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    Summary
    EudraCT Number:2014-003371-34
    Sponsor's Protocol Code Number:CDI-CS-002
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-12-14
    Trial results View 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 ConcernedGermany - BfArM
    A.2EudraCT number2014-003371-34
    A.3Full title of the trial
    An open-label Phase 1/2a study of oral BAL101553 in adult patients with advanced solid tumors and in adult patients with recurrent or progressive glioblastoma or high-grade glioma
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Oral BAL101553 in Patients with Advanced Solid Tumors or with Brain Cancer
    A.4.1Sponsor's protocol code numberCDI-CS-002
    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 SponsorBasilea Pharmaceutica International Ltd.
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBasilea Pharmaceutica International Ltd
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBasilea Pharmaceutica International Ltd.
    B.5.2Functional name of contact pointMedical Information
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 487
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4005
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number00410616061400
    B.5.5Fax number00410615881614
    B.5.6E-mailmedical.information@basilea.com
    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 nameCDI
    D.3.2Product code BAL101553
    D.3.4Pharmaceutical form Capsule, hard
    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 INNlisavanbulin
    D.3.9.1CAS number 1387574-54-0
    D.3.9.2Current sponsor codeBAL101553
    D.3.9.3Other descriptive nameCDI
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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.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
    Advanced or recurrent solid tumors, recurrent or progressive glioblastoma, or high-grade glioma
    E.1.1.1Medical condition in easily understood language
    Advanced or recurrent solid tumors or brain cancer
    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 LLT
    E.1.2Classification code 10065147
    E.1.2Term Malignant solid tumor
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase 2a dose expansion portion (Simon’s two-stage design):
    To determine the efficacy of daily oral BAL101553 in patients with recurrent GBM whose tumor tissue is positive for end-binding protein 1 (EB1) based on immunohistochemistry (IHC) based on the objective response rate as per RANO criteria. A tissue-screening program adhering to local standards in selected countries will be established to support the identification of potential patients.
    E.2.2Secondary objectives of the trial
    Phase 2a dose expansion portion (Simon’s two-stage design):
    - To evaluate the efficacy of BAL101553 based on overall survival (OS), progression-free
    survival (PFS) and the proportion of patients with PFS at 6 months after start of study drug treatment (PFS6).
    - To evaluate the safety and tolerability of daily oral BAL101553.
    - To evaluate BAL101553 and BAL27862 pharmacokinetics (PK).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age 18 years or older.
    2. Patients who have in the Phase 2a dose expansion portion (Simon’s two-stage design):
    Recurrent, histologically confirmed, GBM with tumor tissue positive for EB1 by IHC as determined by central laboratory testing; eligible are patients with de novo GBM after prior radical chemoradiotherapy or secondary GBM after prior chemotherapy or radiotherapy; patients must be neurologically stable, without progression of neurologic symptoms, within 15 days prior to starting study drug.
    3. Phase 2 a dose expansion portion (Simon’s two-stage design): Patients with recurrent glioblastoma must be evaluable per RANO, defined by contrast-enhancing MRI, within 15 days prior to starting study drug.
    4. Life expectancy ≥ 12 weeks.
    5. Acceptable organ and marrow function documented within 15 days prior to starting study drug, defined as follows:
    - Absolute neutrophil count ≥ 1.5 × 109/L.
    - Platelets ≥ 100 × 109/L.
    - Hemoglobin ≥ 9 g/dL.
    - Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN),
    unless the patient has known Gilbert’s syndrome.
    - Aspartate amino transferase (AST) and alanine amino transferase (ALT) ≤ 2.5 × institutional ULN or ≤ 5 × ULN in presence of liver
    metastasis.
    - Serum creatinine ≤ 1.5 × institutional ULN, or creatinine clearance ≥ 60 mL/min by Cockcroft-Gault formula.
    - Serum sodium ≥ the institutional lower limit of normal (LLN).
    6. Patients with advanced solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and patients with recurrent or progressive glioblastoma must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
    7. Female patients who are not pregnant or breast-feeding and meet one of the following conditions:
    - Postmenopausal
    - Post-hysterectomy and/or post-bilateral salpingectomy or
    ovariectomy.
