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Phase II Study of MEDI4736 Monotherapy or in Combinations With Tremelimumab in Metastatic Pancreatic Ductal Carcinoma

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ClinicalTrials.gov Identifier: NCT02558894
Recruitment Status : Completed
First Posted : September 24, 2015
Results First Posted : August 2, 2018
Last Update Posted : August 2, 2018
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE August 27, 2015
First Posted Date  ICMJE September 24, 2015
Results First Submitted Date  ICMJE May 28, 2018
Results First Posted Date  ICMJE August 2, 2018
Last Update Posted Date August 2, 2018
Actual Study Start Date  ICMJE November 16, 2015
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
Objective Response Rate (ORR) in All Patients Using Investigator Assessments According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: 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).
Original Primary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
Objective response rate in all patients using Investigator assessments according to Response Evaluation Criteria in Solid Tumors 1.1 [ Time Frame: From date of first infusion until confirmed disease progression or death for up to 3 years ]
Change History Complete list of historical versions of study NCT02558894 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 9, 2018)
  • Progression-free Survival (PFS) Using Investigator Assessments According to RECIST 1.1 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • Presence of antidrug antibodies(ADAs) for MEDI4736 and tremelimumab. (confirmatory results: positive or negative; titers) [ Time Frame: Up to 1 year ]
    To investigate the immunogenicity of MEDI4736 monotherapy and MEDI4736 + tremelimumab combination therapy
  • Pharmacokinetics of tremelimumab: Peak concentration (Cmax) [ Time Frame: Up to 1 year ]
    Peak concentration in MEDI4736 + tremelimumab combination therapy
  • Pharmacokinetics of MEDI4736: Trough concentration (Ctrough) [ Time Frame: Up to 1 year ]
    Trough concentration in MEDI4736 monotherapy and in combination with tremelimumab
  • Pharmacokinetics of tremelimumab: Trough concentration (Ctrough) [ Time Frame: Up to 1 year ]
    Trough concentration in MEDI4736 + tremelimumab combination therapy
  • Pharmacokinetics of MEDI4736: Peak concentration (Cmax) [ Time Frame: Up to 1 year ]
    Peak concentration in MEDI4736 monotherapy and in combination with tremelimumab
  • Duration of response [ Time Frame: From date of first infusion until confirmed disease progression or death for up to 3 years ]
    To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of duration of response
  • Disease control rate [ Time Frame: From date of first infusion until confirmed disease progression or death for up to 3 years ]
    To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of disease control rate
  • Progression-free survival [ Time Frame: From date of first infusion until confirmed disease progression or death for up to 3 years ]
    To further assess the efficacy of the combination of MEDI4736 and tremelimumab and MEDI4736 alone in terms of progression-free survival
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase II Study of MEDI4736 Monotherapy or in Combinations With Tremelimumab in Metastatic Pancreatic Ductal Carcinoma
Official Title  ICMJE A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination With Tremelimumab in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
Brief Summary A Phase II Open-Label, Multi-Center Study of MEDI4736 Evaluated as Single Agent or in Combination with Tremelimumab in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.
Detailed Description 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Pancreatic Ductal Adenocarcinoma
Intervention  ICMJE
  • Drug: MEDI4736 monotherapy
    MEDI4736 via IV infusion.
  • Drug: tremelimumab+MEDI4736
    tremelimumab+MEDI4736 via IV infusion.
Study Arms  ICMJE
  • Experimental: MEDI4736 monotherapy
    MEDI4736 via IV infusion.
    Intervention: Drug: MEDI4736 monotherapy
  • Experimental: tremelimumab+MEDI4736
    MEDI4736+tremelimumab via IV infusion.
    Intervention: Drug: tremelimumab+MEDI4736
Publications * 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 Jul 18. doi: 10.1001/jamaoncol.2019.1588. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 8, 2017)
65
Original Estimated Enrollment  ICMJE
 (submitted: September 23, 2015)
130
Actual Study Completion Date  ICMJE June 15, 2017
Actual Primary Completion Date June 15, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Germany,   Korea, Republic of,   Netherlands,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02558894
Other Study ID Numbers  ICMJE D4198C00001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Eileen M O'Reilly, M.D Memorial Sloan Kettering Cancer Center, 300 East 66th Street,New York,NY 10065
PRS Account AstraZeneca
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP