Clinical Trials /

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

NCT03616886

Description:

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

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Paclitaxel + Carboplatin + Durvalumab With or Without Oleclumab for Previously Untreated Locally Recurrent Inoperable or Metastatic TNBC
  • 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

Clinical Trial IDs

  • ORG STUDY ID: IJB-SYNERGY-012017
  • NCT ID: NCT03616886

Conditions

  • Triple Negative Breast Cancer

Interventions

DrugSynonymsArms
PaclitaxelPhase I and Phase II Arm A
CarboplatinPhase I and Phase II Arm A
MEDI4736DurvalumabPhase I and Phase II Arm A
MEDI9447OleclumabPhase I and Phase II Arm A

Purpose

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

Detailed Description

      The trial consists of two parts:

      PHASE I Part 1 is a phase I trial examining the combination of paclitaxel, carboplatin,
      durvalumab and oleclumab in order to define the recommended phase II dose (RP2D) of oleclumab
      in this treatment combination.

      The period for DLT evaluation is defined as the time from receiving the first dose of
      oleclumab until the planned administration of the third dose; this corresponds to 28 days
      after receiving the first dose of oleclumab in case no treatment interruption occured.

      Patients who develop a DLT will stop study treatment permanently.

      PHASE II Part 2 is a multicenter, randomized, open-label trial investigating the role of an
      anti-CD73 monoclonal antibody (oleclumab) in combination with an anti-PD-L1 antibody
      (durvalumab) plus chemotherapy (paclitaxel + carboplatin) as first-line treatment for locally
      recurrent inoperable or metastatic TNBC.

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

      PHASE I and PHASE II

      Paclitaxel and carboplatin will be given weekly for a total of 12 injections. Immunotherapy
      (durvalumab with or without oleclumab) will be given as long as the patient benefits.
      Premature discontinuation of paclitaxel/carboplatin or discontinuation of
      durvalumab/oleclumab is indicated in case of:

        -  Progressive disease (PD) using RECIST v1.1 criteria or iRECIST assessed locally

        -  Unacceptable toxicity

        -  Intercurrent illness that necessitates discontinuation of study treatment

        -  Investigator's decision to withdraw the subject

        -  Pregnancy

        -  Subject noncompliance with the study treatment or procedure requirements

        -  Withdrawal of consent to treatment

        -  Death

        -  Administrative reasons requiring cessation of study treatment.

      Initial disease status will be evaluated by imaging studies (contrast-enhanced CT scan of the
      chest, the abdomen and the pelvis or MRI of the chest, the abdomen and the pelvis) during the
      screening phase. Disease status will be followed by imaging studies at weeks 8 (± 3 days), 16
      (± 3 days) and 24 (± 3 days) post start of treatment (allowing efficacy data to be captured
      as close to 24 weeks post start of study treatment as possible for a more accurate evaluation
      of DCR). Thereafter imaging will continue every 12 weeks (± 3 days; contrast-enhanced CT scan
      or MRI) independent of any treatment delays.

      Patients who stopped all study treatments for reasons other than PD will continue
      post-treatment imaging studies for disease status follow-up as described in the schedule of
      assessment until verified PD, start of a new anti-cancer treatment, withdrawal of consent to
      study participation, death, or end of the study whichever comes first.

      Note: Pseudo-progression related to immunotherapy: Patients experiencing PD as defined by
      RECIST v1.1 can continue the study treatment in case of good clinical condition assessed by a
      stable or even improved ECOG performance status. If the next assessment of tumour burden (8
      weeks later) confirms PD (as defined by iRECIST) study treatment must be discontinued.
      Unconfirmed PD as defined by iRECIST (iUPD) can only be assigned for the first 2 imaging
      assessments (week 8 and week 16) and several times as long as confirmed progression (iCPD) is
      not confirmed at the next assessment. If PD is not confirmed, reassessments continue as
      originally planned.
    

Trial Arms

NameTypeDescriptionInterventions
Phase I and Phase II Arm AExperimentalPatients are treated with paclitaxel, carboplatin, durvalumab and oleclumab.
  • Paclitaxel
  • Carboplatin
  • MEDI4736
  • MEDI9447
Phase II Arm BActive ComparatorPatients are treated with paclitaxel, carboplatin and durvalumab.
  • Paclitaxel
  • Carboplatin
  • MEDI4736

Eligibility Criteria

        Inclusion Criteria:

          1. Age of ≥ 18 years

          2. Female

          3. Life expectancy of a least 12 weeks

          4. Body weight above 35kg

          5. The locally recurrent or metastatic relapse must be histologically confirmed TNBC in
             patients not previously treated with systemic treatment and which cannot be treated
             with curative intent. 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
             criteria58

          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 locally59 Note:
             patients initially diagnosed with hormone receptor-positive and/or HER2-positive
             breast cancer are eligible if the tumor biopsy obtained from a local recurrence or
             distant metastasis site confirms the TNBC disease.

          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 only, frozen/fresh cores are not
             mandatory. In case of a de-novo metastatic disease, a biopsy of the primary lesion is
             acceptable.

         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). In case of
             neoadjuvant treatment (before surgery), the diagnostic biopsy is preferable.

         11. At least 6 months elapsed between the completion of treatment with curative intent
             (e.g., the date of primary breast tumour surgery or the date of last 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 done within the 28 days before treatment start. 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. Known hypersensitivity reactions to the study drugs or to any of the excipients,
             premedications (acetaminophen/paracetamol, diphenhydramine or equivalent antihistamine
             and methylprednisolone or equivalent glucocorticoid) and to other platinum containing
             compounds

         10. 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

         11. 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.

         12. Uncontrolled intercurrent illness, including but not limited to,

               1. Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina
                  pectoris, cardiac arrhythmia. Patients previously treated with anthracyclines are
                  eligible if a recent cardiac work up (< 6 months) demonstrated a normal left
                  ventricular ejection fraction (LVEF≥50%).

               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

         13. 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

         14. Pregnant or lactating women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I:The adverse events (AEs)
Time Frame:Through the Phase I, approximately 7 months
Safety Issue:
Description:Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs).

Secondary Outcome Measures

Measure:Phase I: Recommended phase II dose (RP2D) of oleclumab in combination with chemotherapy and durvalumab
Time Frame:through study completion, approximately 50 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:DOR is defined as the time from documentation of first tumour response to disease progression based on RECIST v1.1.
Measure:Phase II: the progression-free survival (PFS)
Time Frame:through study completion, approximately 50 months
Safety Issue:
Description: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.)
Measure:Phase II: overall survival (OS)
Time Frame:through study completion, approximately 50 months
Safety Issue:
Description: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.)
Measure:Phase II: AEs assessment based on CTCAE 5.0.
Time Frame:through study completion, approximately 50 months
Safety Issue:
Description:Frequency, duration and severity of AEs assessment based on CTCAE 5.0.
Measure: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
Safety Issue:
Description: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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jules Bordet Institute

Trial Keywords

  • Breast cancer
  • Triple negative
  • Metastatic
  • Previously untreated
  • Locally Recurrent Inoperable

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