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Anatomic Stage IV Breast Cancer AJCC v8Phase 1NCT04756505

Immunotherapy (NHS-IL12 & Bintrafusp Alfa) and Radiation Therapy for the Treatment of Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer, the REINA Trial

A Phase 1 study testing Bintrafusp Alfa, Immunocytokine NHS-IL12 and Radiation Therapy in people with Anatomic Stage IV Breast Cancer AJCC v8 and Hormone Receptor Positive Breast Adenocarcinoma, run by M.D. Anderson Cancer Center.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This phase I trial is to find out the best dose, possible benefits and/or side effects of NHS-IL12 given together with bintrafusp alfa and radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other places in the body (metastatic). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Bintrafusp Alfa, Immunocytokine NHS-IL12 and Radiation Therapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
7 Mar 2021to 16 Feb 2022
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
  • Is age >= 18 years at time of study entry
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Men on study also must be using contraception. Women of childbearing potential (WOCBP) are women who have not been postmenopausal greater than 1 year or undergone a hysterectomy or bilateral oophorectomy
  • Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease. Eligible patients must have estrogen receptor (ER) and/or progesterone (PR) expression 10% or greater by immunohistochemistry (IHC). HER2 negative or nonamplified 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:
  • IHC 3+ based on circumferential membrane staining that is
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  • Complete, intense
  • ISH positive based on:
  • Single-probe average HER2 copy number >= 6.0 signals/cell
  • Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number >= 4.0 signals/cell
  • Dual-probe HER2/CEP17 ratio >= 2.0 with an average HER2 copy number < 4.0 signals/cell
  • 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. This can include areas of metastatic disease to the bone, but one additional of the sites of metastatic disease must be amenable to biopsy
  • Has measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  • 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
  • Hemoglobin >= 10.0 g/dL
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
  • Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only upon treating physician, principle investigator (PI) or co-PI approval
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x ULN
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, examinations, and assessments (including follow up)
  • Protocol participation is such that the treatment will be administered as an outpatient. Inpatient status is not required and change in status does not necessitate removal from protocol
  • 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

Who cannot join

  • Anticancer treatment within 14 days before the start of trial treatment (e.g. cytoreductive therapy, radiotherapy etc.), or surgery within 4 weeks of start of trial treatment
  • History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease =< 3 years before the first dose of study drug and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ
  • QT interval corrected for heart rate (QTc) >= 470 ms
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  • Current or prior use of immunosuppressive medication within 28 days before the first dose of M7824 or NHS-IL-12, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects with vitiligo, hypo- or hyperthyroid disease, or psoriasis not requiring systemic treatment are not excluded
  • Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
  • Significant acute or chronic infections including, among other:
  • Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
  • Active hepatitis B virus (HBV surface antigen positive) or hepatitis C virus (HCV antibody positive and/or HCV RNA positive)
  • Subjects with known active tuberculosis (history of exposure or history of positive tuberculosis test plus presence of clinical symptoms, physical or radiographic findings)
  • History of allogeneic organ transplant
  • History of hypersensitivity to M7824 or NHS-IL-12 or any excipient of either compound
  • History of uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of a psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Known history of previous clinical diagnosis of tuberculosis
  • Subjects with active central nervous system (CNS) metastases causing clinical symptoms or metastases that require therapeutic intervention, including leptomeningeal disease, are excluded. Subjects with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible unless they have demonstrated no progression for at least 1 month, and do not require continued steroid therapy.
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving study drugs
  • Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
  • Any condition, including chronic medical condition, that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
  • Subjects with uncontrolled seizures
  • Any absolute contraindication to protocol specified radiotherapy based on prior radiotherapy (determined by radiation oncologist)
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) for metastatic breast cancer. Or, if patient has had prior immune-oncology therapies in the neoadjuvant or adjuvant setting within the past 12 months.

About this study

Official title: REINA: A Phase I Study of Radiation Enhanced IL 12-Necrosis Attraction in Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients

This phase I trial is to find out the best dose, possible benefits and/or side effects of NHS-IL12 given together with bintrafusp alfa and radiation therapy in treating patients with hormone receptor positive, HER2 negative breast cancer that has spread to other places in the body (metastatic). Immunotherapy with NHS-IL12, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with bintrafusp alfa, a bifunctional fusion protein composed of the monoclonal antibody avelumab and TGF-beta, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving NHS-IL12, bintrafusp alfa, and radiation therapy may kill more tumor cells.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the safety and tolerability of bintrafusp alfa (M7824) in combination with immunocytokine NHS-IL12 (NHS-IL-12) and radiation therapy in patients with metastatic hormone receptor positive (HR+)/HER2- breast cancer.

II. To determine the recommended phase II dose (RP2D) of NHS-IL-12 in combination with M7824 and radiation therapy in patients with metastatic HR+/HER2- breast cancer.

SECONDARY OBJECTIVES:

  1. To assess immunologic/molecular responses, specifically percent (%) change in tumor infiltrating lymphocytes (TIL) pre and post therapy to M7824 in combination with NHS-IL-12 and radiation therapy in patients with HR+/HER2- metastatic breast cancer.

