Preliminary Assessment of Safety and Tolerability of Dostarlimab in Combination Antiretroviral Therapy (cART) Refractory HIV Associated Kaposi Sarcoma
This is a phase 1b, open label, single arm study evaluating the safety and tolerability of the drug dostarlimab in combination antiretroviral therapy (cART) refractory HIV-associated Kaposi Sarcoma (KS), a rare type of cancer usually seen in people with the HIV infection. Dostarlimab is a type of immunotherapy, and is a monoclonal antibody that has been designed to inhibit the receptor programmed death-1 (PD-1). One of the two ligands for PD-1 has been shown to be upregulated in KS patients, the PDL-1 ligand. By preventing PDL-1 form binding to PD-1, dostarlimab increases the body's immune response to attack more cancer cells. The safety profile of dostarlimab in this specific cancer has not been explored. The primary aim of this study is therefore to provide confirmatory evidence of safety of dostarlimab in KS patients and to preliminary evaluate its effects on HIV reservoirs and assess how it causes its anti-cancer effects through studying tumour tissue before and after treatment. This study will be conducted in two parts and will recruit a total of up to 20 patients. Upon completion of screening investigations inclusive of a fresh tumour biopsy within a 28-days window, patients will receive dostarlimab at the fixed dose of 500 mg dose every 3 weeks for the first 4 doses followed by a fixed 1000 mg dose every 6 weeks. Treatment will be continued until loss of clinical benefit, unacceptable toxicity, patients' withdrawal or completion of a total of 48 weeks of treatment. Part 1 will consist of 6 patients being dosed and observed for toxicity for 21 days following first dose. A trial steering committee will evaluate any treatment related adverse events (AEs) and dose-limiting toxicities (DLTs) reported before deciding on whether to continue onto part 2, where a further 14 patients may be enrolled.
• Histologically proven diagnosis of Kaposi Sarcoma.
• Available pretreatment biopsy, either fresh (optimal) or archival (acceptable).
• Established on cART for at least 3 months and no symptomatic or laboratory AE associated with cART \> grade 1 by CTCAE criteria v 5.0.
• Note: modifications of cART during screening are allowed provided patients meet all other eligibility criteria and are on effective new regimen for at least 2 weeks.
• Have an HIV VL\<200 cp/ml and CD4+ T-cell count \>100/mm3 at screening.
• Have disease that is measurable by modified AIDS Clinical Trial Group (ATCG) Kaposi sarcoma response criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Be of ≥ 18 years of age
• Have adequate haematological and organ function, defined as follows:
• Absolute neutrophil count \>1.500/mcL, Platelet count \>100.000/mcL, Haemoglobin \>90 g/L, Total bilirubin ≤1.5x upper limit of normal (ULN) or ≤2xULN for patients with Gilbert's syndrome or on HIV protease inhibitors, Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5x ULN (up to 5x ULN if liver metastases are present), Serum creatinine ≤2.5x ULN or creatinine clearance (CrCl) \>60 ml/min in subjects with serum creatinine ≤1.5x ULN. Calculation of CrCl should follow institutional standards.
• International normalized ratio (INR) or prothrombin time (PT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤1.5× ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Female participants must have a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agree use a highly effective method of contraception from screening through 120 days after the last dose of study treatment or is of nonchildbearing potential. Nonchildbearing potential is defined as follows (by other than medical reasons):
‣ ≥45 years of age and has not had menses for \>1 year
⁃ Patients who have been amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
⁃ Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure, otherwise the patient must be willing to use an adequate birth control method throughout the study, starting with the screening visit through 120 days after the last dose of study treatment. See Section 5.4 for a list of acceptable birth control methods. Information must be captured appropriately within the site's source documents. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
⁃ Participant must agree to not breastfeed during the study or for 90 days after the last dose of study treatment.
⁃ Male participant agrees to use a highly effective method of contraception (see Section 5.4 for a list of acceptable birth control methods) starting with the first dose of study treatment through 120 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
⁃ Participant receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.