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

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.

• MEDI4736 in combination with nab-paclitaxel and gemcitabine (Drug): MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion
• MEDI4736 in combination with AZD5069 (Drug): MEDI4736 via IV infusion and oral AZD5069

Primary outcomes

• Number of Participants With Dose-Limiting Toxicities (DLT) [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.]: 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.
• Number of Participants With AEs [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.]: 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.
• Objective Response Rate (ORR) in Cohort 2 [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.]: 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).

Secondary outcomes

• Duration of Response (DoR) in Cohort 2 [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.]: 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.
• Disease Control Rate (DCR) in Cohort 2 [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]: 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.
• Median Progression-Free Survival (PFS) in Cohort 2 [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.]: 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.
• Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2 [RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months]: 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.
• Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2 [RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months]: 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.
• Median Overall Survival (OS) in Cohort 2 [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.]: 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).
• Overall Survival at 6 Months (OS6) in Cohort 2 [From first dose of study treatment (Day 1) up to 6 months]: 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.
• Overall Survival at 12 Months (OS12) in Cohort 2 [From first dose of study treatment (Day 1) up to 12 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.
• Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2 [On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose]: 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 Plasma Concentrations of MEDI4736 in Cohort 2 [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]: Mean peak and trough plasma concentrations of MEDI4736 are presented.
• Mean Plasma Concentrations of AZD5069 in Cohort 2 [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]: Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile.

Sex: All, ages: 18 Years to 130 Years

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior chemotherapy regimen or treatment-naïve patients
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
4. MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy cohort: treatment-naïve patients with metastatic PDAC who have received no previous systemic chemotherapy 5 MEDI4736 + Cohort: Patient should receive no more than 1 prior systemic chemotherapy regimen.

6\. Life expectancy ≥ 12 weeks. 7. ECOG PS of 0 or 1 8. Adequate organ and bone marrow function 9. Ability to undergo during screening a tumor biopsy that is adequate for biomarker analysis.

Exclusion Criteria:

1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
2. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
3. Major surgical procedure within 21 days prior to the first dose of IP.
4. Patients weighing less than 30 kg
5. History of leptomeningeal carcinomatosis
6. Ascites requiring intervention
7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy
8. Current or prior use of immunosuppressive medication within 14 days of first dose
9. Brain metastases or spinal cord compression.
10. Medi4736+AZD5069 Cohort only: received any potent and moderate cytochrome CYP3A4 inhibitors, potent and moderate CYP3A4 inducers, P-gp substrates, BCRP substrates, sensitive CYP2B6 substrates, warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment
11. Uncontrolled intercurrent illness
12. Other malignancy within 5 years except for noninvasive malignancies
13. Mean QT interval ≥470 ms
14. Active infection
15. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP
16. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control
17. Prior exposure to immune-mediated therapy
18. Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies

Participant flow

Outcome results

• Number of Participants With Dose-Limiting Toxicities (DLT) (Primary), Count of participants, Participants: Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine) 0; Cohort 2 (MEDI4736 + AZD5069) 4
• Number of Participants With AEs (Primary), Count of participants, Participants: Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine) 3; Cohort 2 (MEDI4736 + AZD5069) 20
• Objective Response Rate (ORR) in Cohort 2 (Primary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 5.6 (0.58 to 19.95)
• Duration of Response (DoR) in Cohort 2 (Secondary), Median, weeks: Cohort 2 (MEDI4736 + AZD5069) 18.29 (18.29 to 18.29)
• Disease Control Rate (DCR) in Cohort 2 (Secondary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 11.1
• Median Progression-Free Survival (PFS) in Cohort 2 (Secondary), Median, months: Cohort 2 (MEDI4736 + AZD5069) 1.6 (1.29 to 1.68)
• Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2 (Secondary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 11.1 (3.91 to 22.55)
• Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2 (Secondary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 11.1 (3.91 to 22.55)
• Median Overall Survival (OS) in Cohort 2 (Secondary), Median, months: Cohort 2 (MEDI4736 + AZD5069) 2.8 (1.68 to 3.79)
• Overall Survival at 6 Months (OS6) in Cohort 2 (Secondary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 22.2 (11.19 to 35.59)
• Overall Survival at 12 Months (OS12) in Cohort 2 (Secondary), Number, percentage of participants: Cohort 2 (MEDI4736 + AZD5069) 14.8 (5.74 to 27.92)
• Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2 (Secondary), Count of participants, Participants: Cohort 2 (MEDI4736 + AZD5069) 3
• Mean Plasma Concentrations of MEDI4736 in Cohort 2 (Secondary), Mean, nanograms per milliliter: Cohort 2 (MEDI4736 + AZD5069) 1444.730 +/- 1010.7667
• Mean Plasma Concentrations of AZD5069 in Cohort 2 (Secondary), Mean, nanomoles per liter: Cohort 2 (MEDI4736 + AZD5069) 10.60 +/- 42.933

Adverse events

Time frame: 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.

Serious adverse events by term

Other adverse events by term

53 more terms not shown.

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

• Study Protocol (PDF, 2018-02-08)
• Statistical Analysis Plan (PDF, 2018-08-02)

• Jeff Evans, M.D, Principal investigator, Beatson Institute, University of Glasgow, Garscrube Estate, Switchback Rd. Glasgow, UK, G61 1BD