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Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

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Official Title

A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination with Tremelimumab in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

Phase II Study of MEDI4736 monotherapy or in combinations with Tremelimumab in Metastatic Pancreatic Ductal Carcinoma

This is a Phase II, open-label, multi-center study to determine the efficacy and safety of MEDI4736 evaluated as single agent or in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) whose disease has progressed on fluoropyrimidine containing or gemcitabine-containing first-line chemotherapy.This study will consist of Part A, lead-in, as well as a possible expansion Part B.

NCT ID

Patient Level Data

Therapeutic Area

Research Site

A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination with Tremelimumab in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Age Continuous

Sex: Female, Male

Race (NIH/OMB)

Ethnicity (NIH/OMB)

All patients in the FAS who were randomised to treatment were included in the baseline analysis.

Study consisted of Part A Lead-in and 2 possible options for Part B: non-randomised expansion or randomised controlled trial. Criteria to open either option for Part B were not met and study was closed prematurely. Only Part A was conducted.

Confirmed responses only

Confirmed and unconfirmed responses

ORR was defined as the percentage of patients with at least one visit response of confirmed complete response (CR) or partial response (PR). CR was defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have had reduction in short axis to <10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters. A confirmed response meant that a response of CR/PR was 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 response was first observed with no evidence of progression between the initial and CR/PR confirmation visits. Results are reported as percentage of patients with a confirmed response and percentage of patients with confirmed or unconfirmed responses (i.e., including single visit responses).

The FAS included all randomised patients.

Objective Response Rate (ORR) in all patients using Investigator assessments according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)

PFS was defined as the time from the date of randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient had withdrawn from randomised therapy or had received another anti-cancer therapy prior to progression. Results are reported as median time from randomisation to PFS, calculated using the Kaplan-Meier technique.

Progression-free survival (PFS) using Investigator assessments according to RECIST 1.1

PFS rate at 3 months

PFS rate at 6 months

PFS was defined as the time from the date of randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient had withdrawn from randomised therapy or had received another anti-cancer therapy prior to progression. PFS rates were calculated using Kaplan-Meier estimates of the cumulative probability of PFS. The PFS rate at 3 months and 6 months was equivalent to the percentage of patients with PFS after 3 months and 6 months, respectively.

PFS rate at 3 months and at 6 months

OS was defined as the time from the date of randomisation until death due to any cause. Results are reported as median OS, calculated using the Kaplan-Meier technique.

Overall Survival (OS)

Survival rate at 6 months

Survival rate at 12 months

OS was defined as the time from the date of randomisation until death due to any cause. OS rates were calculated using Kaplan-Meier estimates of the cumulative probability of survival at each indicated time period. The OS rate at 6 months and 12 months was equivalent to the percentage of patients with OS after 6 months and 12 months, respectively.

Survival status, presented as OS rate, at 6 months and at 12 months

Response: Total

Response: CR

Response: PR

Non-response: Total

Non-response: Stable disease ≥6 weeks

Non-response: Progression of disease

Non-response: Not evaluable

BoR was calculated based on the overall visit responses from each RECIST assessment. It was the best response a patient had following date of first dosing but prior to starting any subsequent cancer therapy and prior to RECIST progression or last evaluable assessment in absence of RECIST progression. Categorisation of BoR was based on RECIST using the following response categories: CR and PR for status of ‘Response’; Stable Disease (SD) ≥6 weeks, Progressive Disease (PD) and Not Evaluable (NE) for status of ‘Non-response’. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of diameters of TLs taking as reference the smallest sum on study. NE was only relevant if any of the TLs were not assessed or not evaluable or had a lesion intervention at this visit. Results are reported as number of patients with BoR for each of the indicated categories.

Best Objective Response (BoR) using Investigator assessments according to RECIST 1.1

At 3 months

At 6 months

At 12 months

DCR at 3 months was defined as the percentage of patients who have a BoR of CR or PR in the first 3 months or who have demonstrated SD for a minimum interval of 13 weeks following the start of treatment. DCR at 6 months was defined as the percentage of patients who have a BoR of CR or PR in the first 6 months or who have demonstrated SD for a minimum interval of 26 weeks following the start of treatment. DCR at 12 months was defined as the percentage of patients who have a BoR of CR or PR in the first 12 months or who have demonstrated SD for a minimum interval of 52 weeks following the start of treatment. Results are reported as the percentage of patients with disease control for each of the indicated categories.

