample size and overall duration. With the agreement from the European (Rapporteur and Co-Rapporteu...
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NCT01578707
12.4
Interim Analysis
12.4. Interim Analysis A pre-specified interim analysis for both superiority and futility (non-binding) will be performed after approximately 117 IRC confirmed PFS events are reported. Futility will be evaluated by a one-sided test. One-hundred and seventeen (117) PFS events correspond to 66.5% of the revised planned n...
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NCT01578707
12.5
Final Analysis
12.5. Final Analysis The final analysis for the PFS will be conducted after approximately 176 PFS events are confirmed by the IRC. The two-sided significance level for the final analysis for primary and all secondary endpoints will be adjusted to account for interim alpha spending so the overall twosided significance l...
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NCT01578707
12.6
Analysis Populations
12.6. Analysis Populations
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NCT01578707
12.6.1
Intent-to-Treat (ITT) Population
12.6.1. Intent-to-Treat (ITT) Population The ITT population is defined as all patients who were randomized. All efficacy analysis will be performed using the ITT population and patients in the ITT population will be analyzed as randomized. In addition, ITT population will be used to summarize demographics, and baseline...
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NCT01578707
12.6.2
Safety Population
12.6.2. Safety Population The safety population includes all patients who received at least one dose of study drug. The safety analysis will be performed using the safety population and patients in the safety population will be analyzed as treated.
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NCT01578707
12.6.3
Pharmacokinetic (PK) Evaluable Population
12.6.3. Pharmacokinetic (PK) Evaluable Population Pharmacokinetic (PK) evaluable population includes patients who received at least 1 dose of study drug and had at least one post-treatment sample obtained.
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NCT01578707
12.6.4
Biomarker Population
12.6.4. Biomarker Population Biomarker population includes patients whose biomaterial is available and who have consented to participate in the study's biomarker evaluation.
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NCT01578707
12.7
Control for Bias
12.7. Control for Bias The following study design components will facilitate the control for bias: - Large (approximately 350 patients) - Multicenter - Randomized The randomization code will be controlled through a centralized procedure and will not be known to sponsor personnel directly involved with study conduct or ...
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NCT01578707
12.8
Efficacy Analyses
12.8. Efficacy Analyses All the stratified analyses will be based on the two randomization stratification factors: 1) refractory disease (presence versus absence) to purine analog and anti-CD20 containing chemoimmunotherapy regimen, and 2) status of 17p del (presence versus absence).
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NCT01578707
12.8.1
Primary Endpoint and Methods
12.8.1. Primary Endpoint and Methods The primary efficacy endpoint is PFS, which is defined as the time from the date of randomization until disease progression (assessed by the IRC per IWCLL 2008 criteria) or death from any cause, whichever occurs first. Patients who withdraw from the study or are considered lost to f...
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NCT01578707
12.8.2
Secondary Endpoints and Methods
12.8.2. Secondary Endpoints and Methods
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NCT01578707
12.8.2.1
Overall Survival (OS) and Survival Rate at Landmark Points
12.8.2.1. Overall Survival (OS) and Survival Rate at Landmark Points Patients will be followed for survival status until end of study. OS is defined as the time from date of randomization until date of death due to any cause. Patients who are known to be alive or whose survival status is unknown will be censored at the...
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NCT01578707
12.8.2.2
Overall Response Rate
12.8.2.2. Overall Response Rate Overall response rate (ORR) is defined as the proportion of patients who achieve a CR, CRi, nPR, or PR over the course of the study as evaluated by the IRC using IWCLL 2008 criteria. Patients who do not have any post-baseline response assessment will be considered as non-responders. A Co...
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NCT01578707
12.8.2.3
Patient-Reported Outcome (PRO) Measures
12.8.2.3. Patient-Reported Outcome (PRO) Measures PRO as measured by FACiT-Fatigue will be summarized as the change in scores from baseline to each assessment.
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NCT01578707
12.8.2.4
Hematological Improvements
12.8.2.4. Hematological Improvements In the subset of patients with cytopenia(s) at baseline (Hgb ≤11 g/dL, platelets ≤100,000/μL, or ANC ≤1500/μL), time to sustained improvement and percentage of patients with sustained hematological improvement will be measured. Sustained hematological improvement is defined as impro...
