A Study of Dato-DXd Versus Investigators Choice Chemotherapy in Patientswith Locally Recurrent Inoperable or Metastatic Triple-negative Breast Cancer, who are not Candidates for PD-1/PD-L1 Inhibitor Therapy
- Conditions
- Malignant neoplasm of breast of unspecified site,
- Registration Number
- CTRI/2022/10/046630
- Lead Sponsor
- AstraZeneca Pharma India Ltd
- Brief Summary
This is a Phase III, randomised, open-label, 2-arm, multicentre,international study assessing the efficacy and safety of Dato-DXd compared withICC in participants with locally recurrent inoperable or metastatic TNBC whoare not candidates for PD-1/PD-L1 inhibitor therapy.
The primary purpose of the study is to determine the efficacy and safetyof Dato -DXd compared with investigator’s choice single agent chemotherapy inthe target population.
Approximately 800 participants with TNBC will be screened/enrolled toachieve
approximately 600 randomised to study intervention ({andomised 1:1 toeither Dato-DXd 6.0 mg/kg IV Q3W or ICC (Paclitaxel, Nab-paclitaxel,Capecitabine, Eribulin mesylate, Carboplatin)} .
Randomisation will be stratified by the following prognostic factors:
Geographic region (Region 1 [US,Canada, Europe] versus Region 2 [Rest of World])
DFI history (de novo versus priorDFI ï‚£ 12 months versus prior DFI > 12 months)
PD-L1 status (positive [CPS ≥ 10]versus negative [CPS < 10])
A recruitment cap of 20% of the randomised participants will be appliedto participants who have a DFI ≤ 12 months.
A recruitment cap of approximately 10% of the randomised participantswill be applied to participants who have PD-L1-positive (CPS ≥ 10) tumours whowould otherwise be eligible for pembrolizumab but do not have regulatory accessto pembrolizumab (participant’s country does not have regulatory approval atthe time of screening).
All participants will receive study intervention untilinvestigator-defined disease progression according to RECIST 1.1, or untilunacceptable toxicity, withdrawal of consent, or another criterion fordiscontinuation is met. Intervention beyond RECIST 1.1-defined radiological progressionis not permitted in this study. No crossover between study treatment arms willbe allowed. Switching between ICC chemotherapy agents is not permitted.
Tumor evaluation scan will be performed at screening (as baseline)followed by every 6 weeks (± 7 days) from randomisation for 48 weeks, thenevery 9 weeks
(±7 days) thereafter until RECIST 1.1 disease progression (as assessed bythe
investigator), regardless of study intervention discontinuation or startof subsequent anti-cancer therapy. Following disease progression, 1 additionalfollow-up tumour imaging assessment should be performed per imaging schedule(ie, either 6 weeks or 9 weeks later).
The study will compare PFS, OS and other measures of efficacy between thestudy treatment groups and further characterize the safety and tolerabilityprofile of Dato DXt.
Duration of Treatment: Unless specific treatment discontinuation criteriaare met or the patient withdraws consent, all patients will continue receivingtreatment until disease progression. For patients randomized to theinvestigator’s choice single agent chemotherapy arm, crossover to Dato-DXd willnot be permitted.
Follow-up of Participants Post-discontinuation of Study Intervention:After study intervention discontinuation, all participants will undergo anend-of-treatment visit (within 7 days of the decision to discontinue treatment)and will be followed up for safety assessments 28 + 7 days after their lastdose of study intervention (ie, the safety follow-up visit).
Participants who have discontinued study intervention in the absence ofRECIST 1.1-defined radiological progression (by investigator assessment) willbe followed up with tumour assessments according to the SoA until RECIST1.1-defined PD (as assessed by the investigator) or death regardless of whetheror not the participant started a subsequent anti-cancer therapy, unless theyhave withdrawn all consent to study-related assessments.
