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

Phase 1

Completed

• Conditions: Breast Cancer; Recurrent Breast Cancer; Metastatic Breast Cancer
• Interventions: Radiation: Radiation; Drug: Imiquimod; Drug: Cyclophosphamide

• Registration Number: NCT01421017
• Lead Sponsor: NYU Langone Health

Brief Summary

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.

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 Timeline

• Study First Submitted: 2011-08-17
• Study First Submitted QC: 2011-08-18
• Study Start: 2011-08-19
• Study First Posted: 2011-08-22
• Primary Completion: 2016-07-01
• Study Completion: 2016-08-06
• Results First Submitted: 2020-09-08
• Status Verified: 2021-10
• Results First Submitted QC: 2021-10-25
• Last Update Submitted: 2021-10-25
• Results First Posted: 2021-11-18
• Last Update Posted: 2021-11-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 31

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CTX/RT	Radiation	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.
CTX/IMQ/RT	Radiation	* 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.
IMQ+RT	Radiation	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.
IMQ+RT	Imiquimod	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.
CTX/IMQ/RT	Imiquimod	* 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.
CTX/IMQ/RT	Cyclophosphamide	* 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.
CTX/RT	Cyclophosphamide	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.

Primary Outcome Measures

Name	Time	Method
Systemic Tumor Response Rates (Complete Response+Partial Response)	9 weeks from the start of the treatment of RT	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).

Secondary Outcome Measures

Name	Time	Method
Local Skin Tumor Response Rates (Complete Response + Partial Response)	9 weeks from the start of the treatment	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).

Trial Locations

Locations (1)

New York University Medical Center; 🇺🇸 New York, New York, United States