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NCT01578707
12.8.3
Exploratory Endpoints and Methods
12.8.3. Exploratory Endpoints and Methods
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NCT01578707
12.8.3.1
Investigator-Assessed PFS
12.8.3.1. Investigator-Assessed PFS Investigator-assessed PFS is defined as time from randomization until disease progression (assessed by the Investigator per IWCLL 2008 criteria) or death from any cause, whichever occurs first. Analysis methods for Investigator-assessed PFS will be similar to those described for PFS ...
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NCT01578707
12.8.3.2
Investigator-Assessed ORR
12.8.3.2. Investigator-Assessed ORR Investigator-assessed ORR will be summarized and analyzed similarly to IRC-assessed ORR.
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NCT01578707
12.8.3.3
Improvement of Disease-related Symptoms
12.8.3.3. Improvement of Disease-related Symptoms Disease-related symptoms including weight loss, fatigue, fever, night sweats, abdominal pain due to splenomegaly, or anorexia) will be assessed by at each assessment compared to baseline. Percentage of patients with improvement will be compared using χ2 test.
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NCT01578707
12.8.3.4
Patient-Reported Outcome (PRO) Measures
12.8.3.4. Patient-Reported Outcome (PRO) Measures Patient Reported Outcome (PRO) measures include EORTC QLQ-C30 and EQ-5D-5L. For EORTC QLQ-C30, change in scores from baseline to each assessment will be summarized. For EQ-5D-5L, change in weighted utility score from baseline to each assessment will be summarized. The s...
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NCT01578707
12.8.3.5
Biomarker Analysis
12.8.3.5. Biomarker Analysis Analyses are to identify biomarkers that are predictive of response (or resistance) to ibrutinib. Analyses will be performed within each treatment group in total and stratified by clinical covariates or molecular subgroups. The associations of biomarkers with clinical response or time-to-ev...
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NCT01578707
12.8.3.6
Medical Resource Utilization (MRU) Associated with the Therapy
12.8.3.6. Medical Resource Utilization (MRU) Associated with the Therapy Parameters collected for MRU associated with the therapy include number of hospitalizations, number of emergency department visits, number of blood product transfusions, and number of use of hematopoietic growth factors. Those parameters will be s...
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NCT01578707
12.8.3.7
Pharmacokinetic (PK) Analysis
12.8.3.7. Pharmacokinetic (PK) Analysis The plasma concentration data for ibrutinib will be summarized using descriptive statistics at each timepoint. Population PK analysis of plasma concentration-time data of ibrutinib will be performed using nonlinear mixed-effects modeling. Data may be combined with data from other...
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NCT01578707
12.9
Safety Analyses
12.9. Safety Analyses Safety summaries will include tabulations in the form of tables and listings. The safety analysis will be conducted using the safety population. Patients will be analyzed according to the actual treatment received. Study drug exposure including duration and dosage as well as dose modifications of ...
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NCT01578707
12.9.1
Adverse Events (AEs)
12.9.1. Adverse Events (AEs) Adverse events (AEs) will be graded by the Investigator according the NCI CTCAE v4.0 for non-hematological AEs. Hematologic toxicity will be assessed by the IWCLL 2008 criteria for grading hematologic toxicity in CLL studies. Verbatim descriptions of AEs will be coded using the current vers...
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NCT01578707
12.9.2
Laboratory Evaluations
12.9.2. Laboratory Evaluations All laboratory values will be converted to standard international (SI) units and classified as normal, low, or high based on normal ranges supplied by the central laboratory. Hematologic parameters including platelet count, hemoglobin, and neutrophils will be assessed by the IWCLL 2008 cr...
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NCT01578707
12.9.3
Vital Signs
12.9.3. Vital Signs Vital signs will be classified as normal, low, or high and change from baseline will be summarized descriptively by treatment arm at scheduled timepoints. Patients with markedly abnormal changes will be listed and tabulated.
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NCT01578707
12.9.4
Other Safety Assessments
12.9.4. Other Safety Assessments Physical examination, ECG, and eye examination results will be listed.
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NCT01578707
13
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
13. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS
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NCT01578707
13.1
Regulatory and Ethical Compliance
13.1. Regulatory and Ethical Compliance This clinical study was designed and will be implemented in accordance with the protocol, the ICH Harmonized Tripartite Guidelines for Good Clinical Practices, with applicable local regulations (including US Code of Federal Regulations [CFR] Title 21 and European Directive 2001/2...
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NCT01578707
13.2
Institutional Review Board (IRB), Research Ethics Board (REB) and Independent Ethics Committee (IEC) Approval
13.2. Institutional Review Board (IRB), Research Ethics Board (REB) and Independent Ethics Committee (IEC) Approval The Investigator will submit this protocol, the ICF, [IB,](#page-93-2) and any other relevant supporting information (eg, all advertising materials or materials given to the patient during the study) to t...
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NCT01578707
13.3
Informed Consent
13.3. Informed Consent The ICF and process must comply with the US regulations (§ 21 CFR Part 50) as well as country specific national regulations and/or local laws. The ICF will document the study-specific information the Investigator or his/her designee provides to the patient and the patient's agreement to participa...
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NCT01578707
13.4
Quality Control and Quality Assurance
13.4. Quality Control and Quality Assurance Sponsor shall implement and maintain quality control and quality assurance procedures to ensure that the study is conducted and data are generated, documented and reported in compliance with the protocol, GCP, and applicable regulatory requirements. This study shall be conduc...
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NCT01578707
13.5
Protected Patient Health Information Authorization
13.5. Protected Patient Health Information Authorization Information on maintaining patient confidentiality in accordance to individual local and national patient privacy regulations must be provided to each patient as part of the informed consent process (refer to [Section 13.3\)](#page-85-3), either as part of the IC...
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NCT01578707
13.6
Study Files and Record Retention
13.6. Study Files and Record Retention The Investigator must keep a record that lists all patients considered for enrollment (including those who did not undergo screening) in the study. For those patients subsequently excluded from enrollment, the reason(s) for exclusion is to be recorded. The Investigator/study staff...
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NCT01578707
13.7
Case Report Forms and Record Maintenance
13.7. Case Report Forms and Record Maintenance Case report forms (CRFs) will be used to collect the clinical study data and must be completed for each enrolled patient with all required study data accurately recorded such that the information matches the data contained in medical records (eg, physicians' notes, nurses'...
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NCT01578707
13.8
Investigational Study Drug Accountability
13.8. Investigational Study Drug Accountability Ibrutinib and any comparator used must be kept in a locked limited access room. The study drug must not be used outside the context of the protocol. Under no circumstances should the Investigator or other site personnel supply ibrutinib or comparator to other Investigator...
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NCT01578707
13.9
Study Monitoring/Audit Requirements
13.9. Study Monitoring/Audit Requirements Representatives of Pharmacyclics or its designee will monitor this study until completion. Monitoring will be conducted through personal visits with the Investigator and site staff, remote monitoring, as well as any appropriate communications by mail, fax, email, or telephone. ...
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NCT01578707
13.10
Investigator Responsibilities
13.10. Investigator Responsibilities A complete list of Investigator responsibilities are outlined in the clinical trial research agreement and the Statement of Investigator Form FDA 1572, both of which are signed by the Investigator before commencement of the study. In summary, the Investigator will conduct the study ...
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NCT01578707
13.11
Sponsor Responsibilities
13.11. Sponsor Responsibilities A complete list of the Sponsor responsibilities is outlined in the clinical trial research agreement and in the laws and regulation of the country in which the research is conducted. In summary, the Sponsor will select qualified Investigators, provide them with the information they need ...
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NCT01578707
13.12
Financial Disclosure
13.12. Financial Disclosure A separate financial agreement will be made between each Principal Investigator and Pharmacyclics or its authorized representative before the study drug is delivered. For this study, each Investigator and Subinvestigator (as designated on the Form FDA1572) will provide a signed Financial Dis...
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NCT01578707
13.13
Liability and Clinical Trial Insurance
13.13. Liability and Clinical Trial Insurance In the event of a side effect or injury, appropriate medical care as determined by the Investigator/ designee will be provided. If a bodily injury is sustained, resulting directly from the use of the study drug, Pharmacyclics will reimburse for reasonable physician fees and...
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NCT01578707
13.14
Protocol Amendments
13.14. Protocol Amendments Pharmacyclics will initiate any change to the protocol in a protocol amendment document. The amendment will be submitted to the IRB/REB/IEC together with, if applicable, a revised model ICF. Written documentation of IRB/REB/IEC and required site approval must be received by Pharmacyclics befo...
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NCT01578707
13.15
Publication of Study Results
13.15. Publication of Study Results Pharmacyclics may use the results of this clinical study in registration documents for Regulatory Authorities in the US or abroad. The results may also be used for papers, abstracts, posters, or other material presented at scientific meetings or published in professional journals or ...
