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Testing the Addition of an Anti-cancer Drug, M6620, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative or Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT04052555
Recruitment Status : Not yet recruiting
First Posted : August 12, 2019
Last Update Posted : November 19, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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.

Condition or disease Intervention/treatment Phase
Bilateral Breast Carcinoma Breast Carcinoma Recurrent Breast Carcinoma Triple-Negative Breast Carcinoma Drug: ATR Kinase Inhibitor M6620 Other: Quality-of-Life Assessment Other: Questionnaire Administration Radiation: Radiation Therapy Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : November 22, 2019
Estimated Primary Completion Date : October 31, 2020
Estimated Study Completion Date : October 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Treatment (ATR kinase inhibitor M6620, radiation therapy)
Patients receive ATR kinase inhibitor M6620 IV over 60 minutes 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.
Drug: ATR Kinase Inhibitor M6620
Given IV
Other Names:
  • M 6620
  • M6620
  • VX-970

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Radiation: Radiation Therapy
Undergo RT
Other Names:
  • Cancer Radiotherapy
  • Irradiate
  • Irradiated
  • irradiation
  • Radiation
  • Radiation Therapy, NOS
  • Radiotherapeutics
  • RADIOTHERAPY
  • RT
  • Therapy, Radiation




Primary Outcome Measures :
  1. Recommended phase II dose of ATR kinase inhibitor M6620 [ Time Frame: Up to 4 weeks post treatment ]
    The maximum tolerated dose will be defined as the highest dose level with a dose-limiting toxicity rate closest to 0.25 and =< .33.


Secondary Outcome Measures :
  1. Incidence of adverse events (AEs) [ Time Frame: Up to 3 years ]
    Will be defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and will be summarized descriptively for each dose level and the entire cohort. The number and severity of all AEs (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ AEs will also be described and summarized in a similar fashion.

  2. Time to progression [ Time Frame: From study registration until the tumor recurs in the ipsilateral breast, chest wall, axillary, supracavicular or internal mammary nodes (if before or synchronous with a systemic recurrence), assessed up to 3 years ]
    Locoregional control will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.

  3. Disease-free survival (DFS) [ Time Frame: From study registration until the tumor recurs or the patient dies, whichever comes first, assessed up to 3 years ]
    Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.

  4. Distant DFS [ Time Frame: From study registration until distant disease recurs or the patient dies, whichever comes first, assessed up to 3 years ]
    Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.

  5. Overall survival [ Time Frame: From study registration until death due to any cause, assessed up to 3 years ]
    Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.

  6. Change in patient-related outcomes (PRO) [ Time Frame: Baseline up to 3 years ]
    Patient reported physical well-being, fatigue, skin toxicity (as measured by the PRO-CTCAE) and overall quality of life (as measured by the Breast-Q) will be summarized. The PRO-CTCAE data will be evaluated for data quality, to characterize baseline symptom status of patients on study and the change over time, to explore the development of symptomatic AEs and the change over time, and to explore the patient scores with other relevant clinical information, including clinician graded AEs. Changes in Breast-Q scores through time will be analyzed using graphical methods separately for each treatment level.

  7. Germline alterations in deoxyribonucleic acid (DNA) damage response and repair genes [ Time Frame: Up to 3 years ]
    Will include effectors and regulators of homologous recombination (HR) and be correlated with HR deficiency with disease-free survival. Descriptive statistics (i.e., mean, median, standard deviation, and range) and graphical methods (i.e., boxplots, jitter plots) will be used to summarize and compare the relapses by different dose levels. The number of relapses between the HR-deficient vs. the HR-proficient patients will be compared using a Chi-square test or independence or Fisher's Exact test. DFS for the HR-deficient and HR-proficient patients will be analyzed using Kaplan-Meier methods.

  8. Somatic alterations in DNA damage response and repair genes [ Time Frame: Up to 3 years ]
    Will include effectors and regulators of HR and be correlated with HR deficiency with DFS. Descriptive statistics (i.e., mean, median, standard deviation, and range) and graphical methods (i.e., boxplots, jitter plots) will be used to summarize and compare the relapses by different dose levels. The number of relapses between the HR-deficient vs. the HR-proficient patients will be compared using a Chi-square test or independence or Fisher's Exact test. DFS for the HR-deficient and HR-proficient patients will be analyzed using Kaplan-Meier methods.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04052555


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Robert W Mutter Mayo Clinic Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04052555     History of Changes
Other Study ID Numbers: NCI-2019-05187
NCI-2019-05187 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10291 ( Other Identifier: Mayo Clinic Cancer Center LAO )
10291 ( Other Identifier: CTEP )
UM1CA186686 ( U.S. NIH Grant/Contract )
First Posted: August 12, 2019    Key Record Dates
Last Update Posted: November 19, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Progesterone
Estrogens
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs