This phase Ib trial studies the best dose of M6620 when given together with the usual
treatment (radiation therapy) in treating patients with triple negative or estrogen receptor
and/or progesterone receptor positive, HER-2 negative breast cancer. M6620 may stop the
growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation
therapy uses high energy rays to kill tumor cells and shrink tumors. Giving M6620 and
radiation therapy may kill tumor cells more effectively than radiation alone or shrink or
stabilize breast cancer for longer than radiation therapy alone.
PRIMARY OBJECTIVE:
I. To determine the recommended phase 2 dose of twice weekly ATR kinase inhibitor M6620
(M6620) administered concurrently with conventionally fractionated radiation therapy (RT) to
the breast/chest wall and regional nodes.
SECONDARY OBJECTIVES:
I. To describe the nature of toxicity that develops when an ATR inhibitor is administered
concurrently with RT for breast cancer using provider assessments.
II. To assess long-term locoregional control, disease-free survival, distant disease-free
survival, and overall survival of patients treated with this approach.
III. To explore symptomatic adverse events and tolerability of M6620 being administered
concurrently with RT using patient-reported outcomes (PROs).
IV. To assess for germline and somatic alterations in deoxyribonucleic acid (DNA) damage
response and repair genes, including effectors and regulators of homologous recombination
(HR), in pre-chemotherapy biopsy specimens and post-chemotherapy surgical resection specimens
using whole exome sequencing (WES), and to correlate HR deficiency with disease-free
survival.
EXPLORATORY OBJECTIVES:
I. To compare the baseline and post-treatment skin microbiome and make exploratory
correlations with severe provider and patient-reported toxicity.
II. To assess for germline DNA repair alterations and correlate with severe provider and
patient-reported toxicity.
III. To explore dose-volume parameters associated with acute and late toxicity provider and
patient-reported toxicity following M6620 administration concurrent with RT.
OUTLINE: This is a dose-escalation study of ATR kinase inhibitor M6620.
Patients receive ATR kinase inhibitor M6620 intravenously (IV) over 60 minutes twice weekly
(BIW) for 5 weeks in the absence of disease progression or unacceptable toxicity. Patients
also undergo RT 5 days a week for 5-6 weeks depending on the type of surgery undergone.
After completion of study treatment, patients are followed up weekly for 4 weeks, at 12
months, then yearly for up to 3 years.
Inclusion Criteria:
- Males or females with non-metastatic, histologically confirmed primary or
locoregionally recurrent estrogen receptor (ER) < 10%, progesterone receptor (PR) <
10%, and HER2-negative breast cancer (triple negative breast cancer [TNBC]) either
using the baseline biopsy specimen or the post-neoadjuvant chemotherapy (NAC) residual
surgical specimen and residual cancer burden (RCB)2 or RCB3, as defined by Symmans et
al., 2007, after completion of neoadjuvant anthracycline and/or taxane-based
chemotherapy OR males or females with non-metastatic, histologically confirmed primary
or locoregionally recurrent ER >= 10% and/or PR >= 10%, HER2-negative breast cancer
with RCB3 after completion of neoadjuvant anthracycline and/or taxane-based
chemotherapy and grade 3 or clinical regional nodal stage N3 at presentation
- Note: Local laboratory (lab) results documented in the medical record are
acceptable for the purpose of determining study eligibility
- Patients who have undergone either total mastectomy or a lumpectomy with axillary
staging are eligible, and the margins of the resected lumpectomy or mastectomy
specimens must be free of invasive tumor and ductal carcinoma in situ (DCIS)
- For patients who have undergone mastectomy, immediate reconstruction is allowed
- Patients must have completed their final breast surgery including re-excision of
margins for invasive cancer and DCIS within 90 days prior to registration but no
sooner than 21 days prior to the initiation of RT. The patient must have recovered
from surgery with the incision completely healed and no signs of infection prior to RT
administration
- Patients must be proceeding with breast/chest wall and regional nodal irradiation
including internal mammary node treatment. Patients may receive adjuvant systemic
therapy (e.g. adjuvant capecitabine) but it may not begin less than 28 days from the
last fraction of RT. Bilateral breast cancer is permitted provided that RT is
indicated and administered only to one side
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Willing to provide tissue and blood samples for correlative research
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional ULN
- Creatinine =< institutional ULN OR
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with creatinine
levels above ULN
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Negative urine or serum pregnancy test for individuals of childbearing potential.
Note: The effects of M6620 (VX-970) on the developing human fetus are unknown. For
this reason and because DNA-damage repair inhibitors as well as radiation used in this
trial are known to be teratogenic, women of child-bearing potential and men must agree
to use adequate contraception (hormonal or barrier method of birth control;
abstinence) prior to study entry and for the duration of study participation, and for
6 months after completion of M6620 administration. Should a woman become pregnant or
suspect she is pregnant while she or her partner is participating in this study, she
should inform her treating physician immediately. Men treated or enrolled on this
protocol must also agree to use adequate contraception prior to the study, for the
duration of study participation, and 6 months after completion of M6620 (VX-970)
administration
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy within 4 weeks prior to entering the study
- Prior RT to the ipsilateral chest wall or ipsilateral breast or thorax. Individuals
with prior RT to the contralateral breast or chest wall are eligible
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia and grade
1-2 taxane-induced neuropathy which will be permitted
- Patients who are receiving any other investigational agents or concomitant
anti-neoplastic treatment, except endocrine therapies and bisphosphonates which are
permitted without restriction even during protocol treatment
- Patients with definitive clinical or radiologic evidence of metastatic disease, as
documented by the treating institution
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to M6620 (VX-970)
- M6620 is primarily metabolized by CYP3A4; therefore, concomitant administration with
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin,
ritonavir, indinavir, nelfinavir, and saquinavir) or inducers of CYP3A4 (e.g.,
rifampin, phenytoin, carbamazepine, phenobarbital, St. John's wort) should be avoided.
Patients requiring any medications or substances that are strong inhibitors or
inducers of CYP3A during the course of the study and for 14 days prior to enrollment
are ineligible. Because the lists of these agents are constantly changing, it is
important to regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product
- Patients with uncontrolled intercurrent illness. This includes but is not limited to,
ongoing uncontrolled serious infection requiring IV antibiotics at the time of
registration, symptomatic congestive heart failure, unstable angina pectoris,
symptomatic/uncontrolled cardiac arrhythmia, or psychiatric illness/social situations
that would limit compliance with study requirements.
- Active systemic lupus, scleroderma, or dermatomyositis with a CPK level above normal
- Pregnant women are excluded from this study because M6620 as a DNA damage repair
inhibitor may have the potential for teratogenic or abortifacient. Because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with M6620, breastfeeding should be discontinued if the mother
is treated with M6620
- Patients with known hereditary syndromes predisposing to radiosensitivity such as Li
Fraumeni syndrome and ataxia telangiectasia are excluded from the study. Patients with
mutations in breast cancer predisposition genes such as BRCA1, BRCA2, PALB2, CHEK2,
and ATM are eligible
- Patients with a prior or concurrent malignancy, excluding non-melanoma skin cancers
and non-invasive cancers whose natural history or treatment does not have the
potential to interfere with the safety or efficacy assessment of the investigational
regimen