Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at UC Davis
Dates
study started
estimated completion
Principal Investigator
Scott D. Christensen (ucdavis)

Description

Summary

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.

Official Title

A Phase 1b Study of M6620 in Combination With Radiation Therapy to Overcome Therapeutic Resistance in Chemotherapy Resistant Triple Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer

Details

PRIMARY OBJECTIVE:

  1. To determine the recommended phase 2 dose of twice weekly berzosertib (M6620) administered concurrently with conventionally fractionated radiation therapy (RT) to the breast/chest wall and regional nodes.

SECONDARY OBJECTIVES:

  1. 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.

  1. To identify somatic alterations in circulating cell-free DNA (cfDNA) at baseline, mid-treatment, end-of-treatment, and follow-up and to correlate cfDNA with disease-free survival.

EXPLORATORY OBJECTIVES:

  1. 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.

IV. To identify circulating tumor cell (CTC) positivity at baseline, mid-treatment, end-of-treatment, and follow-up and to correlate CTC positivity or the combination of CTC positivity and cfDNA with disease-free survival.

  1. To evaluate pre-treatment and post-treatment differential abundance of peripheral blood immune cell populations identified by cytometry by time-of flight (CyTOF).

VI. To evaluate associations of the pre-treatment and post-treatment peripheral blood immune phenotype (as assessed by CyTOF) with disease-free survival, distant disease-free survival and overall survival.

OUTLINE: This is a dose-escalation study of berzosertib.

Patients receive berzosertib 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.

Keywords

Bilateral Breast Carcinoma HER2 Negative Breast Carcinoma Non-Metastatic Breast Carcinoma Recurrent Breast Carcinoma Triple-Negative Breast Carcinoma Carcinoma Breast Neoplasms Berzosertib Quality-of-Life Assessment Radiation Therapy

Eligibility

You can join if…

Open to people ages 18 years and up

  • Males or females with non-metastatic, histologically confirmed primary 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 RCB2 or RCB3, as defined by Symmans et al., 2007, after completion of neoadjuvant anthracycline and/or taxane-based chemotherapy or locoregionally recurrent TNBC.

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: Results from any Clinical Laboratory Improvement Act (CLIA)-certified lab 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 >= institutional lower limit of normal (LLN)
  • Absolute neutrophil count >= institutional LLN
  • Platelets >= institutional LLN
  • 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 =< 1.1 mg/dL OR
  • Glomerular filtration rate (GFR) >= 45 mL/min/1.73 m2 for patients with creatinine levels above 1.1 mg/dL

  • 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

You CAN'T join if...

  • 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

Locations

  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento California 95817 United States
  • Mayo Clinic Hospital in Arizona accepting new patients
    Phoenix Arizona 85054 United States

Lead Scientist at UC Cancer

  • Scott D. Christensen (ucdavis)
    Professor, Hematology and Oncology. Authored (or co-authored) 18 research publications.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
National Cancer Institute (NCI)
ID
NCT04052555
Phase
Phase 1
Study Type
Interventional
Last Updated