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    Summary
    EudraCT Number:2021-000042-17
    Sponsor's Protocol Code Number:M21SAD
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-12-07
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-000042-17
    A.3Full title of the trial
    Sarcomas and DDR-Inhibition; a neoadjuvant phase I combined modality study – SADDRIN-1
    Sarcomen in combinatie met remmers van DNA schade: een fase I studie met een gecombineerde behandeling van remmers en radiotherapie.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Chemoradiotherapy at soft tissue sarcomas
    Chemoradiotherapie bij weke delen sarcomen
    A.3.2Name or abbreviated title of the trial where available
    SADDRIN-1
    A.4.1Sponsor's protocol code numberM21SAD
    A.5.4Other Identifiers
    Name:CCMONumber:NL76411.031.21
    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 SponsorNetherlands Cancer Institute
    B.1.3.4CountryNetherlands
    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 supportAstraZeneca
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNetherlands Cancer Institute
    B.5.2Functional name of contact pointradiation oncologist
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31205129111
    B.5.6E-mailr.haas@nki.nl
    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 No
    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 nameAZD1390
    D.3.2Product code AZD1390
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNnot yet available
    D.3.9.1CAS number 2089288-03-7
    D.3.9.2Current sponsor codeAZD1390
    D.3.9.3Other descriptive name7-FLUORO-3-METHYL-8-[6-(3-PIPERIDIN-1-YLPROPOXY)PYRIDIN-3-YL]-1-PROPAN-2-YLIMIDAZO[4,5-C]QUINOLIN-2-ONE
    D.3.9.4EV Substance CodeSUB195770
    D.3.10 Strength
    D.3.10.1Concentration unit % percent
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number95 to 102
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 2
    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, INN-durvalumab
    D.2.1.1.2Name of the Marketing Authorisation holderAstraZeneca AB, SE-151 85 Södertälje, Sweden
    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.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDurvalumab
    D.3.9.1CAS number 1428935-607
    D.3.9.4EV Substance CodeSUB176342
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Yes
    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
    soft tissue sarcomas
    E.1.1.1Medical condition in easily understood language
    soft tissue sarcomas
    weke delen sarcoom
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10041293
    E.1.2Term Soft tissue neoplasms malignant and unspecified NEC (excl sarcomas)
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10024628
    E.1.2Term Liposarcomas malignant
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10024190
    E.1.2Term Leiomyosarcomas
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10041298
    E.1.2Term Soft tissue sarcomas histology unspecified
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level HLT
    E.1.2Classification code 10016634
    E.1.2Term Fibrosarcomas malignant
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess the safety and tolerability profile, in the pre- and perioperative period (up to 30 days post-surgery), of combined modality treatment (CMT) by administering DDRi and RT concurrently treating newly diagnosed, non-metastatic soft tissue sarcoma patients with DDRi-based CMT, in the specific context of systemic toxicities, wound healing post-surgery and in defining the RP2D for the combinations to support further clinical evaluation
    E.2.2Secondary objectives of the trial
    • To describe any pathological evidence of tumor regression after pre-operative DDRi-based CMT
    • To determine local control rates
    • To determine the rate of R0 resection
    • To determine the rate of R1 resection
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, for which the standard treatment is a combination of radiotherapy and surgery (In other words: either deep seated and/or > 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition);
    • Patients staged by at least a CT scan of the chest (and a CT scan of the abdomen, if deemed indicated according to local practices, e.g. in case of a myxoid liposarcoma). Staging may also be performed by FDG-PET scanning and or total body MRI scans. This staging procedure should not reveal metastatic disease. If, however, a low metastatic burden is detected such that this does not preclude the application of both preoperative radiotherapy and definitive surgery, patients are allowed to participate;
    • WHO Performance Status ≤ 2;
    • Able and willing to undergo preoperative radiotherapy;
    • Able and willing to undergo definitive surgery;
    • Able and willing to comply with regular follow-up visits;
    • Able and willing to swallow and retain oral medication;
    • Age ≥ 18 years;
    • Body weight >30kg;
    • Must have a life expectancy of at least 12 weeks;
    • Adequate organ function as defined in Table 5;
    • Signed written informed consent prior to any study specific procedures or sampling
    E.4Principal exclusion criteria
    Pathological diagnosis
    • Patients with any type soft tissue sarcoma located above the clavicles;
    • Patients with recurrent sarcomas who underwent prior radiotherapy to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative radiotherapy, patients are eligible);
    • Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), bone sarcomas;

