| Eligibility |
Inclusion Criteria:
1 Participant must be >18 years of age inclusive, at the time of signing the informed
consent.
2 Patients who are willing and 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.
3 Participants with pathologically documented breast cancer that:
- is unresectable or metastatic
- HER2-positive expression (IHC 3+ or IHC 2+ with ISH positive) as confirmed by
laboratory assessment within last 1 year of study enrolment.
- was previously treated with an anti HER-2 based regimen 4 Adequate bone marrow
function, within 14 d before enrolment, defined as:
a. Absolute neutrophil count = 1.5 × 109/L (granulocyte colony-stimulating factor
administration is not allowed within 1 wk prior to Screening assessment); b. Platelet
count = 100 × 109/L (Platelet transfusion is not allowed within 1 wk prior to
Screening assessment); c. Hemoglobin level = 9.0 g/dL (Red blood cell transfusion is
not allowed within 1 wk prior to Screening assessment).
5 Adequate renal function within 14 d before enrolment, defined as:
- Creatinine clearance = 30 mL/min, as calculated using the Cockcroft-Gault equation
(CLcr (mL/min) = [140 - age (years)] × weight (kg) {× 0.85 for females}; 72 × serum
creatinine (mg/dL) 6 Adequate hepatic function within 14 d before enrolment, defined
as:
- Total bilirubin = 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, and
- Aspartate transaminase (AST)/alanine transaminase (ALT) = 3 × ULN
7 Adequate blood clotting function within 14 d before enrolment, defined as:
- International normalized ratio/prothrombin time = 1.5 × ULN and either partial
thromboplastin or activated partial thromboplastin time = 1.5 × ULN 8 Female subjects
of reproductive/childbearing potential must agree to use a highly effective form of
contraception or avoid intercourse during and upon completion of the study and for at
least 7 mo after the last dose of trastuzumab deruxtecan. Male subjects must agree to
inform all potential female partners that they are participating in a clinical trial
of a drug that may cause birth defects. Male subjects must also agree to either avoid
intercourse or that they and/or any female partners of reproductive/childbearing
potential will use a highly effective form of contraception during and upon completion
of the study and for at least 4.5 mo after the last dose of trastuzumab deruxtecan.
Methods considered as highly effective methods of contraception include:
- Combined (estrogen and progestogen containing) hormonal contraception associated with
inhibition of ovulation:
o Oral
o Intravaginal
o Transdermal
- Progestogen-only hormonal contraception associated with inhibition of ovulation:
o Oral
o Injectable
o Implantable
- Intrauterine device
- Intrauterine hormone-releasing system
- Bilateral tubal occlusion
- Vasectomized partner
- Complete sexual abstinence defined as refraining from heterosexual intercourse during
and upon completion of the study and for at least 7 mo for female subjects (4.5 mo for
male subjects) after the last dose of trastuzumab deruxtecan. True abstinence must be
in line with the preferred and usual lifestyle of the subject. Periodic abstinence
(calendar, symptothermal, postovulation methods) is not an acceptable method of
contraception.
Non-childbearing potential is defined as pre-menopausal females with a documented tubal
ligation or hysterectomy; or postmenopausal defined as 12 mo of spontaneous amenorrhea (in
questionable cases, a blood sample with simultaneous follicle-stimulating hormone > 40
mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory). Females on hormone
replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1
of the contraception methods outlined for women of childbearing potential if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at
least 2 to 4 wk will elapse between the cessation of therapy and the blood draw; this
interval depends on the type and dosage of HRT. Following confirmation of their
postmenopausal status, they can resume use of HRT during the study without use of a
contraceptive method.
9 Male subjects must not freeze or donate sperm throughout the study period beginning at
Cycle 1 Day 1 and for at least 4.5 mo after the last dose of trastuzumab deruxtecan or
Preservation of sperm should be considered prior to enrollment in this study.
10 Female subjects must not donate ova or retrieve them for their own use from the time of
Screening and throughout the study treatment period, and for at least 7 mo after the last
dose of trastuzumab deruxtecan
Exclusion Criteria:
1. Prior treatment with T-DXd
2. Uncontrolled or significant cardiovascular disease, including any of the following:
1. History of myocardial infarction within 6 months before enrolment
2. History of symptomatic congestive heart failure (New York Heart Association Class
II to IV);
3. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (male);
4. LVEF < 50% within 28 d prior to treatment initiation.
3. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at
Screening.
4. Spinal cord compression or clinically active central nervous system (CNS) metastases,
defined as untreated or symptomatic, or requiring therapy with corticosteroids or
anticonvulsants to control associated symptoms.
- Subjects with clinically inactive brain metastases may be included in the study.
- Subjects with treated brain metastases that are no longer symptomatic and who
require no treatment with corticosteroids or anticonvulsants may be included in
the study if they have recovered from the acute toxic effect of radiotherapy. A
minimum of 2 wk must have elapsed between the end of whole brain radiotherapy and
study enrollment.
5. Has a history of severe hypersensitivity reactions to either the drug substances or
inactive ingredients in the drug product or to other mAbs.
6. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
7. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C
infection.
8. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other
than alopecia) not yet resolved to Grade = 1 or baseline. Subjects with chronic Grade
2 toxicities may be eligible per the discretion of the investigator after consultation
with the Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced
neuropathy).
9. Therapeutic radiation therapy or major surgery within 4 wk before enrolment or
palliative stereotactic radiation therapy within 2 wk before enrolment.
10. Systemic treatment with anticancer therapy (immunotherapy [non-antibody-based
therapy], retinoid therapy, or hormonal therapy) within 3 wk before enrolment;
antibody-based-anticancer-therapy within 4 wk before enrolment; or treatment with
nitrosoureas or mitomycin C within 6 wk before randomization; or treatment with
small-molecule targeted agents within 2 wk or 5 half-lives before enrolment, whichever
is longer.
11. Participation in a therapeutic clinical study within 3 wk before enrolment (for
small-molecule targeted agents, this non-participation period is 2 wk or 5 half-lives,
whichever is longer), or current participation in other investigational procedures.
12. Pregnant, breastfeeding, or planning to become pregnant.
13. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses
including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli
within 3 months of the study enrollment, severe asthma, severe chronic obstructive
pulmonary disease [COPD], restrictive lung disease, pleural effusion etc), and any
autoimmune, connective tissue or inflammatory disorders with pulmonary involvement
(ie, rheumatoid arthritis, Sjögren's, sarcoidosis etc), or prior pneumonectomy
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