Trial Title:
Trastuzumab Deruxtecan (T-DXd): Tailoring Treatment and Companion Diagnostics (CDx) by Liquid Biopsy
NCT ID:
NCT05919212
Condition:
Metastatic Breast Cancer
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Diagnostic
Masking:
None (Open Label)
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
HER2-D is the use of a non-invasive liquid biopsy method to non-invasively and objectively assess HER2 status at recruitment
Description:
We study the circulating changes associated with resistance to T-DXd, including changes
in HER2 status,studied through a new approach called HER2-2D that simultaneously assesses
HER2 amplification and overexpression in blood
Arm group label:
Patients with HER2 positive Breast cancer Stage IV
Summary:
This is a prospective single-center pilot study phase II non randomized designed to
explore the role of liquid biopsy in metastatic HER2-positive breast cancer patients
treated with Trastuzumab deruxtecan (T-Dxd) as second line treatment according to
international guidelines.
All eligible patients to T-Dxd as second line treatment will receive T-Dxd intravenous at
dose of 5,4 mg/kg every three weeks until progression disease or unacceptable toxicities.
Subjects eligible to T-Dxd, who agree to participate in the study, will undergo serial
blood samples for liquid biopsy (LB) until progression disease.
The timing of blood drawing will be scheduled as follows:
At each T-DXd administration for the first four cycles of T-Dxd (every three weeks). The
next blood drawings will be done every three cycles of T-Dxd (every 9 weeks) until the
thirteenth cycle. The next blood drawings will be done every six cycles of T-Dxd (every
18 weeks) until progression disease (documented by medical imaging) For all enrolled
patients with available tumour tissue from primary diagnosis or last biopsy from
recurrence, tissue samples will be requested for exploratory analysis.
Detailed description:
Human epidermal growth factor receptor 2-positive breast cancer represents 15%-20% of
breast malignancies. In addition to this subtype characterized by HER2 overexpression or
amplification, at least another 35% of breast cancer expresses HER2 at lower but
detectable levels. These HER2-low tumors were defined as HER2 1+ and 2+ scores by
immunohistochemistry (IHC) in the absence of gene amplification by in situ hybridization
(ISH). There is evidence that HER2 overexpression/amplification may decrease during
treatment HER2 blockade (4), determining that tumors of the 15% of HER2-positive group
merge into the 35% of HER2-low group. Unfortunately, it is presently unclear how many
HER2 overexpressing/amplified tumors are bound to join the HER2-low group, at which time
during progression, and whether this may coincide to some extent with HER2 blockade
inefficacy.
Traditionally, HER2 status is assigned: (a) at one point only (diagnosis), once and
forever; (b) in tumor tissue only; (c) on a binary (yes/no) scale; and (d) with the
limited aim of assigning conventional anti-HER2 therapy only. However, it is becoming
increasingly clear that HER2 functional expression is not binary, but distributed along a
continuum and intrinsically bimodal, e.g. (over)expression and copy number variations
must be co-factored. It also appears that novel agents, such as Trastuzumab-deruxtecan
(t-Dxd), may not be 'adapted' to the existing diagnostic scenario, but they may need a
dedicated companion diagnostic (CDx). Moreover, IHC or ISH tissue diagnostic scheme is no
longer applicable to the variety of available clinical HER2 blockade regimens and is in
need of replacement. In this regard, liquid biopsy, with a comprehensive pan HER2 'unity
solution', may be useful to capture HER2 on the wane as well as resistance traits, enable
reallocation of patients to different subtypes, and assign treatment in a potentially
practice-changing setting.
Preliminary data regarding the progressive HER2 loss during HER2 blockade and the
potential of liquid biopsy in the metastatic HER-positive setting derive from the
LiqBreasTrack trial (5). This is a small, single-center study exploring the role of
liquid biopsy (at different time point from time zero until disease progression) in 22
HER2-positive breast cancer patients, treated with Trastuzumab emtansine (T-DM1) as per
standard of care in 2nd or more line of therapy. Tumor DNA and circulating tumor DNA were
tested by two commercial ThermoFisher targeted next generation sequencing (NGS) panels
spanning about 50 (essentially overlapping) genes: the Ion AmpliSeqTM Cancer Hotspot and
the OncomineTM Pan-Cancer panels. This study was designed to determine the potential
impact of liquid biopsy in: 1) circulant tumor DNA (ctDNA) anticipation of clinical
progression; 2. identification of recurrent mutational patterns on progression (e.g.
