D4198C00001

AstraZeneca

One Medimmune Way, Gaithersburg, United States, MD 20878

Global Clinical Lead, AstraZeneca, 1 3013980000, ClinicalTrialTransparency@astrazeneca.com

Global Clinical Lead, AstraZeneca, 1 3013980000, ClinicalTrialTransparency@astrazeneca.com

No

No

No

Final

15 Jun 2017

Yes

15 Jun 2017

Yes

15 Jun 2017

Yes

To assess the efficacy of durvalumab (MEDI4736) monotherapy and durvalumab (MEDI4736) + tremelimumab combination therapy in terms of Objective Response Rate (ORR).

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 Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological Samples.

16 Nov 2015

No

No

Canada: 20

Germany: 5

Netherlands: 8

Korea, Republic of: 24

Spain: 4

United States: 4

65

17

0

0

0

0

0

0

40

25

0

Overall Study (overall period)

Randomised - controlled

Yes

Durvalumab

MEDI4736

Solution for infusion

Intravenous use

Patients received 1.5 g durvalumab via IV infusion q4w (up to 13 doses) administered as a 50 mg per millilitre (mg/mL) solution.

Tremelimumab

Solution for infusion

Intravenous use

Patients received 75 mg tremelimumab via IV infusion q4w (up to 4 doses) administered as a 20 mg/mL solution.

Durvalumab

MEDI4736

Solution for infusion

Intravenous use

Patients received 1.5 g durvalumab via IV infusion q4w (up to 13 doses) administered as a 50 mg/mL solution.

Durvalumab (MEDI4736) plus tremelimumab

Durvalumab (MEDI4736) monotherapy

Durvalumab (MEDI4736) plus tremelimumab

Durvalumab (MEDI4736) monotherapy

ORR was defined as percentage of patients with at least 1 visit response of confirmed complete response (CR) or partial response (PR). CR 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 defined as at least a 30% decrease in sum of diameters of TLs, taking as reference the baseline sum of diameters. A confirmed response meant a response of CR/PR recorded at 1 visit and confirmed by repeat imaging, preferably at next regularly scheduled imaging visit and not less than 4 weeks after visit when response was first observed with no evidence of progression between initial and CR/PR confirmation visits. Results reported as percentage of patients with confirmed response and percentage of patients with confirmed or unconfirmed responses (i.e., including single visit responses). Analysis performed on full analysis set (FAS), comprising all randomised patients.

Primary

From date of first infusion until confirmed disease progression or death (up to approximately 18 months for the data analysis cut-off)

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 reported as median time from randomisation to PFS, calculated using the Kaplan-Meier technique. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until confirmed disease progression or death (up to approximately 18 months for the data analysis cut-off)

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. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until confirmed disease progression or death (up to 3 months and 6 months)

OS was defined as the time from the date of randomisation until death due to any cause. Results reported as median OS, calculated using the Kaplan-Meier technique. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until death (up to approximately 18 months for the data analysis cut-off)

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. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until death (up to 6 months and 12 months)

BoR was based on the overall visit responses from each RECIST assessment. It was 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 20% increase in 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 reported as number of patients with BoR for each of indicated categories. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until confirmed disease progression or death (up to approximately 18 months for the data analysis cut-off)

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 reported as the percentage of patients with disease control for each of the indicated categories. Analysis performed on FAS, comprising all randomised patients.

Secondary

From date of first infusion until confirmed disease progression or death (up to 3 months, 6 months and 12 months)

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 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 + 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 reported as mean pre- and 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 receiving at least 1 dose of IP who had evaluable PK data post-dose.

Secondary

Blood samples were collected pre-dose on Day 1 (Week 0), Week 4, Week 12 and Week 24, post-dose on Day 1, Week 12 and Week 24, and additionally at 3 months after the last dose (follow-up).

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. Results are reported as mean pre- and 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. The PK analysis set included all patients receiving at least 1 dose of IP who had evaluable PK data post-dose.

Secondary

Blood samples were collected pre-dose on Day 1 (Week 0), Week 4 and Week 12, post-dose on Day 1 and Week 12, and additionally at 3 months after the last dose (follow-up).

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 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.

Secondary

Immunogenicity samples were collected on Day 1 (Week 0), Week 4, Week 12 and Week 24, and additionally at 3 months and 6 months after the last dose (follow-up).

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 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.

Secondary

Immunogenicity samples were collected on Day 1 (Week 0), Week 4 and Week 12, and additionally at 3 months and 6 months after the last dose (follow-up).

Adverse event (AE) data is reported for the treatment period (up to 12 months) + follow-up (up to 90 days). Overall timeframe: up to approximately 15 months.

Treatment-emergent AEs were defined with an onset date on or after date of first dose or pre-treatment AEs that increased in severity on or after date of first dose up to and including 90 days following date of last dose of study treatment or up to and including date of initiation of the first subsequent therapy (whichever occurred first).

20.0

Durvalumab (MEDI4736) plus tremelimumab

Durvalumab (MEDI4736) monotherapy