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NCT01578707
13.16
Study Discontinuation
13.16. Study Discontinuation The Sponsor reserves the right to terminate the study at any time. Should this be necessary, both the Sponsor and the Investigator will arrange discontinuation procedures. In terminating the study, the Sponsor and the Investigator will assure that adequate consideration is given to the prot...
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NCT01578707
14
REFERENCE LIST
14. REFERENCE LIST Arzerra® [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. Burger JA, O'Brien S, Fowler N, et al. The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is well tolerated and demonstrates promising clinical activity in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (...
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NCT01578707
15
APPENDICES
15. APPENDICES Product: IBRUTINIB (PCI-32765) Protocol PCYC-1112-CA 28 September 2016 IND # 102,688 Version: Amendment 7 Appendix A: Schedule of Assessments | | | | | | | | | | | | | Treatment Phase | | | Follow-Up Phase | | |----------------------|---------------------------------------------|--------------------|---|...
[ "Appendix B: ECOG Status Scores", "Appendix C: Inhibitors and Inducers of CYP3A", "Appendix D: Hematologic Adverse Event Grading Scheme [\\(Hallek 2008\\)](#page-93-4)", "Hematologic Grading Scheme", "Appendix E: EORTC QLQ-C30", "Appendix G: FACiT-Fatigue", "Appendix H: Cumulative Illness Rating Scale (...
NCT01582269
1
Protocol H9H-MC-JBAL(a) A Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Glioblastoma
1. Protocol H9H-MC-JBAL(a) A Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Glioblastoma Confidential Information The information contained in this protocol is confidential and is intended for the use of cl...
[ "Confidential Information", "LY2157299 Monohydrate" ]
NCT01582269
2
Synopsis
2. Synopsis Study Rationale Transforming growth factor beta (TGF-β) is an important protein that regulates immune response to and metastatic spread of tumor cells. It is also an important regulator of neoangiogenesis. LY2157299 monohydrate is a small molecule designed to selectively inhibit the serine/threonine kinase...
[ "Study Rationale", "Clinical Protocol Synopsis: Study H9H-MC-JBAL", "Objectives:", "The secondary objectives of the study are:", "Pharmacokinetic (PK)", "Safety", "Pharmacodynamic (PD) – prognostic and predictive marker assessment", "Efficacy", "Health Outcomes", "Test Product, Dosage, and Mode of...
NCT01582269
3
Table of Contents
3. Table of Contents
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NCT01582269
A
Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Glioblastoma
A Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Glioblastoma | Section | Page | |-----------------------------------------------------------------------------------------------------------------------------...
[ "List of Tables", "List of Figures", "List of Attachments", "4. Abbreviations and Definitions" ]
NCT01582269
A
Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Malignant Glioma
A Phase 2 Study of LY2157299 Monohydrate Monotherapy or LY2157299 Monohydrate plus Lomustine Therapy compared to Lomustine Monotherapy in Patients with Recurrent Malignant Glioma 5. Introduction 5.1. Glioblastoma Glioblastoma (GB) is the most common and most aggressive malignant primary brain tumor in humans, account...
[ "5. Introduction", "5.1. Glioblastoma", "5.2. First-line Treatment for Glioblastoma", "5.3. Second-Line Treatment for Glioblastoma", "5.4. Gene Expression Profiling in Glioblastoma", "5.5. TGF- Signaling and its Role in Glioblastoma", "5.6. LY2157299 – Nonclinical and Clinical Experience", "5.6.1. Non...
NCT01622543
A
RANDOMIZED PHASE II STUDY OF REOLYSIN IN COMBINATION WITH FOLFOX6/BEVACIZUMAB OR FOLFOX6/BEVACIZUMAB ALONE IN PATIENTS WITH METASTATIC COLORECTAL CANCER
A RANDOMIZED PHASE II STUDY OF REOLYSIN IN COMBINATION WITH FOLFOX6/BEVACIZUMAB OR FOLFOX6/BEVACIZUMAB ALONE IN PATIENTS WITH METASTATIC COLORECTAL CANCER NCIC CTG Protocol Number: IND.210 STUDY CHAIRS: PATRICIA TANG DEREK JONKER SENIOR INVESTIGATOR: LESLEY SEYMOUR SENIOR BIOSTATISTICIAN: DONGSHENG TU STUDY COORDINATOR...
