Toll-like Receptor (TLR) 7 Agonist, Cyclophosphamide, and Radiotherapy for Breast Cancer With Skin Metastases

Phase I/II Study of TLR7 Agonist Imiquimod, Cyclophosphamide, and Radiotherapy in Breast Cancer Patients With Chest Wall Recurrence or Skin Metastases

This study is to find an optimal dose of Imiquimod (IMQ) in the first part (Phase I) and test the effectiveness of the combination treatment of IMQ, cyclophosphamide (CTX), and radiotherapy (RT) in patients with skin metastases from breast cancer in the second part (Phase II). Currently this trial is in its Phase II part.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Metastatic Breast Cancer; Recurrent Breast Cancer
• Intervention / Treatment: Drug: Cyclophosphamide; Radiation: Radiation; Drug: Imiquimod

Detailed Description

By harnessing the cytocidal and immunostimulatory properties of two local treatment modalities, RT and IMQ, an effective, adaptive immune response can be generated, resulting in systemic control of metastatic breast cancer after local treatment of cutaneous metastases. Additionally, based on investigators' recent preclinical data, the investigators intend to estimate in patients with metastatic breast cancer, if the addition of immunomodulatory cyclophosphamide can increase anti-tumor responses.

This trial originally had one treatment arm IMQ/RT(patients were treated with IMQ and RT). Recent evidence has emerged that the addition of immunomodulatory cyclophosphamide (CTX) increased anti-tumor responses, therefore the IMQ/RT arm is closed and the trial will continue with two additional cohorts (CTX/IMQ/RT and CTX/RT) which include cyclophosphamide.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • New York University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Patients with biopsy-confirmed breast cancer.
2. Patients with at least measurable skin metastases and distant, measurable metastases (outside of skin) by Response Evaluation Criteria in Solid Tumors (RECIST). For patients without distant measurable metastases, an area of the skin metastases designated to not receive local therapy can be substituted. Patients with multiple (>= 2) metastatic sites (skin involvement not required), with at least one site measurable by RECIST, will be eligible for the CTX/RT cohort.
3. Age >= 18 years.
4. Eastern Cooperative Oncology Group performance status 0-2.
5. Patients must agree to tumor fine-needle aspiration required by protocol.
6. Concurrent systemic cancer therapy (hormones, biologics or chemotherapy) can be continued if distant metastases are non-responsive (i.e. no complete response or partial response) on that regimen for >= 8 weeks as assessed by the investigator.

7. Patients must have adequate organ and bone marrow function as defined below:

   • absolute neutrophil count >= 1,300/microliter
   • hemoglobin >= 9.0 grams/deciliter
   • platelets >= 75,000/microliter
   • total bilirubin =< 1.5 X institutional upper limit of normal
   • AST (aspartate aminotransferase) =< 2.5 X institutional upper limit of normal
   • ALT (alanine aminotransferase) =< 2.5 X institutional upper limit of normal
   • creatinine =< 2 X institutional upper limit of normal if patient has chronic renal insufficiency and creatinine has been stable for > 4 months)
8. Informed consent.

Exclusion Criteria:

1. Brain metastases unless resected or irradiated and stable >= 4 weeks.
2. Concurrent treatment with other investigational agents.
3. Patients who have received any local therapy (radiotherapy, high-potency corticosteroids, intralesional therapy, laser therapy or surgery) other than biopsy to the target area within 4 weeks prior to first dosing of study agent.
4. Patients who have received hyperthermia to the target area within 10 weeks prior to first dosing of study agent.
5. Patients with an uncontrolled bleeding disorder.
6. Patients (with skin metastases only) who will be therapeutically anticoagulated with heparins or coumadin at the time of the biopsy (they are eligible if anticoagulation can be held prior to biopsy as per investigator). Patients on aspirin and other platelet agents are eligible.
7. Patients with known immunodeficiency or receiving immunosuppressive therapies.
8. History of allergic reactions to imiquimod or its excipients.
9. Uncontrolled intercurrent medical illness or psychiatric illness/social situations that would limit compliance with study requirements.
10. Pregnancy or lactation.
11. Women of childbearing potential not using a medically acceptable means of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IMQ+RT; This arm has been closed as of 6/4/2014.; Weeks 1-2: RT given to one metastatic skin site at 6 Gy on days 1, 3, 5, 8 and 10 (M-W-F-M-W); Weeks 1-8: day 1-5 of each week: imiquimod 5% cream applied to all skin sites overnight, starting on day 1 after RT, day 6-7 of each week: rest period.; Week 9: response assessment Patients may continue to receive additional cycles (same schedule, RT given to a different site), provided that patients wish to continue, are without clinically significant progression and further treatment may be beneficial in the opinion of the investigator.	Radiation: Radiation; Drug: Imiquimod; Other Names: ALDARA
Experimental: CTX/IMQ/RT; Week -1 (day-7): cyclophosphamide 200mg/m2 IV as single infusion; Weeks 1-2: RT given to one metastatic skin site at 6 Gy on days 1, 3, 5, 8 and 10 (M-W-F-M-W); Weeks 1-8: day 1-5 of each week: imiquimod 5% cream applied all sites overnight, starting on day 1 after RT, day 6-7 of each week: rest period.; Week 9: response assessment Patients may continue to receive additional cycles (same schedule, RT given to a different site), provided that patients wish to continue, are without clinically significant progression and further treatment may be beneficial in the opinion of the investigator.	Drug: Cyclophosphamide; Other Names: Cytoxan; Radiation: Radiation; Drug: Imiquimod; Other Names: ALDARA
Experimental: CTX/RT; For patients with only non-skin metastatic sites First cycle (Cycle 1): Week -1 (day -7): cyclophosphamide 200mg/m2 IV as single infusion; Weeks 1-2: RT given to one site at 6 Gy on days 1, 3, 5, 8 and 10 (M-W-F-M-W); Week 9: response assessment Patients may continue to receive additional cycles (same schedule, RT given to a different site), provided that patients wish to continue, are without clinically significant progression and further treatment may be beneficial in the opinion of the investigator.	Drug: Cyclophosphamide; Other Names: Cytoxan; Radiation: Radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systemic Tumor Response Rates (Complete Response+Partial Response)	The systemic tumor response refers to the response at the time of best overall response. The response criteria are specially adapted from Response Evaluation Criteria in Solid Tumor for Immunotherapies (Wolchok, et al., 2009).	9 weeks from the start of the treatment of RT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local Skin Tumor Response Rates (Complete Response + Partial Response)	The response refers to the best overall response, based on European Organization for Research and Treatment of Cancer's definitions for chest wall tumors (Kouloulias, et al., 2002).	9 weeks from the start of the treatment

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General 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.
• Kouloulias VE, Dardoufas CE, Kouvaris JR, Gennatas CS, Polyzos AK, Gogas HJ, Sandilos PH, Uzunoglu NK, Malas EG, Vlahos LJ. Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial. Clin Cancer Res. 2002 Feb;8(2):374-82.

Study record dates

Study Major Dates

• Study Start (Actual): August 19, 2011
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): August 6, 2016

Study Registration Dates

• First Submitted: August 17, 2011
• First Submitted That Met QC Criteria: August 18, 2011
• First Posted (Estimate): August 22, 2011

Study Record Updates

• Last Update Posted (Actual): November 18, 2021
• Last Update Submitted That Met QC Criteria: October 25, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: immunotherapy; combination therapy; radiation therapy; immune response modifier; immunostimulatory; immunomodulator
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adjuvants, Immunologic; Interferon Inducers; Cyclophosphamide; Imiquimod
• Other Study ID Numbers: 11-00598; 1R01CA161891-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes