Clinical Trials /

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

NCT04052555

Description:

This phase Ib trial studies the best dose of berzosertib 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. Berzosertib 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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Berzosertib, to the Usual Treatment (Radiation Therapy) for Chemotherapy-Resistant Triple-Negative and Estrogen and/or Progesterone Receptor Positive, HER2 Negative Breast Cancer
  • Official Title: A Phase 1b Study of Berzosertib 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-05187
  • SECONDARY ID: NCI-2019-05187
  • SECONDARY ID: 10291
  • SECONDARY ID: 10291
  • SECONDARY ID: UM1CA186686
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT04052555

Conditions

  • Bilateral Breast Carcinoma
  • HER2 Negative Breast Adenocarcinoma
  • Localized Breast Carcinoma
  • Recurrent Breast Carcinoma
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
Berzosertib2-Pyrazinamine, 3-(3-(4-((Methylamino)methyl)phenyl)-5-isoxazolyl)-5-(4-((1-methylethyl)sulfonyl)phenyl)-, M 6620, M6620, VX 970, VX-970, VX970Treatment (berzosertib, radiation therapy)

Purpose

This phase Ib trial studies the best dose of berzosertib 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. Berzosertib 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.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the recommended phase 2 dose of twice weekly berzosertib 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 berzosertib 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.

      V. 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:

      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 berzosertib 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.

      V. 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (berzosertib, radiation therapy)ExperimentalPatients receive berzosertib 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.
  • Berzosertib

Eligibility Criteria

        Inclusion Criteria:

          -  Patient 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, and received neoadjuvant anthracycline and/or
             taxane-based chemotherapy OR Patient has non-metastatic, histologically confirmed
             primary ER > 10% and/or PR > 10%, HER2-negative breast cancer with RCB3 and received
             neoadjuvant anthracycline and/or taxane-based chemotherapy OR Patient has
             locoregionally recurrent TNBC or ER >10% and/or PR >10%, HER2-negative breast cancer.
             Note: Results from any Clinical Laboratory Improvement Act (CLIA)-certified lab are
             acceptable for the purpose of determining study eligibility.

               -  Note: For patients with primary breast cancer, there is no minimum number of
                  neoadjuvant cycles required provided the patient received an anthracycline or
                  taxane preoperatively. Patients with locoregionally recurrent breast cancer are
                  not required to have received preoperative chemotherapy

          -  Patient has undergone total mastectomy or wide local excision with axillary staging,
             and the margins of the resected wide local excision or mastectomy specimens are free
             of invasive tumor and ductal carcinoma in situ (DCIS) or patient has undergone
             axillary surgery for regionally recurrent breast cancer. Unresected axillary level
             III, internal mammary, and supraclavicular nodal disease is permitted.

               -  Note: 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 but not fewer than 21 days prior to
             registration unless patient received postoperative chemotherapy in which case patients
             must have completed their adjuvant chemotherapy within 90 days but not fewer than 28
             days prior to registration

          -  The patient must have recovered from surgery with the incision completely healed and
             no signs of infection prior to registration

          -  Patients must be proceeding with breast/chest wall and regional nodal irradiation
             including internal mammary node treatment. For patients with bilateral breast cancer,
             RT must be 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 m^2 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 berzosertib 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 berzosertib 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 berzosertib
             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. Postoperative
             chemotherapy is allowed but must be discontinued >28 days prior to registration

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to berzosertib

          -  Berzosertib 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 berzosertib 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 berzosertib, breastfeeding should be discontinued if the
             mother is treated with berzosertib

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose of berzosertib
Time Frame:Up to 4 weeks post treatment
Safety Issue:
Description: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

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 3 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:Locoregional control will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.
Measure: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
Safety Issue:
Description:Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.
Measure:Distant DFS
Time Frame:From study registration until distant disease recurs or the patient dies, whichever comes first, assessed up to 3 years
Safety Issue:
Description:Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.
Measure:Overall survival
Time Frame:From study registration until death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be split by each dose level and analyzed descriptively using Kaplan-Meier methodology.
Measure:Change in patient-related outcomes (PRO)
Time Frame:Baseline up to 3 years
Safety Issue:
Description: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.
Measure:Germline alterations in deoxyribonucleic acid (DNA) damage response and repair genes
Time Frame:Up to 3 years
Safety Issue:
Description: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 versus (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.
Measure:Somatic alterations in DNA damage response and repair genes
Time Frame:Up to 3 years
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 28, 2021