HIV-1 Infection
Conditions
Keywords
CD4, Clinical trial, Dose escalation assessment lenalidomide, Human immunodeficiency virus-1 (HIV-1), HIV, Immunomodulatory, Infection, Lenalidomide, Phase I/II, Vaccine, Vacc-4x
Brief summary
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
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.
Interventions
DRUGLenalidomide
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
Capsules are identical to the active Lenalidomide capsules used.
DRUGVacc-4X
Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.
DRUGrhuGM-CSF
Granulocyte macrophage colony stimulating factor as a local adjuvant
Sponsors
Celgene Corporation
Bionor Immuno AS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Men, age ≥ 18 and ≤ 55 years at the time of screening. 2. 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. 3. Clinically stable on ART for the last 18 months (changes in therapy are allowed as long as the viral load is stable). 4. Well controlled with no treatment failure due to ART resistance in the past 5. 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. 6. Screening CD4 cell count ≥ 200x10\^6 cells/L and ≤500x10\^6 cells/L. (Rescreening is allowed) 7. 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 8. Signed informed consent 9. Willingness to adhere to Global Pregnancy Prevention Risk Management Plan Lenalidomide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: To Establish Highest Tolerated Dose of Lenalidomide, Dose-Limiting Toxicity | 31 days | Number of participants in each of the three groups that experienced any dose-limiting toxicity. |
| Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | 31 days | — |
| Part B: Change in CD4 Count | Week 26 | Change in CD4 count from baseline to Week 26. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part B: Change in CD8 Count | 26 weeks | Change in CD8 count from baseline to week 26. |
| Part A and B: Safety and Tolerability | Part A: 31 days and Part B: 26 weeks | — |
| Part B: Evaluate the Effect on HIV Viral Load | 26 weeks | 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. |
| Part B: Incidents of Delayed-type Hypersensitivity | 26 weeks | Delayed-type hypersensitivity measured by induration and erythema. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Lenalidomide 5 mg Intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide 5 mg | 3 |
| Part A: Lenalidomide 10 mg Intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide 10 mg | 3 |
| Part A: Lenalidopmide 25 mg Intradermal Vacc-4x (1.2 mg) given with Leukine® (rhu-GM-CSF) (0.06 mg) and oral lenalidomide 25 mg | 6 |
| Part B: Lenalidomide 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.
Lenalidomide: 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
Vacc-4X: Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.
rhuGM-CSF: Granulocyte macrophage colony stimulating factor as a local adjuvant | 12 |
| Part B: Lenalidomide Placebo 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.
Lenalidomide placebo: Capsules are identical to the active Lenalidomide capsules used.
Vacc-4X: Vacc-4x is a peptide-based HIV immunotherapy administered intradermally. Vacc-4x peptides are reconstituted in sterile water.
rhuGM-CSF: Granulocyte macrophage colony stimulating factor as a local adjuvant | 12 |
| Total | 36 |
Baseline characteristics
| Characteristic | Part A: Lenalidomide 5 mg | Total | Part B: Lenalidomide Placebo | Part B: Lenalidomide | Part A: Lenalidopmide 25 mg | Part A: Lenalidomide 10 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 43.7 years STANDARD_DEVIATION 4.16 | 42.9 years STANDARD_DEVIATION 7.34 | 41.5 years STANDARD_DEVIATION 8.04 | 44.4 years STANDARD_DEVIATION 7.97 | 46.2 years STANDARD_DEVIATION 5.42 | 35.7 years STANDARD_DEVIATION 3.06 |
| BMI | 23.7 kg/m^2 STANDARD_DEVIATION 2.32 | 24.1 kg/m^2 STANDARD_DEVIATION 3.74 | 23.5 kg/m^2 STANDARD_DEVIATION 3.44 | 23.6 kg/m^2 STANDARD_DEVIATION 3.85 | 24.4 kg/m^2 STANDARD_DEVIATION 1.75 | 27.9 kg/m^2 STANDARD_DEVIATION 7.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 36 Participants | 12 Participants | 12 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gender Male | 3 Participants | 36 Participants | 12 Participants | 12 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 33 Participants | 11 Participants | 12 Participants | 6 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 2 / 3 | 6 / 6 | 10 / 12 | 9 / 12 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 6 | 1 / 12 | 0 / 12 |
Outcome results
Primary
Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time
Time frame: 31 days
Population: ITT analysis set was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Baseline | 437.3 10^6 cells/mL | Standard Deviation 38.3 |
| Part A: Lenalidomide 5 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 1 | 393.0 10^6 cells/mL | Standard Deviation 167.56 |
