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    Summary
    EudraCT Number:2017-001491-35
    Sponsor's Protocol Code Number:CB103-C-101
    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:2017-07-11
    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 number2017-001491-35
    A.3Full title of the trial
    A Phase I/IIA, Multi-Centre, Open-Label, Dose-Escalation Study with Expansion Arms to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of CB-103 Administered Orally in Adult Patients with Advanced or Metastatic Solid Tumours and Haematological Malignancies Characterised by Alterations of the NOTCH Signalling Pathway
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Assess the Safety, Tolerability, Blood levels and Efficacy of oral test drug CB-103 in Adult Patients with certain types of cancer
    A.4.1Sponsor's protocol code numberCB103-C-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03422679
    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 SponsorCellestia Biotech AG
    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 supportCellestia Biotech AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCovance Clinical and Periapproval Services Limited
    B.5.2Functional name of contact pointGlobal Regulatory Submissions
    B.5.3 Address:
    B.5.3.1Street AddressOsprey House, Maidenhead Office Park, Westacott Way
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 3QH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone numberno number
    B.5.5Fax numberno number
    B.5.6E-mailsubmissions@covance.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.3.2Product code CB-103
    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 INNnot applicable
    D.3.9.1CAS number 218457-67-1
    D.3.9.2Current sponsor codeCB-103
    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.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 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.3.2Product code CB-103
    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 INNnot applicable
    D.3.9.1CAS number 218457-67-1
    D.3.9.2Current sponsor codeCB-103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 3
    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.3.2Product code CB-103
    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 INNnot applicable
    D.3.9.1CAS number 218457-67-1
    D.3.9.2Current sponsor codeCB-103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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: 4
    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.3.2Product code CB-103
    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 INNnot applicable
    D.3.9.1CAS number 218457-67-1
    D.3.9.2Current sponsor codeCB-103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 5
    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.3.2Product code CB-103
    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 INNnot applicable
    D.3.9.1CAS number 218457-67-1
    D.3.9.2Current sponsor codeCB-103
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 metastatic solid tumours and haematological malignancies
    E.1.1.1Medical condition in easily understood language
    advanced or metastatic (spread from a part of the body to another) solid tumours (abnormal malignant mass of tissue) and haematological malignancies (blood cancer)
    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 LLT
    E.1.2Classification code 10049280
    E.1.2Term Solid tumour
    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 20.1
    E.1.2Level PT
    E.1.2Classification code 10066476
    E.1.2Term Haematological malignancy
    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 I, Part A - Dose Escalation
    • determine the MTD or RP2D of CB-103 as a single agent on adult patients with advanced or metastatic solid tumours and haematological malignancies, who have progressed despite curative therapy or for whom no curative therapy exists

    Phase IIA, Part B - Expansion
    • assess preliminary anti-tumour and anti-lymphoma activity of single agent CB-103 in the different expansion arms across the different indications
    E.2.2Secondary objectives of the trial
    Secondary objectives - part A&B
    • characterise the PK characteristics of CB-103 in patients after single and repeated administration at various dose levels

    Secondary objectives - Part A only
    • characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies
    • assess preliminary anti-tumour and anti-lymphoma activity of single agent CB-103

    Secondary objectives - part B only
    • characterise safety and tolerability of the MTD/RP2D of CB-103 in patients with selected solid tumours and haematological malignancies, stratified into separate expansion arms for the respective indications and with tumours characterised by genetic alterations and activation of the NOTCH pathway

    Exloratory objectives
    • explore potential correlations of PK, biomarkers, PD (genes/proteins) with safety and efficacy parameters in tissue samples (tumour, blood, hair follicles)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Disease
    a.Patients with histologically or cytologically confirmed solid tumours that are surgically unresectable, locally advanced, or metastatic whose disease has progressed on at least one line of systemic therapy and for whom no standard curative therapy exists
    b.The following solid tumour indications are allowed to be enrolled into Part A:
    •Breast cancer (TNBC, ER+/-, HER2+/-), gastrointestinal (GI) cancers (colorectal cancer, CCC), sarcomas (osteosarcoma, liposarcoma, rhabdomyosarcoma, fibrosarcoma), desmoid tumours, adenoid cystic carcinoma, and malignant glomus tumour
    c.Patients with histologically or cytologically confirmed, advanced haematological malignancies whose disease has relapsed or progressed upon standard therapy and for whom at that point no standard therapy exists:
    •Non-Hodgkin lymphomas (NHL): Follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), Burkitt lymphoma, nodal marginal zone lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), mantle cell lymphoma MCL), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL, ALK-positive and ALK-negative)
    Specific criteria per type of lymphoma:
    •B-cell NHL: relapsed/refractory upon at least one line of chemo-immunotherapy, no standard therapy available
    •T-cell NHL: relapsed/refractory upon at least one line of chemotherapy, no standard curative therapy available
    d.Solid tumours: ≥1 measurable lesion according to RECIST v1.1 guideline for solid tumours
    e.Lymphomas: ≥1 measurable lesion according to The Lugano Classification
    f.Patients in Part B: must have tumours characterised by activation of the NOTCH signalling pathway. All patients should have sufficient archival biopsy tissue not older than 6 months prior to pre-screening (or if not available-a fresh tumour biopsy must be taken)
    g.Patients in Part B: willing to provide a fresh pre-dose and, if feasible, on-treatment and an EOT tumour biopsy
    h.Patients in Part A: must have sufficient archival tumour tissue samples preferably not older than 6 months prior to screening (or if not available a fresh pre-dose tumour biopsy)

