Breast Cancer Metastatic, HER2-positive Metastatic Breast Cancer, HER2 Low Breast Carcinoma, Advanced Breast Cancer
Conditions
Brief summary
ICARUS-BREAST02 is an open-label, multicenter, phase 1b/2, platform study that aims to evaluate the safety, tolerability, and efficacy of HER3-DXd monotherapy and in combination with other anti-cancer agents in patients with ABC. The first 2 modules will evaluate: i. safety and efficacy of HER3-DXd with olaparib in patients with HER2-low and HER2-positive ABC progressed on T-DXd (Module 1) and HER3-DXd monotherapy in patients with HER2-low ABC progressed on T-DXd (Module 0). The main objective of Part 1 is to assess the safety and tolerability of HER3-DXd monotherapy and combination and to determine the recommended phase 2 dose (RP2D) of the combination containing HER3-DXd. The main objective of Part 2 is to assess the efficacy of study therapies in each module based on investigator assessment as evaluated by the objective response rate (ORR) at 6 months.
Interventions
5.6 mg/kg every 21 days
DRUGOlaparib
100 mg b.i.d PO days 8-14 every 21 days
Sponsors
Daiichi Sankyo
Gustave Roussy, Cancer Campus, Grand Paris
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have received prior treatment with T-DXd and presented disease progression while on T-DXd treatment or within 2 months from T-DXd interruption/discontinuation for any reason, without requiring to be the last line of treatment. Patients who have received other lines of treatment after T-DXd and before study entry is capped at 10 patients for each cohort. 2. Patients with HER2-positive tumors must have received prior treatment with trastuzumab and taxanes. They may have received prior treatment with T-DM1 and pertuzumab. 3. Patients with HER2-low tumors must have been treated with taxanes. Patients with HR-positive tumors must have received ET and CDK4/6 inhibitors (patients may have received prior treatment with sacituzumab govitecan) If a patient has a tumor that was previously HER2-pos and became HER2-low, she/he will be included in cohort 2 and meet the inclusion criteria for HER2-low tumors. If a patient has a tumor that was previously HR-pos and became HR-neg, prior therapy with CDK4/6 inhibitors is not mandatory. 4. Patients with germline pathogenic BRCA1/2 mutations and HER2-positive or HER2-low breast cancer are eligible to the study but must have received a prior treatment with PARP inhibitor (olaparib or talazoparib) 5. Female or male patient aged ≥18 years on the day of the ICF signature 6. Patient who has histologically confirmed diagnosis of breast cancer with unresectable loco regional or metastatic disease 7. Patient must have an ECOG PS ≤1 at the time of screening 8. Patients must have HER2-pos (IHC 3+ or IHC2+/ISH positive) or HER-2 low (IHC2+/ISH negative or IHC 1+) tumors with any HR status, any time before T-DXd exposure 9. Patient must have at least one radiologically measurable lesion (different from the biopsy site) according to response evaluation criteria in solid tumors (RECIST) V1.1 criteria. At least one predominantly lytic or mixed lytic-blastic bone lesion with identifiable soft tissue component that can be evaluated by Computerized Tomography (CT)/Magnetic Resonance Imaging (MRI) must be present in patients with only bone metastasis 10. Patient must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patients must have accepted to perform pre-treatment, on-treatment, and end-of-treatment biopsies 11. Patient must have adequate bone marrow reserve and organ function, based on local laboratory data within 14 days prior to Cycle 1, Day 1, defined per the protocol 12. Female patients of reproductive/childbearing potential must have a negative pregnancy test at screening (serum test within 24 hours before C1D1 or urine test within 72 hours of C1D1) and must and must agree to use a highly effective form of contraception or avoid intercourse during and till the end of treatment and for at least 8 months after the last dose of study drug. The following contraception methods are considered highly effective: 1. Intrauterine device (IUD) 2. Bilateral tubal occlusion 3. Vasectomized partner 4. Complete sexual abstinence defined as refraining from heterosexual intercourse during and till the end of treatment and for at least 8 months for females after the last dose of study drug. Periodic abstinence not an acceptable method of contraception 13. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 8 months after the final study drug administration 14. Male patients must be surgically sterile or must withhold heterosexual intercourse, or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 5 months following the last dose of study drug 15. Male patients must not freeze or donate sperm starting at screening and throughout the study period, and for at least 5 months after the final study drug administration. 16. Patient must understand, sign and date the written informed consent form (ICF) prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedure as per protocol 17. Patient must be affiliated to a social security system or beneficiary of the same
Exclusion criteria
The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DLTs (dose-limiting toxicity) for part 1a and 1b | 21 months after the beginning of enrolment | DLTs |
| Frequency of safety event for part 1a and 1b | 21 months after the beginning of enrolment | frequency of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0 |
| Severity of safety event for part 1a and 1b | 21 months after the beginning of enrolment | severity of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0 |
| Proportion of treatment modification due to AEs for part 1a and 1b | 21 months after the beginning of enrolment | Proportion of treatment discontinuations, interruptions, and dose reductions due to any AEs |
| frequency of laboratory abnormalities for part 1a and 1b | 21 months after the beginning of enrolment | frequency of laboratory abnormalities defined by NCI-CTCAE v5.0 laboratory findings |
| Severity of laboratory abnormalities for part 1a and 1b | 21 months after the beginning of enrolment | Severity of laboratory abnormalities defined by NCI-CTCAE v5.0 laboratory findings |
| radiographic changes potentially consistent with ILD/pneumonitis or any other pulmonary signs/symptoms for part 1a and 1b | 21 months after the beginning of enrolment | Evaluations must include CT (preferably high-resolution CT) and pulmonologist consultation (when the Investigator is not a pulmonologist). Those will be reviewed by an internal multidisciplinary team at GRCC. |
| ORR for part 2 | 51 months | ORR is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators after 6 months of treatment initiation. The objective response will be radiologically assessed every 6 weeks during the first year than every 12 weeks thereafter using RECIST v1.1. |
| DOR for part 2 | 51 months | DOR is defined as the time from the date of the first documentation of confirmed response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause, whichever occurs first. Duration of response will be measured for responding patients (CR or PR) only |
| PFS for part 2 | 51 months | PFS is defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, PFS will be censored at the date of last adequate radiological assessment without progression |
| CBR for part 2 | 51 months | CBR is defined as the presence of at least a confirmed PR or CR, or a stable disease (SD) ≥ 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Severity of laboratory abnormalities for part 2 | 39 months from the beginning of enrolment | Severity of laboratory abnormalities defined by NCI-CTCAE v5.0; |
| radiographic changes potentially consistent with ILD/pneumonitis or any other pulmonary signs/symptoms for part 2 | 39 months from the beginning of enrolment | Evaluations must include CT (preferably high-resolution CT) and pulmonologist consultation (when the Investigator is not a pulmonologist). Those will be reviewed by an internal multidisciplinary team at GRCC. |
| ORR for part 1 | 45 months | ORR is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) assessed by investigators after 6 months of treatment initiation. The objective response will be radiologically assessed every 6 weeks during the first year than every 12 weeks thereafter using RECIST v1.1. |
| ADA analysis for part 2 | 39 months from the beginning of enrolment | Serum concentration of HER3-DXd (Anti-HER3-ac-DXd total, anti-HER3 antibody and DXd), plasma concentration of olaparib, will be assessed incidence and prevalence of anti-drug antibody (ADA) for HER3-DXd. Estimation of the proportion of deconjugated payload-linker complex binding with circulating albumin will also be assessed. |
| PK analysis for part 2 | 39 months from the beginning of enrolment | Serum concentration of HER3-DXd (Anti-HER3-ac-DXd total, anti-HER3 antibody and DXd), plasma concentration of olaparib, will be assessed for PK analysis. Estimation of the proportion of deconjugated payload-linker complex binding with circulating albumin will also be assessed. |
| DOR for part 1 | 45 months | DOR is defined as the time from the date of the first documentation of confirmed response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause, whichever occurs first.Duration of response will be measured for responding patients (CR or PR) only |
| PFS for part 1 | 45 months | PFS is defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, PFS will be censored at the date of last adequate radiological assessment without progression. |
| CBR for part 1 | 45 months | CBR is defined as the presence of at least a confirmed PR or CR, or a stable disease (SD) ≥6 months |
| PK analysis for part 1 | 45 months | Serum concentration of HER3-DXd (Anti-HER3-ac-DXd total, anti-HER3 antibody and DXd), plasma concentration of olaparib, will be assessed for PK analysis. Estimation of the proportion of deconjugated payload-linker complex binding with circulating albumin will also be assessed. |
| ADA analysis for part 1 | 45 months | Serum concentration of HER3-DXd (Anti-HER3-ac-DXd total, anti-HER3 antibody and DXd), plasma concentration of olaparib, will be assessed for incidence and prevalence of anti-drug antibody (ADA) for HER3-DXd. Estimation of the proportion of deconjugated payload-linker complex binding with circulating albumin will also be assessed. |
| DLTs for part 2 | 39 months from the beginning of enrolment | — |
| Frequency of safety event for part 2 | 39 months from the beginning of enrolment | Frequency of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0; |
| Severity of safety event for part 2 | 39 months from the beginning of enrolment | Frequency of any AEs, TEAEs, SAEs, AESIs graded by NCI-CTCAE v5.0; |
| proportion of treatment modification event for part 2 | 39 months from the beginning of enrolment | proportion of treatment discontinuations, interruptions, and dose reductions due to any AEs |
| frequency of laboratory abnormalities for part 2 | 39 months from the beginning of enrolment | frequency of laboratory abnormalities defined by NCI-CTCAE v5.0; |
Countries
France
Contacts
Primary ContactBarbara Pistilli
Backup ContactFernanda Mosele
Outcome results
None listed