    - Congenital or acquired condition that prevents childbearing.
    - Women of childbearing potential must have a negative serum human chorionic gonadotropin (hCG) pregnancy test result and must use highly effective contraceptive methods for the duration of the study and for an additional 90 days after the last dose of study drug. Highly effective contraceptive methods include: male or female sterilization (bilateral tubal occlusion or vasectomy), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), combined (estrogen and progestogen containing) hormonal
    contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), total heterosexual abstinence.
    8. Male patients must agree not to donate sperm from the first dose of study drug until 90 days after the end of treatment. Male patients, without a vasectomy or other conditions resulting in azoospermia and with a partner of childbearing potential, must agree to use condoms during the study and for at least 90 days after the end of treatment.
    9. Signed, written informed consent.
    10. Patients must be able and willing to comply with the required food intake restrictions.
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria at screening must not be enrolled in the study:
    1. Patients with advanced or recurrent solid tumors who have received chemotherapy, radiotherapy, immunotherapy, or investigational agents within 4 weeks (2 weeks for single fraction of palliative radiotherapy, 6 weeks for nitrosoureas or mitomycin C) prior to starting study drug, or who have not recovered to ≤ Common Terminology Criteria for Adverse Events version 4.03 grade ≤ 1 from all side effects of prior therapies except for residual toxicities, such as alopecia, which do not pose an ongoing medical risk.
    • Patients with prostate cancer must have discontinued anti-androgens (e.g., bicalutamide, nilutamide) for at least 6 weeks prior to starting study drug; chemical castration with luteinizing hormone-releasing hormone analogues can be continued.
    Patients with recurrent or progressive GBM or high-grade glioma who have: received radiotherapy within 6 weeks, unless there is a new area of enhancement consistent with recurrent tumor outside the radiation field, or there is histological confirmation of unequivocal tumor progression; received administration of prior anti-tumor chemotherapy within 4 weeks, or within 6 weeks for nitrosoureas; undergone surgical resection within 4 weeks (Phase2a: 2 weeks) or a stereotactic biopsy/core biopsy within 1 week prior to starting study drug.
    2. Patients who have had prior exposure to BAL101553.
    3. Inability to swallow oral medication.
    4. Increase in steroid dose in GBM or high-grade glioma patients within 5 days prior to first study-drug administration.
    5. Patients with gastrointestinal disease or those who have had a procedure that is expected to interfere with the oral absorption or tolerance of BAL101553 (e.g., functionally relevant gastrointestinal obstruction, or frequent vomiting).
    6. Symptomatic brain metastases or leptomeningeal disease, indicative of active disease, in patients with advanced or recurrent solid tumors.
    7. Peripheral neuropathy ≥ CTCAE grade 2.
    8. Known human immunodeficiency virus (HIV) infection.
    9. Known acute or chronic hepatitis B or hepatitis C infection.
    10. Systolic blood pressure ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg at the screening visit. Patients with an initial clinic BP ≥ 140/90 mmHg may be included if SBP < 140 mmHg and DBP < 90 mmHg is confirmed in two subsequent BP measurements on the same day, or if subsequent daytime average from ABPM is SBP < 130 mmHg and DBP < 85 mmHg.
    11. Blood pressure combination treatment with more than two antihypertensive medications.
    12. Any history of cerebral hemorrhage, cerebral aneurysm, or ischemic stroke; or a history of transient ischemic attack within 24 months prior to screening in patients with advanced or recurrent solid tumors.
    Acute intratumoral hemorrhage in patients with recurrent or progressive GBM or high-grade glioma, considered by the study Investigator to be clinically significant.
    • Patients with MRI or CT demonstrating old hemorrhage or subacute bleed after a neurosurgical procedure (biopsy or resection) will be eligible for treatment.
    13. Significant cardiac disease or abnormality, including any one of the following:
    • Left ventricular ejection fraction < 50% at screening (assessed by echocardiography).
