PRO 140 in Treatment-Experienced HIV-1 Subjects

Study Overview
=================
Brief Summary
-----------------
The primary objectives of the trial are to assess the efficacy, clinical safety and tolerability parameters of PRO 140 in combination with failing ART during the initial one-week treatment period, and in combination with Optimized Background Therapy during the subsequent 24-week treatment period.

Detailed Description
-----------------
PRO 140, in combination with other antiretroviral agents, is indicated for treatment experienced adult HIV-1 patients infected with CCR5-tropic virus. These patients must demonstrate evidence of HIV-1 replication despite ongoing antiretroviral therapy and have documented genotypic or phenotypic resistance to at least one ART drug within three drug classes (or within two or more drug classes with limited treatment option). The options may be limited as a result of drug antiviral class cross-resistance, documented treatment intolerance, documented objective assessments such as renal or hepatic insufficiency (e.g. high creatinine at baseline, limiting treatment options due to potential for toxicity), past adverse reactions such as hypersensitivity reactions or neuropsychiatric issues that could limit use of currently approved drugs. Study population includes treatment-experienced HIV-infected patients with CCR5-tropic virus who demonstrates evidence of HIV-1 replication despite ongoing antiretroviral therapy with documented genotypic or phenotypic resistance to ART drugs within three drug classes (or within two drug classes with limited treatment option). The primary objectives of the trial are to assess the efficacy, clinical safety and tolerability parameters of PRO 140 in combination with failing ART during the initial one-week treatment period, and in combination with Optimized Background Therapy during the subsequent 24-week treatment period.

Official Title
-----------------
A Multi-center, Two-Part, Single-Arm, Open Label, 25-Week Trial With PRO 140 in Treatment-Experienced HIV-1 Subjects

Conditions
-----------------
HIV-1-infection

Intervention / Treatment
-----------------
* Drug: PRO 140


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females, age ≥18 years Exclusive CCR5-tropic virus at Screening Visit as determined by Monogram Biosciences Trofile® Assay Have a history of at least 3 months on current antiretroviral regimen Treatment-experienced HIV-infected patients with documented genotypic or phenotypic resistance to at least one ART drug within three drug classes OR Treatment-experienced HIV-infected patients with documented genotypic or phenotypic resistance to at least one ART drug within two drug classes and have limited treatment option. The options may be limited as a result of drug antiviral class cross-resistance, documented treatment intolerance, documented objective assessments such as renal or hepatic insufficiency (e.g. high creatinine at baseline, limiting treatment options due to potential for toxicity), past adverse reactions such as hypersensitivity reactions or neuropsychiatric issues that could limit use of currently approved drugs. Be willing to remain on treatment without any changes or additions to the OBT regimen, except for toxicity management or upon meeting criteria for treatment failure Plasma HIV-1 RNA ≥ 400 copies/mL at Screening Visit as determined by Human Immunodeficiency Virus 1 (HIV-1) Quantitative, RNA (Roche Taqman® Real-Time PCR) and documented detectable viral load (HIV-1 RNA >50 copies/ml) within the last 3 months prior to Screening Visit Laboratory values at Screening of: Absolute neutrophil count (ANC) ≥750/mm3 Hemoglobin (Hb) ≥10.5 gm/dL (male) or ≥ 9.5 gm/dL (female) Platelets ≥75,000 /mm3 Serum alanine transaminase (SGPT/ALT) <5 x upper limit of normal (ULN) Serum aspartate transaminase (SGOT/AST) <5 x ULN Bilirubin (total) <2.5 x ULN unless Gilbert's disease is present or subject is receiving atazanavir in the absence of other evidence of significant liver disease Creatinine ≤1.5 x ULN Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator Both male and female patients and their partners of childbearing potential must agree to use 2 medically accepted methods of contraception (e.g., barrier contraceptives [male condom, female condom, or diaphragm with a spermicidal gel], hormonal contraceptives [implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings], and intrauterine devices) during the course of the study (excluding women who are not of childbearing potential and men who have been sterilized). Females of childbearing potential must have a negative serum pregnancy test at Screening visit and negative urine pregnancy test prior to receiving the first dose of study drug Willing and able to participate in all aspects of the study, including use of SC medication, completion of subjective evaluations, attendance at scheduled clinic visits, and compliance with all protocol requirements as evidenced by providing written informed consent Note: Subjects diagnosed with either substance dependence or substance abuse or any history of a concomitant condition (e.g., medical, psychologic, or psychiatric) may be enrolled if in the opinion of site investigator these circumstances would not interfere with the subject's successful completion of the study requirements Exclusion Criteria: Documented CXCR4-tropic virus or Dual/Mixed tropic (R5X4) virus as determined by HIV-1 tropism assay Patients with no viable treatment options ( i.e., no fully active antiretroviral drug available which can be effectively combined to form a viable new OBT) Any active infection or malignancy requiring acute therapy (with the exception of local cutaneous Kaposi's sarcoma) Note: Subjects infected by the hepatitis B virus or hepatitis C virus will be eligible for the study if they have no signs of hepatic decompensation and meet the liver function tests eligibility criteria Laboratory test values of ≥ grade 3 DAIDS laboratory abnormality with the exception of the absolute CD4+ count criterion of <200/mm3 Females who are pregnant, lactating, or breastfeeding, or who plan to become pregnant during the study Unexplained fever or clinically significant illness within 1 week prior to the first study dose Any vaccination within 2 weeks prior to the first study dose Subjects weighing < 35kg History of anaphylaxis to oral or parenteral drugs History of Bleeding Disorder or patients on anti-coagulant therapy Participation in an experimental drug trial(s) within 30 days of the Screening Visit Any known allergy or antibodies to the study drug or excipients Treatment with any of the following: Radiation or cytotoxic chemotherapy with 30 days prior to the screening visit Immunosuppressants within 60 days prior to the screening visit Immunomodulating agents (e.g., interleukins, interferons), hydroxyurea, or foscarnet within 60 days prior to the screening visit Oral or parenteral corticosteroids within 30 days prior to the Screening Visit. Subjects on chronic steroid therapy >5 mg/day will be excluded with the following exception: Subjects on inhaled, nasal, or topical steroids will not be excluded Any other clinical condition that, in the Investigator's judgment, would potentially compromise study compliance or the ability to evaluate safety/efficacy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Leronlimab (PRO 140)<br>Subjects will be on existing ART for one week followed by PRO 140 700mg weekly SC Inj. + existing ART for the next week. Subsequently, all subjects will enter the 24-week single-arm, open-label treatment period. During this period, all subjects will receive PRO 140 SC injection and Optimized Background Therapy. | Drug: PRO 140<br>* 2 injections of PRO 140 (2 X 2 mL/inj.)<br>* Other names: Leronlimab;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with ≥ 0.5 log10 reduction in HIV-1 RNA viral load from baseline at the end of the initial 1-week treatment period |  | 1-week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with ≥ 1 log10 reduction in HIV-1 RNA viral load from baseline at the end of the initial 1-week treatment period |  | 1-week | 
| Mean change from Baseline in HIV-1 RNA levels (log10 copies/mL) at the end of the initial 1-week treatment period |  | 1-week | 
| Percentage of participants achieving HIV-1 RNA < 400 copies/mL at week 25 |  | week 25 | 
| Percentage of participants achieving HIV-1 RNA < 50 copies/mL at week 25 |  | week 25 | 
| Mean change from Baseline in HIV-1 RNA levels (log10 copies/mL) |  | week 25 | 
| Mean change from Baseline in CD4 cell count at the end of the initial 1-week treatment period |  | 1-week | 
| Mean change from Baseline in CD4 cell count at week 25 |  | week 25 |