Safety and Impact of Dasatinib on Inflammation and AIDS virus in People under treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

28 Jun 2024 → ongoing

Decision date (initial)

2024-06-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Instituto de Salud Carlos III-Ministero Ciencia e Innovación-Ayudas Investigación Clínica Indep.

External identifiers

EU CT number

2024-513714-36-01

ClinicalTrials.gov

NCT05780073

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

· To evaluate the safety and tolerability of dasatinib administered at 70 mg once daily during 24 weeks in PWH on suppressive ART.
· To evaluate the on-target/biological effect of dasatinib administered at 70 mg once daily during 24 weeks in PWH on suppressive ART on the reduction of SAMHD1 phosphorylation upon in-vitro T-cell activation, and its durability after completion of dasatinib treatment.

Secondary objectives 1

1. · To evaluate the effect of of dasatinib administered at 70 mg once daily during 24 weeks in PWH on suppressive ART and its maintenance after completion of dasatinib treatment, in the following additional on-target/biological effects attributed to dasatinib: a- Proviral reactivation capacity upon in-vitro T-cell activation b- Resistance to HIV infection c- Plasma levels of homeostatic cytokines d- CMV and HIV-specific cytotoxic activity in NK and CD8+/CD4+ T cells · To evaluate the impact of dasatinib administered at 70 mg once daily during 24 weeks in PWH on suppressive ART and its maintenance after completion of dasatinib treatment on: a- Inflammation and immune activation b- HIV-1 reservoir c- CD4 T cell counts, CD4% and CD4/CD8 levels · To characterize dasatinib concentrations in plasma when administered at a 70 mg once daily dose in PWH on suppressive ART and its relationship with the abovementioned effects. · To identify predictors of maintenance of dasatinib effects in HIV reservoir and inflammatory biomarkers after dasatinib interruption.

Conditions and MedDRA coding

Human immunodeficiency virus

Study design 1 period

Regulatory references

Plan to share IPD

No

IPD plan description

No individual participant data will be shared

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Males and females aged at least 18 years on the day of screening.
2. 2. Confirmed HIV-1 infection.
3. 3. Receiving suppressive cART for at least 3 years (defined as maintained plasma viral load <50 copies/mL, allowing for isolated blips [<200 cop/ml, non-consecutive, representing <20% total determinations]).
4. 4. Being on the same ART regimen within at least 4 weeks prior to baseline visit.
5. 5. Willing and able to be adherent to their ART regimen for the duration of the study.
6. 6. Willing to comply with the requirements of the protocol and available for follow-up for the planned duration of the study.
7. 7. In the opinion of the Principal Investigator, the candidate has understood the information provided and can give written Informed Consent.
8. 8. If heterosexually active female of childbearing potential1, using an effective method of contraception (hormonal contraception, intra-uterine device (IUD), or anatomical sterility in self or partner) from 14 days prior to the first IMP administration and commit to use it until 3 months after the last IMP administration. All female candidates of childbearing potential who are not heterosexually active at screening, must agree to utilize an effective method of contraception if they become heterosexually active during the study.
9. 9. If heterosexually active male, regardless of reproductive potential, sterilized or agree on the use of an effective method of contraception by his female partner (hormonal contraception, intra-uterine device (IUD), or anatomical sterility2) from the day of the first IMP administration until 3 months after the last IMP administration. All male candidates who are not heterosexually active at screening, must agree to utilize an effective method of contraception if they become heterosexually active during the study.
10. 10. If female, willing to undergo urine pregnancy tests at the designated time points.
11. 11. Willing to accept blood draws at time points specified in the Schedule of Events.

