Study of Immune Response Modifier in the Treatment of Breast, Ovarian, Endometrial and Cervical Cancers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the anti-tumor activity of 852A when used to treat metastatic breast, ovarian, endometrial or cervical cancer not responding to standard treatment.

Detailed Description
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852A will be administered as a subcutaneous injection (SC) 2 times per week for 12 weeks (24 doses) with provisions for dose escalation or reduction based on tolerability.

Official Title
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Phase II Study of 852A Administered Subcutaneously in Patients With Metastatic Refractory Breast, Ovarian, Endometrial and Cervical Cancers

Conditions
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Breast Cancer, Ovarian Cancer, Endometrial Cancer, Cervical Cancer

Intervention / Treatment
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* Drug: 852A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adequate performance status: Breast - Karnofsky score > 50; Ovarian, endometrial or cervical - Gynecologic Oncology Group (GOG) performance score ≤2 If female and of childbearing potential, are willing to use adequate contraception (hormonal, barrier method, abstinence) prior to study entry and for the duration of study participation. Normal organ function within 14 days of study entry Diagnosis of one of the following malignancies: Metastatic breast cancer (BR) Metastatic ovarian cancer (OV) Metastatic endometrial cancer (EM) Metastatic cervical cancer (CX) Breast Cancer Inclusion Criteria: Measurable metastatic disease (>1cm) in at least one site other than bone-only Progression on or failure to respond to at least one previous chemotherapy regimen for metastatic disease Progression on prior therapy with a hormonal agent if estrogen receptor or progesterone receptor positive, and/or with trastuzumab if HER2-neu positive. If patient has progressed through hormone or trastuzumab therapy only, must have received one chemotherapy regimen. Ovarian Cancer Inclusion Criteria: Measurable metastatic disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Primary tumor must have been diagnosed histologically as either epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer (not borderline or low malignant potential epithelial carcinoma). Subjects must have failed at least two previous chemotherapy regimens. Paclitaxel must have been a component of one or both regimens and cisplatin or carboplatin must have been a component of one or both regimens. Endometrial Cancer Inclusion Criteria: Measurable metastatic disease Histologically proven recurrent or persistent endometrial cancer that is not amenable to curative treatment with surgery and/or radiation therapy AND has failed 2 previous treatment regimens Cervical Cancer Inclusion Criteria: Measurable metastatic disease Histologically proven recurrent or persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix that is not amenable to curative treatment with surgery and/or radiation therapy AND has failed 2 previous treatment regimens. Exclusion Criteria: Had/have the following prior/concurrent therapy: Systemic corticosteroids (oral or injectable) within 7 days of first dose of 852A (topical or inhaled steroids are allowed) Investigational drugs/agents within 14 days of first dose of 852A Immunosuppressive therapy, including cytotoxic agents within 14 days of first dose of 852A (nitrosoureas within 30 days of first dose) Drugs known to induce QT interval prolongation and/or induce Torsades de pointes unless best available drug required to treat life-threatening conditions Radiotherapy within 3 weeks of the first dose of 852A Hematopoietic cell transplantation within 4 weeks of first dose of 852A Evidence of active infection within 3 days of first dose of 852A Active fungal infection or pulmonary infiltrates (prior treated disease stable for 2 weeks is allowable) Cardiac ischemia, cardiac arrhythmias or congestive heart failure uncontrolled by medication History of, or clinical evidence of, a condition which, in the opinion of the investigator, could confound the results of the study or put the subject at undue risk Uncontrolled intercurrent or chronic illness Active autoimmune disease requiring immunosuppressive therapy within 30 days Active coagulation disorder not controlled with medication Pregnant or lactating Concurrent malignancy (if in remission, at least 5 years disease free) except for localized (in-situ) disease, basal carcinomas and cutaneous squamous cell carcinomas that have been adequately treated Any history of brain metastases or any other active central nervous system (CNS) disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intent-To-Treat<br>Patients treated with at least one dose - 852A subcutaneous injection. | Drug: 852A<br>* 0.2% 852a subcutaneous injection, 2 times per week for 12 weeks (24 doses) starting at 0.6 mg/m2; subsequent dose escalation for additional courses may be increased by 0.2 mg/m2 not to exceed 1.2 mg/m2.<br>* Other names: Toll-like receptor-7;|
| Experimental: Evaluable Cohort<br>Patients who received all 24 doses of 852A per protocol. | Drug: 852A<br>* 0.2% 852a subcutaneous injection, 2 times per week for 12 weeks (24 doses) starting at 0.6 mg/m2; subsequent dose escalation for additional courses may be increased by 0.2 mg/m2 not to exceed 1.2 mg/m2.<br>* Other names: Toll-like receptor-7;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Tumor Response (Response Evaluation Criteria in Solid Tumors) Who Received All 24 Doses of 852A. | Assessment of anti-tumor activity of 852A using Response Evaluation Criteria in Solid Tumors (RECIST) criteria to evaluate tumor response after 24 doses. Complete Response (CR)= disappearance of all target lesions, Partial Response (PR) = at least 30% decrease in sum of longest diameter of target lesions, Progressive Disease (PD) = at least 25% increase in sum of longest diameter of target lesions, Stable Disease = neither PR or PD. | after 12 weeks (24 doses of 852A) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Difference Values for Interleukin 1 Receptor Antagonist (IKL1ra) | Measures the difference of IL1ra (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 hours after Dose 1 | 
| Mean Difference Values for 10 kDa Interferon-gamma-induced Protein (IP-10) | Measures differences in IP-10 (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 Hours Post-Dose | 
| Mean Difference Values for Macrophage Inflammatory Protein-1 Alpha (MIP-1a) | Measures difference in MIP-1a (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 Hours Post-Dose | 
| Mean Difference Values for Macrophage Inflammatory Protein-1 Beta (MIP-1b) | Measures difference in Macrophage Inflammatory Protein-1 Beta (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 Hours Post-Dose | 
| Mean Difference Values for Soluble CD40 Ligand (sCD40L) | Measures difference in Soluble CD40 ligand (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 Hours Post-Dose | 
| Mean Difference Values for Tumor Necrosis Factor-alpha (TNF-a) | Measures difference in Tumor necrosis factor-alpha (cytokine) values as a means of immune activation pre-treatment and 6 hours post-treatment in patients that received at least one dose of study treatment with 852A. | Prior to Dose 1 and 6 Hours Post-Dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IRM, Breast, Ovarian, Endometrial, Cervical, Metastatic, 852A, Oncology, Metastatic Cervical Cancer, Metastatic Ovarian Cancer, Metastatic Breast Cancer, Metastatic Endometrial Cancer