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    Summary
    EudraCT Number:2019-001358-24
    Sponsor's Protocol Code Number:B9991040
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-08-21
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2019-001358-24
    A.3Full title of the trial
    A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination with Bempegaldesleukin (NKTR-214) with or without Talazoparib or Enzalutamide in Participants with Locally Advanced or Metastatic Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 1b/2 Study to Evaluate Safety and Clinical Activity of Avelumab in Combination with Bempegaldesleukin with or without Talazoparib or Enzalutamide in Participants with Locally Advanced or Metastatic Solid Tumors
    A.3.2Name or abbreviated title of the trial where available
    JAVELIN IL-2 Medley
    A.4.1Sponsor's protocol code numberB9991040
    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 SponsorPfizer 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 supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post code10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18007181021
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 Yes
    D.2.1.1.1Trade name Bavencio
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameAvelumab
    D.3.2Product code MSB0010718C
    D.3.4Pharmaceutical form Concentrate for solution for 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 INNAVELUMAB
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameAnti PD-L1
    D.3.9.4EV Substance CodeSUB180078
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    D.2.1.1.1Trade name Talzenna
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTalazoparib
    D.3.2Product code PF-06944076 1 mg
    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 INNTALAZOPARIB
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive namePF-06944076-15, MDV3800, BMN 673
    D.3.9.4EV Substance CodeSUB180394
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 Xtandi
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameENZALUTAMIDE
    D.3.2Product code PF-04998299
    D.3.4Pharmaceutical form Capsule, soft
    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 INNENZALUTAMIDE
    D.3.9.1CAS number 915087-33-1
    D.3.9.2Current sponsor codePF-04998299
    D.3.9.3Other descriptive nameMDV3100
    D.3.9.4EV Substance CodeSUB77412
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.3.1Product nameNKTR-214
    D.3.4Pharmaceutical form Powder for solution for injection
    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 INNbempegaldesleukin
    D.3.9.1CAS number 1939126-74-5
    D.3.9.2Current sponsor codeNKTR-214
    D.3.9.3Other descriptive nameBEMPEGALDESLEUKIN
    D.3.9.4EV Substance CodeSUB196365
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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) Yes
    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 Yes
    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 Yes
    D.2.1.1.1Trade name Talzenna
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Europe MA EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameTalazoparib
    D.3.2Product code PF-06944076 0,25 mg
    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 INNTALAZOPARIB
    D.3.9.1CAS number 1373431-65-2
    D.3.9.2Current sponsor codePF-06944076
    D.3.9.3Other descriptive namePF-06944076-15, MDV3800, BMN 673
    D.3.9.4EV Substance CodeSUB180394
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.25
    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
    Locally recurrent (not amenable for curative intent) or metastatic squamous cell carcinoma of the of the oral cavity, oropharynx, hypopharynx, or larynx;
    metastatic castration-resistant prostate cancer without small cell features
    E.1.1.1Medical condition in easily understood language
    Locally recurrent or metastatic squamous cell carcinoma of the head and neck;
    metastatic castration-resistant prostate cancer without small cell features
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10076506
    E.1.2Term Castration-resistant prostate cancer
    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 21.1
    E.1.2Level PT
    E.1.2Classification code 10063569
    E.1.2Term Metastatic squamous cell carcinoma
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10060121
    E.1.2Term Squamous cell carcinoma of head and neck
    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
    Phase 1b:
    •To assess the dose-limiting toxicity (DLT) rate of avelumab in combination with bempegaldesleukin (NKTR-214) (Combination A) and talazoparib (Combination B) or enzalutamide (Combination C) in order to determine the recommended Phase 2 dose (RP2D) for the combinations.

    Phase 2:
    •Combination A: To assess ORR of avelumab in combination with bempegaldesleukin (NKTR-214) in participants with locally recurrent or metastatic SCCHN

    •Combination B: To assess soft tissue ORR of avelumab in combination with bempegaldesleukin (NKTR-214) and talazoparib in participants with DDR defect positive mCRPC.

    •Combination C: To assess the PSA response rate of avelumab in combination with bempegaldesleukin (NKTR-214) and enzalutamide in participants with mCRPC after progression on abiraterone.
    E.2.2Secondary objectives of the trial
    1. To assess the overall safety and tolerability of the combinations (A, B and C).
    2. To assess other measures of anti tumor activity
    3. To characterize the PK of avelumab, bempegaldesleukin (NKTR-214), and talazoparib or enzalutamide when given in combination.
    4. To assess the immunogenicity of avelumab and bempegaldesleukin (NKTR-214) when combined together and with talazoparib or enzalutamide.
    5. To assess the correlation of anti-tumor activity with PD-L1 expression level in baseline tumor tissue.
    6. Combination A: To assess the correlation of anti-tumor activity with PD-L1 expression level in on-treatment tumor tissue.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    SCCHN and mCRPC
    - >/= 18 years of age and give consent
    - Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures as specified in the protocol
    - Contraceptive use must meet requirements outlined in the protocol and should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    - COG of 0 or 1
    - Participants must have adequate bone marrow function without hematopoietic growth factor or transfusion support within 14 days prior to and including C1D1 per protocol
    - Participants must have adequate liver function by C1D1 per protocol
    - Participants must have adequate renal function by C1D1 per protocol
    - All participants must provide tumor tissue as described in protocol
    Combination A- SCCHN
    - Histological diagnosis of locally recurrent (not amenable for curative intent) or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and both of the following:
    - No prior systemic treatment for unresectable locally recurrent or metastatic disease
    Exception: If prior systemic chemotherapy treatment was given as part of chemoradiotherapy treatment, disease-free interval after the last administration of systemic chemotherapy treatment must be at least 6 months
    - Measurable disease by RECIST v1.1 with at least 1 measurable lesion
    Combination B & C- mCRPC
    - mCRPC without small cell features meeting the following criteria:
    - Castration as defined by both of the following:
    - Serum testosterone ≤1.73 nmol/L (50 ng/dL) at the time of enrollment (prior to treatment with study drug on C1D1)
    - Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration)
    - Progressive disease at the time of enrollment (prior to treatment with study drug on C1D1) defined as 1 or more of the following 3 criteria:
    - A minimum of 3 consecutive rising PSA values with an interval of at least 1 week between determinations. The screening PSA value must be ≥2 µg/L (2 ng/mL) if qualifying solely by PSA progression
    - Radiographic soft tissue disease progression as defined by RECIST v1.1 for soft tissue
    - Radiographic bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic lesions on bone scan (confirm ambiguous results by other imaging modalities)
    Combination B only (mCRPC)
    - Progressed on at least 1 line of second generation anti-androgen therapy (e.g. enzalutamide and/or abiraterone acetate/prednisone) for treatment of mCRPC
    - Have received at least 1, but no more than 1, prior taxane-based chemotherapy regimens for mCRPC or were deemed unsuitable, declined, or did not have access to these therapies
    o Participants may have received radium -223, which does not count for a line of prior chemotherapy regimen
    - Measurable disease by RECIST v1.1 with at least 1 measurable lesion
    Phase 2 Only:
    - Required to have their disease assessed for a genomic defect in one or more pre-defined DDR genes based on testing de novo or archival tumor tissue using the Foundation One® Test
    Combination C only (mCRPC)
    - Participants with non-measurable disease (including disease affecting bone only) as determined by RECIST v1.1 are allowed
    - Participants must have progressed on 1 line of abiraterone acetate/prednisone anti-androgen therapy for treatment of mCRPC
    - Participants must have not had any prior chemotherapy for the treatment of mCRPC
    - Prior treatment with radium 223 is allowed and it does not count as a prior chemotherapy regimen
    E.4Principal exclusion criteria
    SCCHN and mCRPC
    - Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCT CTCAE v4.03 Grade ≥3)
    - Known history of: immune-mediated colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis
    - Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
    - Prior organ transplantation
    - Vaccination within 4 weeks prior to C1D1 and while on trial is prohibited except for administration of inactivated vaccines
    - Known symptomatic brain lesions requiring steroids
    - Exception: participants with previously diagnosed brain lesions are eligible if they meet all of the following criteria:
    have newly diagnosed small brain lesions which do not require treatment
    have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to C1D1
    have discontinued corticosteroid treatment for these lesions for at least 4 weeks prior to C1D1; and are neurologically stable
    Known history of testing positive for HIV or known AIDS
    - Positive HBV surface antigen, or positive HCV RNA if anti-HCV antibody screening tests positive
    - Active infection requiring systemic therapy within 14 days prior to C1D1.
    - Other acute or chronic medical or psychiatric conditions
    - Clinically significant (i.e., active) cardiovascular disease including the following:
    Documented left ventricular ejection fraction < 45%
    Cerebral vascular accident/stroke, Myocardial infarction (<6 months prior to C1D1)
    Unstable angina
    Congestive heart failure
    Serious cardiac arrhythmia requiring medication
    - Diagnosis of any other malignancy within 2 years prior to C1D1, except for adequately treated basal cell or quamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix
    - Prior immunotherapy with IL-2 agents or anti PD-1, anti PD-L1, anti PD-L2, or anti- CTLA-4 antibody. Prior treatment with Sipuleucel-T for participants with mCRPC is allowed
    - Current use of immunosuppressive medication at the time of C1D1, EXCEPT for the following permitted steroids:
    Intranasal, inhaled, topical steroids, eye drops or local steroid injection; systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone; steroids as premedication for hypersensitivity reactions
    - Bisphosphonate or denosumab dosage that was not stable for at least 2 weeks before C1D1 for participants receiving these therapies
    - Prior radiation therapy within 14 days prior to C1D1. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed > 14 days prior to C1D1 and no clinically significant toxicities are expected
    - Major surgery within 4 weeks prior to C1D1
    - Participation in other studies involving investigational drug(s) within 2 weeks prior to C1D1
    - Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia and sensory neuropathy Grade ≤2, or other Grade ≤2 AEs not constituting a safety risk, based on Investigator's judgment (I’s), are acceptable
    - I site staff members or participants who are Pfizer employees, directly involved in the conduct of the study and their family, site staff members otherwise supervised by the I
    Combination A
    - Participants will be excluded if they have a history of prostate cancer except in the cases below:
    - Low-Grade prostate cancer on surveillance with no plans for treatment intervention, provided that the following criteria are met:
    Stage T2N0M0 or lower
    PSA below lower limit of normal by local laboratory is allowed
    Prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is also allowed
    Combination B
    - Prior treatment with a PARP inhibitor
    Current (within 7 days prior to C1D1) or anticipated use of medications: including strong P-gp inhibitors, strong P-gp inducers, strong inhibitors of breast cancer resistance protein
    -Conditions that may impair intake or absorption of talazoparib as follows: inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1
    Combination C
    - Prior treatment with second generation androgen receptor antagonist other than abiraterone/prednisone
    - Current (within 7 days prior to C1D1) or anticipated use of medications (strong/moderate inducers for CYP3A4, strong CYP2C8 inducers and CYP2C8 inhibitors, and substrates of CYP3A4, CYP2C9, and CYP2C19)
    - Conditions that may impair intake or absorption of enzalutamide as follows: inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1
    E.5 End points
    E.5.1Primary end point(s)
    Phase 1b:
    •DLT during the DLT evaluation period (Cycle 1)

