Trial Title:
Phase 1b Study of EZH1/2 Inhibitor Valemetostat in Combination With Trastuzumab Deruxtecan in Subjects With HER2 Low/Ultra-low/Null Metastatic Breast Cancer
NCT ID:
NCT05633979
Condition:
Breast Cancer
Conditions: Official terms:
Breast Neoplasms
Trastuzumab
Trastuzumab deruxtecan
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Trastuzumab deruxtecan
Description:
Given by IV (vein)
Arm group label:
Group 1
Intervention type:
Drug
Intervention name:
Valemetostat
Description:
Given by PO
Arm group label:
Group 1
Arm group label:
Group 2
Summary:
To find a recommended dose of valemetostat that can be given in combination with
trastuzumab deruxtecan to patients with low/ultra-low HER2-expressing metastatic breast
cancer.
Detailed description:
Primary Objectives:
Dose escalation part:
1. To evaluate the safety and determine the maximum tolerated dose (MTD)/recommended
dose for expansion (RDE) of valemetostat in combination with trastuzumab deruxtecan
(T-DXd).
Dose expansion part:
2. To evaluate the objective response rate (ORR) of valemetostat at the RDE in
combination with T-DXd.
Secondary Objectives:
Dose escalation:
1. To determine ORR; defined as a percentage of subjects who achieve complete response
(CR) or partial response (PR) by RECIST 1.1 criteria.
2. To determine survival outcomes, including duration of response (DoR), progression
free survival (PFS), and overall survival (OS).
3. To determine the Clinical Benefit Rate (CBR) defined as stable disease (SD) ≥ 16
weeks + PR + CR.
Dose expansion:
1. To determine survival outcomes, including DoR, PFS, and OS.
- DOR of the proposed treatment: the time from observing response to the
valemetostat treatment until objective tumor progression (PD)
- PFS: the time from starting valemetostat treatment until objective tumor
progression (PD) or death due to any cause.
- Overall survival (OS): the time from starting valemetostat treatment until
death due to any cause.
2. To determine the CBR defined as SD ≥16 weeks + PR + CR.
3. To evaluate safety of valemetostat in combination with T-DXd.
4. To evaluate the pharmacokinetics (PK) of both the drugs in combination.
5. To evaluate the immunogenicity of T-DXd
Exploratory Objectives:
1. To investigate pharmacodynamic biomarkers.
2. To investigate biomarkers that may aid in identifying subjects who may derive
clinical benefit.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. ≥18 years of age or the minimum legal adult age (whichever is greater) at the time
the informed consent form (ICF) is signed.
2. Pathologically confirmed HER2 low/ultra-low/null breast cancer. HER2 low is defined
as IHC 2+/ISH- or IHC 1+/(ISH- or undefined), HER2 ultra-low is defined as IHC 0
with detectable faint/barely perceptible incomplete staining in ≤10% tumor cells and
HER2 null is defined as IHC 0 without any observed tumor cell staining, regardless
of hormone receptor expression status, and as determined by the Ventana 4B5 IHC
assay The accrual numbers of HER2 ultra-low/null and HER2 low should be
approximately 1:1 in the dose-escalation and dose-expansion cohort (i.e., 6 subjects
for HER2 ultra-low/null and 6 subjects for HER2 low in dose-escalation cohort, 10
subjects for HER2 ultra-low/null and 10 subjects for HER2 low in dose-expansion
cohort). Initial subject inclusion may be based on previously obtained HER2 testing
results, however final HER2 status determination (HER2 low, ultra-low, or null) will
be based on centralized pathologist (re)evaluation of HER2 IHC staining using the
Ventana 4B5 assay at MDA Department of Pathology laboratory.
If HER2 eligibility assessment and subject inclusion are based on results from a
previous HER2 IHC test performed with an IHC assay different from the Ventana 4B5
assay, or if the IHC slides from the initial test are not available for
re-evaluation, adequate material for HER2 testing using the Ventana 4B5 assay must
be provided to MDA Department of Pathology laboratory.
3. MBC or locally progressive breast cancer that is not a surgical candidate.
4. Has progressed on and would no longer benefit from endocrine therapy in hormone
receptor-positive subjects.
5. Has been treated with at least 1 prior line of chemotherapy in the metastatic or
locally progressive setting.
6. Has adequate treatment washout period by the time of enrollment, defined as:
Treatment Washout Period Major surgery ≥ 4 weeks Radiation therapy including
palliative stereotactic radiation to chest ≥ 4 weeks Palliative stereotactic
radiation therapy to other anatomic areas ≥ 2 weeks Anti-cancer chemotherapy
(Immunotherapy [non-antibody based therapy]), retinoid therapy, hormonal therapy
- 3 weeks Targeted agents and small molecules ≥ 2 weeks or 5 half-lives,
whichever is longer Nitrosoureas or mitomycin C ≥ 6 weeks Antibody-based
anti-cancer therapy ≥ 4 weeks Chloroquine/Hydroxychloroquine >14 days
7. Has at least one measurable lesion per RECIST (except for up to the first 5 subjects
who enroll in dose escalation part where the measurable lesions meeting RECIST
definition are not mandatory).
8. Is willing to provide fresh tumor tissue via tumor biopsy only if the participant
has a disease that can be safely accessed through a CT-guided/US-guided or
percutaneous biopsy for multiple core biopsies judged by the investigator. If the
participant doesn't have a disease that can be safely accessed, they are still
eligible.
9. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1.
10. Negative serum pregnancy test within 72 hours of receiving the first dose of the
study medication for women of childbearing potential as per institutional
guidelines. Post-menopausal women (defined as having no menses for at least 1 year)
and surgically sterilized women are not required to undergo pregnancy tests.
