Clinical Trial Results:
A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients with Metastatic Pancreatic Ductal Adenocarcinoma
Summary
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EudraCT number |
2015-003639-37 |
Trial protocol |
GB |
Global end of trial date |
09 Jul 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
30 May 2019
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First version publication date |
30 May 2019
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
D4198C00003
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02583477 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
AstraZeneca
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Sponsor organisation address |
35 Gatehouse Drive, Waltham, Massachusetts, United States, 02451
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Public contact |
Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
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Scientific contact |
Global Clinical Lead, AstraZeneca, +1 302 885 1180, ClinicalTrialTransparency@astrazeneca.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Jul 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
09 Jul 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Cohort 1: To assess the safety and tolerability of MEDI4736 in combination with nab-paclitaxel + gemcitabine.
Cohort 2: To assess the safety, tolerability and objective response rate (ORR) for MEDI4736 + AZD5069 in combination.
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Protection of trial subjects |
This study was performed in accordance with the ethical principles that have their origin in the
Declaration of Helsinki and that are consistent with International Conference on
Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca
policy on Bioethics and Human Biological Samples.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
25 Mar 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 24
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
27
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EEA total number of subjects |
24
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
20
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From 65 to 84 years |
7
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85 years and over |
0
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Recruitment
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Recruitment details |
This study consisted of 2 independent cohorts, each of which ran at separate times between 25 March 2016 and 09 July 2018. In Cohort 1, participants were recruited from 1 center in the United States; in Cohort 2, participants were recruited from 6 centers in the United Kingdom. | ||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants underwent screening evaluations to determine eligibility within 4 weeks (28 days) prior to first administration of the Investigational Product (IP). A total of 27 participants (3 participants in Cohort 1 and 24 participants in Cohort 2) were enrolled into the study, of which 23 participants received treatment. | ||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine) | ||||||||||||||||||||||||||||||
Arm description |
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
MEDI4736
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Investigational medicinal product code |
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Other name |
Durvalumab
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
MEDI4736 1.5 g IV infusion on Day 1 of each 28-day cycle.
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Investigational medicinal product name |
Nab-paclitaxel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Nab-paclitaxel 125 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.
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Investigational medicinal product name |
Gemcitabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Gemcitabine 1000 mg/m^2 IV infusion over 30 minutes immediately after the completion of nab-paclitaxel administration on Days 1, 8, and 15 of each 28-day cycle.
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Arm title
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Cohort 2 (MEDI4736 + AZD5069) | ||||||||||||||||||||||||||||||
Arm description |
Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
AZD5069
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
A starting dose of 80 mg orally bid (with dose reductions to 40 mg bid or 20 mg bid for toxicity allowable) in the morning and evening. AZD5069 was provided as 40 mg and 10 mg tablets.
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Investigational medicinal product name |
MEDI4736
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Investigational medicinal product code |
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Other name |
Durvalumab
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
MEDI4736 1.5 g IV infusion on Day 1 of each 28-day cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
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Reporting group description |
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2 (MEDI4736 + AZD5069)
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Reporting group description |
Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
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Reporting group description |
Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||
Reporting group title |
Cohort 2 (MEDI4736 + AZD5069)
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Reporting group description |
Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. |
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End point title |
Number of Participants With Dose-Limiting Toxicities (DLT) [1] | |||||||||
End point description |
DLT period was defined as first treatment cycle for Cohort 1, and first dose of AZD5069 and MEDI4736 to end of Cycle 1 or until a participant experienced a DLT, whichever occurs first for Cohort 2. A DLT was any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 during DLT period. •Liver transaminase elevation >= 5× but <= 8× upper limit of normal (ULN) that doesn’t resolve to Grade 2 within 5 days •Transaminase elevation > 8× ULN or total bilirubin > 5× ULN •Any Grade 4 immune-related AE (irAE) not attributed to local tumor response, Grade >=3 colitis, Grade >=2 pneumonitis that doesn’t resolve to <= Grade 1 within 7 days, Grade 3 irAE, that doesn’t resolve to Grade <=1 or baseline status within 14 days •Any Grade >=3 non-irAE toxicity that doesn’t resolve to Grade <=1 or baseline status within 14 days. A DLT was any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period. The DLT evaluable set analysed.
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End point type |
Primary
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End point timeframe |
Cohort 1: From time of first dose of MEDI4736 on Day 1 up to Day 28 of Cycle 1 and Cohort 2: From time of first dose of AZD5069 and MEDI4736 on Day 1 up to Day 28 of Cycle 1 or until a participant experiences a DLT, whichever occurs first.
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistical analysis was performed for the outcome measure. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With AEs [2] | ||||||||||||||||||||||||||||||||||||
End point description |
An AE is development of an undesirable medical condition or deterioration of a pre-existing medical condition following or during exposure to study treatment, whether or not considered causally related to study treatment. An undesirable medical condition can be symptoms, signs or abnormal results of an investigation. A serious AE (SAE) is an AE that fulfills one or more following criteria: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital abnormality or birth defect, and an important medical event that may jeopardize participant or may require medical intervention to prevent one of outcomes listed above. AEs leading discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs presented. The safety analysis set analysed.
