A Phase 3, Open-label, Randomised Study of Datopotamab Deruxtecan (Dato-DXd) Versus Investigator's Choice of Chemotherapy in Patients Who Are Not Candidates for PD-1/PD-L1 Inhibitor Therapy in First-line Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer (TROPION Breast02)

Official Summary

This is a Phase III, randomised, open-label, 2 arm, multicentre, international study assessing the efficacy and safety of Dato-DXd compared with ICC in participants with locally recurrent inoperable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 644 participants

Study Arms

• Dato-DXd (EXPERIMENTAL)
  Arm 1: Dato-DXd
• Investigator's Choice of Chemotherapy (ICC) (ACTIVE_COMPARATOR)
  Arm 2: If no prior taxane, or prior taxane in the (neo)adjuvant setting and DFI \> 12 months, paclitaxel or nab-paclitaxel If prior taxane and DFI ≤ 12 months: capecitabine, carboplatin, or eribulin.

Interventions

• DRUG: Dato-DXd — Experimental drug. Provided in 100mg vials. IV infusion.
• DRUG: Paclitaxel — IV Infusion. Active comparator
• DRUG: Nab-paclitaxel — IV infusion. Active comparator
• DRUG: Carboplatin — IV infusion. Active comparator
• DRUG: Capecitabine — Tablet. Oral route of administration. Active comparator

Primary Outcomes

• Progression Free Survival (PFS) (From randomization until progression as assessed by BICR or death due to any cause (anticipated to be up to 26 months))
• Overall Survival (OS) (From randomisation until the date of death due to any cause (approximately 42 months))

Secondary Outcomes

• Objective Response Rate (ORR) (From randomisation up until progression (anticipated to be up to 26 months))
• Duration of Response (DoR) (From the date of first documented confirmed 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 26 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 26 months))
• Disease Control Rate (DCR) (At least 11 weeks after randomization to 23 months)
• Time to deterioration (TTD) in pain in participants treated with Dato DXd compared with ICC (From the date of randomisation to the date of deterioration (from randomization to 18 weeks post-progression))

Eligibility Criteria

Inclusion Criteria:

Age

1. Participant must be ≥ 18 years at the time of screening. Type of Participant and Disease Characteristics
2. Histologically or cytologically documented locally recurrent inoperable TNBC, which cannot be treated with curative intent, or metastatic TNBC. TNBC is defined as:

   * Negative for ER with \< 1% of tumour cells positive for ER on IHC.
   * Negative for progesterone receptor with \< 1% of tumour cells positive for progesterone receptor on IHC.
   * Negative for HER2 with 0 or 1+ intensity on IHC or 2+ intensity on IHC and negative by in situ hybridisation per the ASCO-CAP HER2 guideline
3. No prior chemotherapy or other systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.
4. Not a candidate for PD-1/PD-L1 inhibitor therapy, defined as:

   * Participants whose tumours are PD-L1-negative, or
   * Participants whose tumours are PD-L1-positive and have:

     1. relapsed after prior PD-1/PD-L1 inhibitor therapy for early-stage breast cancer,
     2. comorbidities precluding PD-1/PD-L1 inhibitor therapy, or
     3. no regulatory access to pembrolizumab \[participant's country does not have regulatory approval at the time of screening\]).
5. At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI), and is suitable for accurate repeated measurements.
6. ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing.
7. Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin), based on DFI and prior taxane exposure, per investigator assessment.
8. Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:

   * Major surgery: ≥ 3 weeks.
   * Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative radiation therapy to other areas ≥ 2 weeks).
   * Corticosteroid therapy for central nervous system metastatic disease: \> 3 days.
   * Anti cancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer).
   * Nitrosoureas or mitomycin C: ≥ 6 weeks.
   * Antibody-based anti cancer therapy: ≥ 4 weeks with the exception of receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for the treatment of bone metastases).
   * Immunotherapy (non-antibody-based therapy), retinoid therapy: ≥ 2 weeks or 5 times the terminal elimination half-life of the agent, whichever is longer.
   * Chloroquine/hydroxychloroquine: \> 14 days.
9. Written confirmation of tumour sample needs to be available prior to enrolment and tumour samples should be available prior to randomisation. All participants must have a FFPE metastatic (excluding bone) or locally recurrent inoperable tumour sample (block preferred, or a minimum of 20 freshly cut slides) available, collected ≤ 3 months prior to screening. If neither an adequate FFPE block nor the minimum of 20 slides are available from the most recent biopsy, or if a biopsy is not feasible for safety reasons, and this is clearly documented, an archival tumour specimen obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted, pending approval by the Global Study Team.
10. Participants with a history of previously treated neoplastic spinal cord compression or asymptomatic, stable brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they are no longer symptomatic and have recovered from acute toxic effects of radiotherapy. A minimum of 2 weeks must have elapsed between the end of radiotherapy and Cycle 1 Day 1. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for central nervous system metastatic disease and Cycle 1 Day 1.
11. Adequate organ and bone marrow function within 7 days before randomisation as follows:

    * Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
    * Absolute neutrophil count ≥ 1.5 × 10\^9/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
    * Platelet count ≥ 100 × 10\^9/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
    * Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) or \< 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia).
    * Except in the setting of HBV, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN for AST/ALT (\< 5 × ULN in participants with liver metastases). See Exclusion Criterion 5 for requirements in the

Trial Locations

• Research Site, Duarte, California, United States
• Research Site, Los Angeles, California, United States
• Research Site, San Francisco, California, United States
• Research Site, Grand Junction, Colorado, United States
• Research Site, Longmont, Colorado, United States
• Research Site, New Haven, Connecticut, United States
• Research Site, Washington D.C., District of Columbia, United States
• Research Site, Miami, Florida, United States
• Research Site, Miami, Florida, United States
• Research Site, Atlanta, Georgia, United States
• ...and 10 more locations

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