A Phase III, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) With or Without Durvalumab Compared With Investigator's Choice of Chemotherapy (Paclitaxel, Nab-paclitaxel or Gemcitabine + Carboplatin) in Combination With Pembrolizumab in Patients With PD-L1 Positive Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION-Breast05)

Official Summary

This is a Phase III, randomised, open-label, 3-arm, multicentre, international study assessing the efficacy and safety of Dato-DXd with or without durvalumab compared with investigator's choice chemotherapy in combination with pembrolizumab in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 625 participants

Study Arms

• Dato-DXd + durvalumab (EXPERIMENTAL)
  Arm 1: Dato-DXd + durvalumab
• Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (ACTIVE_COMPARATOR)
  Arm 2: Investigator's Choice of Chemotherapy (ICC) in combination with pembrolizumab (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin)
• Dato-DXd (EXPERIMENTAL)
  Arm 3: Dato-DXd

Interventions

• DRUG: Dato-DXd — Provided in 100mg vials. IV infusion. Experimental drug.
• DRUG: Durvalumab — Provided in 500mg vials. IV infusion. Experimental drug.
• DRUG: Paclitaxel — IV infusion. Active comparator.
• DRUG: Nab-paclitaxel — IV infusion. Active comparator.
• DRUG: Gemcitabine — IV infusion. Active comparator.

Primary Outcomes

• Progression Free Survival (PFS) (From randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause (anticipated to be up to 33 months).)

Secondary Outcomes

• Overall Survival (OS) (From randomisation until the date of death due to any cause (anticipated to be up to 64 months).)
• Objective Response Rate (ORR) (From randomisation up until progression (anticipated to be up to 33 months).)
• Duration of Response (DoR) (From the date of first documented response until date of documented progression per RECIST 1.1, as assessed by BICR/investigator assessment or death due to any cause (anticipated to be up to 33 months).)
• Progression-Free Survival (PFS) by Investigator assessment (From randomisation until progression per RECIST 1.1 as assessed by the investigator, or death due to any cause (anticipated to be up to 33 months).)
• Clinical Benefit Rate (CBR) at 24 weeks (From randomisation up until progression, or the last evaluable assessment in the absence of progression (anticipated to be up to 33 months).)

Eligibility Criteria

Key Inclusion Criteria

* Histologically or cytologically documented locally recurrent inoperable, which cannot be treated with curative intent, or metastatic TNBC, as defined by the ASCO-CAP guidelines.
* ECOG PS 0 or 1.
* Participants are expected to provide an FFPE tumour sample collected from a locally recurrent inoperable or metastatic tumour. Alternatively, an archival FFPE tumour sample can be submitted; it must have been collected ≤ 3 years prior to the participant signing informed consent (screening start).
* PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor designated central laboratory.
* No prior chemotherapy or other systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.

  \- Patients with recurrent disease will be eligible if they have completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months have elapsed between completion of treatment with curative intent and the first documented recurrence.
* Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin).
* Measurable disease as per RECIST 1.1.
* Adequate bone marrow reserve and organ function.
* Male and female participants of childbearing potential must agree to use protocol-specified method(s) of contraception.

Key Exclusion Criteria

* As judged by investigator, any evidence of diseases (such as severe or uncontrolled medical conditions including systemic diseases, uncontrolled hypertension, serious gastrointestinal conditions associated with diarrhoea, chronic diverticulitis or previous complicated diverticulitis, history of allogeneic organ transplant, and active bleeding diseases, ongoing and active infection, significant cardiac conditions, substance abuse, psychiatric illness/social situation or psychological conditions) which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before Cycle 1 Day 1 and of low potential risk for recurrence.
* Participants with a history of previously treated neoplastic spinal cord compression or treated, clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy.

  \- Participants with treated clinically inactive brain metastases that are no longer symptomatic, who require no treatment with corticosteroids or anticonvulsants, may be included in the study if they have recovered from acute toxic effects of radiotherapy.
* Uncontrolled infection requiring IV antibiotics, antivirals or antifungals.
* Active or uncontrolled hepatitis B or C virus infection.
* Known HIV infection that is not well controlled.
* Uncontrolled or significant cardiac disease.
* History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Clinically severe pulmonary function compromise.
* Clinically significant corneal disease.
* Active or prior documented autoimmune or inflammatory disorders.
* Prior exposure to any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I and TROP2-targeted therapy.
* Any concurrent anti-cancer treatment.
* Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors or Dato-DXd.
* Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.

Trial Locations

• Research Site, Daphne, Alabama, United States
• Research Site, Springdale, Arkansas, United States
• Research Site, Duarte, California, United States
• Research Site, Glendale, California, United States
• Research Site, Sacramento, California, United States
• Research Site, Santa Rosa, California, United States
• Research Site, Aurora, Colorado, United States
• Research Site, New Haven, Connecticut, United States
• Research Site, Jacksonville, Florida, United States
• Research Site, Miami, Florida, United States
• ...and 10 more locations

Contact Information

• AstraZeneca Clinical Study Information Center — CONTACT
  Phone: 1-877-240-9479
  Email: information.center@astrazeneca.com
• AstraZeneca Breast Cancer Study Locator Service — CONTACT
  Phone: +1-877-400-4656
  Email: az-bcsl@careboxhealth.com

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