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.

• MEDI4736 monotherapy (Drug): MEDI4736 via IV infusion.
• tremelimumab+MEDI4736 (Drug): tremelimumab+MEDI4736 via IV infusion.

Primary outcomes

• Objective Response Rate (ORR) in All Patients Using Investigator Assessments According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [From date of first infusion until confirmed disease progression or death (up to approximately 18 months for the data analysis cut-off)]: 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).

Secondary outcomes

• Progression-free Survival (PFS) Using Investigator Assessments According to RECIST 1.1 [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disease progression or death (by any cause in the absence of progression) regardless of whether the patient had withdrawn from randomised therapy or had received another anti-cancer therapy prior to progression.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 are reported as median time from randomisation to PFS, calculated using the Kaplan-Meier technique.
• PFS Rate at 3 Months and at 6 Months [From date of first infusion until confirmed disease progression or death (up to 3 months and 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.
• Overall Survival (OS) [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. Results are reported as median OS, calculated using the Kaplan-Meier technique.
• Survival Status, Presented as OS Rate, at 6 Months and at 12 Months [From date of first infusion until death (up to 6 months and 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.
• Best Objective Response (BoR) Using Investigator Assessments According to RECIST 1.1 [From date of first infusion until confirmed disease progression or death (up to approximately 18 months for the data analysis cut-off)]: 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.
• Disease Control Rate (DCR) Using Investigator Assessments According to RECIST 1.1 [From date of first infusion until confirmed disease progression or death (up to 3 months, 6 months and 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.
• Pharmacokinetics (PK) of Durvalumab (MEDI4736) [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 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.
• PK of Tremelimumab [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).]: 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.
• Presence of Antidrug Antibodies (ADAs) for Durvalumab (MEDI4736) [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 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.
• Presence of ADAs for Tremelimumab [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).]: 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.

Sex: All, ages: 18 Years to any

Inclusion Criteria: -

1. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior chemotherapy regimen
2. Eastern Cooperative Oncology Group 0 or 1
3. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements

Exclusion Criteria:

1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
2. History of leptomeningeal carcinomatosis
3. Ascites requiring intervention
4. Brain metastases or spinal cord compression.

Participant flow

Outcome results

• Objective Response Rate (ORR) in All Patients Using Investigator Assessments According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Primary), Number, Percentage of participants: Durvalumab (MEDI4736) Plus Tremelimumab 3.1 (0.08 to 16.22); Durvalumab (MEDI4736) Monotherapy 0 (0 to 10.58)
• Progression-free Survival (PFS) Using Investigator Assessments According to RECIST 1.1 (Secondary), Median, Months: Durvalumab (MEDI4736) Plus Tremelimumab 1.5 (1.2 to 1.5); Durvalumab (MEDI4736) Monotherapy 1.5 (1.3 to 1.5)
• PFS Rate at 3 Months and at 6 Months (Secondary), Number, Percentage of participants: Durvalumab (MEDI4736) Plus Tremelimumab 9.4 (2.4 to 22.3); Durvalumab (MEDI4736) Monotherapy 10.9 (3.0 to 24.7)
• Overall Survival (OS) (Secondary), Median, Months: Durvalumab (MEDI4736) Plus Tremelimumab 3.1 (2.2 to 6.1); Durvalumab (MEDI4736) Monotherapy 3.6 (2.7 to 6.1)
• Survival Status, Presented as OS Rate, at 6 Months and at 12 Months (Secondary), Number, Percentage of participants: Durvalumab (MEDI4736) Plus Tremelimumab 36.2 (20.0 to 52.7); Durvalumab (MEDI4736) Monotherapy 34.9 (19.2 to 51.1)
• Best Objective Response (BoR) Using Investigator Assessments According to RECIST 1.1 (Secondary), Count of participants, Participants: Durvalumab (MEDI4736) Plus Tremelimumab 1; Durvalumab (MEDI4736) Monotherapy 0
• Disease Control Rate (DCR) Using Investigator Assessments According to RECIST 1.1 (Secondary), Number, Percentage of participants: Durvalumab (MEDI4736) Plus Tremelimumab 9.4 (1.98 to 25.02); Durvalumab (MEDI4736) Monotherapy 6.1 (0.74 to 20.23)
• Pharmacokinetics (PK) of Durvalumab (MEDI4736) (Secondary), Mean, Micrograms per millilitre (mcg/mL): Durvalumab (MEDI4736) Plus Tremelimumab 217.338 +/- 345.4913; Durvalumab (MEDI4736) Monotherapy
• PK of Tremelimumab (Secondary), Mean, mcg/mL: Durvalumab (MEDI4736) Plus Tremelimumab 13.114 +/- 11.7182
• Presence of Antidrug Antibodies (ADAs) for Durvalumab (MEDI4736) (Secondary), Count of participants, Participants: Durvalumab (MEDI4736) Plus Tremelimumab 1; Durvalumab (MEDI4736) Monotherapy 5
• Presence of ADAs for Tremelimumab (Secondary), Count of participants, Participants: Durvalumab (MEDI4736) Plus Tremelimumab 2

Adverse events

Time frame: Treatment-emergent adverse event (TEAE) data is reported for the treatment period (up to 12 months) + follow-up (up to 90 days). Overall timeframe: up to approximately 15 months.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: 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.

• Results publication: O'Reilly EM, Oh DY, Dhani N, Renouf DJ, Lee MA, Sun W, Fisher G, Hezel A, Chang SC, Vlahovic G, Takahashi O, Yang Y, Fitts D, Philip PA. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019 Oct 1;5(10):1431-1438. doi: 10.1001/jamaoncol.2019.1588. PMID 31318392

• Study Protocol (PDF, 2015-08-17)
• Statistical Analysis Plan (PDF, 2017-02-27)

• Eileen M O'Reilly, M.D, Principal investigator, Memorial Sloan Kettering Cancer Center, 300 East 66th Street,New York,NY 10065