TRUDI: A phase II study of neoadjuvant Trastuzumab deruxtecan and Durvalumab for stage III, HER2-expressing Inflammatory Breast Cancer

ENROLLING
Protocol # :
22-544
Conditions
Invasive Breast Cancer
Inflammatory Breast Cancer Stage III
HER2-positive Breast Cancer
HER2 Low Breast Adenocarcinoma
Breast Cancer
Phase
II
Disease Sites
Breast
Principal Investigator
Lynce, Filipa
Site Research Nurses
Bowers, Jordan
Campbell, Margaret
Cung, Connie
Dishman, Rachel, C.
Ficociello, Samantha
Jeon, Maryangel, H.
Kasparian, Elizabeth
Loeser, Wendy
Orechia, Meghan
Patel, Nikita
Roche, Kathleen, A.

Trial Description

The purpose of this study is to test the safety and effectiveness of an investigational drug
combination (trastuzumab deruxtecan and durvalumab) to learn whether the intervention works
in treating Human Epidermal growth factor Receptor-2 (HER2)-expressing inflammatory breast
cancer.

The names of the study drugs involved in this study are:

- Trastuzumab deruxtecan

- Durvalumab

Eligibility Requirements

Inclusion Criteria:

- Participants must have a histological or cytological diagnosis of invasive breast
cancer.

- All histologic subtypes are eligible.

- Participants must have a clinical diagnosis of stage III inflammatory breast cancer
within the past 6 months

- HER2-positive status as determined locally by the current ASCO/CAP guidelines or
HER2-low tumor expression (IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested) (note:
ISH may be determined by either fluorescence in situ hybridization [FISH] or dual in
situ hybridization [DISH])

- Any ER and PR expressions are permitted but must be known

- Participants must be treatment-naïve

- Participants must agree to undergo two research biopsies of the tumor (if safely
accessible, as determined by the treating investigator): at baseline (prior to the
first treatment) and after the first week of treatment on C1D8. Previously collected
archival tissue will also be obtained on all participants. For participants for whom
the tumor is not safely accessible, this archival tissue needs to be located and
availability confirmed at time of registration.

- Pre- and postmenopausal women or male patients ≥ 18 years of age

- ECOG performance status 0-1 (Karnofsky > 60%, see Appendix A).

- LVEF ≥ 50% within 28 days prior to enrollment

- Participants must have normal organ and marrow function prior to enrollment as defined
below:

- Absolute neutrophil count ≥2,000/mcL

- Platelets ≥100,000/mcL

- Hemoglobin ≥ 9.0 g/dl

- INR/PT/aPTT ≤1.5 × ULN unless participant is receiving anticoagulant therapy as
long as PT or aPTT is in therapeutic range of anticoagulant

- Total bilirubin ≤1.5 × institutional upper limit of normal (ULN)(or ≤2.0 x ULN in
patients with documented Gilbert's Syndrome)

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN

- Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 30 mL/min/
1.73m2 for participants with creatinine levels above institutional ULN.

- Serum albumin ≥2.5 g/dL

- International normalized ratio (INR)/prothrombin time (PT) and either partial
thromboplastin or activated partial thromboplastin time (aPTT) ≤1.5 × ULN

- Women of childbearing potential (WOCBP) and WOCBP who are partners of male
participants must agree to use one highly effective non-hormonal form of contraception
or two effective forms of non-hormonal contraception for the duration of study
treatment with durvalumab and 7 months after the last dose of study treatment

- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment with durvalumab and 4
months after the last dose of study treatment

- Must have a life expectancy of at least 12 weeks

- Body weight >30 kg

- The participant must be capable of understanding and complying with the protocol and
willing to sign a written informed consent document

Exclusion Criteria:

- Has received prior systemic anti-cancer therapy for the current diagnosis of
inflammatory breast cancer, including chemotherapy, immunotherapy, or targeted therapy

- Has received any radiotherapy or surgery for the current diagnosis of inflammatory
breast cancer. Tumor biopsies are not considered surgery for the purpose of
enrollment.