11. Subjects of childbearing potential must be willing to use effective birth control
methods or be surgically sterile or abstain from heterosexual activity for the
course of the study through at least 4 months after the last dose of the study drug
(for males) and 7 months after last dose of study drug (for females). Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for at least 1 year.
12. Female subjects 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 3 months after
the final study drug administration.
13. Male subjects must not freeze or donate sperm starting at Screening and throughout
the study period, and for at least 3 months after the final study drug
administration.
14. The patient must have adequate organ function as determined by the following
laboratory values:
1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × the
upper limit of normal (ULN). For those with liver metastasis, ALT and AST ≤5.0
× ULN.
2. Total bilirubin ≤1.5 × ULN, except for subjects with Gilbert's syndrome (e.g.,
a gene mutation in UGT1A1), who can have total bilirubin <3.0 mg/dL.
3. Absolute neutrophil count (ANC) ≥1500/mm3 (granulocyte colony-stimulating
factor administration is not allowed within 1 week prior to Screening
assessment).
4. Hemoglobin ≥9.0 g/dL (red blood cell transfusion is not allowed within 1 week
prior to Screening assessment).
5. Platelet count ≥100,000/mm3 (Platelet transfusion is not allowed within 1 week
prior to Screening assessment).
6. Creatinine clearance ≥30 mL/min (measured by the Cockcroft-Gault equation*).
- Female: ([140-age] × weight in kg)/(serum creatinine × 72) × 0.85 Male:
([140-age] × weight in kg)/(serum creatinine × 72)
7. Serum Albumin ≥ 2.5 g/dL
15. Acute non-hematologic toxic effects (as evaluated by National Cancer Institute [NCI]
Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0) of any prior
therapy (except alopecia) resolved as shown below:
1. Peripheral neuropathy: Grade ≤2
2. Fatigue: Grade ≤2
3. All others: Grade ≤1
Exclusion Criteria:
1. Has previously been treated with any anti-HER2 therapy, including T-DXd, or EZH
inhibitors.
2. Has spinal cord compression or clinically active central nervous system metastases,
defined as untreated and 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 weeks must
have elapsed between the end of whole brain radiotherapy and study registration.
3. Prior malignancy active within the previous 2 years except for locally curable
cancer that is currently considered as cured, such as cutaneous basal or squamous
cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an
incidental histological finding of prostate cancer
4. Uncontrolled or significant cardiovascular disease, including the following:
1. LVEF < 50% within 28 days
2. Evidence of prolongation of QT/QTc (e.g., repeated episodes of QT corrected for
heart rate using Fridericia's method [QTcF] >450 ms) (average of triplicate
determinations; over a 5 min time window when the subject has been supine
position for at least 10 min without any environmental stimuli).
3. Diagnosed or suspected long QT syndrome, or known family history of long QT
syndrome
4. History of clinically relevant ventricular arrhythmias, such as ventricular
tachycardia, ventricular fibrillation, or Torsade de Pointes
5. Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial
fibrillation may be enrolled), or asymptomatic persistent ventricular
tachycardia
6. Subject has clinically relevant bradycardia of 50 bpm unless the subject has a
pacemaker
7. 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, within 6
months prior to Screening
8. Myocardial infarction within 6 months prior to Screening
9. Angioplasty or stent graft implantation within 6 months prior to Screening
10. Uncontrolled angina pectoris within 6 months prior to Screening
11. New York Heart Association (NYHA) Class 2-4 congestive heart failure
12. Coronary/peripheral artery bypass graft within 6 months prior to Screening
13. Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or
diastolic blood pressure >110 mmHg)
14. Complete left or right bundle branch block
5. Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note:
Short-course systemic corticosteroids (e.g., prevention/treatment for transfusion
reaction) or use for a non-cancer indication (e.g., adrenal replacement) is
permissible.
6. Female who is pregnant or breastfeeding or intends to become pregnant during the
study
7. Has known human immunodeficiency virus (HIV) infection or active hepatitis B or C
infection (screen test is not required). Subjects positive for hepatitis C (HCV)
antibody are eligible only if the polymerase chain reaction is negative for HCV RNA.
8. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection
requiring treatment with intravenous antibiotics, antivirals, or antifungals. Note:
Subjects with localized fungal infections of skin or nails are eligible.
9. Any active uncontrolled systemic diseases or other medical conditions considered to
be poorly controlled by the investigator, including, but not limited to, bleeding
diatheses
10. 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.
11. 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 registration, severe asthma, severe COPD, restrictive lung
disease, pleural effusion etc.).
12. 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 subjects who are included in the study.
13. Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table 17)
14. Prior complete pneumonectomy
15. Medical history or complication considered inappropriate for participation in the
study, or a serious physical or psychiatric disease, the risk of which may be
increased by participation in the study in the investigator's opinion
16. A history of substance abuse or medical conditions such as clinically significant
cardiac or pulmonary diseases or psychological conditions that may, in the opinion
of the Investigator, interfere with the subject's participation in the clinical
study or evaluation of the clinical study results.
17. Known or suspected hypersensitivity to valemetostat and T-DXd or any of the
excipients.
18. Subjects with symptomatic brain metastases, or subjects with treated brain
metastases that are no longer symptomatic but who require treatment with steroids.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Senthil, MD, PHD
Phone:
713-792-2817
Email:
sdamodaran@mdanderson.org
Investigator:
Last name:
Senthil Damodaran, MD, PHD
Email:
Principal Investigator
Start date:
February 9, 2023
Completion date:
December 31, 2032
Lead sponsor:
Agency:
M.D. Anderson Cancer Center
Agency class:
Other
Collaborator:
Agency:
Daiichi Sankyo
Agency class:
Industry
Source:
M.D. Anderson Cancer Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05633979
http://WWW.mdanderson.org
