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

NCT02583477 | Completed Phase 1 Results FDA Drug

• 1 other identifier: D4198C00003
• Study Type: interventional
• Target: 23
• Locations: 2 countries
• Sites: 7

Brief Summary

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

Conditions

Metastatic Pancreatic Ductal Adenocarcinoma

Keywords

Pancreatic Ductal Adenocarcinoma, PDAC, immunotherapy, PDL1, AZD5069, MEDI4736

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Dose-Limiting Toxicities (DLT)

  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.

  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.

• Number of Participants With AEs

  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.

  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.

• Objective Response Rate (ORR) in Cohort 2

  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).

  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.

Secondary Outcomes (11)

• 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.

• 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

• 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.

• 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

• 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

Study Arms (2)

MEDI4736 +nab-paclitaxel + gemcitabine

EXPERIMENTAL

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

Drug: MEDI4736 in combination with nab-paclitaxel and gemcitabine

MEDI4736+AZD5069

EXPERIMENTAL

MEDI4736 via IV infusion and oral AZD5069

Drug: MEDI4736 in combination with AZD5069

Interventions

MEDI4736 in combination with nab-paclitaxel and gemcitabine DRUG

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

MEDI4736 +nab-paclitaxel + gemcitabine

MEDI4736 in combination with AZD5069 DRUG

MEDI4736 via IV infusion and oral AZD5069

MEDI4736+AZD5069

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior chemotherapy regimen or treatment-naïve patients
• Eastern Cooperative Oncology Group 0 or 1
• 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
• 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.
• \. 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.

You may not qualify if:

• Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.
• Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
• Major surgical procedure within 21 days prior to the first dose of IP.
• Patients weighing less than 30 kg
• History of leptomeningeal carcinomatosis
• Ascites requiring intervention
• Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy
• Current or prior use of immunosuppressive medication within 14 days of first dose
• Brain metastases or spinal cord compression.
• 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
• Uncontrolled intercurrent illness
• Other malignancy within 5 years except for noninvasive malignancies
• Mean QT interval ≥470 ms
• Active infection
• Receipt of live attenuated vaccine within 30 days prior to the first dose of IP

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (7)

Research Site

Rochester, New York, 14642, United States

Location

Research Site

Cambridge, CB2 0QQ, United Kingdom

Location

Research Site

Glasgow, G12 0YN, United Kingdom

Location

Research Site

London, SE1 9RY, United Kingdom

Location

Research Site

London, W12 0NN, United Kingdom

Location

Research Site

Manchester, M20 4BX, United Kingdom

Location

Research Site

Metropolitan Borough of Wirral, CH63 4JY, United Kingdom

Location

Related Links

• CSP redacted
• SAP redacted

MeSH Terms

Conditions

Anophthalmia with pulmonary hypoplasia

Interventions

durvalumab; 130-nm albumin-bound paclitaxel; Gemcitabine; N-(2-(2,3-difluoro-6-benzylthio)-6-(3,4-dihydroxybutan-2-yloxy)pyrimidin-4-yl)azetidine-1-sulfonamide

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring

Limitations and Caveats

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

Results Point of Contact

• Title: Global Clinical Lead
• Organization: AstraZeneca

ClinicalTrialTransparency@astrazeneca.com

+1 302 885 1180

Study Officials

• Jeff Evans, M.D

  Beatson Institute, University of Glasgow, Garscrube Estate, Switchback Rd. Glasgow, UK, G61 1BD

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 20, 2015
• First Posted: October 22, 2015
• Study Start: March 25, 2016
• Primary Completion: July 9, 2018
• Study Completion: July 9, 2018
• Last Updated: August 14, 2019
• Results First Posted: August 14, 2019

Record last verified: 2019-07

Locations

US (1); GB (6)