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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

PHASE3RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2023-11-14

Primary completion: 2028-03-29

Study completion finish: 2030-08-28

Study type

TREATMENT

Phase

PHASE3

Trial ID

NCT06112379

Intervention or treatment

DRUG: Dato-DXd

DRUG: Durvalumab

DRUG: Pembrolizumab

DRUG: Doxorubicin

DRUG: Epirubicin

DRUG: Cyclophosphamide

DRUG: Paclitaxel

DRUG: Carboplatin

DRUG: Capecitabine

DRUG: Olaparib

Conditions

• Breast Cancer

Condition: Breast Cancer
DRUG: Dato-DXd and other drugs
Darlinghurst, Not Specified, Australia and more
Sponsor: AstraZeneca

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Find a site

Closest Location:

Research Site

Research sites nearby

Select from list below to view details:

Research Site
Darlinghurst, Not Specified, Australia
Research Site
East Melbourne, Not Specified, Australia
Research Site
Heidelberg, Not Specified, Australia
Research Site
Herston, Not Specified, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/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
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

Participant Group/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

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

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Pathologic Complete Response (pCR) in the experimental vs control arms	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.	At the time of definitive surgery
Event-free survival (EFS) in the experimental vs control arms	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.	Date of randomization to date of the EFS event, up to 68 months after the first subject randomized

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Overall Survival (OS) in the experimental vs control arms	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.	Date of randomization to date of death due to any cause, up to 82 months after the first subject randomized
Distant disease-free survival (DDFS) in the experimental vs control arms	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.	Date of randomization to date of the DDFS event, up to 68 months after the first subject randomized
Participant-reported breast and arm symptoms in the experimental vs. control arms	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.	From Cycle 1 Day 1 of neoadjuvant treatment until pre-surgery safety FU visit (for approximately 24 weeks) or EOT - whichever occurs first.
Participant-reported physical function in the experimental vs. control arms	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.	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).
Participant-reported fatigue in the experimental vs. control arms	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.	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).
Participant-reported Global health status/Quality of life (GHS/QoL)in the experimental vs. control arms	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.	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).
Pharmacokinetics of Dato-DXd (in combination with durvalumab)	Plasma concentrations of Dato-DXd (ug/ml )	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit
Pharmacokinetics of Dato-DXd (in combination with durvalumab)	Plasma concentrations of total anti-TROP2 antibody (ug/ml )	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit
Pharmacokinetics of Dato-DXd (in combination with durvalumab)	Plasma concentrations of DXd (MAAA-1181a) (ng/ml)	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit
Immunogenicity of Dato-DXd (in combination with durvalumab)	Presence of antidrug antibodies (ADAs) for Dato-DXd (confirmatory results: positive or negative, titres).	Day 1 of cycles 1,2,4,8 (Each cycle is 21 days) and at pre-surgery safety follow up visit
Safety of Dato-DXd (in combination with durvalumab)	Safety and tolerability will be evaluated in terms of AEs graded by CTCAE version 5.0	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

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References

Clinical Trials Gov: 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