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    Summary
    EudraCT Number:2021-001029-32
    Sponsor's Protocol Code Number:PBI-200-101
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-06-21
    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 number2021-001029-32
    A.3Full title of the trial
    A Phase 1/2 Study of PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1/2 Study of PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    A.4.1Sponsor's protocol code numberPBI-200-101
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04901806
    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 SponsorPyramid Biosciences, Inc.
    B.1.3.4CountryUnited States
    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 supportPyramid Biosciences, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPyramid Biosciences, Inc.
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address330 Bear Hill Road, Suite 302
    B.5.3.2Town/ cityWaltham, MA
    B.5.3.3Post code02451
    B.5.3.4CountryUnited States
    B.5.6E-mailclinicaltrials@pyramidbio.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 namePBI-200
    D.3.2Product code PBI-200
    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 INN(R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-a] pyrimidine
    D.3.9.2Current sponsor codePBI-200
    D.3.9.3Other descriptive namePBI-4050
    D.3.9.4EV Substance CodeSUB179215
    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: 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.3.1Product namePBI-200
    D.3.2Product code PBI-200
    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 INN(R)-5-(2-(2,5-difluorophenyl) pyrrolidin-1-yl)-3-(4-(trifluoromethyl)-1H-pyrazol-1-yl) pyrazolo[1,5-a] pyrimidine
    D.3.9.2Current sponsor codePBI-200
    D.3.9.3Other descriptive namePBI-4050
    D.3.9.4EV Substance CodeSUB179215
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 Yes
    D.2.1.1.1Trade name Norvir
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Deutschland GmbH & Co. KG
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameritonavir
    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 INNRitonavir
    D.3.9.1CAS number 155213-67-5
    D.3.9.4EV Substance CodeSUB10342MIG
    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
    One of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists:
    • NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor
    • NTRK-gene amplified, locally advanced or metastatic solid tumor (Phase 1 only)
    • EWSR1-WT1-positive DSRCTs (Phase 1 only)
    E.1.1.1Medical condition in easily understood language
    Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors
    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 SOC
    E.1.2Classification code 10029104
    E.1.2Term Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 1:
    - To determine the safety and tolerability, maximum tolerated dose (MTD), and dose limiting toxicities (DLTs) of PBI-200 alone and coadministered with ritonavir (PBI-200/ritonavir) in subjects with NTRK-fusion-positive or NTRK-amplified advanced or metastatic refractory solid tumors or refractory EWSR1-WT1-fusion-positive desmoplastic small round cell tumors (DSRCTs).
    - To establish the Recommended Phase 2 Dose (RP2D) of PBI-200/ritonavir
    • Phase 2:
    - To evaluate the antitumor activity of PBI-200 in subjects with NTRKfusion-positive advanced or metastatic refractory solid tumors as follows:
    Cohort A: Non-Brain Primary Tumors
    - Objective response rate (ORR) based on RECIST v1.1 by Independent Radiology Review (IRR)
    Cohort B: Primary Brain Tumors
    - ORR based on Response Assessment in Neuro-Oncology (RANO) criteria by IRR
    E.2.2Secondary objectives of the trial
    • Phase 1:
    - To evaluate the pharmacokinetics (PK) of PBI-200 and metabolite PBI-
    200-M15
    - To evaluate the antitumor activity of PBI-200 as follows: Non-Brain Primary Tumors
    - ORR, duration or response (DoR), and progression-free survival (PFS)
    based on RECIST v1.1 by Inv Assessment and by IRR.
    - Intracranial ORR (IORR), DoR (iDoR), and PFS (IPFS) based on RANOBM
    by Inv Assessment and by IRR for subjects with measurable brain
    metastasis at Screening
    Primary Brain Tumors
    - ORR, DoR, and PFS based on RANO criteria by Inv Assessment and by
    IRR
    • Phase 2
    - Non-Brain Primary Tumors
    -- DoR and PFS based on RECIST v1.1 by IRR
    -- IORR, iDoR, and IPFS based on RANO-BM by IRR for subjects with
    measurable brain mets at Screening
    - Primary Brain Tumors
    -- DoR and PFS based on RANO criteria by IRR
    - To evaluate antitumor activity by Inv Assessment
    - To confirm the safety and tolerability of PBI-200 at the RP2D
    - To further evaluate the PK of PBI-200 and metabolite PBI-200-M15

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject has one of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists (subjects who have received a prior TRK inhibitor may be eligible after progression or intolerance of therapy):
    •NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor
    •NTRK-gene amplified, locally advanced or metastatic solid tumor
    (Phase 1 only)
    •EWSR1-WT1-positive DSRCTs (Phase 1 only)
    Note: Subjects with any grade of glioma previously treated with systemic therapy and documented NTRK gene fusion or amplification are eligible.