| Part A: Lenalidomide 5 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 4 | 442.0 10^6 cells/mL | Standard Deviation 121.77 |
| Part A: Lenalidomide 5 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 5 | 432.7 10^6 cells/mL | Standard Deviation 242.47 |
| Part A: Lenalidomide 10 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 5 | 449.0 10^6 cells/mL | Standard Deviation 71.04 |
| Part A: Lenalidomide 10 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Baseline | 436.3 10^6 cells/mL | Standard Deviation 60.05 |
| Part A: Lenalidomide 10 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 4 | 399.3 10^6 cells/mL | Standard Deviation 15.95 |
| Part A: Lenalidomide 10 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 1 | 317.0 10^6 cells/mL | Standard Deviation 18.52 |
| Part A: Lenalidopmide 25 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 5 | 452.3 10^6 cells/mL | Standard Deviation 66.28 |
| Part A: Lenalidopmide 25 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 1 | 342.2 10^6 cells/mL | Standard Deviation 27.13 |
| Part A: Lenalidopmide 25 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Week 4 | 450.7 10^6 cells/mL | Standard Deviation 147.02 |
| Part A: Lenalidopmide 25 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, CD4 Counts Over Time | Baseline | 454.2 10^6 cells/mL | Standard Deviation 86.59 |
Primary
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.
Time frame: 31 days
Population: ITT analysis set was used.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Lenalidomide 5 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, Dose-Limiting Toxicity | 0 Participants |
| Part A: Lenalidomide 10 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, Dose-Limiting Toxicity | 0 Participants |
| Part A: Lenalidopmide 25 mg | Part A: To Establish Highest Tolerated Dose of Lenalidomide, Dose-Limiting Toxicity | 0 Participants |
Primary
Part B: Change in CD4 Count
Change in CD4 count from baseline to Week 26.
Time frame: Week 26
Population: Analysis was performed for both the Intent To Treat (ITT) and Per Protocol (PP) analysis set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part B: Change in CD4 Count | ITT | 90.9 10^6 cells/L | Standard Deviation 98.79 |
| Part A: Lenalidomide 5 mg | Part B: Change in CD4 Count | PP | 106.3 10^6 cells/L | Standard Deviation 101 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD4 Count | ITT | 42.2 10^6 cells/L | Standard Deviation 81.4 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD4 Count | PP | 49.1 10^6 cells/L | Standard Deviation 81.58 |
Secondary
Part A and B: Safety and Tolerability
Time frame: Part A: 31 days and Part B: 26 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part A and B: Safety and Tolerability | With any TEAE | 3 participants |
| Part A: Lenalidomide 5 mg | Part A and B: Safety and Tolerability | With TESAE | 0 participants |
| Part A: Lenalidomide 5 mg | Part A and B: Safety and Tolerability | With any AE resultiung in withdrawal | 0 participants |
| Part A: Lenalidomide 5 mg | Part A and B: Safety and Tolerability | Deaths | 0 participants |
| Part A: Lenalidomide 10 mg | Part A and B: Safety and Tolerability | With any TEAE | 2 participants |
| Part A: Lenalidomide 10 mg | Part A and B: Safety and Tolerability | Deaths | 0 participants |
| Part A: Lenalidomide 10 mg | Part A and B: Safety and Tolerability | With TESAE | 0 participants |
| Part A: Lenalidomide 10 mg | Part A and B: Safety and Tolerability | With any AE resultiung in withdrawal | 0 participants |
| Part A: Lenalidopmide 25 mg | Part A and B: Safety and Tolerability | Deaths | 0 participants |
| Part A: Lenalidopmide 25 mg | Part A and B: Safety and Tolerability | With TESAE | 0 participants |
| Part A: Lenalidopmide 25 mg | Part A and B: Safety and Tolerability | With any AE resultiung in withdrawal | 0 participants |
| Part A: Lenalidopmide 25 mg | Part A and B: Safety and Tolerability | With any TEAE | 6 participants |
| Part B: Lenalidomide | Part A and B: Safety and Tolerability | With any TEAE | 10 participants |
| Part B: Lenalidomide | Part A and B: Safety and Tolerability | With TESAE | 1 participants |
| Part B: Lenalidomide | Part A and B: Safety and Tolerability | Deaths | 0 participants |
| Part B: Lenalidomide | Part A and B: Safety and Tolerability | With any AE resultiung in withdrawal | 0 participants |
| Part B: Lenalidomide Placebo | Part A and B: Safety and Tolerability | Deaths | 0 participants |
| Part B: Lenalidomide Placebo | Part A and B: Safety and Tolerability | With any AE resultiung in withdrawal | 0 participants |
| Part B: Lenalidomide Placebo | Part A and B: Safety and Tolerability | With TESAE | 0 participants |
| Part B: Lenalidomide Placebo | Part A and B: Safety and Tolerability | With any TEAE | 9 participants |
Secondary
Part B: Change in CD8 Count
Change in CD8 count from baseline to week 26.