Exclusion criteria 17

1. 1. If female, pregnant or planning a pregnancy during the entire study or lactating.
2. 2. Current treatment with ART regimen that includes ritonavir, cobicistat or with any other drug with known relevant drug-drug interactions with dasatinib.
3. 3. Has received any immunotherapy with intent to cure or prevent HIV, including monoclonal antibodies, therapeutic or preventive vaccines within 6 months prior to baseline visit.
4. 4. Prior history of exposure to dasatinib or any other TKI.
5. 5. Prior history of pleural effusion.
6. 6. Prior history or clinical manifestations of any physical or psychiatric disorder that could impair the subject’s ability to complete the study.
7. 7. Any active AIDS-defining disease or progression of HIV-related disease, except cutaneous Kaposi’s sarcoma not requiring systemic therapy.
8. 8. Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal, or penile intraepitelial neoplasia.
9. 9. Ongoing diabetes mellitus with poor metabolic control (requiring insulin therapy initiation, hospitalization or documented HbA1c >8% within the last 3 months).
10. 10. Systemic treatment for cancer within 1 year of study entry.
11. 11. Known hypersensitivity to any component of the IMP formulation, or severe or multiple allergies to drugs or pharmaceutical agents.
12. 12. Potential participant received or plans to receive: a. Licensed live attenuated vaccines within 28 days before or after inflammation and immune biomarkers visit (weeks 0, 2, 24 and 48). b. other vaccines (eg, tetanus, hepatitis A, hepatitis B, rabies, pneumococcal, recombinant Herpes Zoster, Influenza, COVID-19 vaccines) within 14 days before or after inflammation and immune biomarkers visits (weeks 0, 2, 24 and 48)1.
13. 13. Receipt of blood products within 3 months of study entry.
14. 14. Current or recent use (within last 3 months) of interferon or systemic corticosteroids or other immunosuppressive agents (use on inhaled steroids for asthma or topic steroids for localized skin conditions are permitted).
15. 15. Any other current or prior therapy which, in the opinion of the investigator, would make the individual unsuitable for the study or influence the results of the study.
16. 16. Any laboratory abnormalities including: Hematology · Hemoglobin <10.0 g/dl, · absolute neutrophil count ≤3,000 /mm3, · Platelets ≤100,000/mm3, Biochemistry · eGFR <60 ml/min, · AST > 2.5 x ULN, · ALT > 2.5 x ULN, Microbiology · Positive for hepatitis B surface antigen, · Positive for hepatitis C antibody, unless confirmed clearance of HCV infection (spontaneous or following treatment) · Positive serology indicating active syphilis requiring treatment2
17. 17. Has a QTc interval ≥470 msec (males) or ≥480 msec (females) upon confirmation on recheck at screening, has a history of risk factors for Torsades de Pointes (eg, heart failure/cardiomyopathy or family history of long QT syndrome), or is taking concomitant medications that prolong the QT/QTc interval.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. · Proportion of participants that develop Grade 3 or 4 treatment-related adverse events or laboratory abnormalities during the study, based on the CTCAE v5.0 grading scale.
2. · Proportion of SAMHD1 phosphorylation in CD4+ T cells upon in-vitro T cell activation at weeks 0, 2, 12, 24, 28, 36 and 48.

Secondary endpoints 3

1. Antiviral effect of dasatinib and its durability:Proviral reactivation capacity upon in-vitro T-cell activation, Resistance to HIV infection, Homeostatic proliferation, Immunomodulatory effects
2. Impact of dasatinib and its durability on: Inflammation and immune activation, HIV-1 reservoir, CD4+ T cell populations
3. Pharmacokinetics of dasatinib: · Dasatinib concentrations in plasma at weeks 0, 2, 12 and 24.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Sponsor organisation

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Address

Carretera De Can Ruti

City

Barcelona

Postcode

08916

Country

Spain

Scientific contact point

Organisation

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Contact name

Jessica Soria Izquierdo

Public contact point

Organisation

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Contact name

Jessica Soria Izquierdo

Sponsor responsibilities

Article 77 compliance

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Contact point sponsor

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Article 77 implementation

Instituto De Investigacion En Ciencias De La Salud Germans Trias I Pujol

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications