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A Phase III Randomised Study to Evaluate Dato-DXd and Durvalumab for Neoadjuvant/Adjuvant Treatment of Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT06112379
Recruitment Status : Recruiting
First Posted : November 1, 2023
Last Update Posted : May 14, 2024
Sponsor:
Collaborator:
Daiichi Sankyo
Information provided by (Responsible Party):
AstraZeneca

Study Description
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Brief Summary:
This is a Phase III, 2-arm, randomised, open-label, multicentre, global study assessing the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy compared with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Dato-DXd Drug: Durvalumab Drug: Pembrolizumab Drug: Doxorubicin Drug: Epirubicin Drug: Cyclophosphamide Drug: Paclitaxel Drug: Carboplatin Drug: Capecitabine Drug: Olaparib Phase 3

Detailed Description:
The primary objectives of the study are to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor low/HER2-negative breast cancer, by central assessment of pCR and/or to demonstrate superiority of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy relative to neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab with or without chemotherapy in participants with previously untreated TNBC or hormone receptor-low/HER2-negative breast cancer, by investigator assessment of EFS
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1728 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomised in a 1:1 ratio to one of two intervention groups.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase III, Open-label, Randomised Study of Neoadjuvant Datopotamab Deruxtecan (Dato-DXd) Plus Durvalumab Followed by Adjuvant Durvalumab With or Without Chemotherapy Versus Neoadjuvant Pembrolizumab Plus Chemotherapy Followed by Adjuvant Pembrolizumab With or Without Chemotherapy for the Treatment of Adult Patients With Previously Untreated Triple-Negative or Hormone Receptor-low/HER2-negative Breast Cancer (D926QC00001; TROPION-Breast04)
Actual Study Start Date : November 14, 2023
Estimated Primary Completion Date : March 29, 2028
Estimated Study Completion Date : August 28, 2030

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Dato-DXd plus durvalumab

Participants receive durvalumab every 3 weeks (Q3W) + Dato-DXd Q3W as neoadjuvant therapy prior to surgery; followed by 9 cycles of durvaluamb Q3W as adjuvant therapy post-surgery. Adjuvant chemotherapy may be given in combination with durvalumab only if participants have residual disease.

Olaparib may be given for participants with gBRCA-positive tumours and residual disease

Adjuvant chemotherapy may be one of these:

  1. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) and carboplatin (weekly or Q3W) for 4 cycles (12 weeks);
  2. Doxorubicin (Q3W) or epirubicin (Q3W) + cyclophosphamide (Q3W) for 4 cycles (12 weeks) followed by paclitaxel (weekly) for 4 cycles (12 weeks);
  3. Carboplatin (weekly or Q3W) + paclitaxel (weekly) for 4 cycles (12 weeks);
  4. Capecitabine (Q3W) for 8 cycles.
 Drug: Dato-DXd
Experimental drug IV infusion
Other Name: Datopotamab deruxtecan (Dato-DXd, DS-1062a)

Drug: Durvalumab
Experimental drug IV Infusion
Other Name: MEDI4736

Drug: Doxorubicin
IV infusion Experimental/Active Comparator

Drug: Epirubicin
IV Infusion Experimental/Active Comparator

Drug: Cyclophosphamide
IV infusion Experimental/Active Comparator

Drug: Paclitaxel
IV infusion Experimental/Active Comparator

Drug: Carboplatin
IV infusion Experimental/Active Comparator

Drug: Capecitabine
Tablet Oral route of administration Experimental/Active Comparator
Other Name: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord

Drug: Olaparib
Tablet Oral route of administration Experimental/Active Comparator
Other Name: LYNPARZA®
Active Comparator: Pembrolizumab plus chemotherapy
Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Adjuvant capecitabine (Q3W) for 8 cycles may be given in combination with pembrolizumab only if participants have residual disease. Olaparib may be given for participants with gBRCA-positive tumours and residual disease.
 Drug: Pembrolizumab
IV Infusion Active comparator
Other Name: KEYTRUDA®

Drug: Doxorubicin
IV infusion Experimental/Active Comparator

Drug: Epirubicin
IV Infusion Experimental/Active Comparator

Drug: Cyclophosphamide
IV infusion Experimental/Active Comparator

Drug: Paclitaxel
IV infusion Experimental/Active Comparator

Drug: Carboplatin
IV infusion Experimental/Active Comparator

Drug: Capecitabine
Tablet Oral route of administration Experimental/Active Comparator
Other Name: XELODA®, Capecitabine Cell Pharm, Capecitabine EG, Capecitabine Accord

Drug: Olaparib
Tablet Oral route of administration Experimental/Active Comparator
Other Name: LYNPARZA®


Outcome Measures
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Primary Outcome Measures :
  1. Pathologic Complete Response (pCR) in the experimental vs control arms [ Time Frame: At the time of definitive surgery ]

    pCR rate is defined as the proportion of participants who have no evidence by haematoxylin and eosin staining of residual invasive disease at the time of definitive surgery in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0) by blinded central evaluation.

    The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest will be the difference between the pCR rates.


  2. Event-free survival (EFS) in the experimental vs control arms [ Time Frame: Date of randomization to date of the EFS event, up to 68 months after the first subject randomized ]

    EFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: disease progression precluding surgery, disease recurrence (local, regional, distant, or contralateral), second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence).

