The Effect of Ixazomib on the Latent HIV Reservoir

• ClinicalTrials.gov Identifier: NCT02946047
• Recruitment Status: Completed
• First Posted: October 26, 2016
• Results First Posted: January 6, 2022
• Last Update Posted: January 6, 2022
• Sponsor: Mayo Clinic
• Collaborator: Takeda
• Information provided by (Responsible Party): Nathan W. Cummins, M.D., Mayo Clinic

Tracking Information

• First Submitted Date: October 24, 2016
• First Posted Date: October 26, 2016
• Results First Submitted Date: December 8, 2021
• Results First Posted Date: January 6, 2022
• Last Update Posted Date: January 6, 2022
• Actual Study Start Date: March 20, 2017
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 8, 2021)

Incidence of Treatment-Emergent Adverse Events [ Time Frame: 7 months ]

Number of treatment-emergent adverse events experienced by subjects as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Original Primary Outcome Measures (submitted: October 25, 2016)

Safety [ Time Frame: 7 months ]

Time to complete one dosing regimen of Ixazomib

Current Secondary Outcome Measures (submitted: December 8, 2021)

• Cell Associated HIV DNA in CD4 T Cell Subsets [ Time Frame: 24 weeks ]
  HIV copies per million CD4 T cells
• Culturable HIV by Quantitative Viral Outgrowth Assay [ Time Frame: 24 weeks ]
  Infectious units per million CD4 T cells
• Absolute CD4 T Cell Count [ Time Frame: 24 weeks ]
  Cells per microliter
• Absolute CD8 T Cell Count [ Time Frame: 24 weeks ]
  Cells per microliter
• CD4/CD8 Ratio [ Time Frame: 24 weeks ]
  CD4/CD8 T cell count ratio

Original Secondary Outcome Measures (submitted: October 25, 2016)

• Change in cell associated HIV DNA in CD4 T cell subsets (HIV copies per million cells) [ Time Frame: 26 weeks ]
• Change in culturable HIV by quantitative viral outgrowth assay (infectious units per million CD4 T cells) [ Time Frame: 26 weeks ]
• Change in absolute CD4 T cell (cells per microliter) [ Time Frame: 26 weeks ]
• Change in absolute CD8 T cell count (cells per microliter) [ Time Frame: 26 weeks ]
• Change in CD4/CD8 T cell count ratio [ Time Frame: 26 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effect of Ixazomib on the Latent HIV Reservoir
• Official Title: Pilot Study of Ixazomib to Reduce the Number of HIV DNA Positive Lymphoid Cells
• Brief Summary: The primary purpose of the trial is to determine the safety and tolerability of ixazomib in HIV infected patients on antiretroviral therapy. The secondary purpose is to determine the effect of ixazomib on the size of the HIV reservoir.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Human Immunodeficiency Virus (HIV)

Intervention

• Drug: Ixazomib 1 MG
  1 mg on days 1, 8 and 15 for three 28 days cycles, then be reviewed by DSMB and based upon their recommendation patients will receive ixazomib once weekly for 12 weeks or ixazomib 1 mg on days 1, 8 and 15 for three 28 days cycles. Visits 3-15 will have a window of ± 3 days.
  Other Name: Ninlaro
• Drug: Ixazomib 2 MG
  2mg on days 1, 8 and 15 for three 28 days cycles, then be reviewed by DSMB and based upon their recommendation patients will receive ixazomib once weekly for 12 weeks or ixazomib 2 mg on days 1, 8 and 15 for three 28 days cycles. Visits 3-15 will have a window of ± 3 days.
  Other Name: Ninlaro
• Drug: Ixazomib 3 MG
  3 mg on days 1, 8 and 15 for three 28 days cycles, then be reviewed by DSMB and based upon their recommendation patients will receive ixazomib once weekly for 12 weeks or ixazomib 3 mg on days 1, 8 and 15 for three 28 days cycles. Visits 3-15 will have a window of ± 3 days.
  Other Name: Ninlaro
• Drug: Ixazomib 4 MG
  4 mg on days 1, 8 and 15 for three 28 days cycles, then be reviewed by DSMB and based upon their recommendation patients will receive ixazomib once weekly for 12 weeks or ixazomib 4 mg on days 1, 8 and 15 for three 28 days cycles. Visits 3-15 will have a window of ± 3 days.
  Other Name: Ninlaro

Study Arms

• Experimental: Ixazomib 1 mg
  Cohort A: Patients will receive ixazomib 1mg 3 times monthly for 12 weeks, then weekly for 12 weeks.
  Intervention: Drug: Ixazomib 1 MG
• Experimental: Ixazomib 2 mg
  Cohort B: Patients will receive ixazomib 2mg 3 times monthly for 12 weeks, then weekly for 12 weeks.
  Intervention: Drug: Ixazomib 2 MG
• Experimental: Ixazomib 3 mg
  Cohort C: Patients will receive ixazomib 3 mg 3 times monthly for 12 weeks, then weekly for 12 weeks.
  Intervention: Drug: Ixazomib 3 MG
• Experimental: Ixazomib 4 mg
  Cohort D: Patients will receive ixazomib 4mg 3 times monthly for 12 weeks, then weekly for 12 weeks.
  Intervention: Drug: Ixazomib 4 MG

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 25, 2016): 17
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: August 19, 2019
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• The following laboratory values obtained <=14 days prior to registration.
• ANC ≥ LLN (lower limit of normal) and ≤ULN (upper limit of normal), Hgb ≥ LLN and ≤ULN, PLT ≥ LLN and ≤ULN
• Total bilirubin ≤ULN and the direct bilirubin must be ≤ ULN; AST <1.5 x ULN and ALT <1.5 x ULN
• Creatinine <2.0 x ULN and an estimated creatinine clearance > 60 ml/min
• HIV infection with suppressed viral replication on at least 3 active drug ART for at least 6 months
• Suppressed viral replication is defined by plasma HIV viral load <20copies/mL.
• Patient must have HIV viral load <20 copies/ml on two occasions at least 3 months apart.
• In the opinion of the treating physician, patients must have available other regimens likely to suppress HIV should their current regimen fail.
• Male or female patients age >=18 years
• A plasma HIV RNA viral load demonstrating a measure of <20 copies/mL within 30 days prior to study initiation.
• CD4 count >500 cells/mm3 within 30 days prior to study enrollment
• Females must have a negative pregnancy test prior to receiving the 1st dose of ixazomib and be postmenopausal for at least 1 year before the screen visit, or surgically sterile,

• Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree to one of the following:

  • Agree to practice effective barrier contraception AND a second method of contraception for female partners of childbearing potential during the entire study treatment period and through 90 days after the last dose of ixazomib,
  • OR
  • Agree to practice true abstinence when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
  • AND
  • Agree to forego sperm donation for the same period as above.

Exclusion Criteria:

• The following laboratory values obtained <=14 days prior to registration.

  • ANC < LLN and >ULN, Hgb < LLN and >ULN, PLT < LLN and >ULN
  • Total bilirubin >ULN or the direct bilirubin is > ULN; AST >1.5 x ULN or AST >1.5 x ULN
  • Creatinine >=2.0 x ULN or an estimated creatinine clearance <=60mL/min
• Diagnosed and treated for a malignancy within 5 years before randomization, or previously diagnosed with a malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection
• Any infection except HIV (excluding benign conditions that is unlikely to be affected or modulated by treatment with ixazomib, e.g. stye or furuncle), or treatment with anti-infective agents within 14 days of enrollment.
• Pregnant women
• Women of childbearing potential and Nursing women
• Men who are unwilling to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking the drug and for 90 days after stopping ixazomib.
• Any history of peripheral neuropathy, or peripheral neuropathy detected during the screening period.
• Major surgery within 14 days before study registration
• Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin,carbamazepine, phenytoin, phenobarbital), or use of St. John's wort.
• Evidence of current uncontrolled cardiovascular conditions, including serious cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months.
• QTc > 450 milliseconds (msec) for men and >470 milliseconds for women (83) on a 12 lead ECG obtained during the Screening period.
• Known hepatitis B DNA positive status and/or HBsAg positive and/or HBeAg positive, or active hepatitis C replication (HCV RNA positive) or currently on hepatitis C treatment.
• Known history of cirrhosis or active liver inflammation, including "fatty liver" or non-alcohol steatohepatitis (NASH).
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Known allergy to any of the study medications, their analogues or excipients in the various formulations.
• Any other recent or concurrent medical condition that, in the Investigator's opinion, would impose any risk to the patient
• Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing.
• Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02946047
• Other Study ID Numbers: 16-001938
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Nathan W. Cummins, M.D., Mayo Clinic
• Original Responsible Party: Same as current
• Current Study Sponsor: Mayo Clinic
• Original Study Sponsor: Nathan W. Cummins, M.D.
• Collaborators: Takeda

Investigators

• Principal Investigator: Nathan Cummins, MD; Mayo Clinic

• PRS Account: Mayo Clinic
• Verification Date: December 2021