Background:
* Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV-associated KS have worse survival than HIV-infected patients without KS.
* As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy.
* KS is an immune responsive tumor as interferon-alpha, pomalidomide, and restoring T-cell function in HIV + patients treated with antiretroviral drugs can result in clinical benefit and remission of KS.
* Published Phase I/II studies by our group demonstrated that IL-12 alone and in combination with liposomal doxorubicin led to clinical responses in patients with advanced KS.
* PDS01ADC is an immunocytokine with affinity to both single and double stranded DNA allowing for targeting of exposed DNA, which is commonly seen in necrotic tumors. This agent is able to deliver IL-12 to the tumor microenvironment promoting local immunomodulation, that results in less systemic toxicity than IL-12 systemic administration.
* M7824 is a novel bifunctional fusion protein composed of a monoclonal antibody against human PD-L1 (avelumab) fused with the extracellular domain of human TGF-beta receptor II (TGF-betaRII), which functions as a TGF-beta trap .
* Anti-PD-L1 and anti-PD-1 agents have been found to be active in certain virus-induced cancers, including Kaposi sarcoma, and to be safe and active in patients with HIV infection.
* Currently, no clinical data exists for the combination of PDS01ADC and M7824. Preclinical data suggest synergy between these agents from existing ongoing studies and the available clinical data both in KS and other tumor subtypes suggest that the combination of PDS01ADC with M7824 is likely to be well-tolerated and has scientific rationale. This combination offers a new treatment approach for patients with advanced KS who have received prior therapies.
Objectives:
-Evaluate the safety, tolerability, and activity of single agent PDS01ADC and the combination of PDS01ADC with M7824 in participants with advanced KS
Eligibility:
* Age \>=18 years
* Histologically confirmed Kaposi sarcoma (KS)
* KS requiring systemic therapy, with or without a history of prior systemic therapy
* At least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions.
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) \<= 2
* Participant must be willing to give informed consent.
* Participants can be HIV positive or negative.
* Antiretroviral therapy (ART) for HIV+ participants for 8 or more weeks prior to entry with an HIV viral load of \<400 copies/ml and CD4+ T-cell count \>50 cells/microliter.
* Participants with bleeding from visceral sites of KS or requiring blood transfusions in the 2 weeks prior to study entry will not be eligible.
Design:
* This is a Phase I/II study assessing the safety and efficacy of PDS01ADC alone or in combination with M7824 in participants with advanced KS. Participants will receive therapy until optimal tumor response, unacceptable toxicity, the participant s request to discontinue therapy, PI decision, up to a total of 96 weeks, or 24 cycles.
* Monotherapy: Participants with history of prior systemic therapy will receive PDS01ADC alone with a 3+3 design applicable to the first 3-6 participants at a starting dose of 16.8 microgram/kg on day 1 of a 28-day cycle. Two dose de-escalation levels (Dose Level -1: 12 microgram/kg or Dose Level -2: 8 microgram/kg) will be permitted if there is evidence of 2 or more dose limiting toxicities within the first 6 weeks of therapy. An expansion cohort will investigate the activity of PDS01ADC in participants with and without prior systemic therapy for KS.
* Combination Therapy: The combination arm will open following accrual and completion of the DLT period for participants in the monotherapy arm. Up to 28 participants will be treated with M7824 (1200 mg IV, every 2 weeks) and PDS01ADC (MTD dose from the monotherapy arm). The DLT period for this arm will be 6 weeks.
