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    Summary
    EudraCT Number:2022-004167-25
    Sponsor's Protocol Code Number:NKI-AVLM22TGA
    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:2023-03-06
    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 number2022-004167-25
    A.3Full title of the trial
    Phase I/II study with galunisertib combined with capecitabine in patients with advanced chemotherapy resistant colorectal cancer with peritoneal metastases
    Phase I/II studie van galunisertib gecombineerd met capecitabine bij chemotherapie resistent colorectaal carcinoom met peritoneale metastasen
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Galunisertib combined with capecitabine in bowel cancer with peritoneal metastases
    Galunisertib in combinatie met capecitabine bij naar het buikvlies uitgezaaide darmkanker
    A.3.2Name or abbreviated title of the trial where available
    Galunisertib combined with capecitabine in advanced CRC
    A.4.1Sponsor's protocol code numberNKI-AVLM22TGA
    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 SponsorDepartment of Medical Oncology and Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hosp
    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 supportThe Netherlands Cancer Institute
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationThe Netherlands Cancer Institute
    B.5.2Functional name of contact pointMs Alaa Embaby
    B.5.3 Address:
    B.5.3.1Street AddressPlesmanlaan 121
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1066CX
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310205129111
    B.5.6E-maila.embaby@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 nameGalunisertib
    D.3.4Pharmaceutical form 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 INNGalunisertib
    D.3.9.1CAS number 700874-72-2
    D.3.9.4EV Substance CodeSUB126321
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number80 to 150
    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 Yes
    D.3.11.13.1Other medicinal product typeTGF-beta inhibitor: targeted therapy
    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 colorectal cancer with peritoneal metastases
    E.1.1.1Medical condition in easily understood language
    Bowel cancer with metastases in peritoneum
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Phase I: To determine the safety and recommended phase 2 dose (RP2D) of galunisertib plus capecitabine in patients with advanced chemotherapy resistant CRC with PM, who progressed after standard chemotherapy.

    Phase II: To determine the anti-tumor activity, as measured by objective response rate (ORR) of galunisertib in combination with capecitabine in patients with advanced chemotherapy resistant CRC with PM. Secondary objectives include the safety and tolerability of the combination therapy, duration of response (DOR), time to response (TTR), progression free survival (PFS), overall survival (OS), the pharmacokinetic profile of galunisertib in combination with capecitabine and exploratory genetic determinants of response and resistance (e.g. TGF-b expression)
    E.2.2Secondary objectives of the trial
    Secondary objectives include the safety and tolerability of the combination therapy (phase II), duration of response (DOR), time to response (TTR), progression free survival (PFS), overall survival (OS), the pharmacokinetic profile of galunisertib in combination with capecitabine and exploratory genetic determinants of response and resistance (e.g. TGF-b expression)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histological or cytological proof of CRC with at least confirmed peritoneal metastases (presence of additional extraperitoneal metastases is allowed);
    2. Disease progression or relapse upon treatment for advanced CRC with fluoropyrimidine containing chemotherapy as single agent or in combination with other anti-cancer drugs, with no treatment options at time of inclusion (combinations with oxaliplatin, irinotecan, bevacizumab and cetuximab/panitumumab are allowed);
    3. Age ≥ 18 years;
    4. Able and willing to give written informed consent and informed consent form must have been signed before start of the trial;
    5. WHO performance status of ≤1;
    6. Able and willing to undergo blood sampling for PK analysis;
    7. Able and willing to undergo tumor biopsy before start, during treatment and at the end of treatment;
    8. Life expectancy > 3 months allowing adequate follow up of toxicity and anti-tumor activity;
    9. Evaluable disease according to RECIST 1.1 criteria (measurable disease for the phase II part; evaluable disease is sufficient for the phase I part);
    10. Minimal acceptable safety laboratory values
    a. ANC of ≥1.5 x 109 /L
    b. Platelet count of ≥100 x 109 /L
    c. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 3.0 x ULN, or ALAT and ASAT < 5 x ULN in patients with liver metastases
    d. Renal function as defined by serum creatinine ≤ 1.5 x ULN
    e. Creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula or MDRD);
