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Radiation Therapy and M7824 in Treating Patients With Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT03524170
Recruitment Status : Recruiting
First Posted : May 14, 2018
Last Update Posted : May 22, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase I trial studies the side effects and best dose of anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) when given together with radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other parts of the body. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. M7824 is a drug that targets specific proteins on immune cells in order to activate immune responses against tumor cells. Giving M7824 together with radiation therapy may work better in treating patients with breast cancer.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Estrogen Receptor Positive HER2/Neu Negative Progesterone Receptor Positive Prognostic Stage IV Breast Cancer AJCC v8 Drug: Anti-PD-L1/TGFbetaRII Fusion Protein M7824 Radiation: Radiation Therapy Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the recommended phase II dose (RP2D) of M7824 and radiation therapy in patients with metastatic hormone receptor positive (HR+)/HER2 negative (-) breast cancer.

II. To evaluate the safety and tolerability of M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer.

SECONDARY OBJECTIVES:

I. To assess immunologic/molecular responses, specifically percentage (%) change in tumor-infiltrating lymphocytes (TIL) pre and post therapy to M7824 and radiation therapy in patients with HR+/HER2- metastatic breast cancer.

II. To explore progression free survival (PFS) and overall survival (OS) to power future definitive trial.

III. To evaluate the in-field and abscopal effect of treatment with anti-PD-L1/TGF-beta trap (M7824) and radiation therapy.

EXPLORATORY OBJECTIVES:

I. To characterize the effect of anti-PD-L1/TGF-beta trap (M7824) and radiation therapy on immune biomarkers including PD-L1 expression and fibrosis changes in tumor microenvironment in tumor tissue obtained from subjects pre- and post-treatment.

II. To characterize circulating immune cell populations and cytokine profiles in tumor and circulation following treatment with M7824.

III. To conduct ribonucleic acid sequencing (RNAseq), RNA Scope, whole exome sequencing (WES) targeted sequencing and tissue IO gene expression.

OUTLINE:

Patients receive M7824 intravenously (IV) over 1 hour every 14 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Beginning within 48 hours after second dose of M7824, patients undergo radiation therapy once a day (QD) for 5 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 90 days.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: RACHEL1: A Phase I Radiation and Checkpoint Blockade Trial in Patients With Metastatic Hormone Receptor Positive, HER2 Negative Breast Cancer
Actual Study Start Date : April 30, 2018
Estimated Primary Completion Date : September 24, 2019
Estimated Study Completion Date : September 24, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (M7824, radiation therapy)
Patients receive M7824 IV over 1 hour every 14 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Beginning within 48 hours after second dose of M7824, patients undergo radiation therapy QD for 5 days in the absence of disease progression or unacceptable toxicity.
Drug: Anti-PD-L1/TGFbetaRII Fusion Protein M7824
Given IV
Other Names:
  • Anti-PDL1/TGFb Trap MSB0011359C
  • M7824
  • MSB0011359C

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




Primary Outcome Measures :
  1. Recommended phase II dose (RP2D) of M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer determined by dose limiting toxicity (DLT) [ Time Frame: 6 weeks after first administration of M7824. ]
    RP2D defined as the highest dose level with no more than 1 patient with DLT out of 6 patients that are treated.

  2. Safety and tolerability of M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer. [ Time Frame: Start of study drug up to 30 days after study drug stopped ]
    Safety determined by National Cancer Institute - Common Terminology Criteria for AEs (CTCAE), version 4.03.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Start of study drug up to 90 days after study drug stopped ]
    Progression-free survival (PFS) defined as the time from treatment until objective tumor progression or death, whichever occurs first.

  2. Overall survival (OS) [ Time Frame: Start of study drug up to 90 days after study drug stopped ]
    Overall survival (OS) defined as the time from treatment until death from any cause.

  3. Immunologic/molecular response [ Time Frame: 56 days ]
    Immunologic/molecular response defined as % change in tumor infiltrating lymphocytes (TIL) pre and post therapy to M7824 and radiation therapy in patients with HR+/HER2- metastatic breast cancer.

  4. Evaluation of the size of metastasis after treatment with anti-PD-L1/TGF-β Trap (M7824) with radiation (in-field) and non-irradiated (abscopal) sites determined by RECIST [ Time Frame: 56 days ]


Information from the National Library of Medicine

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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:

  • Is willing and able to provide written informed consent for the trial and has signed the appropriate written informed consent form, approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  • Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first trial administration, for the duration of trial treatment, and at least for 4 months after stopping trial treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.
  • Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease. HR defined as positive if expression greater than 10% by immunohistochemistry (IHC). HER2 negative or non-amplified is determined by the current American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) criteria which are as follows: HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if: i. IHC 3+ based on circumferential membrane staining that is a. complete, intense ii. ISH positive based on: a. single-probe average HER2 copy number >= 6.0 signals/cell. b. Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell c. Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell d. Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number >= 6.0 signals/cell.
  • Has at least 2 identified sites of metastatic disease by imaging.
  • Has received no more than 5 previous lines of chemotherapy and has received at least one line of therapy with an endocrine therapy or endocrine therapy combination.
  • White blood cell (WBC) count >= 3 x 10^9/L.
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.
  • Lymphocyte count >= 0.5 x 10^9/L.
  • Platelet count >= 100 x 10^9/L.
  • Hemoglobin (Hgb) >= 9 g/dL.
  • Total bilirubin level =< 1.5 x the upper limit of normal (ULN).
  • Aspartate aminotransferase (AST) level =< 2.5 x ULN.
  • Alanine aminotransferase (ALT) level =< 2.5 x ULN.
  • International normalized ratio (INR) < 1.5.
  • Adequate renal function defined by an estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula or be measure for creatinine clearance from 24 hour urine collection.
  • Has not had major surgery within 28 days prior to starting study treatment. Central venous access surgeries and/or placements would not be considered as major surgery.
  • Is eligible for palliative radiotherapy as determined by the treating radiation oncologist.

Exclusion Criteria:

  • Anticancer treatment within 14 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative radiotherapy delivered in a normal organ-sparing technique], immune therapy, or cytokine therapy).
  • Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted).
  • Systemic therapy with immunosuppressive agents within 7 days before the start of treatment; or use of any investigational drug within 28 days before the start of trial treatment.
  • Subjects with active central nervous system (CNS) metastases with significant neurological compromise or symptoms are excluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy), who show no evolving new neurological symptoms are eligible for the study.
  • Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but with the exception of transplants that do not require immunosuppression (e.g., corneal transplant, hair transplant).
  • Significant acute or chronic infections including, among others: a. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. b. Active hepatitis B virus (HBV) (HBV surface antigen positive) or hepatitis C virus (HCV) (HCV RNA positive). c. Subjects with known active tuberculosis (history of exposure or history of positive tuberculosis test plus presence of clinical symptoms, physical or radiographic findings).
  • Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: a. subjects with type I diabetes, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible b. subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses 10 mg of prednisone or equivalent per day.
  • Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association classification class > II), or serious cardiac arrhythmia.
  • Clinically relevant diseases (for example, inflammatory bowel disease) and /or uncontrolled medical conditions, which, in the opinion of the investigator, might impair the subject's tolerance or ability to participate in the trial.
  • Vaccine administration within 4 weeks of M7824 administration. Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines is allowed (for example, inactivated influenza vaccines).
  • Pregnancy and breast feeding.

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): NCT03524170


Contacts
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Contact: Jennifer Litton 713-792-2817 jlitton@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Jennifer K. Litton    713-792-2817      
Principal Investigator: Jennifer K. Litton         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jennifer K Litton M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT03524170     History of Changes
Other Study ID Numbers: 2017-0499
NCI-2018-00961 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2017-0499 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: May 14, 2018    Key Record Dates
Last Update Posted: May 22, 2019
Last Verified: May 2019

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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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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs