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Immunotherapy in Combination With Chemoradiation in Patients With Advanced Solid Tumors (CLOVER)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03509012
Recruitment Status : Active, not recruiting
First Posted : April 26, 2018
Last Update Posted : September 29, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE March 12, 2018
First Posted Date  ICMJE April 26, 2018
Last Update Posted Date September 29, 2020
Actual Study Start Date  ICMJE May 2, 2018
Estimated Primary Completion Date April 4, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 2, 2019)
  • Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: From first dose of durvalumab until 28 days after completion of radiation therapy ]
  • Number of subjects with Adverse Events (AEs) [ Time Frame: From first dose of durvalumab up to 90 days after the last dose of study treatment ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
  • Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: From the time of the first dose of durvalumab until 28 days after completion of radiation therapy ]
    A DLT is defined as the occurrence of a severe AE (specified per protocol) that is at least possibly related to durvalumab or tremelimumab. AEs will be graded according to the National Cancer Institute (NCI CTCAE) version 4.03. Collected only for Part A
  • Number of subjects with Adverse Events (AEs) [ Time Frame: From baseline up to 90 days after the last dose of study treatment ]
    AEs will be graded according to the National Cancer Institute (NCI CTCAE) version 4.03.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 2, 2019)
  • Progression-free survival (PFS) [ Time Frame: From first dose until the date of objective disease progression or death, in the absence of progression at 12, 18 and 24 months, up to 4 years. ]
  • Overall Survival (OS) [ Time Frame: From first dose until death due to any cause through study completion, up to 4 years ]
  • Objective response rate (ORR) [ Time Frame: From first dose until disease progression, or the last evaluable assessment in the absence of progression, assessed up to 4 years. ]
    Number (%) of patients with an overall response of complete response (CR) or partial response (PR).
  • Best objective response (BoR) [ Time Frame: From first dose until disease progression, or the last evaluable assessment in the absence of progression, assessed up to 4 years. ]
    The best response based on the overall visit responses from each RECIST 1.1 assessment or the last evaluable assessment in the absence of RECIST 1.1 progression.
  • Duration of response (DoR) [ Time Frame: From first dose until disease progression, or death, in the absence of progression, assessed up to 4 years. ]
    Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression.
  • Disease control rate (DCR) [ Time Frame: From first dose until disease progression, at 18 weeks and 48 weeks. ]
  • Disease-free survival (DFS) [ Time Frame: From first dose until disease progression or death, in the absence of progression at 12, 18 and 24 months, assessed up to 4 years. ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2018)
  • Progression-free survival at 12 months (PFS12) [ Time Frame: From baseline until the date of objective disease progression or death, whichever came first, at 12 months. ]
    Defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the Investigator). NSCLC and SCLC cohorts.
  • Overall Survival (OS) [ Time Frame: From the date of the first dose until death due to any cause, through study completion, up to 4 years. ]
    Defined as the time from the date of first dose until death due to any cause. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. NSCLC and SCLC cohorts
  • Objective response rate (ORR) [ Time Frame: From baseline up until disease progression, or the last evaluable assessment (RECIST 1.1) in the absence of progression, assessed through study completion, up to 4 years. ]
    Number (%) of patients with an overall response of complete response (CR) or partial response (PR).
  • Best objective response (BoR) [ Time Frame: From baseline until disease progression, follow up assessments (RECIST 1.1) starts at week 16 (post first dose of durvalumab) and continue every 8 weeks until week 48 and after every 12 weeks, assessed through study completion, up to 4 years. ]
    The best response based on the overall visit responses from each RECIST 1.1 assessment or the last evaluable assessment in the absence of RECIST 1.1 progression.
  • Duration of response (DoR) [ Time Frame: From baseline until disease progression, follow up assessments (RECIST 1.1) starts at week 16 (post first dose of durvalumab) and continue every 8 weeks until week 48 and after every 12 weeks, assessed through study completion, up to 4 years. ]
    Time from the date of first documented response until the first date of documented progression or death in the absence of disease progression. (NSCLC and SCLC cohorts only)
  • Disease control rate (DCR) [ Time Frame: From baseline until disease progression, follow up assessments (RECIST 1.1) starts at week 16 (post first dose of durvalumab) and continue every 8 weeks until week 48, assessed through study completion, up to 4 years. ]
    The percentage of patients who have a BoR of CR or PR in the first 12 or 48 weeks, respectively, or who have demonstrated stable disease (SD) for a minimum interval of 12 or 48 weeks, respectively following the start of study treatment.
  • Disease-free survival (DFS) [ Time Frame: From baseline until disease progression, follow up assessments (RECIST 1.1) starts at week 16 (post first dose of durvalumab) and continue every 8 weeks until week 48 and after every 12 weeks, assessed through study completion, up to 4 years. ]
    Kaplan-Meier estimate of disease-free survival. (HNSCC cohort only)
  • Progression-free survival at 18 months (PFS18) [ Time Frame: From baseline until the date of objective disease progression or death, whichever came first, at 18 months. ]
    Defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by the Investigator). NSCLC and SCLC cohorts.
  • Disease-free survival at 48 weeks (DFS48) [ Time Frame: From baseline until disease progression or death, whichever came first at 48 months. ]
    Kaplan-Meier estimate of disease-free survival. (HNSCC cohort only)
  • Disease-free survival at 96 weeks (DFS96) [ Time Frame: From baseline until disease progression or death, whichever came first at 96 months. ]
    Kaplan-Meier estimate of disease-free survival. (HNSCC cohort only)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Immunotherapy in Combination With Chemoradiation in Patients With Advanced Solid Tumors
Official Title  ICMJE A Phase I Multicenter Study of Immunotherapy in Combination With Chemoradiation in Patients With Advanced Solid Tumors (CLOVER)
Brief Summary This is an open-label, multicenter, phase I study to evaluate the safety and tolerability of durvalumab ± tremelimumab in combination with chemoradiation in patients with advanced solid tumors
Detailed Description This study will initially treat up to approximately 300 patients with advanced solid tumors at approximately 30 sites, worldwide. The study will be composed of a dose-limiting toxicity (DLT) assessment phase (Part A) and an expansion phase (Part B).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Carcinoma, Squamous Cell of Head and Neck
  • Carcinoma, Non-Small-Cell Lung
  • Small Cell Lung Carcinoma
Intervention  ICMJE
  • Drug: Durvalumab
    IV (intravenous)
    Other Name: MEDI4736
  • Drug: Tremelimumab
    IV
  • Drug: Cisplatin (dose level 4)
    IV
  • Drug: Cisplatin (dose level 3)
    IV
  • Drug: Carboplatin (dose level 1)
    IV
  • Drug: Carboplatin (dose level 2)
    IV
  • Drug: Etoposide (dose level 1)
    IV
  • Drug: Etoposide (dose level 2)
    IV
  • Drug: Paclitaxel
    IV
  • Drug: Pemetrexed
    IV
  • Radiation: External beam radiation (dose level 1)
    radiation therapy
  • Radiation: External beam radiation (dose level 2)
    radiation therapy
  • Radiation: External beam radiation (hyperfractionated)
    radiation therapy
  • Drug: Cisplatin (dose level 1)
    IV
  • Drug: Cisplatin (dose level 2)
    IV
  • Radiation: External beam radiation (standard)
    radiation therapy
Study Arms  ICMJE
  • Experimental: HNSCC Arm 1
    Durvalumab + cisplatin with radiation in patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC)
    Interventions:
    • Drug: Durvalumab
    • Drug: Cisplatin (dose level 4)
    • Radiation: External beam radiation (dose level 1)
  • Experimental: NSCLC Arm 1
    Durvalumab + cisplatin and etoposide with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC)
    Interventions:
    • Drug: Durvalumab
    • Drug: Etoposide (dose level 1)
    • Radiation: External beam radiation (dose level 2)
    • Drug: Cisplatin (dose level 1)
  • Experimental: NSCLC Arm 2
    Durvalumab + carboplatin and paclitaxel with radiation in patients with locally advanced, unresectable (Stage III) non-small-cell lung cancer (NSCLC)
    Interventions:
    • Drug: Durvalumab
    • Drug: Carboplatin (dose level 1)
    • Drug: Paclitaxel
    • Radiation: External beam radiation (dose level 2)
  • Experimental: NSCLC Arm 3
    Investigator's choice of carboplatin and pemetrexed OR cisplatin and pemetrexed
    Interventions:
    • Drug: Durvalumab
    • Drug: Carboplatin (dose level 2)
    • Drug: Pemetrexed
    • Radiation: External beam radiation (dose level 2)
    • Drug: Cisplatin (dose level 2)
  • Experimental: SCLC Arm 1
    Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin
    Interventions:
    • Drug: Durvalumab
    • Drug: Cisplatin (dose level 3)
    • Drug: Carboplatin (dose level 2)
    • Drug: Etoposide (dose level 2)
    • Radiation: External beam radiation (standard)
  • Experimental: SCLC Arm 2
    Patients with limited-stage small-cell lung cancer (SCLC) should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin
    Interventions:
    • Drug: Durvalumab
    • Drug: Cisplatin (dose level 3)
    • Drug: Carboplatin (dose level 2)
    • Drug: Etoposide (dose level 2)
    • Radiation: External beam radiation (hyperfractionated)
  • Experimental: SCLC Arm 3
    Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin. Note: Arm 3 will only be opened if the regimen in SCLC Arm 1 is safe and tolerable.
    Interventions:
    • Drug: Durvalumab
    • Drug: Tremelimumab
    • Drug: Cisplatin (dose level 3)
    • Drug: Carboplatin (dose level 2)
    • Drug: Etoposide (dose level 2)
    • Radiation: External beam radiation (standard)
  • Experimental: SCLC Arm 4
    Patients should start with cisplatin, but if cisplatin is not tolerated, they have the option to switch to carboplatin Note: Arm 4 will only be opened if the regimen in SCLC Arm 2 is safe and tolerable.
    Interventions:
    • Drug: Durvalumab
    • Drug: Tremelimumab
    • Drug: Cisplatin (dose level 3)
    • Drug: Carboplatin (dose level 2)
    • Drug: Etoposide (dose level 2)
    • Radiation: External beam radiation (hyperfractionated)
Publications * Not Provided

*   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 Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 28, 2020)
105
Original Estimated Enrollment  ICMJE
 (submitted: April 25, 2018)
300
Estimated Study Completion Date  ICMJE April 4, 2022
Estimated Primary Completion Date April 4, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  • World Health Organization (WHO)/ECOG performance status of 0 or 1
  • Body weight >30 kg at enrollment and treatment assignment
  • At least 1 measurable lesion, not previously irradiated
  • No prior exposure to immune-mediated therapy (including therapeutic anticancer vaccines)
  • For patients with oropharyngeal HNSCC HPV status has to be known

Exclusion criteria:

  • Patients with simultaneous primary malignancies or bilateral tumors
  • Active or prior documented autoimmune or inflammatory disorders
  • Brain metastases or spinal cord compression
  • Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus (HIV; positive HIV 1/2 antibodies)
  • Has a paraneoplastic syndrome (PNS) of autoimmune nature
  • HNSCC cohort: Head and neck cancer that does not include unresectable, locally advanced cancer of oral cavity, larynx, oropharynx or hypopharynx. HNSCC of unknown primary are also excluded
  • NSCLC and SCLC cohort: Mixed SCLC and NSCLC histology
  • SCLC cohort: Extensive-stage SCLC
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 110 Years   (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 Japan,   Korea, Republic of,   Spain,   Taiwan,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03509012
Other Study ID Numbers  ICMJE D933BC00001
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
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date September 2020

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