[ "STUDY ACKNOWLEDGMENT/DISCLOSURE", "TREATMENT SCHEMA", "SAMPLE SIZE", "ELIGIBILITY", "All patients:", "PRE-TREATMENT EVALUATIONS", "TREATMENT", "Arm B:", "DRUG ADMINISTRATION SCHEDULE", "ON TREATMENT EVALUATIONS", "DURATION OF TREATMENT", "1.0 OBJECTIVES", "1.1 Primary Objective", "1.2 Sec...
NCT01673646
1
Background
1 Background
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NCT01673646
1.1
Overview of acromegaly and pituitary gigantism pathogenesis, epidemiology and current treatment
1.1 Overview of acromegaly and pituitary gigantism pathogenesis, epidemiology and current treatment Acromegaly and pituitary gigantism are diseases both resulting from excessive secretion of growth hormone (GH) and manifested by characteristic clinical symptoms including enlargement of hands and feet, facial features, ...
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NCT01673646
1.2
Introduction to investigational study treatment(s) and other study treatment(s)
1.2 Introduction to investigational study treatment(s) and other study treatment(s)
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NCT01673646
1.2.1
Overview of pasireotide (SOM230)
1.2.1 Overview of pasireotide (SOM230) Pasireotide (SOM230), a new chemical entity, is an injectable somatostatin analogue. It is a novel cyclohexapeptide containing the amino acids lysine, tryptophane, phenylglycine, aminoethylcarbamoyl-hydroxyproline, phenylalanine and O-benzyltyrosine, with the following structural ...
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NCT01673646
1.2.1.1
Non-clinical experience
1.2.1.1 Non-clinical experience Preclinical data on binding affinity and functional activity in vitro and efficacy on hormone secretion in vivo have been obtained with the s.c. formulation in rats, dogs, mice and monkeys. Long-term in vivo studies performed using drug application by osmotic mini-pumps ([Bruns 2002,](#p...
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NCT01673646
1.2.1.2
Clinical experience
1.2.1.2 Clinical experience Pasireotide s.c. Single doses of pasireotide s.c. up to 1500 µg q.d. and multiple s.c. doses up to 1500 µg q.d.,750 µg b.i.d., and 2100 µg b.i.d., and continuous (7-day) s.c. infusion by a pump, have been well tolerated by healthy volunteers and patients with acromegaly, metastatic carcinoi...
[ "Pasireotide s.c.", "Pasireotide long acting release (LAR) formulation", "Pasireotide LAR in healthy volunteers", "Pasireotide LAR in acromegaly patients" ]
NCT01673646
2
Rationale
2 Rationale
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NCT01673646
2.1
Study rationale and purpose
2.1 Study rationale and purpose Pasireotide LAR was tested in patients with acromegaly in phase I patient study [CSOM230C2110]. The response rate, the proportion of patients with a reduction of 5-point mean GH levels to <2.5 µg/L and normalization of IGF-1 to within normal limits (age and sex related), at 3 months of s...
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NCT01673646
2.2
Rationale for the study design
2.2 Rationale for the study design This study is a multi-center, open label, randomized phase II study in Japan evaluating the efficacy, safety, PK and pharmacodynamics of pasireotide LAR in patients with active acromegaly and pituitary gigantism. With reference to the design of [CSOM230C2110] in western patients with ...
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NCT01673646
2.3
Rationale for dose and regimen selection
2.3 Rationale for dose and regimen selection Pasireotide LAR doses (20mg, 40mg and 60mg) selected for evaluation in this study were based on evaluation of PK, pharmacodynamics, efficacy and safety/tolerability data from patients (acromegaly, carcinoid disease) treated with pasireotide LAR ([CSOM230C2110]) and Japanese ...
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NCT01673646
2.4
Rationale for choice of combination drugs
2.4 Rationale for choice of combination drugs Not applicable.
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NCT01673646
2.5
Rationale for choice of comparators drugs
2.5 Rationale for choice of comparators drugs Not applicable.
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NCT01673646
3
Objectives and endpoints
3 Objectives and endpoints Objectives and related endpoints are described in [Table 3-1](#page-28-0) below. Table 3-1 Objectives and related endpoints | Objective | Endpoint | Analysis | |------------------------------------------------------------------------------------------------------------------------------------...
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NCT01673646
4
Study design
4 Study design
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