    For phases 1 and 2, subject's prior treatment should include all approved regimens that have demonstrated a survival advantage for the subject's disease, stage, and line of therapy.
    2. Phase 1
    •Subjects with NTRK-fusion-positive solid tumors other than primary brain tumors (non-brain primary tumors) must have previously received treatment with a TRK inhibitor, unless the subject does not have access to TRK-inhibitor therapy (e.g., no TRK inhibitor is marketed and available to the subject in the subject's country) or unless the subject is ineligible for marketed TRK-inhibitor therapy (e.g., subject has a resistance mutation).
    •Subjects with NTRK-gene-amplified solid tumors, primary brain tumors or EWSR1-WT1- positive DSRCTs may have received prior treatment with a TRK inhibitor but this is not required.
    3. Phase 2
    •Has measurable disease by RECIST v1.1 for subjects with non-brain primary tumors or RANO criteria for subjects with primary brain tumors.
    •Subjects with non-brain primary tumors must have previously received treatment with a TRK inhibitor and must have a documented on-target resistance mutation(s) (e.g., solvent front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior TRK-inhibitor treatment based on a tumor biopsy obtained following their most recent systemic therapy. Archival tissue from a prior biopsy taken after the subject completed TRK-inhibitor treatment but prior to additional systemic therapy may be used to meet this eligibility criterion.
    •Subjects with primary brain tumors may have received prior treatment with a TRK inhibitor but this is not required. For these subjects, a tumor biopsy any time following TRK-inhibitor treatment is encouraged, and if analyzed for resistance mechanisms, must demonstrate an on-target resistance mutation (e.g. solvent front, gatekeeper or xDFG mutation) as the mechanism of resistance to their prior TRK-inhibitor treatment.
    However, biopsies of brain tumors are not required for eligibility.
    •Note: Subjects with NTRK-gene amplified tumors or EWSR1-WT1- positive DSRCTs are not eligible in Phase 2.
    4. Subjects with brain tumors and brain metastasis must be neurologically stable. Subjects with asymptomatic brain metastases are eligible.
    5. Age ≥ 18 years at the time of signing the informed consent form (ICF).
    6. Has provided written informed consent.
    7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1.
    8. Acceptable liver, renal, hematologic, and coagulation function
    •Bilirubin ≤ 1.5x ULN
    •AST, ALT ≤ 3.0x ULN
    •Estimated creatinine clearance of ≥ 45 ml/min based on the Cockcroft-
    Gault formula
    •Absolute neutrophil count ≥ 1000/mm3
    •Platelet count ≥ 75,000/mm3
    •Hemoglobin ≥ 8 g/dL
    •INR ≤ 1.5 ULN and aPTT ≤ 1.5 ULN. Study subjects on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use
    9. Ability to swallow capsules or tablets and no gastrointestinal issues that may impact absorption of oral medication.
    10. Women of child-bearing potential must agree to use highly effective contraceptive methods and avoid egg donation during the study treatment and for 6 months after the last dose of study treatment. Due to the potential interaction of PBI-200 and ritonavir with CYP3A substrates such as oral contraceptives, women using hormonal methods of contraception must also use a second non-hormonal highly effective method. A woman is considered to be of child-bearing potential unless she:
    •has had a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy;
    •is age ≥ 60 years and is amenorrhoeic; or
    •is age < 60 years and has been amenorrhoeic for ≥ 12 months
    11. For women of child-bearing potential: A negative serum pregnancy test during Screening and a negative pregnancy test (either serum or urine) predose on Day -2 (the first day of study treatment)
    12. Men of reproductive potential agree to use highly effective contraceptive methods and avoid sperm donation during the study treatment and for 6 months after the last dose of study treatment. A man is considered to be of child-producing potential unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy.
    E.4Principal exclusion criteria
    1. Cytotoxic chemotherapy, biologic agent, or radiation therapy ≤ 3 weeks prior to the first dose of study treatment (6 weeks for nitrosoureas). The
    interval may be reduced to 2 weeks for bone-only radiation therapy or investigational agents not expected to be associated with AEs after 2
    weeks of last administration.
