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    Summary
    EudraCT Number:2022-000394-96
    Sponsor's Protocol Code Number:NEOGAP-CRC-01
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2022-03-31
    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 ConcernedSweden - MPA
    A.2EudraCT number2022-000394-96
    A.3Full title of the trial
    A First-In-Human, Phase I/IIa Trial of the novel T cell Immunotherapy pTTL in Patients with Advanced Colorectal Cancer
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A First-In-Human Trial of the novel T cell Immunotherapy pTTL in Patients with Advanced Colorectal Cancer
    A.4.1Sponsor's protocol code numberNEOGAP-CRC-01
    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 SponsorNEOGAP Therapeutics AB
    B.1.3.4CountrySweden
    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 supportNEOGAP Therapeutics AB
    B.4.2CountrySweden
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCTC Clinical Trial Consultants AB
    B.5.2Functional name of contact pointClinical Research Manager
    B.5.3 Address:
    B.5.3.1Street AddressDag Hammarskjölds väg 10B
    B.5.3.2Town/ cityUppsala
    B.5.3.3Post codeSE-75237
    B.5.3.4CountrySweden
    B.5.4Telephone number00460705292158
    B.5.6E-mailcaroline.hammarstrom@ctc-ab.se
    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 pTTL
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot assigned
    D.3.9.2Current sponsor codepTTL (personalised tumour-trained lymphocytes)
    D.3.9.4EV Substance CodeSUB266933
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1000000 to 10000000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product Yes
    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
    Stage IV colorectal cancer.
    E.1.1.1Medical condition in easily understood language
    Advanced colorectal cancer with metastases
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10061451
    E.1.2Term Colorectal cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To establish that pTTL can be administered to patients with advanced colorectal cancer without unacceptable toxicity.
    E.2.2Secondary objectives of the trial
    - To evaluate treatment efficacy in terms of objective response.
    - To evaluate treatment efficacy in terms of progression free survival and overall survival.

    Exploratory objectives:
    - To explore biomarkers for:
    -pTTL persistence in vivo.
    -pTTL anatomical localisation of pTTL post infusion, with focus on tumour infiltration.
    -pTTL recognition of neoantigens in vivo and pTTL capacity to achieve tumour cell eradication
    - pTTL characteristics

    -To gain early insights in selection of neoantigens. Data on the association between the selected neoantigens, biomarker evaluation and clinical outcome will be collected.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Applicable for both Part I and Part 2:

    1. Signed informed consent.

    2. Adult (age ≥18 years).

    3. Histological or cytological confirmation of colorectal cancer.

    4. Verified metastatic disease (stage IV classification).

    5. Measurable disease according to RECIST1.1.

    6 (no 7 in part 2). Minimum life expectancy of 6 months (part I) or 3 months (part II).

    7 (no 8 in part 2). ECOG performance status 0 to 1
    8 (no 9 in part 2). Adequate bone marrow, hepatic and renal function defined as:
    a. Haemoglobin ≥ 95 g/L (blood transfusion not less than 21 days prior to screening),
    b. Absolute neutrophil count ≥ 1.0 x 109/L, platelets ≥100 x 109/L
    c. Total bilirubin < 1.5 x ULN (does not apply to patients with Gilberts Syndrome)
    d. AST and ALT ≤ 1.5 x ULN (or ≤ 5 x ULN in the presence of liver metastases)
    e. Serum creatinine ≤ ULN (if serum creatinine is between 1 and 1.5 x ULN, patients may be eligible provided that the calculated GFR is at least 35 mL/min using Cockcroft-Gault method).
    f. Albumin ≥24 g/L
    9 (no 10 in part 2). Patients of childbearing potential or their partners of childbearing potential must be willing to take the appropriate precaution to avoid pregnancy or fathering a child for the duration of Part II and practice an approved, highly effective method of birth control during treatment and for 6 months after receiving pTTL. For patients of childbearing potential, appropriate precautions to avoid pregnancy is required also in Part I, as pregnancy would preclude proceeding to Part II of the trial.

    Inclusion criteria in addition to the above

    Applicable only for Part I:
    10. Able to undergo surgery or biopsy to obtain tumour tissue for neoantigen evaluation and to retrieve RNs as starting material for pTTL manufacturing
    11. The area from which the RLN will be obtained shall not have been exposed to radiotherapy.

    Applicable only for Part 2:
    6. Have received all possible standard of care therapies, OR further standard of care therapies are currently not considered to be in the patient’s best interest, OR toxicity from previous therapy limits the choice of suitable standard of care therapy OR scheduled pause in palliative standard of care therapy as judged by the Investigator.
    E.4Principal exclusion criteria
    1.Less than 4 months (Part 1) or 6 months (Part 2) since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or transient ischemic attack (TIA). Atrial fibrillation if treated and well controlled is not considered a bar to inclusion even if diagnosed less than 6 months ago
    2.(Applicable for Part 1) For patients scheduled for trial specific surgery:Left ventricular ejection fraction (LVEF) <45% and/or significant heart valve dysfunction (stenosis or insufficiency) as determined by echocardiogram performed within 3 months of the screening visit (Visit 1).For patients scheduled for standard surgery:congestive heart failure New York Heart Association (NYHA) class III or IV.Echocardiogram for inclusion in Part I is not mandatory due to time limitations prior to standard surgery
    2.(Applicable for Part 2) LVEF <45% and/or significant heart valve dysfunction (stenosis or insufficiency) as determined by echocardiogram performed within 3 month before start of pre conditioning therapy,or more recently if clinically indicated
    3.Significantly reduced lung function with clinical implications.If such is suspected, spirometry should be performed.Spirometry should also be considered in patients who have been hospitalised due to Covid-19 infection during the last 6 months, and in patients with any other lung affectation judged significant by the Investigators, in discussion with Sponsor’s Medical Representative,such as treatment-related pneumonitis or severe lung infection.Spirometry results of less than 65% of the expected value regarding forced expiratory volume in 1 second (FEV1) and/or diffusion capacity (diffusing capacity of the lung for carbon monoxide, DLCO, corrected for haemoglobin value, DLCOco) is regarded as a criterium for exclusion
    For patients scheduled for standard surgery:not applicable - spirometry for inclusion in Part I is not mandatory due to time limitations prior to standard surgery
    4.Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of trial results (as judged by the Investigators, in agreement with Sponsor’s Medical Representative)
    5.Immunodeficiency disorders which may pose a risk for patients treated with pTTL, and/or affect the outcome of the pTTL treatment as judged by the Investigator at the Recruitment, Surgery & Treatment Site.
    6.Autoimmunity disorders which may pose a risk for patients treated with pTTL, and/or affect the outcome of the pTTL treatment,as judged by the Investigator at the Recruitment, Surgery & Treatment Site
    7.Leptomeningeal metastases (patient with previously treated brain metastases are eligible if there is no evidence of disease progression for a minimum of 8 weeks prior to inclusion – in these cases a CNS MRI is required within the screening period.These patients must not have symptoms from their brain metastases or treatment thereof and must not be taking steroid medications for treatment of CNS symptoms)
    8. Systemic immunosuppressive concomitant medications,including chemotherapy for CRC and steroids for antiemetic prophylaxis, must be discountinued at a minimum 2 weeks prior to surgery.Steroid medications are allowed if they are used as substitution or are administrated topically or as inhalation steroids for asthma
    9.Previous Grade 3 or greater immune-related toxicity from checkpoint modulation or other immunotherapy (unless the toxicity has resolved and the patient rechallenged with the therapy without recurrence of toxicity, in which situation the patient can be considered).
    10.Acute or chronic infection with hepatitis B or C or syphilis
    11.HIV infection
    12.Pregnancy or breast-feeding
    13.Investigator considers the patient unlikely to comply with trial procedures, restrictions and requirements