    2.Demography
    a.Men and women ≥ 18 years old on the day of signing informed consent
    b.ECOG performance status 0 or 1
    c.Patients able and willing to swallow capsules

    3.Organ function and laboratory results
    Patients must have the following laboratory values (obtained within 14d of enrolment):
    a.ANC ≥ 1.5x10^9/L (solid tumour indications) or ≥ 1.0x10^9/L (haematological malignancies)
    b.Haemoglobin (Hgb) ≥ 10 g/dL (≥ 100 g/L)
    c.Platelet count ≥ 75 x 109/L (no platelet transfusion or growth factor support in the preceding 7d)
    d.Total serum bilirubin ≤ 1.5xULN
    e.ALP ≤ 2.5xULN (if abnormalities are due to the underlying malignancy and known bone metastases, then ALP must be ≤ 5xULN)
    f.AST/SGOT and ALT/SGPT ≤2.5xULN (if liver function abnormalities are due to the underlying malignancy and known hepatic metastases or bone metastases then AST and ALT must be ≤ 5xULN)
    g.Serum creatinine ≤ 1.5xULN (if serum creatinine > 1.5xULN, then serum creatinine clearance (CrCl) ≥ 50 mL/min
    h to k: Potassium, Total calcium (corrected for serum albumin), Magnesium and Phosphorus levels: within normal limits or correctable with supplements
    l.Serum albumin concentration ≥ 30 g/L
    m.Serum amylase and serum lipase ≤ ULN
    n.PTT ≤ 1.5 x ULN and INR ≤ 1.3 (unless receiving therapeutic anticoagulants)

    4.Contraceptive measures
    a.Women of childbearing potential (serum pregnancy test performed within 7d before start of treatment, negative result must be documented)
    b.Women of childbearing potential and men must agree to use at least two highly effective forms of contraception throughout the entire clinical trial period and for 90d post-treatment completion
    c.Men whose partners could be of childbearing potential must routinely use a condom throughout the clinical trial period and for 90d post-treatment completion. The partner should also use a reliable form of contraception
    d.Azoospermic males and females with sterilisation are exempt
    e.Women who are continuously not heterosexually active are exempt (must still undergo pregnancy testing)

    5.Informed consent
    a.Ability to understand the patient information and ICF and comply with the protocol-related procedures
    b.Signed and dated written informed consent obtained prior to performing any study-related procedure, including pre-screening (part B only) and screening
    E.4Principal exclusion criteria
    1.Medical History
    a.Patients with symptomatic CNS metastases (neurologically unstable or requiring increasing doses of steroids to control their CNS disease)
    b.Hypersensitivity to any of the excipients of CB-103
    c.Patients with unresolved nausea, vomiting, or diarrhoea of CTCAE grade > 1
    d.Impairment of GI function or presence of GI disease that may significantly alter the absorption of CB-103
    e.History of second or other primary cancer with exception of
    •Curatively treated non-melanomatous skin cancer
    •Curatively treated cervical cancer or breast carcinoma in situ
    •Other primary solid tumour treated with curative intent and no known active disease present and no treatment administered during last 2 years

    2.Exclusionary concurrent medical conditions
    a.Impaired cardiac function or clinically significant cardiac diseases, including any one of the following:
    1.Clinically significant cardiac disease including congestive heart failure (NYHA class III or IV), arrhythmia or conduction abnormality requiring medication, or cardiomyopathy
    2.Clinically uncontrolled hypertension (blood pressure > 160/110 mmHg)
    3.Complete left bundle branch block
    4.Right bundle branch block + left anterior hemiblock
    5.Mandatory use of a cardiac pacemaker
    6.Congenital long QT syndrome
    7.History or presence of sustained or symptomatic ventricular tachyarrhythmia
    8.Presence of atrial fibrillation
    9.Clinically significant resting bradycardia (< 50 bpm)
    10.Corrected QTcF > 450 ms for males and > 470 ms for females at the screening ECG
    11.QRS ≥ 110 ms
    12.History of symptomatic congestive heart failure
    13.LVEF < 50%. History of absolute decrease in LVEF of ≥ 15 absolute %, or ≥ 10 absolute % and crossing from > LLN to < LLN on prior anti-HER2 therapy, even if asymptomatic
    14.Angina pectoris ≤ 6 months prior to starting CB-103
    15.Acute myocardial infarction ≤ 6 months prior to starting CB-103
    b.General conditions or other clinically significant diseases, including:
    1.Haemorrhagic, embolic, or thrombotic stroke within 6 months prior to the first planned CB-103 infusion
    2.Prior allogeneic bone marrow/haematopoietic stem cell transplant
    3.Autologous haematopoietic stem cell transplant ≤ 6 months prior to starting study drug
    4.Known infection with HIV or hepatitis B or C requiring treatment
    5.Any active infection requiring the use of parenteral anti-microbial agents or > Grade 2
    6.Non-malignant interstitial lung disease or pneumonitis
    7.Dyspnoea of any cause requiring supplemental oxygen therapy and dyspnoea at rest due to complications of advanced malignancy and co-morbidities
    8.Significant traumatic injury or major surgery within 14d of scheduled dosing day 1
    9.Other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol

    3.Prior Therapy
    a.Cytotoxic chemotherapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C) of scheduled first dose of CB-103 on day 1
    b.Prior cumulative doxorubicin exposure of ≥ 450 mg/m2
    c.Prior cumulative epirubicin exposure of ≥ 900 mg/m2
    d.Any investigational treatment (including NOTCH signalling inhibitors and prior treatments with CB-103) within 4 weeks of scheduled CB-103 dosing d1
    e.PPIs and/or H2-blockers within ≥2 weeks of the scheduled first dose of CB-103 on d1
    f.Concurrent enrolment in another therapeutic clinical trial involving ongoing therapy with any investigational or marketed product or placebo
    g.Radiation therapy within 2 weeks of scheduled CB-103 dosing day 1, unless the radiation comprised a limited field to non-visceral structures
    h.Immunotherapy (including interferons, interleukins, immune-conjugates, immune checkpoint inhibitors), biological therapies (including monoclonal antibodies, antibody drug conjugates or other engineered proteins), targeted small molecules (including but not limited to kinase inhibitors), hormonal therapies within 3 weeks of scheduled CB-103 dosing day 1
    i.Unresolved toxicity CTCAE grade >1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia), or incomplete recovery from previous surgery, unless agreed by Sponsor and Principal Investigator and documented

    4.Concomitant medications
    a.Drugs which prolong QT interval, either with a known or a conditional/ possible risk to induce Torsades de pointes
    b.Acid reducing agents
    c.Patients receiving warfarin and phenytoin that cannot be discontinued at least one week prior to start of treatment with CB-103 and for duration of study
    d.Anticoagulants: Patients receiving coumarin-type anticoagulants who cannot discontinue at least one week prior to start of treatment and for the duration of the study. Low molecular weight heparin and direct oral anticoagulants are permitted

    5.Demography
    a.Patients who are pregnant or breast feeding

    6.Others
    a.Patients unable or unwilling to comply with all study requirements
    E.5 End points
    E.5.1Primary end point(s)
    Phase I, Part A
    • The number of patients experiencing dose-limiting toxicity (DLT) during the first 28 day cycle of CB-103 treatment

    Phase IIA, Part B
    • To assess tumour response rates in each expansion arm:
    ‒ For solid tumour indications: to assess best overall response rate (complete response [CR] + partial response [PR]), assessed by Response Evaluation Criteria in Solid Tumours (RECIST 1.1)
    ‒ For non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification
    E.5.1.1Timepoint(s) of evaluation of this end point
    Phase I, Part A
    Cyc1 d1, 2, 3, 8, 9, 15 & 22

    Phase IIA, Part B
    baseline, Cyc2 d15, after cycle 2 every 8 weeks until EOT or disease progression/overall survival
    E.5.2Secondary end point(s)
    Secondary endpoints - part A and B:
    • The incidence rate, severity and relationship to CB-103 of adverse drug reactions and serious drug reactions according to common terminology criteria for adverse events (CTCAE) V4.03, safety laboratory, vital signs, ECG and ECHO/MUGA assessments in each dose group and expansion arm.

    • CB-103 plasma concentrations, PK parameters: Cmax, tmax, area under the curve (AUC) during 8 and 24 hours (AUC0 8, AUC0 24), AUC from time 0 extrapolated to infinite time (AUC0-∞), apparent volume of distribution (Vd/F), apparent volume of distribution at steady (Vss/F), apparent clearance after oral administration (CL/F), t1/2 and AR.