- Prior hypersensitivity to durvalumab or the excipients of durvalumab or trastuzumab
deruxtecan or history of severe hypersensitivity reactions to other monoclonal
antibodies.

- Major surgery within 4 weeks prior to study treatment initiation. Patients must have
recovered from any effects of any major surgery.

- Uncontrolled intercurrent illness, including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, serious chronic gastrointestinal
conditions associated with diarrhea, or psychiatric illness/social situations that
would limit compliance with study requirements, substantially increase risk of
incurring AEs, or compromise the ability of the patient to give written informed
consent.

- Participant has a medical condition that requires chronic systemic steroid therapy (>
10 mg of prednisone daily or equivalent) or any other form of immunosuppressive
medication (including disease modifying agents) and has required such therapy in the
last 2 years. Replacement therapy (e.g. thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
not considered a form of systemic therapy.

- 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 syndrome,
Wegener syndrome [granulomatosis with polyangiitis], Graves' disease, and rheumatoid
arthritis, hypophysitis, uveitis, etc). The following are exceptions to this
criterion:

-- Patients with vitiligo or alopecia, Patients with hypothyroidism (eg, following
Hashimoto syndrome) stable on hormone replacement, Patients with any chronic skin
condition that does not require systemic therapy, Patients with celiac disease
controlled by diet alone, who may also be included, but only after consultation with
the Principal Investigator, Patients without active disease in the last 5 years, who
may also be included but only after consultation with the Principal Investigator

- History of (non-infectious) ILD/pneumonitis that required steroids, has current
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at
screening.

- Lung-specific intercurrent clinically significant 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,
Sjogren's syndrome, sarcoidosis etc.), and prior pneumonectomy

- Corrected QT interval (QTcF) prolongation to > 470 msec on screening EKG

- 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

- Any of the following procedures or conditions in the 6 months prior to enrollment:
coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction,
angina pectoris, congestive heart failure (New York Heart Association Functional
Classification Grade ≥2), and stroke. Subjects with troponin levels above ULN at
screening (as defined by the manufacturer), and without any myocardial infarction
related symptoms, should have a cardiology consultation before enrollment to rule out
myocardial infarction.

- Cardiac ejection fraction outside institutional range of normal or <50% (whichever is
higher) as measured by echocardiogram (or multiple-gated acquisition [MUGA] scan if an
echocardiogram cannot be performed or is inconclusive).

- History of another primary malignancy, except for Malignancy treated with curative
intent and with no known active disease ≥5 years before the first dose of study
treatment and of low potential risk for recurrence. Adequately treated non-melanoma
skin cancer or lentigo maligna without evidence of disease, Adequately treated
carcinoma in situ without evidence of disease

- History of venous thromboembolism in the past 3 months.

- History of active primary immunodeficiency.

- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and tuberculosis testing in
line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface
antigen [HBsAg] result) or hepatitis C virus (HCV). Patients with a past or resolved
HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and
absence of HBsAg) are eligible. Patients positive for hepatitis C antibody are
eligible only if the polymerase chain reaction is negative for HCV RNA. Some
medications used for these conditions have drug-drug interactions with the study
treatment.

- Known to have previously tested positive for human immunodeficiency virus (HIV)
(positive HIV 1/2 antibodies)(HIV testing is not required for participation on this
study)

- Receipt of a live vaccine within 30 days prior to study treatment initiation. Examples
of live vaccines include, but are not limited to, the following: measles, mumps,
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The use of
the inactivated seasonal influenza vaccine is allowed.

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

- Use of 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)

- Use of hydroxychloroquine in <14 days prior to Day 1 of trastuzumab deruxtecan
treatment

- History of leptomeningeal carcinomatosis

- Female patients who are pregnant, breastfeeding or of reproductive potential who are
not willing to employ effective birth control from screening to 6 months after the
last dose of durvalumab and at least 7 months after the final administration of
trastuzumab deruxtecan due to the potential for teratogenic effects. And unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother

22-544