Fresolimumab and Radiotherapy in Metastatic Breast Cancer

• ClinicalTrials.gov Identifier: NCT01401062
• Recruitment Status: Completed
• First Posted: July 25, 2011
• Results First Posted: April 6, 2017
• Last Update Posted: March 5, 2019
• Sponsor: Weill Medical College of Cornell University
• Collaborator: University of California, Los Angeles
• Information provided by (Responsible Party): Weill Medical College of Cornell University

Study Description

Brief Summary:

The purpose of this study is to test safety of combining fresolimumab and local radiotherapy and to see if the combination can achieve tumor regression.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer	Drug: Fresolimumab; Radiation: Radiation Therapy	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 23 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fresolimumab and Radiotherapy in Metastatic Breast Cancer
• Study Start Date: July 2011
• Actual Primary Completion Date: June 2014
• Actual Study Completion Date: June 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm 1 (Fresolimumab 1 mg/kg); Fresolimumab is administered intravenously (i.v.) at a dose of 1 mg/kg on day 1 of weeks 0, 3, 6, 9 & 12 and radiation administered at 7.5 Gy/fraction in 3 fractions during weeks 1 (to lesion 1) and 7 (to lesion 2).	Drug: Fresolimumab; Other Name: GC1008; Radiation: Radiation Therapy
Experimental: Arm 2 (Fresolimumab 10 mg/kg); Fresolimumab is administered intravenously (i.v.) at a dose of 10 mg/kg on day 1 of weeks 0, 3, 6, 9 & 12 and radiation administered at 7.5 Gy/fraction in 3 fractions during weeks 1 (to lesion 1) and 7 (to lesion 2).	Drug: Fresolimumab; Other Name: GC1008; Radiation: Radiation Therapy

Outcome Measures

Primary Outcome Measures :

1. Abscopal Response Rate [ Time Frame: up to 20 weeks ]
   Defined as the percentage of patients who have responses (complete or partial) outside the irradiated lesions. The abscopal response is assessed at 15 weeks, and confirmed minimum 4 weeks later. The abscopal response is evaluated based on immune-related response criteria (irRC) (Wolchok et al, 2009).

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Biopsy-proven breast cancer, metastatic (persistent or recurrent).
• Failed ≥1 line of therapy (endocrine or chemotherapy) for metastatic disease.
• Min. 3 distinct metastatic sites, at least one measurable lesion which is at least 1 cm or larger in largest diameter.

• Must be ≥4 weeks since all of the following treatments (recovered from toxicity of prior treatment to ≤Grade 1, excluding alopecia):

  • major surgery;
  • radiotherapy;
  • chemotherapy (≥6 weeks since therapy if a nitrosourea, mitomycin, or monoclonal antibodies such as bevacizumab);
  • immunotherapy;
  • biotherapy/targeted therapies.
• >18 years of age.
• Life expectancy >6 months.
• Eastern Cooperative Oncology Group (ECOG) status 0 or 1.

• Adequate organ function including:

  • Hemoglobin ≥10.0g/dL, absolute neutrophil count (ANC) ≥1,500/mm3, and platelets ≥100,000/mm3.
  • Hepatic: Serum total bilirubin ≤1.5x upper limit of normal (ULN) (Patients with Gilbert's Disease may be included if total bilirubin is ≤3.0mg/dL), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤2.5xULN. If patient has known liver metastases, ALT and/or AST ≤5xULN are allowed.
  • Renal: creatinine clearance ≥60mL/min.
  • Prothrombin (PT) and partial thromboplastin times (PTT) <ULN.
• Negative for hepatitis viruses B and C unless consistent with prior vaccination or prior infection with full recovery.
• Patients of childbearing potential must agree to use effective contraception while on study, and for ≥3 months after last treatment.
• Understand and sign written informed consent document. No consent by durable power of attorney.

Exclusion Criteria:

• Second malignancy - unless following curative intent therapy, has been disease free for ≥2 years with probability of recurrence <5%. Curatively treated early-stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are allowed.
• Concurrent cancer therapy.
• Uncontrolled central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or disease that causes or threatens neurologic compromise (e.g. unstable vertebral metastases).
• History of ascites or pleural effusions, unless successfully treated.
• Organ transplant, including allogeneic bone marrow transplant.

• Immunosuppressive therapy including:

  • Systemic corticosteroid therapy, including replacement therapy for hypoadrenalism. Inhaled or topical corticosteroids are allowed (if therapy is <5 days and is limited to systemic steroids as antiemetics);
  • Cyclosporine A, tacrolimus, or sirolimus.
• Investigational agents within 4 weeks prior to study enrollment (≥6 weeks if treatment was long-acting agent such as monoclonal antibody).
• Significant or uncontrolled medical illness, e.g. congestive heart failure (CHF), myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction. Patients with remote history of asthma or active mild asthma may participate.
• Active infection, including unexplained fever (>38.5°C).
• Systemic autoimmune disease (e.g. systemic lupus erythematosus, active rheumatoid arthritis).
• Known allergy to any component of GC1008.
• Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or anti-coagulation therapy (including anti platelet agents i.e. aspirin, clopidogrel, ticlopidine, dipyridamole, other agents inducing long-acting platelet dysfunction). Patients with history of deep venous thrombosis are allowed if treated, completely resolved, and no treatment for >4months.
• Calcium >11.0mg/dL (2.75mmol/L) unresponsive or uncontrolled in response to standard therapy (e.g. bisphosphonates).

• Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems, including, but not limited to:

  • Other serious non-malignancy-associated conditions that may be expected to limit life expectancy or significantly increase the risk of SAEs;
  • Conditions, psychiatric, substance abuse, or other, that, in the opinion of the Investigator, would preclude informed consent, consistent follow-up, or compliance with any aspect of the study;
• Pregnant or nursing women.

Contacts and Locations

Locations

United States, California

David Geffen School of Medicine at UCLA

Los Angeles, California, United States, 90095-1714

United States, New York

New York University Langone Medical Center Cancer Center

New York, New York, United States, 10016

Sponsors and Collaborators

Weill Medical College of Cornell University

University of California, Los Angeles

Investigators

• Principal Investigator: Silvia Formenti, M.D.; NYU Langone Health

More Information

Publications:

Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 Dec 1;15(23):7412-20. doi: 10.1158/1078-0432.CCR-09-1624. Epub 2009 Nov 24.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Formenti SC, Hawtin RE, Dixit N, Evensen E, Lee P, Goldberg JD, Li X, Vanpouille-Box C, Schaue D, McBride WH, Demaria S. Baseline T cell dysfunction by single cell network profiling in metastatic breast cancer patients. J Immunother Cancer. 2019 Jul 11;7(1):177. doi: 10.1186/s40425-019-0633-x.

Sato M, Kadota M, Tang B, Yang HH, Yang YA, Shan M, Weng J, Welsh MA, Flanders KC, Nagano Y, Michalowski AM, Clifford RJ, Lee MP, Wakefield LM. An integrated genomic approach identifies persistent tumor suppressive effects of transforming growth factor-beta in human breast cancer. Breast Cancer Res. 2014 Jun 2;16(3):R57. doi: 10.1186/bcr3668.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT01401062
• Other Study ID Numbers: S11-00533; BC100481 ( Other Grant/Funding Number: DOD )
• First Posted: July 25, 2011
• Results First Posted: April 6, 2017
• Last Update Posted: March 5, 2019
• Last Verified: February 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Weill Medical College of Cornell University:

metastatic breast cancer; TGF-beta; fresolimumab; monoclonal antibody; radiation therapy; abscopal response

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases