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An Open-Label, Multi-Centre, Study to Assess the Safety of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies. (STRONG)

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ClinicalTrials.gov Identifier: NCT03084471
Recruitment Status : Recruiting
First Posted : March 21, 2017
Last Update Posted : September 20, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE March 7, 2017
First Posted Date  ICMJE March 21, 2017
Last Update Posted Date September 20, 2019
Actual Study Start Date  ICMJE April 17, 2017
Estimated Primary Completion Date March 26, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
Safety: Number of patients with adverse events of special interest (AESIs). [ Time Frame: From screening to safety follow up visit (90 days after last dose). ]
To assess the AESIs as a criteria of safety and tolerability variables.
Original Primary Outcome Measures  ICMJE
 (submitted: March 20, 2017)
  • Safety: Number of participants with adverse events of special interest (AESI). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    Information on AESIs reported in participants who are treated with durvalumab and tremelimumab combination therapy or durvalumab monotherapy, using fixed dosing will be collected. This will be a common primary objective for all tumor sub-studies.
  • Safety: Percentage of participants with AESI [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    Information on AESIs reported in participants who are treated with durvalumab and tremelimumab combination therapy or durvalumab monotherapy, using fixed dosing will be collected. This will be a common primary objective for all tumor sub-studies.
Change History Complete list of historical versions of study NCT03084471 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Safety: Number of patients with treatment-emergent adverse events (TEAEs). [ Time Frame: From screening to safety follow up visit (90 days after last dose). ]
    To assess the incidence, severity, nature, seriousness, intervention/treatment, outcome, and causality of TEAEs (including serious adverse events [SAEs])
  • Safety: Number of patients who discontinued treatment due to TEAEs (including SAEs). [ Time Frame: From screening to safety follow up visit (90 days after last dose). ]
    To assess the incidence and frequency of durvalumab ± tremelimumab discontinuation due to TEAEs (including SAEs)
  • Safety: Number of patients who had treatment interrupted due to TEAEs (including SAEs). [ Time Frame: From screening to safety follow up visit (90 days after last dose). ]
    To assess the incidence and frequency of durvalumab ± tremelimumab interruption due to TEAEs (including SAEs).
  • Efficacy: Overall survival (OS) rate [ Time Frame: Up to 5 years following date of first patient treatment initiation. ]
    Overall survival was defined as the time from the first date of treatment until death due to any cause. To assess OS of durvalumab + tremelimumab combination therapy or durvalumab monotherapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 20, 2017)
  • Safety: Number of participants with adverse events (AEs). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Percentage of participants with AEs. [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Number of participants with serious adverse events (SAEs). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Percentage of participants with SAEs. [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Number of participants who discontinued treatment due to treatment-emerging (TEAEs) (including SAEs). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Percentage of participants who discontinued treatment due to TEAEs (including SAEs). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Number of participants who interrupted treatment due to treatment-emerging AEs (including SAEs). [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Safety: Percentage of participants who interrupted treatment due to treatment-emerging AEs (including SAEs) [ Time Frame: From Screening (Day -28) up to Safety follow up visit (90 days after last dose). ]
    This will be a common secondary objective for all tumor sub-studies.
  • Efficacy: Overall survival (OS) rate [ Time Frame: Up to 5 years following date of first patient treatment initiation. ]
    Assessment of OS for Durvalumab monotherapy and Durvalumab + Tremelimumab.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE An Open-Label, Multi-Centre, Study to Assess the Safety of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Official Title  ICMJE An Open-Label, Multi-Centre, Safety Study of Fixed-Dose Durvalumab + Tremelimumab Combination Therapy or Durvalumab Monotherapy in Advanced Solid Malignancies.
Brief Summary To evaluate the safety, tolerability, and anti-tumor activity of the combination of durvalumab + tremelimumab or durvalumab alone in different solid tumors.
Detailed Description

This is an open-label, multi-center, study to determine the short and long term safety of fixed doses of durvalumab 1500 mg + tremelimumab 75 mg combination therapy or durvalumab 1500 mg monotherapy in patients with advanced solid malignancies. This study is modular in design, one or more of the modules will be opened in a given country / region based on local patient population prevalence, and results of feasibility studies. The total number of patients to be enrolled overall and in each module will depend on the types and number of tumor modules added to the main study and country-specific ancillary studies. The number of patients and sites to be involved in individual countries will be dependent on each module or ancillary study. This study consisted of a screening period, a treatment period, a 90 day safety follow-up period and a survival follow-up period. Patients will receive the investigation product (IP) via intravenous (IV) infusion once every 4 weeks (Q4W) in combination therapy or monotherapy as mentioned below - Combination therapy: Durvalumab 1,500 mg + tremelimumab 75 mg on Week 0, for up to a maximum of 4 doses (or cycles) followed by durvalumab 1,500 mg starting 4 weeks after the last infusion of the combination or discontinuation of tremelimumab.

Monotherapy: Durvalumab 1,500 mg on week 0.

Patients will attend a safety follow-up visit 90 days after study treatment discontinuation. Thereafter, patients will be contacted by phone or electronic communication every 3 months for survival status up to 5 years following date of first patient treatment initiation. All patients will be followed for a minimum of 6 months following enrolment of last patient. It is anticipated that the total enrolment period for the overall study will be approximately 2 to 3 years, with an overall duration of approximately 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Solid Malignancies
Intervention  ICMJE
  • Biological: MEDI4736 (Durvalumab)
    A human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on immune cells (IC).
  • Biological: MEDI4736 (Durvalumab) + Tremelimumab

    Durvalumab: A human mAb of IgG 1 kappa subclass that blocks the interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 (B7.1) on IC.

    Tremelimumab: A human Ig G2 mAb that completely blocks the interaction of human CTLA-4 (cluster of differentiation [CD]152) with CD80 and CD86 and increase release of cytokines (interleukin [IL]-2 and interferon [IFN]-γ) from human T cells, peripheral blood mononuclear cells and whole blood.

Study Arms  ICMJE
  • Experimental: Combination therapy

    Combination therapy (durvalumab + tremelimumab) : Patients will receive the combination therapy followed by monotherapy via intravenous (IV) infusion once Q4W:

    • Durvalumab 1,500 mg + tremelimumab 75 mg on Week 0, for up to a maximum of 4 doses (or cycles) and
    • Durvalumab 1,500 mg starting 4 weeks after the last infusion of the combination or discontinuation of tremelimumab.
    Interventions:
    • Biological: MEDI4736 (Durvalumab)
    • Biological: MEDI4736 (Durvalumab) + Tremelimumab
  • Experimental: Monotherapy
    Monotherapy (Durvalumab 1,500 mg): Patients will receive durvalumab 1,500 mg via IV infusion Q4W on Week 0.
    Intervention: Biological: MEDI4736 (Durvalumab)
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 20, 2017)
1200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 26, 2023
Estimated Primary Completion Date March 26, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Must have a life expectancy of at least 12 weeks.
  2. Age ≥ 18 years at the time of screening. For patients aged <20 years and enrolled in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative
  3. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
  4. Disease not amendable to curative surgery
  5. Eastern Cooperative Oncology Group (ECOG) performance status as defined in the specific module.
  6. Body weight >30 kg.
  7. No prior exposure to anti-programmed death (PD) 1 or anti-PD-ligand (L) 1.
  8. Adequate organ and marrow function.
  9. Female patients of childbearing potential (i.e., not surgically sterile or post-menopausal) who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception from the time of screening and must agree to continue using such precautions for 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy.
  10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  11. Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a male condom plus spermicide from screening through 180 days after receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days after receipt of the final dose of durvalumab monotherapy.

For inclusion in the Module A of the study patients should fulfill the following criteria:

  1. Histologically or cytologicaly confirmed locally advanced or metastatic urothelial or non-urothelial carcinoma of the urinary tract (including the urinary bladder, ureter, urethra and renal pelvis)
  2. Disease that has progressed during or after at least one previous platinum or nonplatinum based chemotherapy, either for metastatic disease or progressive disease less than 12 months after adjuvant or neo-adjuvant chemotherapy
  3. ECOG performance status 0-2

Exclusion Criteria:

  1. Involvement in the planning and/or conduct of the study.
  2. Previous IP assignment in the present study.
  3. Concurrent enrollment in another clinical study or another sub-study of this protocol, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
  4. Participation in another clinical study with an IP and receipt of any investigational anticancer therapy during the last / within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.
  5. Any concurrent chemotherapy, investigational agent, biologic, or hormonal therapy for cancer treatment.
  6. Local treatment of isolated lesions for palliative intent is acceptable (e.g., local surgery or radiotherapy).
  7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
  8. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP.
  9. History of allogenic organ transplantation.
  10. Uncontrolled intercurrent illness (ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
  11. History of another primary malignancy, leptomeningeal carcinomatosis and active primary immunodeficiency.
  12. Has untreated central nervous system (CNS) metastases and/or carcinomatous meningitis identified either on baseline brain imaging (please refer to RECIST for details on the imaging modality) obtained during the screening period or identified prior to signing the ICF. Brain metastases will not be recorded as RECIST Target Lesions at baseline.
  13. Active infection including tuberculosis, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (positive HIV ½ antibodies).

14. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.

15. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).

16) Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.

17) Known allergy or hypersensitivity to study drug(s) or compounds of similar biologic composition to the study drug(s), or any of the study drug excipients.

18) Any unresolved NCI CTCAE Grade ≥2 toxicities from prior anti-cancer therapy with the exception of vitiligo, alopecia, and the laboratory values defined in the inclusion criteria.

19) Pregnant or breastfeeding women or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy.

20) Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Canada,   France,   Germany,   Italy,   Korea, Republic of,   Netherlands,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03084471
Other Study ID Numbers  ICMJE D4191C00068
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account AstraZeneca
Verification Date September 2019

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