    Secondary endpoints - part A:
    • to assess tumour response rates
    ‒ For solid tumour indications: to assess best overall response rate (CR + PR), assessed by RECIST 1.1.
    ‒ For non-Hodgkin lymphomas: to assess best overall response rate (CR + PR), assessed by Lugano Lymphoma classification

    • To assess clinical benefit rate
    ‒ For solid tumour indications: clinical benefit rate (CR + PR + SD), assessed by RECIST 1.1.
    ‒ For non-Hodgkin lymphomas: clinical benefit rate (CR + PR + SD), assessed by Lugano Lymphoma classification

    • Duration of response (DOR), time to response, progression-free survival (PFS), OS.

    Exploratory endpoints:
    • To assess plasma levels and PK parameters (Cmax, tmax, Cmin, Clast, tlast, AUC0-8, AUC0-24, AUC0–∞, t1/2 and AR) of metabolite(s) when feasible
    • To evaluate the relationship between CB-103 plasma concentrations and/or PK parameters (eg, Cmax and AUC0-24) and safety, efficacy and PD parameters
    • To assess changes in the expression of NOTCH and NOTCH target genes (NOTCH1 4 receptors, NOTCH ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis from pre- to post- CB-103 treatment in tumour tissue samples, whole blood, plasma and hair follicles to determine on-target effects of CB-103.
    • To assess NOTCH and NOTCH target genes expression (NOTCH1-4 receptors, NOTCH ligands, NICD1-4 and NOTCH target genes) assessed by Nanostring expression analysis in pre- and post-treatment tumour tissue samples, whole blood / plasma samples and hair follicles and assess relation to clinical activity of CB-103.
    • To assess certain genotypes (e.g. cytochrome P450 enzymes or NAT) and assess relation to PK outcome data
    • To assess NOTCH genetic aberrations in pre- and post-treatment tumour tissue samples, whole blood and hair follicles and assess relation to clinical activity of CB 103
    • To assess NOTCH1-4 NICD expression assessed by IHC staining or by Western Blot in pre- and post-treatment tumour tissue samples and to assess relation to clinical activity of CB-103
    • To assess genetic aberrations on DNA derived from blood samples (liquid biopsy with circulating tumour DNA and/or blood cell-derived DNA) and to assess relation to results from corresponding tumour tissue samples.
    • To assess NOTCH mutations by genomic mutation analysis in tumour tissue samples and to assess relation to clinical activity of CB-103 treatment
    • To assess change from baseline cardiac intervals versus increasing plasma CB 103 concentrations
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary
    safety assess. incl. AE/SAEs: Scr., Base, Cyc1 d1, 2, 3, 8, 9, 15 & 22, Cyc2-6 d1 & 15, Cyc7+ d1, EoT, safety FU, unsched. V
    ECOG perf and physic exam.: Scr., Base, Cyc1 d2, 3, 8, 15 & 22 (d2,3 part A only), Cyc2-6 d1 & 15, Cyc7+ d1, EoT, safety FU (only ECOG) and unsched. V
    ECG: Scr., Cyc1 d1, 8, 15 & 22, Cyc2 d1 & 15 (d15 part A only), Cyc3+ d1, EoT and unsched. V
    ECHO/MUGA: Base, Cyc1 d8, Cyc3 d1, EoT, unsched. V
    plasma, pk: Cycle 1 days 1, 2, 3, 8, 9, 15 & 22, Cyc2-6 d1 & 15
    tumour assess.: Base, Cyc2 d15, after cycle 2, every 8 weeks until EOT or disease progress./OS
    pfs: EoT

    Exploratory
    Whole blood, plasma &: base, Cyc2-6 d1
    Hair follicles: base, Cyc1-6 d1
    Tumour biopsy: same as tumor assess.
    Liquid biopsy: same as tumor assesment up to Cyc6, EoT, unsched. V
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    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 Yes
    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) 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.8.2.4Number of treatment arms in the trial1
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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
    Netherlands
    Spain
    Switzerland
    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
    The end-of-study is reached when the last patient in Part B of the study has been on study treatment for up to 12 cycles plus the safety follow-up period of 28 days after the first dose of CB-103. In case the study is stopped before any patient was treated for 12 months, the end-of-study is reached 28 days after the last patient in Part B of the study has received his/her last dose of CB-103
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 145
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 145
    F.4.2.2In the whole clinical trial 165
    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)
    Patients who continue to benefit from treatment after 6cycles (Part A) or 12cyc (B) may continue treatment if agreed by Investigator and Sponsor, potentially through compassionate program and pending study drug availability. If treatment continues beyond 6cyc (A) and 12 cyc (B), visits occur every 4 wks (A) or 8 wks (B) if no med. issue/complication in prev. cycles. Study procedures continue as per schedule of assessments.
    Data from these patients will be reported in a separate abbreviated CSR.
    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 Decision2017-07-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-29
    P. End of Trial
    P.End of Trial StatusOngoing
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