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End point type |
Primary
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End point timeframe |
From first dose of study treatment administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
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Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistical analysis was performed for the outcome measure. |
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No statistical analyses for this end point |
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End point title |
Objective Response Rate in Cohort 2 [3] [4] | ||||||||
End point description |
ORR is defined as the percentage of participants with a confirmed overall response of complete response (CR) or partial response (PR). A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit and not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. CR is defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD were not met. ORR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1). The efficacy analysis set analysed.
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End point type |
Primary
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End point timeframe |
RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
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Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Duration of Response (DoR) in Cohort 2 [5] | ||||||||
End point description |
DoR was defined as the time from the first documentation of CR/PR (which is subsequently confirmed) until the date of progression/death, or the last evaluable RECIST assessment for participants that did not progress or did progress after 2 missed visits of the last evaluable assessment (or first dose). PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. DoR was determined using Investigator assessments according to RECIST v1.1 and was calculated using the Kaplan-Meier technique. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
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Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Disease Control Rate (DCR) in Cohort 2 [6] | ||||||||||||
End point description |
DCR at 6 months is defined as the percentage of participants who had a best objective response (BoR) of CR or PR in the first 6 months (i.e. 24+1=25 weeks to allow for a late assessment within the assessment window) or who had demonstrated stable disease (SD) for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. DCR at 12 months is defined as the percentage of participants who had a BoR of CR or PR in the first 12 months (i.e. 48+1=49 weeks to allow for a late assessment within the assessment window) or who had demonstrated SD for a minimum interval of 48 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 329 days) following the start of treatment. DCR was determined using Investigator assessments according to RECIST v1.1. The efficacy analysis set analysed.
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End point type |
Secondary
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End point timeframe |
RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days for first 48 weeks up to 6 months and 12 months
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Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Median Progression-Free Survival (PFS) in Cohort 2 [7] | ||||||||
End point description |
PFS is defined as the time from the date of first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from allocated therapy or receives another anticancer therapy prior to progression. PFS was determined using Investigator assessments according to RECIST v1.1 and calculated using the Kaplan-Meier technique. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
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Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2 [8] | ||||||||
End point description |
The PFS rate was defined as percentage of participants alive and progression-free after 3 months. The PFS3 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months
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Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2 [9] | ||||||||
End point description |
The PFS6 was defined as percentage of participants alive and progression-free after 6 months. The PFS6 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months
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Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Median Overall Survival (OS) in Cohort 2 [10] | ||||||||
End point description |
OS is defined as the time from the date of first dose until death due to any cause (i.e. date of death or censoring – date of first dose + 1). OS was calculated using the Kaplan-Meier technique. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (censored at end of study). The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.
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Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Overall Survival at 6 Months (OS6) in Cohort 2 [11] | ||||||||
End point description |
OS6 is defined as percentage of participants alive at 6 months from first dose of study treatment. OS6 was calculated using the Kaplan-Meier estimate of OS at 6 months. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment (Day 1) up to 6 months
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Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Overall Survival at 12 Months (OS12) in Cohort 2 [12] | ||||||||
End point description |
OS12 is defined as percentage of participants alive at 12 months from first dose of study treatment. OS12 was calculated using the Kaplan-Meier estimate of OS at 12 months. The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.
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End point type |
Secondary
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End point timeframe |
From first dose of study treatment (Day 1) up to 12 months
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Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2 [13] | ||||||||||||||||||||
End point description |
Samples were measured for the presence of ADAs and ADA-neutralizing antibodies for MEDI4736 using validated assays. Persistently positive is defined as positive at >=2 post-baseline assessments or positive at the last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available. NAB = neutralizing antibody.
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End point type |
Secondary
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End point timeframe |
On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose
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Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Mean Plasma Concentrations of MEDI4736 in Cohort 2 [14] | ||||||||||||||||||||||
End point description |
Mean peak and trough plasma concentrations of MEDI4736 are presented. The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses. 99999 denotes "standard deviation cannot be calculated when only one participant analyzed". Here, 'n' is number of participants analysed at each specific time point.
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End point type |
Secondary
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End point timeframe |
Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and post infusion (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1 and 7
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Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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End point title |
Mean Plasma Concentrations of AZD5069 in Cohort 2 [15] | ||||||||||||||||||||||||
End point description |
Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile. The PK analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses. 99999 denotes "standard deviation cannot be calculated when only one participant analyzed". Here, 'n' is number of participants analysed at each specific time point.
