Overview

Trotabresib in Combination With Vinorelbine and Radiation Therapy for the Treatment of HER2+ Breast Cancer With Central Nervous System or Leptomeningeal Metastasis

Status:
Withdrawn
Trial end date:
2024-03-27
Target enrollment:
0
Participant gender:
All
Summary
This phase I/Ib trial tests the safety, side effects, and best dose of vinorelbine when given in combination with trotabresib in treating patients with HER2 positive breast cancer that has spread to the central nervous system or leptomeninges (metastasis). Cancer cells that make too much HER2 may grow more quickly and are more likely to spread to other parts of the body as metastases, including the central nervous system. Trotabresib is part of a family of drugs called BET inhibitors. Trotabresib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vinorelbine is in a class of medications called vinca alkaloids. It works by slowing or stopping the growth of cancer cells in your body. Giving trotabresib and vinorelbine may increase in the anti-cancer activity of vinorelbine when used in combination with radiation (radiotherapy).
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Northwestern University
Collaborator:
National Cancer Institute (NCI)
Treatments:
Vinorelbine
Criteria
Inclusion Criteria:

- Patients must have histologically or cytologically confirmed diagnosis of HER2+ breast
cancer. Patients may be immunohistochemistry (IHC) 3+ and/or fluorescence in situ
hybridization (FISH) positive for HER2. IHC 2+ HER2 patients are eligible with reflex
FISH-positive testing with the ratio ≥ 2.0. Alternatively, circulating tumor DNA
testing positive for HER2 mutation is accepted for eligibility

- Patients must have newly diagnosed or progressive brain and/or leptomeningeal
metastases, and a change in management and of treatment regimen is indicated. There is
no limit on the number and types of prior systemic or intrathecal therapies

- Subjects must have an estimated life expectancy ≥ 3 months

- At registration, patients must have an interval of at least 2 weeks after the end of
prior cytotoxic chemotherapy or immunotherapy or previous RT, one week from prior
targeted small molecule drug treatment, interval of ≥ 4 weeks from prior bevacizumab
or nitrosourea. At treatment start of trotabresib, there must be an interval of ≥ 4
weeks since last cytotoxic chemotherapy (6 weeks for prior nitrosourea) or
immunotherapy

- Note: Anti-HER2 directed treatment is allowed to continue, however, should be
switched to trastuzumab before initiation of trotabresib. No washout period is
required

- Patients must be age ≥ 18 years on the day of signing consent

- Patients must exhibit Cooperative Oncology Group (ECOG) performance status of ≤ 2

- Leukocytes (WBC) ≥ 3,000/mcL or absolute neutrophil count (ANC) ≥ 1,500/mcL (within 14
days prior to registration)

- Hemoglobin (Hgb) ≥ 10 g/dL (within 14 days prior to registration)

- Platelets (PLT) ≥ 75,000/mcL (within 14 days prior to registration)

- Total bilirubin < 1.5 x upper limit of normal (ULN) (except patient with documented
Gilbert's syndrome, ≤ 5 x ULN) (within 14 days prior to registration)

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 3 x institutional ULN (within 14 days prior to registration)

- Creatinine < 1.5x upper limit of normal (ULN) (within 14 days prior to registration)

- Patients must be able to swallow oral medication

- Patients must have recovered from the toxic effects of prior therapies (≤ Grade 1);
however, persistent alopecia, or other toxicities not constituting a safety risk or
being attributed to the tumor (e.g. neurological symptoms) based on investigator's
judgement are not an exclusion criterion)

- Patients who are currently participating in or have participated in a study of an
investigational agent or device must have discontinued the use of the investigational
drug or device ≥ 4 weeks from registration on this study

- Note: COVID-19 vaccination is allowed prior to and during study treatment

- Patients with a ventriculoperitoneal or ventriculoatrial shunt must have an on/off
device in their shunt systems to be eligible for the study. Patients must be able to
tolerate shunt closure for approximately 4 hours without development of clinical signs
of increased intracranial pressure

- Patients must be able and willing to undergo research blood draws

- Patients must consent to retrieval of archival tissue or pretreatment tumor biopsy for
research purposes if extra tissue is available