In addition, all participants will be followed up for survival statusafter intervention discontinuation every 3 months ± 14 days from the date ofthe safety follow-up visit until death, withdrawal of consent, or the end ofthe study (ie, progression/survival follow-up), per the SoA.
Participants may also be followed up for time tosecond progression or death (PFS2) and subsequent anti-cancer therapy use afterintervention discontinuation every 3 months (± 14 days) from the date of thesafety follow-up visit until death, withdrawal of consent, or the end of the study (ie,progression/survival follow-up), per the SoA.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Yet Recruiting
- Sex
- All
- Target Recruitment
- 600
- Inclusion criteria: 1.
- Participant must be ≥ 18 years (≥ 20 years in Japan) at the time of screening.
- Histologically or cytologically documented locally recurrent inoperable 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 targeted systemic therapy for metastatic or locally recurrent inoperable breast cancer.
- 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]).
- 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.
- ECOG PS 0 or 1 7.
- Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin), per investigator assessment.
- Has had an adequate treatment washout period before Cycle 1 Day 1 9.
- Written confirmation of tumour sample needs to be available prior to enrolment and tumour samples should be available prior to randomisation.
- Participants with a history of previously treated neoplastic spinal cord compression or clinically inactive brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they have recovered from acute toxic effects of radiotherapy.
- Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
- Platelet count ≥ 100 × 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
- Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN for AST/ALT (< 5 × ULN in participants with liver metastases).
- Calculated CrCL ≥ 30 mL/minute as determined by Cockcroft-Gault (using actual body weight) 12.
- Minimum life expectancy of 12 weeks.
- Inclusion criteria: 1.
- Participant must be ≥ 18 years (≥ 20 years in Japan) at the time of screening.
- Histologically or cytologically documented locally recurrent inoperable 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 targeted systemic therapy for metastatic or locally recurrent inoperable breast cancer.
- 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]).
- 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.
- ECOG PS 0 or 1 7.
- Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, capecitabine, carboplatin, or eribulin), per investigator assessment.
- Has had an adequate treatment washout period before Cycle 1 Day 1 9.
- Written confirmation of tumour sample needs to be available prior to enrolment and tumour samples should be available prior to randomisation.
- Participants with a history of previously treated neoplastic spinal cord compression or clinically inactive brain metastases, who require no treatment with corticosteroids or anticonvulsants may be included in the study, if they have recovered from acute toxic effects of radiotherapy.
- Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
- Platelet count ≥ 100 × 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
- Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN for AST/ALT (< 5 × ULN in participants with liver metastases).
- Calculated CrCL ≥ 30 mL/minute as determined by Cockcroft-Gault (using actual body weight) 12.
- Minimum life expectancy of 12 weeks.
- Exclusion criteria: Medical Conditions 1.
- As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant, and active bleeding diseases, ongoing or active infection, or significant cardiac or psychological conditions) which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
- History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence (per investigator assessment).
- Persistent toxicities caused by previous anti-cancer therapy, excluding alopecia, not yet improved to Grade ≤ 1 or baseline.
- Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention may be included (eg, hearing loss) after consultation with the sponsor study clinical lead or designee.
- Uncontrolled infection requiring IV antibiotics, antivirals or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
- Known active or uncontrolled hepatitis B or C virus infection; or is positive for hepatitis B or C virus, based on the evaluation of tests for hepatitis B (hepatitis B virus surface antigen, anti-hepatitis B virus surface antibody, and anti-hepatitis B virus core antibody, or hepatitis B virus DNA) or hepatitis C (hepatitis C antibody or hepatitis C virus ribonucleic acid [RNA]) infection at screening.
- Known human immunodeficiency virus (HIV) infection that is not well controlled.
- Uncontrolled or significant cardiac disease including: Myocardial infarction or uncontrolled/unstable angina within 6 months prior to Cycle 1 Day 1 Congestive heart failure (New York Heart Association Class II to IV), or Uncontrolled or significant cardiac arrhythmia, or Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).
- Investigator judgment of any one of the following: Mean resting corrected QT interval corrected by Fridericia’s formula (QTcF) > 470 ms regardless of gender, obtained from triplicate 12-lead electrocardiograms (ECGs) performed at screening.
- Uncontrolled hypercalcaemia: > 1.5 mmol/L (> 6 mg/dL) ionised calcium, or serum calcium (uncorrected for albumin) > 3 mmol/L (> 12 mg/dL), or corrected serum calcium > ULN, or clinically significant (symptomatic) hypercalcaemia.
- History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening 11.
- Clinically severe pulmonary function compromise resulting from intercurrent clinically significant pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli within 3 months of first dosing, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc.) or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (ie, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc.) where there is documented or suspected pulmonary involvement at the time of screening.
- 12 Leptomeningeal carcinomatosis.
- 13 Clinically significant corneal disease.
- 14 Known active tuberculosis infection.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Radiological Progression-Free Survival (PFS) - time from the date of randomization to first objective evidence of radiographic progression or death, whichever occurs first & For PFS, From Randomization Every 6 weeks (± 7 days) from randomisation for 48 weeks, then every 9 weeks (±7 days) thereafter until RECIST 1.1 disease progression. | For OS, every 3 months ± 14 days following objective PD or treatment discontinuation until the end of the study Overall Survival (OS)-time from randomization to death from any cause For PFS, From Randomization Every 6 weeks (± 7 days) from randomisation for 48 weeks, then every 9 weeks (±7 days) thereafter until RECIST 1.1 disease progression. | For OS, every 3 months ± 14 days following objective PD or treatment discontinuation until the end of the study
- Secondary Outcome Measures
Name Time Method Objective response rate (ORR) Duration of response (DOR) Every 6 weeks (± 7 days) from randomisation for 48 weeks, then every 9 weeks (±7 days) thereafter until RECIST 1.1 disease progression Time to Second Subsequent Therapy (TSST) From randomisation to (each patient visit per protocol) until the start date of the second subsequent anti-cancer therapy after discontinuation of first subsequent treatment, or death due to any cause. Disease control rate (DCR) At 12 weeks is defined as the percentage of participants who have a confirmed CR or PR or who have SD, per RECIST 1.1 From randomisation up until progression. Time to deterioration (TTD) From Randomization to deterioration or End of study at each patient visit. Time to second progression or death (PFS2) Following objective progression that is confirmed by investigator assessment, participants will have their subsequent progression status recorded every 3 months (± 14 days) per local standard clinical practice to assess PFS2.
Trial Locations
- Locations (10)
Apex Wellness Hospital
🇮🇳Nashik, MAHARASHTRA, India
HCG Cancer Centre, (A unit of Health Care Global Enterprises Limited)
🇮🇳Visakhapatnam, ANDHRA PRADESH, India
Jawaharlal Institute of Postgraduate Medical Education Research(Jipmer)
🇮🇳Pondicherry, PONDICHERRY, India
Kailash Cancer Hospital And Research Center, Muni Seva
🇮🇳Vadodara, GUJARAT, India
Kingsway Hospital
🇮🇳Nagpur, MAHARASHTRA, India
Mahatma Gandhi Medical College & Hospital
🇮🇳Jaipur, RAJASTHAN, India
Rajiv Gandhi Cancer Institute & Research Centre
🇮🇳Delhi, DELHI, India
Regional Cancer Centre, Medical College Campus
🇮🇳Thiruvananthapuram, KERALA, India
Sri Shankara Cancer Hospital and Research Centre
🇮🇳Bangalore, KARNATAKA, India
Tata Medical Center
🇮🇳Kolkata, WEST BENGAL, India
Apex Wellness Hospital🇮🇳Nashik, MAHARASHTRA, IndiaDr Shailesh BondardePrincipal investigator9822012427shaileshbondarde1971@gmail.com