IRB Study Number 25-102
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
To demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS as assessed by BICR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
Secondary Objectives
To demonstrate superiority of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of OS in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of ORR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of DoR in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS as assessed by the investigator in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of CBR at 24 weeks in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To assess TTD in breast and arm symptoms in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab.
To assess TTD in pain in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab.
To assess TTD in physical functioning in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab.
To assess TTD in GHS/QoL in participants treated with Dato-DXd + durvalumab compared with ICC + pembrolizumab.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of TFST in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of TSST in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To evaluate efficacy of Dato-DXd + durvalumab relative to ICC + pembrolizumab by assessment of PFS2 in participants with PD-L1 positive locally recurrent inoperable or metastatic TNBC.
To assess the pharmacokinetics of Dato-DXd (6 mg/kg IV Q3W) in combination with durvalumab.
To investigate the immunogenicity of Dato-DXd (6 mg/kg IV Q3W) in combination with durvalumab.
Inclusion Criteria
Age
1 Participant must be ≥18 years at the time of signing the informed consent form (ICF).
Type of Participant and Disease Characteristics
2 Histologically or cytologically documented locally recurrent inoperable, 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 (Wolff et al 2018; Allison et al 2020).
3 ECOG PS 0 or 1 with no deterioration over the previous 2 weeks prior to randomisation.
4 All participants must provide a FFPE tumour sample (primary, metastatic location excluding bone, or locally recurrent inoperable tumour sample) collected ≤ 3 months prior to signing of informed consent (ie, start of screening). Detailed sample requirements will be defined in the study Central Laboratory and Pathology Manual. An existing archival tumour sample from locally recurrent inoperable or metastatic breast cancer is requested. If new tumour sample collection is required, participants will only undergo new tumour specimen collection when the risks are considered medically acceptable by their caring physicians. If a tumour sample to meet requirements is not available, and if a biopsy is not feasible for safety reasons, and this is clearly documented, a tumour sample obtained before the diagnosis of locally recurrent inoperable or metastatic breast cancer may be submitted pending approval by the Global Study Team.
5 PD-L1 positive TNBC based on results from an appropriately validated investigational PD-L1 (22C3) assay (CPS ≥ 10) from a sponsor-designated central laboratory.
6 No prior chemotherapy or targeted systemic anti-cancer therapy for metastatic or locally recurrent inoperable breast cancer.
7 Eligible for one of the chemotherapy options listed as ICC (paclitaxel, nab-paclitaxel, or gemcitabine + carboplatin).
Note: For patients who relapse after being treated for early-stage breast cancer, DFI will be measured as the time between completion of treatment with curative intent (either date of primary breast tumour surgery or date of last dose of systemic anticancer therapy (not including endocrine therapy), whichever occurred last) and the first documented local or distant disease recurrence (either by biopsy or imaging). 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, including patients with prior PD-1/PD-L1 inhibitor treatment for early stage disease.
Note: Adjuvant radiation therapy is not considered treatment with curative intent for the purpose of calculating the DFI. Note: First documentation of local or distant disease recurrence must be in the form of a dated imaging or pathology report. A laboratory report indicating tumour marker elevation cannot be used as documentation of local or distant disease recurrence, unless it is accompanied by a dated imaging or pathology report.
Note: Participants with locally recurrent inoperable or relapsed metastatic TNBC are expected to have been treated with (neo)adjuvant anthracycline, unless anthracycline was contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician.
Note: Participants presenting with de novo metastatic TNBC are eligible for the study, if anthracycline is contraindicated or not considered the best treatment option for the participant in the opinion of the treating physician.
Note: Participants with known germline BRCA pathogenic variants (based on testing performed as part of routine clinical practice) presenting with metastatic or locally recurrent inoperable TNBC are eligible for the study, if another therapy (such as poly adenosine diphosphate-ribose polymerase [PARP] inhibitor) is not considered the best treatment option for the participant in the opinion of the treating physician.
8 Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:
Major surgery: ≥ 3 weeks.
Note: Major surgical procedure or significant traumatic injury within 3 weeks of the first dose of study treatment or an anticipated need for major surgery and/or any surgery requiring general anaesthesia during the study. Exceptions include procedures with less than 3 weeks’ recovery time.
Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative radiation therapy to other areas ≥ 2 weeks).
Ongoing radiation-related toxicities requiring corticosteroids.
Corticosteroid therapy for central nervous system (CNS) metastatic disease: > 3 days.
Anticancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer).
Chloroquine/hydroxychloroquine: > 14 days.
9 Measurable disease by computed tomography (CT) or MRI as per RECIST 1.1. At least 1 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 CT or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements. Bone-only disease is not permitted.
10 Adequate bone marrow reserve and organ function within 7 days before Cycle 1 Day 1 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 × 109/L (granulocyte colony stimulating factor administration 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).
▪ International normalised ratio/prothrombin time and either partial thromboplastin time or activated partial thromboplastin time ≤ 1.5 × the upper limit of normal (ULN).
▪ 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, ALT, and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT, and AST ≤ 5 × ULN. See Exclusion Criterion 7 for requirements in the setting of HBV.
▪ Calculated creatine clearance (CrCL) > 40 mL/minute as determined by Cockcroft-Gault (using actual body weight):
Males: CrCL (mL/min)= Weight (kg) × [140−Age (years)]72 × serum creatinine (mg/dL)
Females: CrCL (mL/min)= Weight (kg) ×[140−Age (years)]72 × serum creatinine (mg/dL) × 0.85
International normalised ratio (INR) or prothrombin time, and either partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT): ≤ 1.5 × ULN.
11 Minimum life expectancy of 12 weeks.
Sex and Contraceptive/Barrier Requirements
12 Male or female.
Reproduction
Contraceptive use by females or males should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix G for further details.
a Female participants:
i. Females not of childbearing potential, see Appendix G for definition.
ii. HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; see Appendix G for further details.
iii. Female participants of childbearing potential must use one highly effective form of contraception or avoid intercourse from enrolment throughout study and for at least 7 months after the last dose of Dato‑DXd. If Dato-DXd had been discontinued more than 7 months previously and durvalumab was still ongoing, then 3 months after the last dose of durvalumab, or as dictated by local prescribing information for SoC if longer; see Appendix G for further details. All FOCBP must have a negative serum pregnancy test documented during screening.
iv. Starting at the time of first dose of study treatment, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato‑DXd. If Dato-DXd had been discontinued more than 7 months previously and durvalumab was still ongoing, then 3 months after the last dose of durvalumab, or as dictated by local prescribing information for SoC if longer. Preservation of ova should be considered prior to randomisation in this study.
b Male participants:
i. Use of a condom plus an additional contraceptive method, or avoid intercourse from enrolment and throughout study for at least4 months after the last dose of Dato‑DXd. If Dato-DXd had been discontinued more than4 months previously and durvalumab was still ongoing, then 3 months after the last dose of durvalumab, or as dictated by local prescribing information for SoC if longer. This is in addition to the female partner using a highly effective contraceptive method; see Appendix G for further details.
ii. Starting at the time of first dose of study treatment, male participants must not freeze or donate sperm at any time during this study and for at least4 months after the last dose of Dato‑DXd. If Dato-DXd had been discontinued more than4 months previously and durvalumab was still ongoing, then 3 months after the last dose of durvalumab, or as dictated by local prescribing information for SoC if longer. Preservation of sperm should be considered prior to randomisation in this study.
Informed Consent
13 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
14 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of sample for optional genetic research that supports Genomic Initiative.
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.
2 History of another primary malignancy except for adequately resected basal cell carcinoma of the skin or squamous cell carcinoma of the skin, in situ disease that has undergone potentially curative therapy, or other solid malignancy treated with curative intent with no known active disease within 3 years before Cycle 1 Day 1 and of low potential risk for recurrence.
3 Persistent toxicities caused by previous anticancer 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 in the opinion of the investigator may be included (eg, hearing loss). Note: per the discretion of the investigator, participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to Cycle 1 Day 1 and managed with SoC treatment) which the investigator deems related to previous anticancer therapy, including (but not limited to):
Chemotherapy-induced neuropathy
Fatigue
Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies which may include:
o Hypothyroidism/hyperthyroidism
o Type I diabetes mellitus
o Hyperglycaemia
o Adrenal insufficiency
o Adrenalitis
o Skin hypopigmentation (vitiligo).
4 Neoplastic spinal cord compression or active brain metastases. 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. 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 CNS metastatic disease and Cycle 1 Day 1.
5 Has significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.
6 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).
Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they:
a. Participants with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with detectable HBV DNA (≥ 10 IU/ml or above the limit of detection per local laboratory standard), treated with antiviral therapy, per institutional practice. Following antiviral therapy initiation, participants must show adequate viral suppression (ie, HBV DNA ≤ 2000 IU/mL) as prior to randomisation. Participants will remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
b. Participants with HBV infection, characterised by positive HBsAg and/or anti-HBcAb with undetectable HBV DNA (< 10 IU/ml or under the limit of detection per local lab standard) do not require antiviral therapy prior to randomisation. These participants will be tested at every cycle to monitor HBV DNA levels; if HBV DNA is detected (≥ 10 IU/ml or above the limit of detection per local lab standard), antiviral therapy must be initiated, continued for the study duration and for 6 months after the last dose of study treatment.
c. Participants positive for HCV antibody are eligible only if PCR is negative for ‘HCV RNA’
7 Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC.
9 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).
10 Mean resting corrected QT interval corrected by Fridericia’s formula (QTcF) >470 ms regardless of gender, obtained from a triplicate 12-lead electrocardiogram (ECG) performed at screening.
11 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.
Note: Participants who are receiving bisphosphonate therapy specifically to prevent skeletal events and who do not have a history of clinically significant (symptomatic) hypercalcaemia are eligible.
12 History of non-infectious ILD/pneumonitis (including radiation pneumonitis) that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.Note: Participants found to have ILD/pneumonitis on baseline screening chest CT are not eligible.
13 Has severe pulmonary function compromise.
14 Leptomeningeal carcinomatosis or history of leptomeningeal carcinomatosis.
15 Clinically significant corneal disease.
16 Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.), autoimmune pneumonitis and autoimmune myocarditis. The following are exceptions to this criterion:
(a) Participants with vitiligo or alopecia.
(b) Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead.
(e) Participants with coeliac disease controlled by diet alone
Prior/Concomitant Therapy
17 Prior exposure to:
(a) Any treatment including ADC containing a chemotherapeutic agent targeting topoisomerase I.
(b) TROP2-targeted therapy.
(c) Chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days prior to randomisation.
18 Any concurrent anticancer treatment.
Note: Approved bone-modifying agents (eg, bisphosphonates or RANKL-targeting agents [eg, denosumab]) to treat or control bone disease are permitted
19 Concurrent use of systemic hormone replacement therapy (HRT; eg, oestrogen and/or progesterone) or hormonal contraception. However, concurrent use of hormones for other non-cancer-related conditions (eg, insulin for diabetes) is acceptable.
20 Current or prior use of immunosuppressive medication within 14 days prior to randomisation. The following are exceptions to this criterion:
(a) Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
(b) Systemic corticosteroids at physiologic doses not to exceed 10 mg/Day of prednisone or its equivalent.
(c) Steroids as pre-medication for hypersensitivity reactions or as an anti-emetic (eg, CT scan pre-medication).
21 Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention (see Appendix I 2).
22 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury ≤ 3 weeks of Cycle 1 Day 1 or an anticipated need for major surgery during the study.
Prior/Concurrent Clinical Study Experience
23 Previous randomisation in the present study.
24 Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dose of study intervention, randomisation into a prior T-DXd, Dato-DXd or durvalumab study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
25 Participants with a known severe hypersensitivity to Dato-DXd or any of the excipients of the product including but not limited to polysorbate 80 or other monoclonal antibodies.
26 Participants with a known severe hypersensitivity to PD-1/PD-L1 inhibitors.
Other Exclusions
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
28 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements.
29 Currently pregnant (confirmed with positive pregnancy test), breastfeeding or planning to become pregnant.
30 Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study treatment, or as dictated by local prescribing information for SoC if longer.