- The effects of trotabresib on the developing human fetus are unknown. Vinorelbineis
known to be teratogenic causing birth defects and fetal loss in animals at
concentrations which are below the human therapeutic dose range. For this reason,
patients of child-bearing potential, patients with sperm-producing reproductive
capacity and partners with child-bearing potential of patients with sperm-producing
reproductive capacity much use contraception as specified below. Additionally,
pregnant patients and patients that are nursing can not participate in this study
because vinorelbine has the potential for teratogenic or abortifacient effects as
described above. Because there is an unknown but potential risk for adverse events in
nursing infants secondary to treatment of the mother with vinorelbine, breastfeeding
should be discontinued if the mother is treated with vinorelbine

- A patient of childbearing potential (POCBP) is a person who: 1) has achieved
menarche at some point, 2) has not undergone a hysterectomy or bilateral
oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following
cancer therapy or other medical condition does not rule out childbearing
potential) for at least 12 consecutive months and verified by an FSH blood test
at screening. FSH test should be >30 mIU/mL but FSH will be low if the subject is
taking hormone replacement therapy or oral contraceptives. The requirement for
FSH testing may be waived for subjects greater than 62 years of age

- Patients of childbearing potential (POCBP) must:

- Either commit to true abstinence from heterosexual intercourse (which must be
reviewed monthly and source documented) or to use one highly effective
contraceptive method. True abstinence is acceptable when this is in line with the
preferred and usual lifestyle of the subject. (Periodic abstinence [e.g.,
calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are
not acceptable methods of contraception). Highly effective contraceptive methods
are combined (containing estrogen and progestogen) or progestogen-only hormonal
contraception associated with inhibition of ovulation (oral, injectable,
intravaginal, patch, or implantable); bilateral tubal ligation; intra-uterine
device; intrauterine hormone-releasing system; or vasectomized partner
sterilization (note that vasectomized partner is a highly effective birth control
method provided that partner is the sole sexual partner of the POCBP trial
participant and that the vasectomized partner has received medical assessment of
the surgical success). These measures should be used from 28 days before the
first dose of study medication, throughout the study, and for 7 months following
the last dose of trotabresib and 6 months after the last dose of vinorelbine,
whichever is longer

- Oocyte donations and nursing are prohibited during the same time period when
highly effective contraception is required. Should a patient of child bearing
potential experience a change in contraception method or become pregnant or
suspect they are pregnant during the time period when highly effective
contraception is required, they should notify the investigator immediately

- Patients of child-bearing potential must have two negative serum or urine
pregnancy tests (beta-subunit of human chorionic gonadotropin or beta-human
chorionic gonadotropin [hCG]) as verified by the investigator prior to starting
the study drugs. The second test should be performed on Day -1 or Day 1 prior to
dosing. The pregnancy test (serum or urine) should have a sensitivity of at least
25 mIU/ml. Patients of child-bearing potential must agree to ongoing pregnancy
testing monthly during dosing and for the same time period when highly effective
contraception is required

- Patients with sperm-producing capacity must agree to contraception use as indicated
below:

- Patient with sperm-producing capacity condom use

- Patients with sperm-producing capacity must practice true abstinence (which must
be reviewed on a monthly basis) or agree to use a condom (a latex or non-latex
synthetic condom is required) during any sexual activity (eg, vaginal, anal,
oral) with a pregnant or nursing person or a person of child-bearing potential
and will avoid conceiving from signing the informed consent form, while
participating in the study, during dose interruptions, and for at least 4 months
after the last dose of trotabresib or 6 months after the last dose of VNB,
whichever is longer, even if they have undergone a successful vasectomy. Patients
with sperm-producing capacity should inform the investigator immediately if they
believes that their partner has become pregnant

- Patients with sperm-producing capacity should not donate sperm for the same
period of time that is required for condom use. Partners who are of child-bearing
potential must use one highly effective form of contraception during the same
time period that the patients with sperm-producing capacity must use a condom

- Patients must have the ability to understand and the willingness to sign a written
informed consent document. Consent must be signed prior to registration on this study

- Cohort S only: Patient must be a candidate for a planned surgical resection of at
least one central nervous system (CNS) metastasis, with an indication for surgical
resection (e.g. mass effect, therapeutic intent in oligometastatic disease, diagnostic
confirmation/determination of histologic and/or molecular tumor characteristics)

