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Trial record 24 of 61 for:    PD-1 and breast cancer | Recruiting, Not yet recruiting, Available Studies

Paclitaxel + Carboplatin + Durvalumab With or Without Oleclumab for Previously Untreated Locally Recurrent Inoperable or Metastatic TNBC (SYNERGY)

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ClinicalTrials.gov Identifier: NCT03616886
Recruitment Status : Recruiting
First Posted : August 6, 2018
Last Update Posted : January 23, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Jules Bordet Institute

Brief Summary:

The combination of chemotherapy with PD-1 immune checkpoint blockade agents demonstrated promising results especially in the neo-adjuvant and early metastatic setting in TNBC. However, a substantial proportion of patients do not derive benefit from this approach.

CD73 is an adenosine-generating enzyme overexpressed in several cancers and associated with poor prognosis and reduced anti-tumor immunity in TNBC. Monoclonal antibodies directed against CD73 could help to reprogram the tumor microenvironement by decreasing the adenosine mediated immunosuppression, particularly as a synergistic immunotherapeutic combination with immune checkpoint blockade.

The SYNERGY trial investigates the role of an anti-CD73 (MEDI9447) in a randomized phase II trial evaluating the efficacy and safety of the combination of chemotherapy (paclitaxel + carboplatin) with immunotherapy (durvalumab [anti-PD-L1] +/- MEDI9447 [anti-CD73]) in previously untreated locally recurrent inoperable or metastatic TNBC.

A large translational research program is planned including baseline and dynamic biomarkers


Condition or disease Intervention/treatment Phase
Triple Negative Breast Cancer Drug: Paclitaxel Drug: Carboplatin Drug: MEDI4736 Drug: MEDI9447 Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 171 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Paclitaxel Plus Carboplatin and Durvalumab (MEDI4736) With or Without Oleclumab (MEDI9447) for Previously Untreated Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer
Actual Study Start Date : December 28, 2018
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase I and Phase II Arm A
Patients are treated with paclitaxel, carboplatin, durvalumab and oleclumab.
Drug: Paclitaxel
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).

Drug: Carboplatin
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).

Drug: MEDI4736
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).
Other Name: Durvalumab

Drug: MEDI9447
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).
Other Name: Oleclumab

Active Comparator: Phase II Arm B
Patients are treated with paclitaxel, carboplatin and durvalumab.
Drug: Paclitaxel
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).

Drug: Carboplatin
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).

Drug: MEDI4736
Patients will be randomized between chemotherapy (paclitaxel and carboplatin) with immunotherapy including durvalumab with or without oleclumab (1:1 ratio).
Other Name: Durvalumab




Primary Outcome Measures :
  1. Phase I:The adverse events (AEs) [ Time Frame: Through the Phase I, approximately 7 months ]
    Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs).

  2. Phase II: Clinical Benefit of oleclumab in combination with chemotherapy and durvalumab by the comparing the CB rate at 24 weeks from the 1st dose of study drug administration between patients treated with or without the anti-CD73 antibody oleclumab [ Time Frame: At 24 weeks from the 1st study drug administration ]
    CB is defined as a patient who achieved CR or PR or demonstrated SD at 24 weeks from the 1st dose of study drug administration based on RECIST v1.1.


Secondary Outcome Measures :
  1. Phase I: Recommended phase II dose (RP2D) of oleclumab in combination with chemotherapy and durvalumab [ Time Frame: through study completion, approximately 50 months ]
    Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs) including Dose limiting toxicities (DLTs) as defined per protocol.

  2. Phase II: Efficacy of oleclumab in combination with chemotherapy and durvalumab by comparing the OR rate (ORR; CR + PR) and the duration of response (DOR) between patients treated with or without the anti-CD73 antibody oleclumab. [ Time Frame: through study completion, approximately 50 months ]
    OR is defined as a patient (in the intent-to treat population) who achieved a CR or PR as best overall response (BOR) based on RECIST v1.1.

  3. Phase II: Efficacy of oleclumab in combination with chemotherapy and durvalumab by comparing the OR rate (ORR; CR + PR) and the duration of response (DOR) between patients treated with or without the anti-CD73 antibody oleclumab. [ Time Frame: through study completion, approximately 50 months ]
    DOR is defined as the time from documentation of first tumour response to disease progression based on RECIST v1.1.

  4. Phase II: the progression-free survival (PFS) [ Time Frame: through study completion, approximately 50 months ]
    PFS is defined as the time from 1st study drug administration to the first documented disease progression based on RECIST v1.1 or death due to any cause, whichever occurs first. (Subjects who are alive and progression free at the time of analysis will be censored at the time-point of their last tumour assessment by imaging.)

  5. Phase II: overall survival (OS) [ Time Frame: through study completion, approximately 50 months ]
    OS is defined as the time from 1st study drug administration to death due to any cause. (Subject without documented death at the time of the analysis will be censored at the date of the last follow-up.)

  6. Phase II: AEs assessment based on CTCAE 5.0. [ Time Frame: through study completion, approximately 50 months ]
    Frequency, duration and severity of AEs assessment based on CTCAE 5.0.

  7. Phase II: Efficacy, clinical and survival benefits of oleclumab in combination with chemotherapy and durvalumab according to PD-L1 and CD73 expression. [ Time Frame: through study completion, approximately 50 months ]
    PD-L1 and CD73 expression will be assessed using immunohistochemistry (IHC) on the screening FFPE tumour tissue lesion biopsy by a central laboratory prior to randomization for stratification purposes



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age of ≥ 18 years
  2. Female
  3. Life expectancy of a least 12 weeks
  4. Body weight above 35kg
  5. Histologically confirmed locally recurrent not previously treated with systemic treatment and which cannot be treated with curative intent or metastatic TNBC not previously treated with systemic treatment. Newly diagnosed patients with de-novo metastatic disease are eligible
  6. Estrogen receptor (ER) and progesterone receptor (PR) negativity (< 1% positive staining cells in the invasive tumour) determined locally using IHC per ASCO/CAP criteria57
  7. Human epidermal growth factor receptor 2 (HER2) negativity (negative IHC staining [score 0 or 1] or negative fluorescence in situ hybridization [FISH] based on the ASCO/CAP guidelines and recommendations from 2013) and determined locally58
  8. Confirmed tumour PD-L1 and CD73 IHC assessment as documented through central testing of a representative tumour tissue specimen for stratification purposes (only for phase II)
  9. Provision of recurrence/metastatic tissue samples (at least 1 FFPE [Formalin-Fixed paraffin-embedded] tumour tissue and 1 frozen core as a priority, if feasible 2 additional fresh tumour tissue cores should be collected too) including those from resections, core-needle biopsies or excisional, incisional, punch, or forceps biopsies. Fine-needle aspiration (FNA) (defined as samples that do not preserve tissue architecture and yield cell suspension and/or smears), brushing, and cell pellets from cytology samples are not acceptable. If the patient has just performed a metastatic lesion biopsy, the patient is eligible only if an archived FFPE tissue sample (or at least 20 unstained slides, freshly cut for the purposes of the study) of the metastatic lesion is available. In this situation, frozen/fresh cores are not mandatory
  10. Provision of an archived FFPE diagnostic biopsy or surgical primary tumour sample (or at least 20 unstained slides, freshly cut for the purposes of the study)
  11. At least 6 months elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumour surgery or date of last adjuvant or (neo)adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence (NOTE: for de-novo metastatic disease not applicable)
  12. At least one measurable disease based on RECIST v1.1. Tumour lesions in a previously irradiated area are considered measurable, if progression has been demonstrated in such lesions
  13. Adequate organ function:

    1. Absolute neutrophil count (ANC) ≥ 1500/µl (without the addition of growth factors)
    2. Platelets [PLT] ≥ 100000/µl (without the addition of growth factors/prior transfusions)
    3. Hemoglobin (Hb) ≥ 10 g/dl (without the addition of growth factors/prior transfusions)
    4. Creatinine ≤ 1.5 x upper limit of normal (ULN) OR estimated glomerular filtration rate (eGFR) ≥ 60 ml/min as calculated using the method standard for the institution. If eGFR is lower than 60 ml/min, a 24-hour urine creatinine clearance can be performed to rule out an underestimation of the eGFR.
    5. Total serum bilirubin (TBL) ≤ 1.5 x ULN unless the subject has documented Gilbert syndrome in which case up to 3 x ULN is acceptable
    6. Aspartate and alanine aminotransferase (AST/ALT) ≤ 2.5 x ULN unless liver metastases are present, in which case it must be ≤ 5 x ULN
    7. International Normalized Ratio (INR) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as INR and activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants
  14. Performance status (PS) of 0 or 1 on the ECOG Performance scale
  15. Female subjects of childbearing potential (FSCP) must be willing to use one highly effective method of contraception (detailed at protocol section 6.6.) for the course of the study through 6 months after the last study drug administration. FSCP must have a negative serum pregnancy test. FSCP are those who have not been surgically sterilized or have not been free of menses for at least 1 year.
  16. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  17. Absence of any concurrent illness that would preclude the evaluation of safety
  18. Agreement to provide tissue and blood samples for research purposes
  19. Written informed consent must be given according to ICH/GCP, and national/local regulations before patient enrolment

Exclusion Criteria:

  1. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

    1. Patients with vitiligo or alopecia
    2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    3. Any chronic skin condition that does not require systemic therapy
    4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
    5. Patients with celiac disease controlled by diet alone
  2. Current or prior treatment with immunosuppressive medication within 14 days prior to enrolment. The following are exceptions to this criterion:

    1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    2. Systemic corticosteroids at physiologic doses not to exceed < 10 mg/day of prednisone or its equivalent
    3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
  3. Any live, attenuated vaccine administered within 28 days prior to enrolment or anticipation that such a live attenuated vaccine will be required during the study
  4. Chronic daily treatment with non-steroidal anti-inflammatory drug (NSAID) (occasional use for the symptomatic relief of medical conditions, for example, headache, fever is allowed)
  5. Active infection including

    1. Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
    2. Hepatitis B (known positive HBV surface antigen (HBsAg) result). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
    3. Hepatitis C. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
    4. Human immunodeficiency virus (positive HIV 1/2 antibodies).
  6. Treatment with systemic immunostimulatory agents, including but not limited to, interferon (IFN)-alpha, IFN-beta, interleukin (IL)-2, conjugated IL-2 cytokines within 42 days or five half-lives of the drug, whichever is longer, prior to screening
  7. Previous treatment with immune checkpoint inhibitors (e.g. anti-PD-1, anti-PD-L1 including durvalumab, anti-Cytotoxic T-lymphocyte-associated molecule-4), anti-CD73 antibodies, adenosine A2A receptor antagonists, or prior treatment with CD137 agonists/OX-40 agonists or any other antibody or drug targeting T-cell co-stimulation or other immunomodulatory therapies
  8. Any unresolved toxicity NCI CTCAE Grade ≥ 2 from previous anticancer therapy with the exception of alopecia, vitiligo and the laboratory values defined in the inclusion criteria
  9. Untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.

    Subjects with previously treated brain metastases with local treatment (stereotactic radiosurgery or whole brain radiation therapy) may participate provided they have stable brain metastases on a recent brain MRI (performed during the 2 weeks prior inclusion) and have measurable disease outside the CNS.

    Note: Known brain metastases are considered active (and not eligible for trial), if any of the following criteria are applicable:

    1. Recent brain imaging demonstrates progression of existing and/or appearance of new lesions
    2. Neurological symptoms attributed to brain metastases have not returned to baseline
    3. Steroids were used for management of symptoms related to brain metastases within 14 days of enrolment
    4. Completion of local therapy for brain metastases within 28 days of enrolment
  10. Major surgical procedure (as defined by the principal investigator) within 28 days prior to enrolment. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  11. Uncontrolled intercurrent illness, including but not limited to,

    1. Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia
    2. Interstitial lung disease
    3. Serious chronic gastrointestinal conditions associated with diarrhoea
    4. Psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  12. Past medical conditions, including,

    1. Class II-IV congestive heart failure
    2. Myocardial infarction within 12 months prior enrolment,
    3. Deep vein thrombosis (DVT) or thrombo-embolic event within 12 months prior to enrolment
    4. History of stroke or transient ischemic attack requiring medical therapy
    5. Intra-abdominal inflammatory process within the last 12 months prior to enrolment such as, but not limited to, diverticulitis, peptic ulcer disease, or colitis
    6. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
    7. History of another primary malignancy except for malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of IP and of low potential risk for recurrence, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated carcinoma in situ without evidence of disease
    8. Status post allogeneic bone marrow transplantation or solid organ transplantation
  13. Pregnant or lactating women.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03616886


Contacts
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Contact: Laurence Buisseret +322541 ext 7366 laurence.buisseret@bordet.be
Contact: Chloé Velghe +322541 ext 7366 chloe.velghe@bordet.be

Locations
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Belgium
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Contact: Aftimos Philippe       philippe.aftimos@bordet.be   
Contact: de Naejier Nathalie       nathalie.denaeijer@bordet.be   
CHU UCL Namur Sainte-Elisabeth Recruiting
Namur, Belgium, 5000
Contact: Vuylsteke Peter       peter.vuylsteke@uclouvain.be   
Contact: Yague Caroline       caroline.yaguesanz@uclouvain.be   
Sponsors and Collaborators
Jules Bordet Institute
AstraZeneca

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Responsible Party: Jules Bordet Institute
ClinicalTrials.gov Identifier: NCT03616886     History of Changes
Other Study ID Numbers: IJB-SYNERGY-012017
First Posted: August 6, 2018    Key Record Dates
Last Update Posted: January 23, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Jules Bordet Institute:
Breast cancer
Triple negative
Metastatic
Previously untreated
Locally Recurrent Inoperable

Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Durvalumab
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs