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    Summary
    EudraCT Number:2021-001648-91
    Sponsor's Protocol Code Number:TRIPLEX
    National Competent Authority:Norway - NOMA
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-06-09
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNorway - NOMA
    A.2EudraCT number2021-001648-91
    A.3Full title of the trial
    Randomized phase III trial investigating the survival benefit of adding thoracic radiotherapy to durvalumab (MEDI4736) immunotherapy plus chemotherapy in extensive stage small-cell lung cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Does radiotherapy given in addition to immunotherapy and chemotherapy prolong survival in patients with extended stage small-cell lung cancer?
    A.3.2Name or abbreviated title of the trial where available
    TRIPLEX
    A.4.1Sponsor's protocol code numberTRIPLEX
    A.5.4Other Identifiers
    Name:230766Number:Regional Ethics Committee - Mid Norway
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNorwegian University of Science and Technology
    B.1.3.4CountryNorway
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportThe national programme for clinical therapy research in the specialist health service
    B.4.2CountryNorway
    B.4.1Name of organisation providing supportAstra Zeneca
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNorwegian University of Science and Technology
    B.5.2Functional name of contact pointBjørn Henning Grønberg
    B.5.3 Address:
    B.5.3.1Street AddressOlav Kyrres gate 10
    B.5.3.2Town/ cityTrondheim
    B.5.3.3Post code7030
    B.5.3.4CountryNorway
    B.5.4Telephone number+4747297878
    B.5.6E-mailbjorn.h.gronberg@ntnu.no
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imfinzi
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB
    D.2.1.2Country which granted the Marketing AuthorisationNorway
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameImfinzi
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Extensive stage small-cell lung cancer
    E.1.1.1Medical condition in easily understood language
    Small-cell lung cancer which has metastasized outside the chest.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10041068
    E.1.2Term Small cell lung cancer extensive stage
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To investigate whether adding thoracic radiotherapy to durvalumab plus chemotherapy improves survival.
    E.2.2Secondary objectives of the trial
    - To investigate whether adding thoracic radiotherapy improves overall response rates, response rates in non-irradiated lesions and PFS.
    - To investigate whether thoracic radiotherapy improves local control.
    - To compare the frequency and severity of adverse events between the treatment arms.
    - To compare the duration of severe adverse events between the treatment arms.
    - To compare the frequency and timing of brain metastases between treatment arms.
    - To compare cognitive function between patients who receive PCI and those who do not.
    - To investigate associations between outcomes of study treatment and biomarkers in tissue, blood and stool (e.g. ctDNA in blood, miRNA, gut microbiome).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. 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.
    2. Age > 18 years at time of study entry.
    3. ECOG performance status of 0 or 1.
    4. Body weight >30 kg.
    5. Adequate normal organ and marrow function as defined below:
    • Haemoglobin ≥10.0 g/dL.
    • Absolute neutrophil count (ANC) ≥1.5 × 109 /L
    • Platelet count ≥100 × 109/L
    • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This does not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology).
    • ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5 x ULN.
    • Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
    6. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
    7. Life expectancy of at least 3 months.
    8. At least 1 lesion, not previously irradiated, that qualifies as a RECIST 1.1 target lesion (TL) at baseline. Tumor assessment by computed tomography (CT) scan or magnetic resonance imaging (MRI) must be performed within 28 days prior to randomization.
    9. At least 1 measurable lesion in the thorax which is possible to irradiate to 30 Gy in 10 fractions.
    10. Histologically or cytologically confirmed SCLC.
    11. Stage IV disease according to the TNM v8. Patients with stage III disease are eligible if the disease is too widespread to be treated as limited stage SCLC.
    12. Pulmonary function: FEV1 >1 L or >30 % of predicted value and DLCO >30 % of predicted value.
    13. Female patients of childbearing potential (postmenarcheal, not postmenopausal [>12 continuous months of amenorrhea with no identified cause other than menopause], and no surgical sterilization) should use highly effective contraception and take active measures to avoid pregnancy while undergoing systemic study therapy and for at least 5 months after the last dose.
    14. Patients with brain metastases are eligible provided they are asymptomatic or treated and stable on steroids and/or anticonvulsants prior to the start of treatment.
    E.4Principal exclusion criteria
    1. Participation in another clinical study with an investigational product during the last 30 days.
    2. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
    3. Previous chemo- or radiotherapy for SCLC. Patients who have undergone surgery, but no adjuvant therapy are eligible.
    4. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
    5. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Chief Investigator.
    6. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Chief Investigator.
    7. Any concurrent chemotherapy, investigational product or biologic cancer therapy.
    8. Any prior checkpoint inhibitor therapy, including durvalumab.
    9. 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 drugs.
    10. Major surgical procedure within 28 days prior to the first dose of study drugs. Note: Local surgery of isolated lesions for palliative intent is acceptable.
    11. History of allogenic organ transplantation.
    12. 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]). The following are exceptions to this criterion:
    a. Patients with vitiligo or alopecia.
    b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement.
    c. Any chronic skin condition that does not require systemic therapy.
    d. Patients without active disease in the last 5 years may be included but only after consultation with the Chief Investigator.
    e. Patients with celiac disease controlled by diet alone.
    13. Uncontrolled intercurrent illness, including but not limited to, 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.
    14. History of another primary malignancy except for:
    a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence.
    b. Localized breast or prostate cancer treated with hormonal therapy alone.
    c. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    d. Adequately treated carcinoma in situ without evidence of disease.
    15. Leptomeningeal carcinomatosis.
    16. Untreated, symptomatic central nervous system (CNS) metastases. Any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be stable either, without the use of steroids, or are stable on steroids and/or anticonvulsants prior to the start of treatment.
    17. History of active primary immunodeficiency.
    18. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
    19. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:
    a. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection).
    b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.
    c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
    20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
    21. Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control.
    E.5 End points
    E.5.1Primary end point(s)
    1-year overall survival
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary survival analysis will be performed 14 months after last patient entry
    E.5.2Secondary end point(s)
    2-year, 3-year, 4-year and 5-year overall survival.
    Overall response rates.
    Response rate in non-irradiated lesions.
    Overall progression-free survival.
    Progression free survival in non-irradiated lesions.
    Local control rates in the thorax.
    Frequency and severity of adverse events.
    Duration of severe adverse events.
    Frequency and timing of brain metastases.
    Cognitive function in patients who receive PCI and those who do not.
    Associations between outcomes of study treatment and biomarkers in tissue, blood and stool (e.g. ctDNA in blood, miRNA and gut microbiome).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Analyses will be performed until 5 years after last patient entry.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Identification of prognostic and predictive biomarkers.
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Chemo- and immunotherapy alone
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Enrolment in the trial is expected to be completed in Q4 2023. We plan to perform the primary analyses in Q2 2025. Study treatment will be completed for all patients by Q4 2025. Follow-up will be completed 5 years after last patient entry, by Q4 2028.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 182
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 112
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state155
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 139
    F.4.2.2In the whole clinical trial 294
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All patients in the trial will be followed with controls at given intervals for a maximum of 5 years after end of treatment. Post-study treatment will be administered according to local routines at participating sites.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-09-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-11-12
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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