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

NCT03616886 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: IJB-SYNERGY-012017
• Study Type: interventional
• Target: 129
• Locations: 2 countries
• Sites: 16

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

Conditions

Triple Negative Breast Cancer

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Phase I:The adverse events (AEs)

  Safety and tolerability will be assessed by monitoring frequency, duration and severity of adverse events (AEs).

  Through the Phase I, approximately 7 months

• 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

  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.

  At 24 weeks from the 1st study drug administration

Secondary Outcomes (7)

• Phase I: Recommended phase II dose (RP2D) of oleclumab in combination with chemotherapy and durvalumab

  through study completion, approximately 50 months

• 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.

  through study completion, approximately 50 months

• 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.

  through study completion, approximately 50 months

• Phase II: the progression-free survival (PFS)

  through study completion, approximately 50 months

• Phase II: overall survival (OS)

  through study completion, approximately 50 months

Study Arms (2)

Phase I and Phase II Arm A

EXPERIMENTAL

Patients are treated with paclitaxel, carboplatin, durvalumab and oleclumab.

Drug: Paclitaxel; Drug: Carboplatin; Drug: MEDI4736; Drug: MEDI9447

Phase II Arm B

ACTIVE COMPARATOR

Patients are treated with paclitaxel, carboplatin and durvalumab.

Drug: Paclitaxel; Drug: Carboplatin; Drug: MEDI4736

Interventions

Paclitaxel DRUG

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 Arm A; Phase II Arm B

Carboplatin DRUG

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 Arm A; Phase II Arm B

MEDI4736 DRUG

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

Also known as: Durvalumab

Phase I and Phase II Arm A; Phase II Arm B

MEDI9447 DRUG

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

Also known as: Oleclumab

Phase I and Phase II Arm A

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of ≥ 18 years
• Female
• Life expectancy of a least 12 weeks
• Body weight above 35kg
• 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
• Estrogen receptor (ER) and progesterone receptor (PR) negativity (\< 1% positive staining cells in the invasive tumour) determined locally using IHC per ASCO/CAP criteria
• 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) and determined locally59 Note: patients initially diagnosed with hormone receptor-positive and/or HER2-positive breast cancer OR de novo metastatic patients with a primary tumor hormone receptor-positive (weak positivity or ER negativity and PR positivity) considered as non-clinically relevant are eligible if the tumor biopsy obtained from a local recurrence or distant metastasis site confirms the TNBC disease.
• 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)
• Provision of recurrence/metastatic tissue samples from resections, core-needle biopsies or excisional, incisional, punch, or forceps biopsies:
• 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)
• 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.
• Note 1: If the patient has just performed a metastatic lesion biopsy, she 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.
• Note 2: In case of a de-novo metastatic disease, if a biopsy of a metastatic lesion is not feasible, the patient is eligible if a biopsy of the primary lesion is available.
• Provision of an archived FFPE diagnostic biopsy or surgical primary breast tumour sample (or at least 20 unstained slides, freshly cut for the purposes of the study).
• Note: In case of neoadjuvant treatment (before surgery), the diagnostic biopsy is preferable.

You may not qualify if:

• 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:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone
• Current or prior treatment with immunosuppressive medication within 14 days prior to enrolment. The following are exceptions to this criterion:
• Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
• Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
• Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication
• 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
• 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)
• Active infection including
• Tuberculosis (TB) (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice)
• 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.

Sponsors & Collaborators

• Jules Bordet Institute: lead
• AstraZeneca: collaborator

Study Sites (16)

Institut Jules Bordet

Brussels, 1000, Belgium

Location

Cliniques universitaires Saint Luc

Brussels, Belgium

Location

Grand Hôpital de Charleroi

Charleroi, Belgium

Location

UZ Leuven Gasthuisberg

Leuven, Belgium

Location

CHU UCL Namur Sainte-Elisabeth

Namur, 5000, Belgium

Location

Clinique St Pierre

Ottignies, Belgium

Location

Sint-Augustinus, GZA Ziekenhuizen

Wilrijk, Belgium

Location

CHU Besançon

Besançon, France

Location

Institut Bergonié

Bordeaux, France

Location

Centre Georges François Leclerc

Dijon, France

Location

Institut Paoli-Calmettes

Marseille, France

Location

Centre Antoine Lacassagne

Nice, France

Location

Institut Curie

Paris, France

Location

CHU Poitiers

Poitiers, 86021, France

Location

Centre Henri Becquerel

Rouen, France

Location

Hôpitaux Universitaires de Strasbourg

Strasbourg, France

Location

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Breast Neoplasms; Neoplasm Metastasis

Interventions

Paclitaxel; Carboplatin; durvalumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Study Officials

• Laurence Buisseret

  Jules Bordet Institute

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2018
• First Posted: August 6, 2018
• Study Start: December 28, 2018
• Primary Completion: March 1, 2025
• Study Completion: December 1, 2025
• Last Updated: December 19, 2024

Record last verified: 2024-12

Locations

BE (7); FR (9)