Trial Title:
Dose-Expansion Modular Study To Explore the Safety, Tolerability, and Anti-tumor Activity of HER3- DXd Monotherapy and Combinations in Patients With Inoperable Advanced Breast Cancer (ABC) After Progression on T-DXd
NCT ID:
NCT06298084
Condition:
Breast Cancer Metastatic
HER2-positive Metastatic Breast Cancer
HER2 Low Breast Carcinoma
Advanced Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Olaparib
Patritumab deruxtecan
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Patritumab deruxtecan
Description:
5.6 mg/kg every 21 days
Arm group label:
Part 1a (safety run-in module 0)
Arm group label:
Part 1b (dose finding module 1 + dose expansion module 0)
Arm group label:
Part 2 (dose expansion module 1 + module 0)
Other name:
U3-1402
Other name:
HER3-DXd
Intervention type:
Drug
Intervention name:
Olaparib
Description:
100 mg b.i.d PO days 8-14 every 21 days
Arm group label:
Part 1b (dose finding module 1 + dose expansion module 0)
Arm group label:
Part 2 (dose expansion module 1 + module 0)
Other name:
Lynparza
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.
Criteria for eligibility:
Criteria:
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 exclusion criteria are applicable for all modules. Patients will be
excluded if they present one of them:
1. Patient with a breast cancer amenable for resection or radiation therapy with
curative intent
2. Patient with any history of ILD (including pulmonary fibrosis or radiation
pneumonitis), has current ILD, or is suspected to have ILD as assessed by imaging
during screening
3. Patient with clinically severe pulmonary compromise (based on investigator's
assessment) resulting from intercurrent pulmonary illnesses including, but not
limited to:
1. Any underlying pulmonary disorder (eg, pulmonary embolism, severe asthma,
severe chronic obstructive pulmonary disease (COPD), restrictive lung disease,
pleural effusion) OR
2. Any autoimmune, connective tissue or inflammatory disorder with pulmonary
involvement (eg, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR
3. Prior pneumonectomy
4. Patient receiving chronic systemic corticosteroids dosed at >10 mg/day prednisone or
equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior
to Cycle 1 Day 1. Patients who require use of bronchodilators, inhaled or topical
steroids, or local steroid injections may be included in the study
5. Patient with evidence of any leptomeningeal disease
6. Patient with clinically significant corneal disease
7. Patient with any evidence of severe or uncontrolled systemic diseases (e.g. active
bleeding diatheses, active infection, or psychiatric illness) which in the
investigator's opinion makes it undesirable for the patient to participate in the
study or which would jeopardize compliance with the protocol. Screening for chronic
conditions is not required for eligibility
8. Evidence of spinal cord compression or brain metastases, defined as being clinically
active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants
to control associated symptoms. Patients with clinically inactive or treated brain
metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not
require treatment with corticosteroids or anticonvulsants) may be included in the
study. Patients must have a stable neurologic status for at least 2 weeks prior to
Cycle 1 Day 1
9. Inadequate washout period prior to Cycle 1 Day 1, defined as:
1. Whole brain radiation therapy or stereotactic brain radiation therapy <14 days
2. Previous treatment with T-DXd < 28 days
3. Any cytotoxic chemotherapy, investigational agents or other anticancer drug(s)
from a previous cancer treatment regimen or clinical study <14 days or 5
half-lives, whichever is longer
4. Endocrine therapy <21 days
5. Monoclonal antibodies <28 days including immune checkpoint inhibitors (ICIs)
6. Major surgery (excluding placement of vascular access) <28 days
7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation <28 days or palliative radiation therapy <14 days
8. Live virus vaccination <28 days
10. Prior treatment with an anti-HER3 antibody
11. Patients with unresolved toxicities from previous anticancer therapy, defined as
toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline, as
defined by National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE) version 5.0. Patients with chronic Grade 2 toxicities (defined as no
worsening to Grade >2 for at least 3 months prior to enrollment and managed with
standard of care treatment) that the Investigator deems related to previous
anticancer therapy, comprising the following, may be enrolled at the discretion of
the Investigator:
- Chemotherapy-induced neuropathy
- Fatigue
- Residual toxicities from prior immuno-oncology treatment: Grade 1 or Grade 2
endocrinopathies provided they are clinically stable and receiving hormone
replacement therapy when applicable which may include:
1. Hypothyroidism/ hyperthyroidism
2. Type I diabetes
3. Hyperglycemia
4. Adrenal insufficient
5. Adrenalitis
6. Skin hypopigmentation (vitiligo)
12. Has known hypersensitivity to either the drug substances or the inactive ingredients
of HER3-DXd and/or T-DXd
13. Patient with a history of severe hypersensitivity reactions to other monoclonal
antibodies or PARP inhibitors
14. Has any malignancy other than locally advanced or ABC within 3 years prior to Cycle
1 Day 1, except adequately resected non-melanoma skin cancer or curatively treated
in-situ disease or other curatively treated solid tumors
15. Documented uncontrolled or significant cardiovascular disorder prior to Cycle 1 Day
1, including:
1. Corrected QT interval >450 ms according to Fridericia's formula (QTcF) based on
triplicate 12-lead ECGs, approximately 1 minute apart
2. LVEF <45% by either ECHO or MUGA or cardiac MRI if clinically indicated
according to the investigator or consulting cardiologist
3. Resting systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg
4. Myocardial infarction within 6 months
5. Symptomatic congestive heart failure (NYHA class from III to IV)
6. Uncontrolled angina pectoris within 6 months
7. Cardiac arrhythmia not controlled by ongoing antiarrhythmic treatment
8. Diagnosed or suspected long QT syndrome, or known family history of long QT
syndrome
9. History of clinically relevant ventricular arrhythmias, such as ventricular
tachycardia, ventricular fibrillation, or Torsade de Pointes
10. Patient has bradycardia of less than 50 bpm (as determined by central reading)
unless the subject has a pacemaker
11. History of second or third degree heart block. Candidates with a history of
heart block may be eligible if they currently have pacemakers, and have no
history of fainting or clinically relevant arrhythmia with pacemakers
12. Coronary/peripheral artery bypass graft within 6 months
13. Complete left bundle branch block
16. Active Hepatitis B and/or Hepatitis C infection, such as those with serologic
evidence of active viral infection within 28 days of Cycle 1, Day 1. Patients with
past or resolved Hepatitis B virus (HBV) infection are eligible if:
1. Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody
(anti-HBc) positive; OR
2. HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to
be ≤ 2000 IU/mL in the absence of anti-viral therapy and during the previous 12
weeks prior to the viral load evaluation with normal transaminases (in the
absence of liver metastasis); OR
3. HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in the
absence of anti-viral therapy and during the previous 12 weeks prior to the
viral load evaluation with liver metastasis and abnormal transaminases AST/ALT
<3 ULN For patients with HBsAg positive, if abnormal liver function is detected
during study drug treatment, viral load should be tested to rule out
reactivation.
Patients with a history of Hepatitis C infection will be eligible for enrollment
only if the viral load according to local standards of detection, is documented to
be below the level of detection in the absence of anti-viral therapy during the
previous 12 weeks (ie, sustained viral response according to the local product label
but not less than 12 weeks, whichever is longer)
17. Female patient who is pregnant or breastfeeding or intends to become pregnant during
the study
18. Has a known human immunodeficiency virus (HIV) infection that is not well
controlled. All the following criteria are required to define an HIV infection that
is well controlled: undetectable viral ribonucleic acid (RNA) load, CD4+
counts/levels of >350 cells/μL, no history of acquired immunodeficiency syndrome
(AIDS)-defining opportunistic infection within the past 12 months, and stable for at
least 3 weeks on same anti-HIV retroviral medications. If an HIV infection meets the
above criteria, the patient's viral RNA load and CD4+ cell count should be monitored
per local standard of care (eg, every 3 months). Patients with a well-controlled HIV
infection may only be enrolled into Part 2 (dose expansion) of the study.
19. Prior or ongoing clinically relevant illness, medical condition, surgical history,
physical finding, or laboratory abnormality that, in the Investigator's judgment,
could affect the safety of the patient; alter the absorption, distribution,
metabolism or excretion of the study drug; or confound the assessment of study
results
20. Adult under legal protection: guardianship, curatorship, or legal protection; or
patient deprived of his/her liberty by a judicial or administrative decision; or
patient incapable of giving his/her consent, or patient under psychiatric care
21. Participation in another clinical trial evaluating an experimental drug during the
last 4 weeks (except non-interventional research) Specific exclusion criteria for
each module
Module 0:
There are no specific exclusion criteria for module 0 (HER3-DXd monotherapy). Module
1 (olaparib)
22. History of hypersensitivity to excipients of olaparib
23. Inadequate washout period prior to Cycle 1 Day 1, defined as:
1. Strong CYP3A inhibitors < 1 week
2. CYP3A inducers for olaparib and phenobarbital < 5 weeks and for any other drug
< 3 weeks
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Gustave Roussy Institut
Address:
City:
Villejuif
Zip:
94805
Country:
France
Status:
Recruiting
Contact:
Last name:
Barbara Pistilli
Phone:
+33 (0)1 42 11 61 62
Email:
barbara.pistilli@gustaveroussy.fr
Contact backup:
Last name:
Fernanda Mosele
Phone:
+33 (0)1 42 11 61 43
Email:
Mariafernanda.MOSELE@gustaveroussy.fr
Start date:
March 21, 2024
Completion date:
June 2029
Lead sponsor:
Agency:
Gustave Roussy, Cancer Campus, Grand Paris
Agency class:
Other
Collaborator:
Agency:
Daiichi Sankyo
Agency class:
Industry
Source:
Gustave Roussy, Cancer Campus, Grand Paris
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06298084
