Vacc-4x + Lenalidomide vs. Vacc-4x +Placebo in HIV-1-infected Subjects on Antiretroviral Therapy (ART)

Study Overview
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Brief Summary
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During the course of HIV infection the number of CD4 cells decreases, resulting in a reduced immunological response and ultimately immune deficiency. Vacc-4x is a peptide-based HIV immunotherapy and the primary objective is to strengthen the immune system's response to HIV p24. By adding Lenalidomide, an immunomodulatory agent, as a supporting drug, it is anticipated that the effect of Vacc-4x might be enhanced.

Detailed Description
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Human immunodeficiency virus (HIV) infects the CD4 subset of T-cells that are critical for initiating immune responses to infection. The level of CD4 cells in the blood is a marker of a patient's immunological status. The number of CD4 cells decreases in the course of the HIV infection and results in a reduced immunological response and eventually immune deficiency. Vacc-4x is one of the few peptide-based therapeutic vaccines tested, and consists of four, slightly modified HIV Gag p24 consensus peptides. Vacc-4x was first tested by intradermal injections using GM-CSF as adjuvant. A recent multinational placebo-controlled study found improvement of vaccine-specific T cell immunity and decrease in viral loads (presented at the AIDS vaccine 2011 conference, Bangkok). Lenalidomide (CC-5013) is a substance in the class of immunomodulatory agents. The lenalidomide mechanism of action includes anti-neoplastic, pro-erythropoietic, and immunomodulatory properties. Lenalidomide inhibits proliferation of certain hematopoietic tumor cells, enhances T cell- and Natural Killer (NK) cell-mediated immunity and increases the number of NK T cells. The anti-HIV p24 immune response resulting from Vacc-4x immunization could in combination with ART potentially improve immune reconstitution in patients who have not fully regained a healthy CD4 level (> 600 x106/L). Adding the immunomodulatory agent Lenalidomide (CC-5013) to Vacc-4x immunization could enhance the immune response to Vacc-4x and further strengthen immune reconstitution.

Official Title
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A Double-blind Placebo Controlled Immunogenicity Study of Vacc-4x + Lenalidomide Versus Vacc-4x With an Initial Open-label Dose Escalation Assessment of Lenalidomide in HIV-1-infected Subjects on Antiretroviral Therapy (ART).