    Concurrent therapies
    • Neoadjuvant chemotherapy to be scheduled between end of radiotherapy and definitive surgery is not allowed. (neoadjuvant chemotherapy before start of study radiotherapy is allowed);
    • Intention to perform an isolated limb perfusion, instead of a tumor resection;
    • 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;

    Medical History
    • Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma;
    • Prior surgical procedure within 28 days prior to the first dose of durvalumab, excluding minor surgical procedures e.g procedures only recuing local anesthesia.
    • Past medical history of interstitial lung disease (ILD ), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease;
    • History or presence of myopathy or raised CK >5 x ULN on 2 occasions at screening. CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase, which may confound interpretation of the results. If CK levels are significantly elevated at baseline (>5 x ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5 x ULN, treatment should not be started;

    Cardiac function
    • Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA Class II/III/IV heart failure, unstable angina or unstable cardiac arrhythmias;
     Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 electrocardiograms (ECGs) (QTc interval will be calculated using Fridericia’s formula);
     Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third degree heart block;
     Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age. Patients stable on concomitant medications known to prolong the QT interval may be allowed to participate in the study provided that their mean resting corrected QT interval (QTcF) is < 470 msec at baseline and after discussion with the Medical Monitor;

    Concurrent and prior medication
    • Concomitant treatment with medicines listed as ‘prohibited’ or ‘excluded’ (section 3.1.4);
    • Treatment with moderate and strong inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John’s Wort);
    • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients;

    Prior and concurrent clinical trials
    • Participation in another clinical study with an investigational product during the last 3 months;
    • Concurrent enrolment in another clinical study or, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study;

    Other
    • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;
    • Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements;
    • Female patients who are pregnant or breast feeding;
    • Male or female patients of reproductive potential who are not willing to employ effective birth control during treatment;

    Additional criteria for durvalumab
    • Past medical history of allogenic organ transplantation;
    • Past medical history of leptomeningeal carcinomatosis;
    • Past medical history or active autoimmune or inflammatory disorders
    • History or presence of primary immunodeficiency;
    • Presence of active hepatitis infections
    • History of a positive test for human immunodeficiency virus
    • Presence of uncontrolled intercurrent illness
    • Treatment with or prior use of immunosuppressive medication within 2 weeks before start
    • Prior anti–PD-1, anti PD-L1 or anti CTLA-4
    • Treatment with a live attenuated vaccine within 30 days prior to start
    E.5 End points
    E.5.1Primary end point(s)
    To be evaluable for toxicity, the minimum required drug dose is 75% of the intended drug dose. Furthermore, the observed toxicity should documented at least as “related to drug”. This does not count if the observed toxicity was “related to RT”. If documented as “unrelated”, this event will not be designated as a DLT I.
    DLT II is defined as dose limiting major wound complications
    E.5.1.1Timepoint(s) of evaluation of this end point
    30 days after surgery
    E.5.2Secondary end point(s)
    • To describe any pathological evidence of tumor regression after pre-operative DDRi-based CMT
    • To determine local control rates
    • To determine the rate of R0 resection
    • To determine the rate of R1 resection
    E.5.2.1Timepoint(s) of evaluation of this end point
    after surgery
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Dose finding study to determine the recommended phase 2 dose and tolerability
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    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 No
    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 No
    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 concerned3
    E.8.5The trial involves multiple Member States No
    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 No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state30
    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)
    none
    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 Decision2021-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-29
    P. End of Trial
    P.End of Trial StatusOngoing
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