Time frame: 26 weeks
Population: Not all patients had quantifiable blood samples/counts at all time points
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part B: Change in CD8 Count | Week 1 | 653.8 10^6 cells/L | Standard Deviation 382.16 |
| Part A: Lenalidomide 5 mg | Part B: Change in CD8 Count | Week 12 | 823.0 10^6 cells/L | Standard Deviation 548.84 |
| Part A: Lenalidomide 5 mg | Part B: Change in CD8 Count | Week 4 | 744.9 10^6 cells/L | Standard Deviation 485.49 |
| Part A: Lenalidomide 5 mg | Part B: Change in CD8 Count | Week 13 | 811.2 10^6 cells/L | Standard Deviation 557.52 |
| Part A: Lenalidomide 5 mg | Part B: Change in CD8 Count | Baseline | 734.2 10^6 cells/L | Standard Deviation 473.14 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD8 Count | Week 13 | 663.6 10^6 cells/L | Standard Deviation 393.95 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD8 Count | Baseline | 655.3 10^6 cells/L | Standard Deviation 325.19 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD8 Count | Week 1 | 784.5 10^6 cells/L | Standard Deviation 372.96 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD8 Count | Week 4 | 794.5 10^6 cells/L | Standard Deviation 452.91 |
| Part A: Lenalidomide 10 mg | Part B: Change in CD8 Count | Week 12 | 760.3 10^6 cells/L | Standard Deviation 432.79 |
Secondary
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.
Time frame: 26 weeks
Population: ITT analysis set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 4 | 6.4 Copies/mL | Standard Deviation 8.17 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 13 | 7.4 Copies/mL | Standard Deviation 19.77 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 1 | 5.1 Copies/mL | Standard Deviation 9.3 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 21 | 1.7 Copies/mL | Standard Deviation 3.89 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 12 | 5.5 Copies/mL | Standard Deviation 11.29 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 26 | 3.5 Copies/mL | Standard Deviation 6.99 |
| Part A: Lenalidomide 5 mg | Part B: Evaluate the Effect on HIV Viral Load | Baseline | 0.8 Copies/mL | Standard Deviation 2.89 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 26 | 2.5 Copies/mL | Standard Deviation 4.52 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Baseline | 2.5 Copies/mL | Standard Deviation 4.52 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 1 | 0.0 Copies/mL | Standard Deviation 0 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 4 | 0.9 Copies/mL | Standard Deviation 3.02 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 12 | 4.3 Copies/mL | Standard Deviation 6.9 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 13 | 1.7 Copies/mL | Standard Deviation 3.89 |
| Part A: Lenalidomide 10 mg | Part B: Evaluate the Effect on HIV Viral Load | Week 21 | 4.2 Copies/mL | Standard Deviation 5.15 |
Secondary
Part B: Incidents of Delayed-type Hypersensitivity
Delayed-type hypersensitivity measured by induration and erythema.
Time frame: 26 weeks
Population: The IIT population was used for this outcome measure. Data for one patient was not reported at week 26.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Lenalidomide 5 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 1, Induration | 0 Participants |
| Part A: Lenalidomide 5 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 26, Induration | 5 Participants |
| Part A: Lenalidomide 5 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 1, Erythema | 0 Participants |
| Part A: Lenalidomide 5 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 26, Erythema | 6 Participants |
| Part A: Lenalidomide 10 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 26, Erythema | 6 Participants |
| Part A: Lenalidomide 10 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 1, Induration | 0 Participants |
| Part A: Lenalidomide 10 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 1, Erythema | 1 Participants |
| Part A: Lenalidomide 10 mg | Part B: Incidents of Delayed-type Hypersensitivity | Week 26, Induration | 2 Participants |