alterations associated with, and possibly causative of, pharmacological resistance to
T-DM1 and HER2 blockade altogether). The LiqBreasTrack trial showed that only five
patients were still belonging to the 'HER2 subtype' (as assessed in blood) before T-DM1
administration. HER2 counterselection went on in all five of them, and a reversal to a
HER2 neutral blood status was completed in the three who went all the way through >10
T-DM1 infusions until progression, whereas it was detectable, but incomplete, in the
remaining two patients who had to discontinue T-DM1 due to rapid progression. Moreover,
the development of a series of specific molecular alterations, either de novo appeared or
progressively accumulated in blood, was associated (only when present in blood) with
short time to progression. This suggests an oncogenic replacement of HER2 addiction by
'bypass' cancer drivers under strong and rapid adaptive selection pressure. This pilot
study, although small, suggests several hypothesis: 1) T-DM1 (but this may apply to
Trastuzumab-deruxtecan as well) rapidly pushes most or all tumors toward a presumably
irreversible HER2 neutral state that had not been achieved by previous therapies; 2) in
at least some cases, HER2-low tumors emerging from extensive HER2 blockade acquire
features (e.g. hormone addiction) reminiscent of the naïve population of HER2-low tumors;
3) replacement of dominant HER2 addition comes at the cost (for the tumor) of developing
alternative vulnerabilities, most of which had not been previously detected in tumor
tissues, e.g. blood only alterations are the optimal biomarkers for cancer progression.
In summary, the HER2 loss may be a frequent event. It also remains to be determined how
this HER2 loss intertwines with escape from HER2 blockade and the acquisition of the (so
far scanty) list of adaptive resistance traits, both 'direct' (HER2 mutations) and
'bypass' (PTEN loss-of-function, PIK3CA mutations, integrin activation, YAP1 and IGF1
activation). In summary, regardless of whether constitutive or adaptively induced, an
'HER2-low status' spans a heterogeneous group of tumors comprising naïve and heavily
pre-treated patients as well. Thus, there is an area of unmet medical need that may
account for as many as 50% of all breast cancers and may include tumors on which neither
conventional HER2 blockade nor hormone suppression strategies can determine a really
clinical impact.
Liquid biopsy may reflect the dynamic changes in breast cancer biology, discriminate
shades and grades of HER2 addiction and may be useful to identify the ideal CDx for
Trastuzumab deruxtecan, the future second line standard of care for HER2-positive
metastatic breast cancer (2). Indeed, liquid biopsy represents a non-invasive,
non-dichotomic, quantitative, longitudinal test suitable for Trastuzumab-deruxtecan
response monitoring and capturing potential mechanisms of resistance.
Based on these data, the DIAMOND study is a pilot, prospective study designed to
primarily assess the ability of blood-based liquid biopsy using NGS to monitor disease
progression to Trastuzumab-deruxtecan (as second line treatment) in patients with
histologically confirmed diagnosis of HER2-positive metastatic disease previously treated
with one treatment line for metastatic disease including pertuzumab with Trastuzumab or
Trastuzumab alone (associated to taxane). The primary objective of the trial is to
dynamically assess circulating alterations associated with resistance to
Trastuzumab-deruxtecan, including changes of the HER2 status by a novel approach named
HER2-2D that simultaneously assesses HER2 amplification and (over)expression in blood.
The primary endpoint is the concordance between the clinical evaluation (progressive
disease versus not progressive disease) based on RECIST criteria and the evaluation of
liquid biopsy, (appearance of a new mutation and/or increasing of an existing one).
Secondary objectives include: 1) molecular stratification of patients (dynamic approach
by liquid biopsy); 2) lead time (anticipation of progression) assessment by liquid
biopsy; 2) HER2-2D: use of a non-invasive liquid biopsy method to non-invasively and
objectively assess HER2 status and to select patients displaying a HER2-low status.
