Triple Negative Breast Neoplasms
Conditions
Keywords
Breast Cancer, TNBC, Triple Negative, Triple Negative Breast Cancer, Triple-Negative Breast Cancer, Triple-Negative Breast Neoplasm, ER-Negative PR-Negative HER2-Negative Breast Cancer, ER-Negative PR-Negative HER2-Negative Breast Neoplasms, PD-L1 high TNBC
Brief summary
This study is designed to determine the efficacy and safety of durvalumab in combination with novel oncology therapies with or without paclitaxel and durvalumab + paclitaxel for first-line metastatic triple negative breast cancer
Detailed description
This is a Phase IB/II, 2-stage, open-label, multicenter study to determine the efficacy and safety of durvalumab in combination with novel oncology therapies (i.e. therapies designed for immune modulation) with or without paclitaxel and durvalumab + paclitaxel as first-line treatment in patients with metastatic triple negative breast cancer (TNBC). The study is designed to concurrently evaluate potential novel treatment combinations with clinical promise using a 2-stage approach. The study will use a Simon 2-Stage design to evaluate which cohorts may proceed to expansion. Part 1 is a Phase IB study of safety and initial efficacy, and Part 2 may expand patient enrollment if adequate efficacy signal is observed in Part 1. The treatment regimens evaluated in Part 2 will depend on the evaluation of safety and efficacy outcomes in Part 1.
Interventions
DRUGDurvalumab
Durvalumab iv Every 4 weeks (q4w) or 3 weeks (q3w) Arm 6, 7 and 8
DRUGCapivasertib
Capivasertib oral bid 4-week cycles; 3 weeks on (dosing on days 2,3,4 and 5) and 1 week off
DRUGOleclumab
Oleclumab iv Every 2 weeks (q2w) for first 2 cycles (days 1 and 15 in cycles 1 and 2), then every 4 weeks (q4w) starting at cycle 3 day 1
DRUGPaclitaxel
Paclitaxel iv 4-week cycles: 3 weeks once weekly (q1w) and 1 week off
DRUGTrastuzumab deruxtecan
Trastuzumab deruxtecan iv 3-week cycles (once weekly) q3w
DRUGDatopotamab deruxtecan
Datopotamab deruxtecan iv 3-week cycles (once weekly) q3w
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1: At least 20 patients in the durvalumab-paclitaxel arm and at least 30 patients in each of the other novel treatment combination arms will be enrolled, for a total of approximately 140 patients (durvalumab + paclitaxel arm and 4 novel treatment combination arms). Additional patients may be enrolled in order to have 20 or 30 evaluable (i.e. dosed) patients per durvalumab - paclitaxel arm or novel treatment combination arm, respectively. Part 2: Approximately 27 patients will be assigned to each treatment arm, for an anticipated total of 57 response-evaluable patients per arm (ie, 30 patients in Part 1 and 27 patients in Part 2 per treatment arm, with the exception of Arm 1, which will enroll 20 patients in Part 1 and will not be expanded to Part 2). Patient expansion from 30 patients in Part 1 to an additional 27 patients from Part 2 will be determined based on a futility analysis utilizing a Simon 2 Stage design.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Female 2. At least 18 years of age at the time of screening 3. Patient must have locally confirmed advanced/unresectable or metastatic TNBC. 4. No prior treatment for metastatic (Stage IV) TNBC 5. Patient must have at least 1 lesion, not previously irradiated, that can be accurately measured 6. WHO/ECOG status at 0 or 1 at enrollment Patients enrolled to Arm 6 (durvalumab and DS-8201a) Must provide documentation of locally determined advanced/unresectable or metastatic TNBC with HER2 low tumor expression (IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) Patients enrolled in Arm 8 (durvalumab + Dato-DXd) Must have PD-L1 positive tumor as determined by an IHC based assay
Exclusion criteria
1. History of allogeneic organ transplantation 2. Active or prior documented autoimmune or inflammatory disorders 3. Active infection including tuberculosis, hepatitis B (known positive HBV surface antigen \[HBsAg\] result), hepatitis C virus (HCV), or human immunodeficiency virus (positive HIV 1/2 antibodies) 4. Untreated CNS metastases 5. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients 6. Any concurrent chemotherapy, IP, or biologic therapy for cancer treatment 7. Female patients who are pregnant, breastfeeding 8. Cardiac Ejection Fraction less than 50% Patients enrolled in Arm 2 only: 1. Potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2C9 or CYP2D6 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort) 2. Diagnosis of diabetes mellitus Type I or diabetes mellitus Type II requiring insulin treatment. 