    • Subjects with either primary brain tumors or brain metastasis who require radiation must have completed brain radiation therapy at least
    12 weeks prior to the brain MRI obtained within 4 weeks of the first dose of study treatment. The Medical Monitor should be consulted if there is an interval of less than 12 weeks if there is reasonable certainty of radiographic disease progression (e.g., new disease outside the radiation therapy field following completion of the radiation therapy) or histopathologic documentation of unequivocal disease progression. Subjects with asymptomatic brain metastases are not required to have received radiation therapy.
    2. Small-molecule kinase inhibitors or hormonal agents ≤ 14 days or within 5 half-lives prior to the first dose of study treatment, whichever is shorter.
    3. For subjects enrolled in Phase 2: Treatment with more than one prior TRK inhibitor.
    Note: Subjects enrolled in the Phase 1 part of the study may have received more than one TRK inhibitor.
    4. Clinically significant AEs that have not returned to baseline or ≤ Grade 1 based on NCI CTCAE v5.0.
    5. Major surgery ≤ 6 weeks or minor surgery ≤ 14 days prior to the first dose of study treatment
    6. Clinically significant intercurrent disease including but not limited to:
    • New York Heart Association Class III or IV heart failure
    • Myocardial infarction or stroke ≤ 26 weeks prior to the first dose of study treatment
    • Unstable angina within ≤ 13 weeks prior to the first dose of study treatment unless the underlying disease has been corrected by procedural
    intervention e.g., stent, bypass
    • Severe aortic stenosis
    • Uncontrolled arrhythmia.
    • Congenital long QT syndrome.
    • QTc > 470 milliseconds by Fredericia criteria (QTcF) based on the average of 3 ECGs taken approximately 1 minute apart and all within 10
    minutes of each other. The subject should be reclining for 5 minutes prior to ECGs. Local readings may be used for this inclusion criterion.
    • Clinically significant active infection requiring systemic antibiotic, antiviral or antifungal medication. Subjects must be medically stable,
    afebrile, no documented evidence of ongoing infection and not taking antimicrobial treatment for ≥ 3 days prior to the first dose of study treatment
    7. Subjects taking sensitive substrates of CYP2B6, CYP2C8, CYP2C9 and CYP3A unless the subject can safely discontinue these medications or
    change to comparable medications that are not sensitive substrates of these CYPs.
    8. Subjects that are taking strong CYP3A inhibitors or inducers unless the subject can safely discontinue these medications or change to
    comparable medications that are not strong inhibitors or inducers of CYP3A at least 5 half-lives or 7 days prior to the first dose of study treatment.
    9. Human immunodeficiency virus (HIV) infection.
    10. Active hepatitis B or C infection.
    11. Previous or concurrent cancer that is distinct in the primary site or histology from the solid tumors under evaluation within 3 years before
    start of study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors (Ta [noninvasive tumor], Tis [carcinoma in situ], and T1 [tumor invades lamina propria]), and asymptomatic localized prostate cancer with no
    requirement for systemic therapy (or requiring only hormonal therapy) and with normal prostate-specific antigen values within ≥12 months
    prior to enrollment.
    12. Women who are pregnant or breastfeeding.
    13. Unwillingness or inability to comply with procedures required in this protocol.
    14. Currently receiving any other anticancer or investigational agent.
    15. Subjects that are taking narrow therapeutic index (NTI) oral P-gp substrate drugs unless the subject can safely discontinue these
    medications or change to comparable medications that are not NTI substrate drugs of P-gp. P-gp.
    16. Subjects with known hypersensitivity (e.g., toxic epidermal
    necrolysis or Stevens-Johnson syndrome) to ritonavir, PBI-200, or any of the ingredients or excipients in either drug.
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1: Dose Escalation
    • Safety as assessed by the incidence of adverse events (AEs) and changes in vital signs, clinical laboratory
    assessments, Eastern Cooperative Oncology Group (ECOG) performance status, and electrocardiogram (ECG) parameters.

    Phase 2: Cohort Expansion
    - Cohort A: Non-Brain Primary Tumors
    • Antitumor (ORR) activity based on RECIST v1.1 by Independent Radiology Review
    - Cohort B: Primary Brain Tumors
    • Antitumor activity (ORR) based on RANO criteria by Independent Radiology Review Secondary Endpoints
    E.5.1.1Timepoint(s) of evaluation of this end point
    This endpoint is to be measured throughout, until the end of the study
    E.5.2Secondary end point(s)
    Phase 1 Dose-Escalation
    • Plasma PK of PBI-200 and metabolite PBI-200-M15 as assessed via:
    − Area under the plasma drug concentration-time curve from 0 to 48 hours (AUC0-48h) after one dose and 0 to 24 hours (AUC0-24h) at steady state.