Trastuzumab Deruxtecan will be administered at the dose of 5.4 mg per kilogram by
intravenous infusion every 3 weeks (standard recommended dose). Treatment will be
maintained until disease progression, severe toxicity or patient refusal. Liquid biopsy
will be performed at baseline and repeated at different time points and/or at progression
disease.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Must be competent and able to comprehend, sign, and date informed consent prior to
any study specific procedures;
- Male or female subjects age ≥ 18 years;
- Subjects with histologically or cytologically proven diagnosis of adenocarcinoma of
the breast with evidence of either locally advanced disease not amenable to
resection or radiation therapy with curative intent or metastatic disease not
amenable to curative therapy;
- Subjects must have confirmed, per local testing on most recent tumor tissue sample
available, an HER2-positive expression, as determined according to American Society
of Clinical Oncology - College of American Pathologists guidelines (as defined in
the 2013 American Society of Clinical Oncology (ASCO) recommendations for HER2
testing [7]) with any ER and/or PgR tumor status;
- Subjects must have received no more than one line of treatment including trastuzumab
plus or not pertuzumab associated to taxane in the advanced/metastatic setting or
progressed within 6 months after neoadjuvant or adjuvant treatment involving a
regimen including trastuzumab and taxane;
- Documented radiologic progression (during or after most recent treatment or within 6
months after completing adjuvant therapy);
- Presence of at least 1 measurable lesion per Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.1 (see Appendix A)
- Non measurable (evaluable) bone-only disease are eligible. Evaluable bone-only
disease must include at least one lytic bone lesion or a mixed lytic-blastic bone
lesion; blastic only metastases are not allowed. Subjects who have had prior
radiation to bone must have at least one evaluable lesion in a non-irradiated area.
Patients with lesions identified only on radionucleotide bone scan are not eligible;
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1;
- Life expectancy > 12 weeks;
- 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 weeks must have elapsed between the end of brain radiotherapy and study
enrolment.
- LVEF ≥ 50% within 28 days before enrolment.
- Adequate organ and bone marrow function within 14 days before enrollment
- Adequate treatment washout period before enrolment
- Evidence of post-menopausal status or negative serum pregnancy test for females of
childbearing potential who are sexually active with a non-sterilized male partner.
For women of childbearing potential, a negative result for serum pregnancy test
(test must have a sensitivity of at least 25 mIU/mL) must be available at the
screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test
prior to each administration of IMP. Women of childbearing potential are defined as
those who are not surgically sterile (i.e. underwent bilateral salpingectomy,
bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be
considered postmenopausal if they have been amenorrheic for 12 months without an
alternative medical cause.
- Agree for periodically blood sample collection for liquid biopsy
Exclusion Criteria:
- Prior treatment with an anti-HER2 Antibody Drug Conjugated (ADC)
- Uncontrolled or significant cardiovascular disease, including any of the following:
a. History of myocardial infarction (MI) within 6 months before enrolment; b.
History of symptomatic congestive heart failure (New York Heart Association Class II
to IV); c. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms
(male) based on average of Screening triplicate 12-lead ECG; d. Left ventricular
ejection fraction (LVEF) < 50% within 28 d prior to enrollment
- 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 criteria: a. Lung-specific intercurrent clinically significant illnesses
including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary
emboli within three months of the study enrolment, severe asthma, severe COPD,
restrictive lung disease, pleural effusion etc.); b. Any autoimmune, connective
tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis
etc.) where there is documented, or a suspicion of pulmonary involvement at the time
of screening. Full details of the disorder should be recorded in the eCRF for
patients who are included in the study; c. Prior pneumonectomy (complete)
- Spinal cord compression or clinically active central nervous system (CNS)
metastases, defined as untreated and symptomatic, or requiring therapy with
corticosteroids or anticonvulsants to control associated symptoms.
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection,
or active hepatitis B or C infection. Patients positive for hepatitis C (HCV)
antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
Subjects should be tested for HIV prior to enrolment if required by local
regulations or institutional review board (IRB)/ethics committee (EC).
- Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral
vaccines are not considered attenuated live vaccines) within 30 days prior to the
first dose of T-Dxd. Note: Patients, if enrolled, should not receive live vaccine
during the study and up to 30 days after the last dose of study treatment.
- Multiple primary malignancies within 3 years, except adequately resected non
melanoma skin cancer, curatively treated in situ disease, other solid tumors
curatively treated, or contralateral breast cancer.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Fondazione Policlinico A. Gemelli - IRCCS
Address:
City:
Rome
Zip:
00168
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Alessandra Fabi
Phone:
+390630157337
Email:
alessandra.fabi@policlinicogemelli.it
Contact backup:
Last name:
Alessandra Fabi
Phone:
+390630156124
Email:
alessandra.fabi@policlinicogemelli.it
Start date:
February 1, 2023
Completion date:
February 1, 2026
Lead sponsor:
Agency:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Agency class:
Other
Source:
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05919212