- Phase I/Ib only: Patients must have evaluable metastatic disease in the CNS and/or
evidence of leptomeningeal disease (LMD) (clinically, on imaging or detected by
circulating tumor cells)

- Phase I/Ib only: Patients must have unequivocal evidence of new and/or progressive
brain metastases, and at least one of the following scenarios:

- Prior treatment with Stereotactic radiosurgery (SRS ) or surgery, and residual
surgically or radiosurgically un-treated lesions remaining. Such participants are
eligible for immediate enrollment on this study providing that at least one
untreated lesion is evaluable or measurable

- Patients who have not previously been treated with cranial irradiation are
eligible to enter the study

- Patients are eligible independent of presence or absence of progressive systemic
disease

- Phase I/Ib only: Patients must have an indication for local CNS-directed therapy, e.g.
new metastases amenanble for radiotherapy or SRS, reduction of mass effect and/or
palliation of symptoms

- Phase I/Ib only: Patients planned radiotherapy needs to be prescribed in accordance to
generally acceptable guidelines and practice, i.e.:

- Patients who have received prior whole brain radiotherapy should only be treated
with stereotactic radiosurgery (SRS)

- A delay of ≥ 3 months should be observed between prior whole-brain radiotherapy
(WBRT) and SRS

- Repeat SRS to a lesion previously treated with SRS is not allowed

- There is no limit to the number of lesions that have previously bee treated with
SRS, and there is no limit to the number of lesions to be treated with SRS, if
clinically indicated

Exclusion Criteria:

- Patients who are on escalating doses of corticosteroids

- Note: Patients must be on a stable or decreasing dose of corticosteroids
equivalent to dexamethasone ≤ 8mg averaged over the last 7 days to be eligible
for the study

- Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to trotabresib and vinorelbine (VNR)

- Patients who have a known additional malignancy that is progressing or requires active
treatment

- Note: Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy

- Patients who have impaired cardiac function or clinically significant cardiac
diseases, including any of the following:

- LVEF < 45% as determined from review of any standard of care echocardiograms
(ECHOs) multigated acquisition scans/(MUGAs) completed in the past 2 years

- Complete left bundle branch or bifascicular block (verified by review of medical
records)

- Congenital long QT syndrome (verified by review of medical records)

- Persistent or clinically meaningful ventricular arrhythmias or atrial
fibrillation (verified by review of medical records)

- Fridericia's correction formula (QTcF) ≥ 480 msec on screening electrocardiogram
(ECG)

- Unstable angina pectoris or myocardial infarction ≤ 6 months prior to starting
therapy (verified by review of medical records)

- Patients who require ongoing treatment with chronic, therapeutic dosing of
anti-coagulants (ex. warfarin, low molecular weight heparin, Factor Xa inhibitors,
thrombin antagonists)

- Note: Low dose low molecular weight heparin for catheter maintenance and for
prophylactic use are permitted if medically indicated

- Patients who have a history of bleeding diathesis

- Patients who have any hemorrhage/bleeding event > Common Terminology Criteria for
Adverse Events (CTCAE) grade 2 or hemoptysis > 1 tsp within 4 weeks prior to treatment
initiation

- Patients who have known prior episodes of non-arteritic anterior ischemic optic
neuropathy should be excluded from the study

- Note: Trotabresib should be used with caution in patients with retinitis
pigmentosa. The Principal Investigator may be consulted

- Patients who have poor bone marrow reserve as indicated by the following scenarios:

- Have received extensive bone radiotherapy

- Have experienced several episodes of bone marrow aplasia in previous treatments

- Confirmed histological bone marrow cancer infiltration

- Require regular hematopoietic support with blood transfusions, erythropoietin or
growth factors

- Patients who have an active infection requiring systemic therapy

- Patients who have had a major surgical procedure or significant traumatic injury
within 21 days prior to day 1 of treatment on study

- Note: Ommaya/programmable shunt placement is allowed

- Patients who have current evidence of any condition, therapy or laboratory abnormality
that might confound the results of the trial, interfere with their participation for
the full duration of the trial or is not in the best interest of the patient to
participate, in the opinion of the treating investigator

- Patients who have a psychiatric illness/social situations that would limit compliance
with study requirements

- Female patients who are pregnant or nursing. Pregnant women are excluded from this
study because vinorelbine has the potential for teratogenic or abortifacient effects