    Exclusion criteria in addition to the above. Applicable only for Part I:
    14.For patients required to undergo trial-specific surgery to obtain starting material:
    a)Less than 3 identifiable enlarged lymph nodes on pre-surgery radiology which could be targeted for surgical excision
    b)Previous surgical removal of the primary CRC tumour (would entail a high risk surgery)
    c)Unable to withstand the planned surgery (including ineligibility for general anaesthesia)

    Applicable only for Part 2:
    14.Less than 4 weeks prior to start of pre-conditioning since stopping previous systemic cancer treatment
    15.Less than 2 weeks prior to start of pre-conditioning since stopping radiotherapy
    16.Less than 4 weeks prior to start of pre-conditioning after major surgery and less than 3 weeks after minor surgery
    17.Participation in any other clinical cancer therapy trial,and planned treatment or treatment with another investigational drug, within the previous 4 weeks prior to start of pre-conditioning
    18.Less than 4 weeks prior to start of pre-conditioning since administration of live attenuated vaccines
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is safety with adverse events (AEs) assessed according to CTCAE v.5. Special focus will be placed on immunological AEs and AEs known to be associated with T cell therapies, which are classified as AEs of special interest (AESI). AESI will include autoimmune reactions potentially resulting from off-target toxicity such as colitis, and immune-mediated reactions associated with immune cell activation, such as cytokine release syndrome (CRS).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluated through:
    - AE reporting and questioning (done regularly during the study from visit 2 until last follow-up).
    - Physical examinations (done regularly during the study from screening until week 26 after treatment administration).
    - Vital signs (done regularly during the study from screening until until week 26 after treatment administration).
    - Safety laboratory parameters (done regularly during the study from screening until week 26 after treatment administration).
    - Electrocardiogram (ECG) (done regularly during the study from visit 3 until day 23 after treatment administration).
    E.5.2Secondary end point(s)
    • Objective response (according to iRECIST).
    • Characterisation of treatment response:
    o time to response
    o duration of response
    • Time to tumour progression assessed using the iRECIST criteria (time
    from inclusion in Part II of the trial until disease progression).
    • Kinetics of tumour progression/growth (compared to pre-treatment)
    • Overall survival (time from inclusion to death of any cause).
    • Progression-free survival (time from inclusion to tumour progression or death of any cause).
    • Disease-specific survival (time to death of disease).

    Exploratory endpoints:
    • Evaluation of biomarkers for:
    o pTTL persistence. T cell receptor sequencing (TCRseq) will be used to characterise the pTTL product and to trace the identified pTTL clones in sequential peripheral blood samples post treatment.
    o pTTL tumour infiltration. If feasible, pre- and post-treatment biopsies will be taken for histological assessment of T cell infiltration and characterisation of tumour-infiltrating T cells.
    o pTTL neoantigen specificity and efficacy:
     Functional T cell assays will be used to evaluate neoantigen-specific responses in the pTTL product and in peripheral blood T cells. The evaluation plan includes investigation of potential tumour killing assays.
     Markers of tumour burden will be evaluated.
    o pTTL characteristics: analysis of the pTTL product and of post therapy peripheral blood samples will be performed to evaluate the functional status, differentiation and lineage-identity of T cells and other immune cells.
    • Correlation of neoantigen selection to clinical outcome. The type of neoantigens targeted will be assessed in the context of clinical outcomes, signals of efficacy and biomarker evaluation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluated through medical imaging and iRECIST assessment. Medical imaging done at visit 2 prior to surgery, visit 3 prior to treatment, and at week 6, 12, 18 and 24. Also done at month 9, 12, 18 and 24, and then yearly for 3 more years.

    Exploratory endpoints:
    Evaluated through biomarker sampling of pTTL, tumour and blood.
    Sampling for biomarkers done at visits prior to treatment administration. Also done after treatment at days 7, 14, 26, and at weeks 6, 12, 18 and 24. Sampling also done at 9, 12, 18 and 24 months and then yearly for 3 years.
    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 No
    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 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 No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 8
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 8
    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 state16
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-01-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-20
    P. End of Trial
    P.End of Trial StatusOngoing
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