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Lenalidomide placebo
* Drug: Vacc-4X
* Drug: rhuGM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men, age ≥ 18 and ≤ 55 years at the time of screening. Women, age ≥ 50 and ≤ 55 years at the time of screening, who are not of childbearing potential (see Exclusion criteria, point 9). Childbearing status must be documented. Clinically stable on ART for the last 18 months (changes in therapy are allowed as long as the viral load is stable). Well controlled with no treatment failure due to ART resistance in the past Screening plasma viral load (HIV-1 RNA) less than 50 copies/mL for the last six months. If screening value is between 50-500 copies/mL rescreening is allowed. Single blips (up to 500 copies/mL) are allowed. Screening CD4 cell count ≥ 200x10^6 cells/L and ≤500x10^6 cells/L. (Rescreening is allowed) Laboratory test results within these ranges: Absolute neutrophil count (ANC) >1.0x10^9 /L, Platelet count >75x10^9 /L and eGRF (MDRD) >60 mL/min Signed informed consent Willingness to adhere to Global Pregnancy Prevention Risk Management Plan Lenalidomide Exclusion Criteria: Reported pre-study AIDS-defining illness within the previous year Malignant disease. On chronic treatment with immunosuppressive therapy. Autoimmune disorders, present or in the past if there is an increased risk of disease exacerbation. Unacceptable values of the hematologic and clinical chemistry parameters (including those associated with hemophilia), as judged by the Investigator or the Sponsor (or designee), including creatinine values >1.5x upper limit of normal (ULN), and AST (SGOT), ALT (SGPT), and alkaline phosphatase values >2.5x ULN. Concurrent chronic active infection such as viral hepatitis B or C or tuberculosis. Previous thromboembolic events or patient is currently immobilized Sexually active subjects who do not adhere to Global Pregnancy Prevention Risk Management Plan Lenalidomide Current participation in other clinical therapeutic studies. Females of childbearing potential will be excluded from this trial. A female of childbearing potential (FCBP) is a sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months). The development of erythema nodosum if characterized by a desquamating rash while previously Incapability of compliance to the treatment protocol, in the opinion of the Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: lenalidomide dose escalation<br>All patient receive intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide in a dose escalation (3+3) design. Dose level -1: 2.5 mg Lenalidomide (CC-5013) in the event Dose level 1 is non tolerated dose (NTD) Dose level 1(start): 5 mg Lenalidomide (CC-5013) Dose level 2: 10 mg Lenalidomide (CC-5013) Dose level 3: 25 mg Lenalidomide (CC-5013) | Drug: Lenalidomide<br>* In Part A a dose escalation design is used (2,5; 5; 10; 25 mg). Part B will use the dose confirmed by Part A<br>* Other names: Lenalidomide capsule;Drug: Vacc-4X<br>* Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.<br>* Other names: Combination of Vacc-10, Vacc-11, Vacc-12 and Vacc-13.;Drug: rhuGM-CSF<br>* Granulocyte macrophage colony stimulating factor as a local adjuvant<br>* Other names: Leukine®;|
| Experimental: Part B: lenalidomide<br>Intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide for 6 immunizations (visit 2, 3, 4, 5, 6 and 7) & lenalidomide (dose determined in Part A) two days prior to and at the day of immunization. | Drug: Lenalidomide<br>* In Part A a dose escalation design is used (2,5; 5; 10; 25 mg). Part B will use the dose confirmed by Part A<br>* Other names: Lenalidomide capsule;Drug: Vacc-4X<br>* Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.<br>* Other names: Combination of Vacc-10, Vacc-11, Vacc-12 and Vacc-13.;Drug: rhuGM-CSF<br>* Granulocyte macrophage colony stimulating factor as a local adjuvant<br>* Other names: Leukine®;|
| Placebo Comparator: Part B: lenalidomide placebo<br>Intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide for 6 immunizations (visit 2, 3, 4, 5, 6 and 7) & lenalidomide placebo two days prior to and at the day of immunization. | Drug: Lenalidomide placebo<br>* Capsules are identical to the active Lenalidomide capsules used.<br>* Other names: placebo;Drug: Vacc-4X<br>* Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.<br>* Other names: Combination of Vacc-10, Vacc-11, Vacc-12 and Vacc-13.;Drug: rhuGM-CSF<br>* Granulocyte macrophage colony stimulating factor as a local adjuvant<br>* Other names: Leukine®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: To Establish Highest Tolerated Dose of Lenalidomide, Dose-Limiting Toxicity | Number of participants in each of the three groups that experienced any dose-limiting toxicity. | 31 days | 
| Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time |  | 31 days | 
| Part B: Change in CD4 Count | Change in CD4 count from baseline to Week 26. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part B: Change in CD8 Count | Change in CD8 count from baseline to week 26. | 26 weeks | 
| Part B: Evaluate the Effect on HIV Viral Load | Results BLQ (<20 HIV copies/mL) have been replaced with BLQ/2 = 10 HIV copies/mL while 'not detected' results have been replaced with 0 HIV copies/mL. | 26 weeks | 
| Part B: Incidents of Delayed-type Hypersensitivity | Delayed-type hypersensitivity measured by induration and erythema. | 26 weeks | 
| Part A and B: Safety and Tolerability |  | Part A: 31 days and Part B: 26 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD4, Clinical trial, Dose escalation assessment lenalidomide, Human immunodeficiency virus-1 (HIV-1), HIV, Immunomodulatory, Infection, Lenalidomide, Phase I/II, Vaccine, Vacc-4x