    The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest will be the Hazard Ratio of EFS.



Secondary Outcome Measures :
  1. Overall Survival (OS) in the experimental vs control arms [ Time Frame: Date of randomization to date of death due to any cause, up to 82 months after the first subject randomized ]

    OS is defined as the time from the date of randomisation until the date of death due to any cause.

    The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest will be the Hazard Ratio of OS.


  2. Distant disease-free survival (DDFS) in the experimental vs control arms [ Time Frame: Date of randomization to date of the DDFS event, up to 68 months after the first subject randomized ]

    DDFS is defined as the time from the date of randomisation until the date of the first occurrence of any of the following events: distant metastasis, occurrence of second primary non-breast invasive cancer (other than squamous or basal cell skin cancer), or death by any cause (in the absence of recurrence).

    The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest will be the Hazard Ratio of DDFS.


  3. Participant-reported breast and arm symptoms in the experimental vs. control arms [ Time Frame: From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first. ]

    Breast and arm symptoms measured by the EORTC IL116. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest is the mean between-arm difference in breast and arm symptom scores.


  4. Participant-reported physical function in the experimental vs. control arms [ Time Frame: From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). ]
    Physical function measured by the PROMIS Physical Function Short Form 8c. The analysis will include all dosed participants. The measure of interest is the mean between-arm difference in physical function scores.

  5. Participant-reported fatigue in the experimental vs. control arms [ Time Frame: From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). ]
    Fatigue measured by the PROMIS Fatigue Short Form 7a. The analysis will include all dosed participants. The measure of interest will be the difference on the proportions of participants reporting different levels of fatigue and mean between-arm difference in the fatigue scores.

  6. Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms [ Time Frame: From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first, and then from Cycle 1 Day 1 of adjuvant treatment until EOT (for approximately 27 weeks). ]

    Global health status/Quality of life measured by EORTC IL172. The analysis will include all randomised participants, as randomised, regardless of whether the participant withdraws from randomised therapy or receives another anticancer therapy.

    The measure of interest is the mean between-arm difference in GHS/QoL scores.


  7. Pharmacokinetics of Dato-DXd (in combination with durvalumab) [ Time Frame: Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit ]
    Plasma concentrations of Dato-DXd (ug/ml )

  8. Pharmacokinetics of Dato-DXd (in combination with durvalumab) [ Time Frame: Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit ]
    Plasma concentrations of total anti-TROP2 antibody (ug/ml )

  9. Pharmacokinetics of Dato-DXd (in combination with durvalumab) [ Time Frame: Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit ]
    Plasma concentrations of DXd (MAAA-1181a) (ng/ml)

  10. Immunogenicity of Dato-DXd (in combination with durvalumab) [ Time Frame: Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit ]
    Presence of antidrug antibodies (ADAs) for Dato-DXd (confirmatory results: positive or negative, titres).

  11. Safety of Dato-DXd (in combination with durvalumab) [ Time Frame: Randomization to final safety follow-up visit, either 90 days after last dose of study intervention for those who complete planned study intervention or 90 days after date of discontinuation for those who discontinue study intervention prematurely ]
    Safety and tolerability will be evaluated in terms of AEs graded by CTCAE version 5.0


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

Inclusion Criteria:

  • Participant must be ≥ 18 years, at the time of signing the ICF.
  • Histologically confirmed Stage II or III unilateral or bilateral primary invasive TNBC or hormone receptor-low/HER2-negative breast cancer
  • ECOG PS of 0 or 1
  • Provision of acceptable tumor sample
  • Adequate bone marrow reserve and organ function
  • Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

Exclusion criteria:

  • History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before randomization and of low potential risk for recurrence.
  • Evidence of distant disease.
  • Clinically significant corneal disease.
  • Has active or uncontrolled hepatitis B or C virus infection.
  • Known HIV infection that is not well controlled.
  • Uncontrolled infection requiring i.v. antibiotics, antivirals or antifungals; suspected infections; or inability to rule out infections.
  • Known to have active tuberculosis infection
  • Resting ECG with clinically significant abnormal findings.
  • Uncontrolled or significant cardiac disease.
  • History of non-infectious ILD/pneumonitis
  • Any prior or concurrent surgery, radiotherapy or systemic anticancer therapy for TNBC or hormone receptor-low/HER2-negative breast cancer
  • For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding, or planning to become pregnant.
  • Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention, or as dictated by local PI for SoC if longer.
Contacts and Locations
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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): NCT06112379


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
Daiichi Sankyo
More Information
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT06112379    
Other Study ID Numbers: D926QC00001
First Posted: November 1, 2023    Key Record Dates
Last Update Posted: May 14, 2024
Last Verified: May 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
Access Criteria: When a request has been approved AstraZeneca will provide access to the deidentified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Breast Cancer;
Dato-DXd; DS1062a;
TROP2;
TNBC;
HR low:
Datopotamab deruxtecan;
Antibody Drug Conjugate;
 ADC;
neoadjuvant therapy;
adjuvant therapy;
durvalumab;
PD-L1;
immune-checkpoint inhibitor (ICI);
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Cyclophosphamide
Carboplatin
Pembrolizumab
Doxorubicin
Capecitabine
Durvalumab
Epirubicin
Olaparib
Antineoplastic Agents, Phytogenic
 Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Antibiotics, Antineoplastic