    − Maximum concentration (Cmax)
    − Time to maximum concentration (Tmax)
    − Half-life (T1/2)
    − Apparent steady state volume of distribution of PBI-200 (Vss/F)
    − Apparent clearance (CL/F) of PBI-200
    • Preliminary antitumor activity for subjects with non-brain primary
    tumors
    -- Subjects with Non-Brain Primary Tumors
    --- ORR, DoR and PFS based on RECIST v1.1 by Investigator assessment
    and Independent Radiology Review.
    --- Intracranial ORR (IORR), iDoR, and IPFS based on RANO-BM by
    Investigator assessment and Independent Radiology Review for subjects
    with measurable brain metastasis by RANO-BM during Screening.
    -- Subjects with Primary Brain Tumors
    --- Preliminary antitumor activity for subjects with primary brain tumors
    based on RANO criteria by Investigator assessment and Independent
    Radiology Review as assessed via ORR, DoR, and PFS
    • Exploratory Endpoints
    − ORR, DoR and PFS based on RECIST v 1.1 and IORR, iDoR and IPFS for
    subjects with Non-Brain Primary Tumors and ORR, DoR and PFS based
    on RANO criteria for subjects with Primary Brain Tumors in patients with
    resistance mutations to prior TRK inhibitors
    − Response assessment of non-measurable intracranial lesions
    − Plasma PK of ritonavir at steady state as assessed by AUC0-24,ss,
    Cmax,ss, Cmin and Tmax

    Phase 2 Cohort Expansion
    Cohort A: Non-Brain Primary Tumors
    • Antitumor activity (DoR, PFS) based on RECIST v1.1 by Independent
    Radiology Review
    • Intracranial antitumor activity (IORR, iDoR, and IPFS) based on RANOBM
    by Independent Radiology Review
    • Antitumor activity (ORR, DoR, PFS) based on RECIST v1.1 by
    Investigator assessment. Intracranial antitumor activity (IORR, iDoR,
    and IPFS) based on RANO-BM by Investigator assessment
    Cohort B: Primary Brain Tumors
    • Antitumor activity (DoR, PFS) based on RANO criteria by Independent
    Radiology Review
    • Antitumor activity (ORR, DoR, and PFS) based on RANO criteria by
    Investigator assessment
    • Safety as assessed by the incidence of treatment-emergent AEs
    (TEAEs) and changes in vital signs, clinical laboratory assessments,
    ECOG performance status, and ECG parameters.
    • Plasma PK of PBI-200 and its metabolite PBI-200-M15 as appropriate,
    as assessed via:
    − AUC0-48h after single dose and AUC0-24h after steady state
    − Cmax
    − Tmax
    − T1/2
    − Vss/F
    − CL/F
    • Exploratory Endpoints
    − ORR, DoR and PFS based on RECIST v 1.1 and IORR, iDoR and IPFS for subjects with Non-Brain Primary Tumors and ORR, DoR and PFS based on RANO criteria for subjects with Primary Brain Tumors for subjects with resistance mutations to prior TRK inhibitors
    − Response assessment of non-measurable intracranial lesions
    − Plasma PK of ritonavir at steady state as assessed by AUC0-24,ss,
    Cmax,ss, Cmin and Tmax
    E.5.2.1Timepoint(s) of evaluation of this end point
    Plasma PK of PBI-200 will be evaluated through Cycle 6 Day 1 and an additional PK sample shold be collected upon assessment of disease progression (prior to discontinuation of study drug)
    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 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.8.3 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 EEA24
    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
    Australia
    Singapore
    United States
    Denmark
    France
    Germany
    Italy
    Spain
    Hong Kong
    Korea, Republic of
    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
    Last visit last subject (LVLS)
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months7
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 31
    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
    In such case the consent will be given by a legal representative or
    impartial witness.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 91
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    All study subjects will be evaluated 28 to 35 days after their last dose
    of study treatment for safety follow-up. Study subjects who discontinue
    treatment for reasons other than DP will continue to be followed for
    response assessments until progression or initiation of new systemic
    anti-cancer therapy. Additional FUP will occur for ongoing treatmentrelated SAEs and CS AEs until resolution or stabilization.
    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 Decision2021-10-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-01-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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