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End point type |
Secondary
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End point timeframe |
Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and postdose (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1, 2, and 7
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Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Due to a programmatic decision, enrolment of additional participants to cohort 1 was not pursued. Therefore, efficacy analysis was performed on Cohort 2 only. |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
From initial IP administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
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Adverse event reporting additional description |
The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Cohort 1 (MEDI4736 + nab-paclitaxel + gemcitabine)
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Reporting group description |
Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Cohort 2 (MEDI4736 + AZD5069)
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Reporting group description |
Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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29 Mar 2016 |
Updated dose rationale and treatment regimens regarding dose of AZD5069 used, inclusion criteria #3 and #9, and exclusion criteria #14, #15, and #20. Replacement criteria for withdrawn participants in Cohort 1/2 and definition of “evaluable patient” for Cohort 2 clarified. Use, type, and period of contraception before, during, and after trial clarified. Footnotes b, d, and j of Tables 2 and 3 were updated. Removal of section regarding tumor assessment in participants who omit Day 15 dose administration. Removal of requirement for central reading of scans. Management of participants was based solely upon results of assessment conducted by Investigator. Electrocardiogram (ECG) frequency for Cohort 2 updated to screening and Day 1 of each cycle. Vital signs collection time points predose, during and post-dose in Section 5.2.4 clarified. Sections 5.4.5, 5.4.7, and 5.5.5 regarding Biobank used in study amended. Updated to state that recording of AEs in also refers to AESIs. Addition of AESIs associated with MEDI4736. Removal of dose reduction or modification guidance of AZD5069 in as this document does not exist. MEDI4736 dosage and strength clarified. Table 9 removed from Section 7.1.1. Removal of omission of Day 15 treatment in case of participant toxicity Figure 3 updated to correct week schedule of MEDI4736 dose 7. Added clarification that use of cannabinoids must be avoided in participants administered with AZD5069 alone and in combination with MEDI4736. Removal of overall survival text from, as it is duplicate of paragraph. Corrected errors in disease control rate and progression free survival calculation. Start date of study clarified. Removal of soluble programmed cell death ligand 1 tests throughout Protocol. Removal of “lesions <2 centimeters biopsied within screening period (fresh tumor biopsy)” as a non-measurable lesion in as it does not pertain to imaging/RECIST 1.1. Updated toxicity management guidelines to current version. |
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14 Dec 2016 |
Language was updated to reflect fact that recruitment to Cohort 1 was stopped after only 3 participants had been enrolled. Efficacy, immunogenicity and exploratory objectives were removed. New exploratory objectives added. Sections of AZD5069 dose rationale were updated to include language on how dosing was to be managed in Cohort 2, including details regarding a dosing regimen being established at time in Study D4660C00004. Updated introduction, inclusion criterion #3, and exclusion criterion #11, #14, #16, and #19. Discontinuation criterion #9 updated to remove “and Investigator determination that participants is no longer benefiting from treatment with IP”. Updated to remove PK, immunogenicity, and biomarker collections from Cohort 1; included collection of circulating soluble factors, pharmacogenetic sample, circulating tumor DNA and updated times for myeloid-derived suppressor cells and peripheral blood mononuclear cells. Updated to specify that 12-lead ECGs were to be recorded in triplicate for Cohort 2. Updated to reflect which samples were to be analyzed for each cohort. Pharmacogenetics section added for Cohort 2. Added toxicity management for AZD5069 40 mg starting dose. Removed all DLT evaluation text for Cohort 1 and included DLT information for Cohort 2. Updated probability table data for Tables 10 and 11. Added table of posterior probabilities of true DLT incidence >33% with various priors as well as explanatory text for Table 12. Disease control rate was to be evaluated at 6 and 12 months, instead of 3 months. Updated to include most current version of “MEDI4736 Dosing Modification and Toxicity Management Guidelines”. Added information regarding dose toxicity management and alternative dosing regimen for AZD5069 80 mg twice daily currently under exploration. |
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17 Jul 2017 |
Language was updated to reflect the initial dosing of AZD5069 at 80 mg orally twice daily, with provision for dose reductions described in Section 6.7.3. Text throughout Protocol has been updated for consistency. Primary objective was clarified to be inclusive of safety and tolerability of MEDI4736 + AZD5069 in combination, thus separate safety objective was removed. Section has been updated to include the most current clinical data available for MEDI4736. Inclusion criterion #3 text was simplified and Cohort 2 progression timeline for prior therapy was removed. Added inclusion criterion #9 (Cohort 2) for taking mandatory tumor biopsy in screening period (or <45 days prior to first dosing if adequate tissue samples are available). Text throughout the Protocol has been updated for consistency. |
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08 Feb 2018 |
Blood sample changed to ‘serum or plasma’ and non-compartmental analysis removed. Potential risks of MEDI4736 updated to reflect MEDI4736 Investigator’s Brochure Edition 12. Neutropenia/neutrophil count decreased was considered expected for regulatory purposes in the respiratory indication only, but not yet in the oncology population (change arising from alignment with the clinical trials facilitation group Guidelines). Additional sensitivity analysis for overall response rate was removed. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Due to a programmatic decision, enrollment of additional participants to cohort 1 was not pursued. Study terminated by sponsor. |