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

Triple Negative Breast Cancer Clinical Trial

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

Status Active, not recruiting

Clinical Trial 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

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

• NCT number: NCT03616886
• Study type: Interventional
• Source: Jules Bordet Institute
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: December 28, 2018
• Completion date: April 2025