    • QTcF > 470 ms on screening electrocardiogram (ECG) or a clinically relevant ECG abnormality.
    • Congenital long QT syndrome.
    • History of sustained ventricular tachycardia, ventricular fibrillation or torsades de pointes.
    • Presence of atrial fibrillation with tachyarrhythmia (ventricular response rate > 100 bpm).
    • Bradycardia (heart rate < 50 bpm).
    • Complete left bundle branch block.
    • Bifascicular block (complete right bundle branch block and anterior or posterior left hemiblock).
    • Myocardial infarction, acute coronary syndrome (including unstable angina), coronary revascularization procedures, or coronary arterial bypass grafting within 6 months prior to starting study drug.
    • Cardiac troponin (either troponin T or troponin I) above institutional ULN.
    • Congestive heart failure of New York Heart Association class III or IV.
    14. Uncontrolled intercurrent illness that would unduly increase the risk of toxicity or limit compliance with study requirements in the opinion of the Investigator; including but not limited to: ongoing or active symptomatic infection, uncontrolled diabetes mellitus, unstable or uncompensated cardiac, hepatic, renal, respiratory, or psychiatric illness.
    15. Current anticoagulation with warfarin potassium or other coumarin derivates. Heparin/low-molecular weight heparin (at prophlylaxis or treatment doses), aspirin or other oral platelet inhibitors are permitted.
    16. Women who are pregnant or breast-feeding. Men or women of reproductive potential who are not willing to apply effective birth control during the study and for at least 30 days after the last dose of study drug in both sexes.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 2a dose expansion portion (Simon’s two-stage design):

    To determine the efficacy of daily oral BAL101553 in patients with recurrent GBM whose tumor tissue is positive for end-binding protein 1 (EB1) based on immunohistochemistry (IHC) based on the objective response rate as per RANO criteria. A tissue-screening program adhering to local standards in selected countries will be established to support the identification of potential patients.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The MTD is determined by DLT assessment. A DLT can occur on any dosing day or at any time thereafter. Objective response is assessed during the whole clinical trial.
    E.5.2Secondary end point(s)
    Overall safety endpoints:
    Type and frequency of AE, SAEs, laboratory, echocardiogram and ECG abnormalities; abnormalities in vital signs, physical examination results, chest X-ray/CT; frequency and causes of study withdrawals and dose modifications.
    Efficacy endpoints:
    - Best objective response according to RECIST 1.1 in patients with solid tumors, based on the change from baseline in tumor measurements as measured in patients with measurable disease, and according to RANO criteria in patients with progressive or recurrent GBM or high-grade glioma (Phase 1 only).
    - Change from baseline in tumor markers (CA-125, PSA) in patients whose disease is characterized by these tumor markers utilizing Rustin criteria for ovarian cancer or PSA Working Group 2 criteria for prostate cancer.
    - Progression-free survival and OS.
    Pharmacokinetic assessments (BAL101553 and BAL27862):
    - Cmax, Tmax, AUC0-t, AUC0-τ, AUC0-last, AUC0-∞, t½, systemic clearance and volume of distribution.
    - Total 24 h urinary excretion of BAL101553 and BAL27862.
    Exploratory endpoints:
    - Change from baseline in biomarkers (including but not limited to numbers of CTCs, CECs, CEPs).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety, tolerability, and anti-tumor activity is assessed during the whole
    clinical trial. Progression-free survival is assessed for 6 months and OS is assessed at 3-month intervals until death.
    Phase 2a dose expansion portion (Simon's two-stage design):
    Pharmacokinetics is assessed at pre-specified time points over 4 weeks
    in Phase 2a.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    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
    Phase 1 dose escalation portion with Phase 2a dose expansion portion
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 concerned4
    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 Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    United Kingdom
    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
    Completion of the last study-related contact with any patient.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 84
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    For patients not qualified or incapable of giving legal consent, written consent must be obtained from the legally acceptable representative.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 104
    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)
    Standard hospital care
    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 Decision2021-02-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-03-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-11-24
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