    Phase 2:

    •Combination A: Confirmed objective response (OR) as determined by the investigator using RECIST v1.1 (Appendix 9).

    •Combination B: Confirmed soft tissue OR as determined by the investigator using RECIST v 1.1 (Appendix 9) with no evidence of confirmed bone disease progression on repeat bone scan at least 6 weeks later per prostate cancer working group 3 (PCWG3) criteria (Appendix 10).

    •Combination C: Confirmed prostate specific antigen (PSA) response decrease ≥ 50% from baseline confirmed by a second consecutive assessment at least 3 weeks later.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Individual timepoints are included in each bullet point above
    E.5.2Secondary end point(s)
    1. a) Adverse events (AEs) as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03), timing, seriousness, and relationship to study therapy.
    b)Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v4.03) and timing.
    2. a)Time-to-event endpoints as determined by the investigator, using RECIST v1.1 (Combination A) and in participants with mCRPC (Combinations B and C), RECIST v1.1 (soft tissue disease) and PCWG3 (bone disease), including time to tumor response (TTR), duration of response (DR), progression free survival (PFS), and Overall Survival (OS).
    b)Combination B: Confirmed PSA response 50% decrease from baseline confirmed by a second consecutive assessment at least 3 weeks later.
    c)Combination C: Confirmed soft tissue OR as determined by the investigator using RECIST v 1.1 (Appendix 9) with no evidence of confirmed bone disease progression on repeat bone scan at least 6 weeks later per PCWG3 criteria (Appendix 10).
    d)Combination C: Circulating tumor cells CTC count conversion (decrease in CTC count from ≥ 5 CTC per 7.5 mL of blood at baseline to < 5 CTC per 7.5 mL of blood at any assessment on treatment), and CTC0 (CTC0 is defined as a CTC count of ≥1 CTC per 7.5 mL of blood at baseline and 0 CTC per 7.5 mL of blood at any assessment on treatment).
    e)Combinations B and C: Time to PSA progression (TTPSAP) defined according to the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.
    3. PK parameters including trough concentrations (Ctrough) for avelumab, bempegaldesleukin (NKTR-214), talazoparib, enzalutamide and N-desmethyl-enzalutamide and maximum concentrations (Cmax) for avelumab and bempegaldesleukin (NKTR-214).
    4. Anti-drug antibody (ADA) and neutralizing antibodies (NAb) against avelumab, bempegaldesleukin (NKTR-214) and IL-2 when combined together and with talazoparib or enzalutamide
    5. PD L1 expression level in baseline tumor tissue
    6.Combination A: PD-L1 expression level in on-treatment tumor tissue
    E.5.2.1Timepoint(s) of evaluation of this end point
    Individual timepoints are included in each bullet point above
    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 Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    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
    dose-range finding toxicity
    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 trial3
    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 EEA19
    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
    Belgium
    Canada
    Italy
    Poland
    Spain
    United States
    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 years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days11
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days16
    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: 32
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 62
    F.4.2.2In the whole clinical trial 127
    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)
    For all combinations, participants clinically benefiting from study treatment without unacceptable toxicity, objective disease progression, or withdrawal of consent will be given the opportunity to continue treatment after study discontinuation by the sponsor. Participants without other options for treatment may continue on treatment with the combination to which they have been assigned upon agreement with the sponsor
    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 Decision2019-11-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-29
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