Disease control rate (DCR) using Investigator assessments according to RECIST 1.1

Cycle 1, Day 1, pre-infusion (Day 1)

Cycle 1, Day 1, post-infusion (Day 1)

Cycle 2, Day 1, pre-infusion (Day 29)

Cycle 4, Day 1, pre-infusion (Day 85)

Cycle 4, Day 1, post-infusion (Day 85)

Cycle 7, Day 1, pre-infusion (Day 169)

Cycle 7, Day 1, post-infusion (Day169)

3-month follow-up

To evaluate PK, blood samples were collected pre- and post-dose and durvalumab (MEDI4736) concentrations in serum were determined. On Day 1 of Cycles 1, 4 and 7 (Weeks 0, 12 and 24), PK samples were collected pre-dose (within 60 minutes prior to treatment with any IP) and post-dose at the end of infusion (within 10 minutes of end of infusion of durvalumab and within 10 minutes of end of infusion of tremelimumab [for patients receiving durvalumab plus tremelimumab]). On Day 1 of Cycle 2 (Week 4), PK samples were collected pre-dose (within 60 minutes prior to treatment with any IP) only. The 3-month follow-up sample for durvalumab was relative to the respective last dose. Results are reported as mean pre- or post-dose durvalumab concentrations as indicated by the individual categories (1 cycle=4 weeks). Samples below lower limit of quantification were treated as missing in the analyses.

The PK analysis set included all patients who received at least 1 dose of IP, and had PK sampling data post-dose without important deviations or events to affect PK (n=64). Only patients with data available at the timepoints of testing were included in the analyses.

Pharmacokinetics (PK) of durvalumab (MEDI4736)

To evaluate PK, blood samples were collected pre- and post-dose and tremelimumab concentrations in serum were determined. On Day 1 of Cycles 1 and 4 (Weeks 0 and 12), PK samples were collected pre-dose (within 60 minutes prior to treatment with any IP) and post-dose at the end of infusion (within 10 minutes of end of infusion of tremelimumab). On Day 1 of Cycle 2 (Week 4), PK samples were collected pre-dose (within 60 minutes prior to treatment with any IP) only. The 3-month follow-up sample for tremelimumab was relative to the respective last dose. Results are reported as mean pre- or post-dose tremelimumab concentrations as indicated by the individual categories (1 cycle=4 weeks). Samples below lower limit of quantification were treated as missing in the analyses.

PK of tremelimumab

ADA prevalence

ADA incidence

ADA pos post-baseline and pos at baseline

ADA pos post-baseline and not detected at baseline

ADA not detected post-baseline and pos at baseline

Treatment-boosted ADA

Persistent positive

Transient positive

Never positive

ADA prevalence was the proportion of the ADA evaluable set who had an ADA positive result at any point in time, baseline or post-baseline. ADA incidence (treatment-emergent ADA) was the sum of both treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA positive patients as a proportion of the evaluable patient population. Treatment-boosted ADA was defined as baseline positive ADA titre boosted to a 4-fold or higher level following IP administration. Persistently positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Results are reported as number of patients with detectable anti-durvalumab antibodies satisfying each of the indicated categories. Note: 'positive' is denoted by 'pos' in some category titles.

The ADA evaluable set included all patients in the safety analysis set (i.e. those who had received any IP) who had non-missing baseline ADA data and at least 1 non-missing post-baseline ADA result.

Presence of antidrug antibodies (ADAs) for durvalumab (MEDI4736)

ADA prevalence was the proportion of the ADA evaluable set who had an ADA positive result at any point in time, baseline or post-baseline. ADA incidence (treatment-emergent ADA) was the sum of both treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA positive patients as a proportion of the evaluable patient population. Treatment-boosted ADA was defined as baseline positive ADA titre boosted to a 4-fold or higher level following IP administration. Persistently positive was defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive was defined as at least 1 post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Results are reported as number of patients with detectable anti- tremelimumab antibodies satisfying each of the indicated categories. Note: 'positive' is denoted by 'pos' in some category titles.

Presence of ADAs for tremelimumab

Overall Study

65 patients were randomised to receive investigational product (IP) and 64 received treatment. One randomised patient in the durvalumab monotherapy arm was withdrawn prior to receiving any IP but was still included in the full analysis set (FAS) which was used for participant flow and baseline analysis.

Global Clinical Lead

To investigate the immunogenicity of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy

Peak concentration in MEDI4736 + tremelimumab combination therapy

Trough concentration in MEDI4736 monotherapy and in combination with tremelimumab

Trough concentration in MEDI4736 + tremelimumab combination therapy

Peak concentration in MEDI4736 monotherapy and in combination with tremelimumab

To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of duration of response

To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of disease control rate

To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of progression-free survival

Arms	Assigned Interventions
Experimental: MEDI4736 monotherapy MEDI4736 via IV infusion.	Drug: MEDI4736 monotherapy MEDI4736 via IV infusion. Other Name: NA
Experimental: tremelimumab+MEDI4736 MEDI4736+tremelimumab via IV infusion.	Drug: tremelimumab+MEDI4736 tremelimumab+MEDI4736 via IV infusion. Other Name: NA

Phase II Study of MEDI4736 monotherapy or in combinations with Tremelimumab in Metastatic Pancreatic Ductal Carcinoma

Official Title

Medical condition

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Healthy volunteers

Study drug

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Actual Enrollment

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Study design

Verification:

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Documents available

redacted csp

Redacted SAP

Trial Results Summaries

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Investigators

Principal Investigator