    11. Negative pregnancy test (urine or serum) for female patients with childbearing poten-tial.
    12. Able and willing to swallow tablets.
    E.4Principal exclusion criteria
    1. Any treatment with investigational drugs within 30 days prior to receiving the first dose of investigational treatment and/or radio- or chemotherapy within the last 2 weeks prior to receiving the first dose of investigational treatment. Palliative radia-tion (1x 8Gy) is allowed; except radiotherapy focused on the liver;
    2. Known or suspected complete or partial dihydropyrimidine dehydrogenase deficien-cy (Mutant for DPD*2A genotype, 1236G>A genotype, 1679T>G genotype and 2846A>T genotype);
    3. Symptomatic or untreated leptomeningeal disease;
    4. Symptomatic brain metastasis. Patients previously treated or untreated for these conditions that are asymptomatic in the absence of corticosteroid therapy are al-lowed to enrol. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of pro-gressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids;
    5. History of cardiac disease, including myocardial infarction within 6 months before first dose of study medication, unstable angina pectoris, New York Heart Associa-tion Class III/IV congestive heart failure, or uncontrolled hypertension, major cardiac abnormalities, a predisposition for developing aneurysms including family history of aneurysms, Marfan syndrome, bicuspid aortic valve, or evidence of damage to the large vessels of the heart;
    6. Treatment with CYP3A4 inducers or inhibitors and/or concomitant treatment with CYP2C9 substrates with narrow therapeutic window, including but not limited to vit-amin K antagonizing anticoagulants (e.g. acenocoumarol, phenprocoumon and war-farin) and phenytoin is not allowed;
    7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral galunisertib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, major small bowel surgery);
    8. Woman who are pregnant or breast feeding;
    9. Patients who have undergone any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery;
    10. Active infection requiring systemic antibiotics or uncontrolled infectious disease;
    11. Patients with a known history of hepatitis B or C or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
    12. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnor-mality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study;
    13. Known hypersensitivity to one of the study drugs or excipients.
    E.5 End points
    E.5.1Primary end point(s)
    Phase I: Number of dose-limiting toxicities (DLT's) and treatment-related adverse events, RP2D of galunisertib in combination with capecitabine. N=6.

    Phase II: anti-tumor activity as measured by ORR of galunisertib in combination with capecitabine. With 6 or more responses out of 25, the treatment will be declared to be effective in the selected patient population
    E.5.1.1Timepoint(s) of evaluation of this end point
    Tumor evaluations by CT scan according to RECIST 1.1 criteria every 8 weeks (every 2 cycles)
    E.5.2Secondary end point(s)
    hase II:
    - To characterize the safety and tolerability of galunisertib in combination with capecitabine as assessed by the incidence and severity of adverse
    events.
    - To assess anti-tumor activity of galunisertib in combination with capecitabine, as measured by duration of response (DOR), time to response (TTR), progression-free survival (PFS) and overall survival (OS).
    - To determine pharmacokinetics of galunisertib in combination with capecitabine as measured by plasma concentrations.
    - To explore biomarkers for response in tissue (such as TGF-beta expression)
    E.5.2.1Timepoint(s) of evaluation of this end point
    DOR, TTR, PFS: Tumor evaluations by CT scan according to RECIST 1.1 criteria every 8 weeks (every 2 cycles)
    OS: Until study completion (incl. follow-up of patients; every 3 months)
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Translational research
    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 I and phase II study, not a FIH study
    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.8.2.4Number 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 concerned2
    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 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
    Last visit of the last subject in the trial
    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 months5
    E.8.9.1In the Member State concerned 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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state35
    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)
    Only patients who have no other treatment options left participate in the the trial.
    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 Decision2023-03-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-05-04
    P. End of Trial
    P.End of Trial StatusOngoing
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