3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, potential for torsades de pointes, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval 4. Prior treatment with PI3K inhibitors, AKT inhibitors, or mammalian target of rapamycin (mTOR) inhibitors. Patients enrolled in Arm 5 only: History of venous thromboembolism in the past 3 months Patients enrolled in Arm 7 and 8 only: Clinically significant corneal disease in the opinion of the Investigator. Patients enrolled in Arm 6, 7 and 8 only: 1. History of or active interstitial lung disease/pneumonitis 2. Use of chloroquine or hydroxychloroquine in \<14 days prior to Day 1 of DS-8201a (Arm 6) or Dato-DXd (DS-1062a; Arm 7 and 8) treatment 3. Patients enrolled in Arm 6 only: Previously been diagnosed as HER2+ or received HER2-targeted therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) Events | From the time of first dose until completion of the first cycle (28 days for Arms 2-5, 21 days for Arms 6-7 (no safety run-in for Arms 1 and 8)) | The occurrence of a severe adverse event (meeting pre-specified criteria) that is at least possibly related to durvalumab and/or the novel oncology therapy in 6 DLT-evaluable patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1) | Percentage of evaluable patients with a confirmed Investigator-assessed response of CR (complete response) or PR (partial response). Confirmed response is defined as at least one visit response of CR or PR confirmed by a follow-up scan at least 4 weeks later showing CR or PR. |
| Progression-free Survival (PFS) | Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1) | Time from date of first dose (at least one study intervention \[durvalumab, paclitxel or novel oncology therapy\]) until the date of objective radiological disease progression using RECIST 1.1 or death (by any cause in the absence of progression) |
| Duration of Response (DoR) | Tumor assessments: every 8 wks (Arms 1-5) or every 6 wks (Arms 6-8) until wk 48, then every 12 wks from first IP dose until radiologic progression, death, withdrawal of consent, or study completion; up to max 54 mos (observed longest duration in Arm 1) | Time from the date of first documented response (which is subsequently confirmed) until the first date of documented progression (PD) or death in the absence of PD (ie, date of PFS event or censoring - date of first response + 1). If a patient does not progress following a response, then their DoR will be censored at the last evaluable disease assessment date |
| Overall Survival (Count) | From date of first dose until date of death due to any cause; up to the maximum of 54 months (observed longest duration in Arm 1) | Number of patients with overall survival, the time from date of first dose (at least one study intervention \[durvalumab, paclitxel or novel oncology therapy\]) until the date of death by any cause |
| Overall Survival (Duration) | From date of first dose of IP until date of death due to any cause; up to the maximum of 54 months (observed longest duration in Arm 1) | Time from date of first dose (at least one study intervention \[durvalumab, paclitxel or novel oncology therapy\]) until the date of death by any cause |
| Progression-free Survival at 6 Months (PFS6) | 6 months following date of first dose | Percentage of patients alive and progression-free at 6 months following date of first dose (at least one study intervention \[durvalumab, paclitxel or novel oncology therapy\]) |
Countries
Canada, Poland, South Korea, Taiwan, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORPeter Schmid, MD, PhD
Barts Cancer Institute
Participant flow
Recruitment details
Data cut-off is 30Jun23 for Arms 1,2,5,6 and 29Nov24 for Arms 7-8
Pre-assignment details
Part 1 evaluated safety (with safety run-in Arms 2, 5, 6 and 7), efficacy, PK and immunogenicity for durvalumab combinations. Enrolment was expanded in Part 2, if pre-defined Part 1 efficacy signals were observed. Per the CSP and SAP, participants from Part 1 and 2 were analyzed together, no separate analyses by Part are available. Arms including Part 1 only: 1, 2, 5, 8. Arms including Part 1 and 2: Arms 6 and 7. No expansion to Part 2 was planned for Arm 8.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 47 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Asian | 101 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants |
| Race/Ethnicity, Customized Other | 1 Participants |
| Race/Ethnicity, Customized White | 124 Participants |
| Sex/Gender, Customized Female | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 14 / 23 | 18 / 31 | 25 / 33 | 22 / 58 | 28 / 62 | 3 / 33 |
| other Total, other adverse events | 22 / 23 | 30 / 31 | 32 / 33 | 57 / 58 | 62 / 62 | 33 / 33 |
| serious Total, serious adverse events | 1 / 23 | 11 / 31 | 4 / 33 | 16 / 58 | 18 / 62 | 5 / 33 |
Outcome results
None listed