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MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion

MEDI4736 via IV infusion and oral AZD5069

MEDI4736 in combination with nab-paclitaxel and gemcitabine

MEDI4736 in combination with AZD5069

Jeff Evans, M.D

A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations (with chemotherapy or AZD5069) in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

This is a Phase Ib and II open-label, multi-center study to evaluate the safety, tolerability, pharmacodynamics, and antitumor activity of MEDI4736 in combination with chemotherapy or AZD5069 in patients with pancreatic ductal adenocarcinoma (PDAC). This study will consist of 2 independent cohorts.

Phase Ib/II Study of MEDI4736 Evaluated in Different Combinations in Metastatic Pancreatic Ductal Carcinoma

A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients With Metastatic Pancreatic Ductal Adenocarcinoma

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 defined as any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 collected 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 defined as any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period.

An AE is the 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 to discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs were presented.

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).

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.

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.

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 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 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.

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).

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.

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.

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. NAB = neutralizing antibody.

Mean peak and trough plasma concentrations of MEDI4736 are presented.

Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile.

AstraZeneca

The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.

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.

Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)

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.

Cohort 2 (MEDI4736 + AZD5069)

Total

Age, Customized

Sex: Female, Male

Race/Ethnicity, Customized

Due to a programmatic decision, enrollment of additional participants to cohort 1 was not pursued. The study was terminated by sponsor.

Global Clinical Lead

For Cohort 1: Participants who completed DLT evaluation period and/or discontinued study treatment early due to a DLT and who have not missed \>=2 infusions of gemcitabine.

For Cohort 2: Participants who received 50% of planned doses of AZD5069 during DLT period as well as MEDI4736 infusion and remained active on study at end of Day 28 of Cycle 1.

Number of Participants With Dose-Limiting Toxicities (DLT)

Any AE

Any AE causally related to treatment (CRT)

Any AE of CTCAE Grade 3 or higher

Any AE of CTCAE Grade 3 or higher CRT

Any AE leading discontinuation of study treatment

Any AE with outcome of death

Any AE with outcome of death CRT

Any SAE

Any SAE CRT

Number of Participants With AEs

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.

Objective Response Rate (ORR) in Cohort 2

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. Participants with confirmed response were evaluated, only one participant showed response.

Duration of Response (DoR) in Cohort 2

At 6 months

At 12 months

Disease Control Rate (DCR) in Cohort 2

Median Progression-Free Survival (PFS) in Cohort 2

Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2

Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2

Median Overall Survival (OS) in Cohort 2

Overall Survival at 6 Months (OS6) in Cohort 2

Overall Survival at 12 Months (OS12) in Cohort 2

Positive at any visit

Both baseline and post-baseline positive

Only post-baseline positive

Only baseline positive

ADA persistently positive

ADA transiently positive

ADA positive participants who are NAB positive

Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2

Cycle 1 Day 1: Predose

Cycle 1 Day 1: Post infusion

Cycle 2 Day 1: Predose

Cycle 3 Day 1: Predose

Cycle 4 Day 1: Predose

Cycle 7 Day 1: Predose

Cycle 7 Day 1: Post infusion

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.

Mean Plasma Concentrations of MEDI4736 in Cohort 2

Cycle 1 Day 1: Postdose

Cycle 2 Day 1: Postdose

Cycle 7 Day 1: Postdose

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.

Mean Plasma Concentrations of AZD5069 in Cohort 2

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.

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.

Spots Global Cancer Trial Database for medi4736 in combination with azd5069