II. To explore preliminary 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 M7824 in combination with NHS-IL-12 and radiation therapy.

EXPLORATORY OBJECTIVES:

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

II. To conduct tissue-based ribonucleic acid sequencing (RNAseq), RNA scope, whole exome sequencing (WES) targeted sequencing.

III. To correlate dosimetry to response (assessed by degree of radiation fibrosis).

IV. To evaluate the pharmacokinetics of NHS-IL-12 in combination with M7824.

OUTLINE: This is a dose-escalation study of immunocytokine NHS-IL12.

Patients receive bintrafusp alfa intravenously (IV) over 1 hour on days 1 and 14 and immunocytokine NHS-IL12 subcutaneously (SC) on day 14. Beginning on day 14 of cycle 1, patients undergo radiation therapy once daily (QD) for up to 4 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Being tested
Bintrafusp Alfa, Immunocytokine NHS-IL12, Radiation Therapy
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bintrafusp AlfaDrug

    Also called Anti-PDL1/TGFb Trap MSB0011359C, M7824, MSB0011359C

    Given IV

  • Immunocytokine NHS-IL12Biological

    Also called M-9241, M9241, NHS-IL-12, NHS-IL12

    Given SC

  • Radiation TherapyRadiation

    Also called Cancer Radiotherapy, ENERGY_TYPE, Irradiate, Irradiated

    Undergo radiation therapy

Study groups in NCT04756505
Study groupRoleWhat they receive
Treatment (bintrafusp alfa, NHS-IL12, radiation therapy)ExperimentalPatients receive bintrafusp alfa IV over 1 hour on days 1 and 14 and immunocytokine NHS-IL12 SC on day 14. Beginning on day 14 of cycle 1, patients undergo radiation therapy QD for up to 4 days. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: Bintrafusp Alfa; Biological: Immunocytokine NHS-IL12; Radiation: Radiation Therapy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of adverse events (AEs)

    Detailed information collected for each AE will include a description of the event, duration, severity, relationship to study treatment, action taken and clinical outcome. Severity of AEs will be grated according to Common Terminology Criteria for Adverse Events version .4.0.

    Measured: Up to 30 days post treatment

  2. Recommended phase II dose (RP2D)

    RP2D will be determined by "3+3" design, and the recommended phase II dose is defined when 6 patients have been treated on that dose with no more than 1 dose-limiting toxicity.

    Measured: Up to 28 days

Secondary outcomes (4)

  1. Progression-free survival (PFS)

    PFS will be estimated for all enrolled patients and patients who receive at least one treatment using Kaplan-Meier method and compared between or among patients' characteristic groups by log-rank test. Univariate Cox regression model may be applied to assess the effect of variables of interest on PFS when appropriate.

    Measured: From start of treatment until objective tumor progression or death, whichever occurs first, assessed up to 1 year

  2. Overall survival (OS)

    OS will be estimated for all enrolled patients and patients who receive at least one treatment using Kaplan-Meier method and compared between or among patients' characteristic groups by log-rank test. Univariate Cox regression model may be applied to assess the effect of variables of interest on OS, when appropriate.

    Measured: From treatment until death from any cause, assessed up to 1 year

  3. Percent (%) change in tumor infiltrating lymphocytes (TIL)

    The % change of TIL pre and post treatment will be estimated along with 95% confidence interval. Wilcoxon signed rank test may be used to examine whether the change in TIL is different from zero.

    Measured: Baseline up to 1 year

  4. Size of metastasis after treatment with both therapeutic agents with radiation (in-field) and nonirradiated (abscopal) sites

    The difference in size of metastasis measured by the longest diameters of the tumor or the shortest diameter of a lymph node by Response Evaluation Criteria in Solid Tumors, before and after treatment will be estimated for both the irradiated site (diff irradiated) and the non-irradiated site (diff non-irradiated). Will also estimate the difference between the two different sites (diff = diff non-irradiated - diff irradiated). May evaluate if diff irradiated, diff non-irradiated, and diff = diff non-irradiated - diff Irradiated are significantly different from 0 by the Wilcoxon signed rank test.

    Measured: Up to 1 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Feb 2021
  2. Study start7 Mar 2021
  3. Primary completion16 Feb 2022
  4. Study completion16 Feb 2022

Why it stopped: Per Sponsor Request-no longer manufacturing the study drug

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04756505
Sponsor's protocol ID
2020-0245
Other IDs
NCI-2021-00434, 2020-0245
Status last verified
Dec 2023
First submitted
11 Feb 2021
Last updated
27 Dec 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Bintrafusp Alfa, Immunocytokine NHS-IL12 and Radiation Therapy in people with Anatomic Stage IV Breast Cancer AJCC v8 and Hormone Receptor Positive Breast Adenocarcinoma, run by M.D. Anderson Cancer Center.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 23 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 27 Dec 2023. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of adverse events (AEs) (time frame: Up to 30 days post treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04756505.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Dec 2023.

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