Kaposi sarcoma (KS) tumors grow on the skin, lymph nodes, lungs, bone, and gastrointestinal
tract. KS often affects people with immune deficiencies, such as among people living with HIV
or those with prior history of transplant. Researchers want to see if 2 non-chemotherapy
drugs can help people with KS. NHS-IL12 triggers the immune system to fight tumors. M7824
blocks the pathways that cancer cells use to stop the immune system from fighting tumors.
To learn if giving NHS-IL12 alone or with M7824 could help the immune system fight KS tumors.
People 18 and older with KS that has been treated with chemotherapy or immunotherapy
Participants will be screened with some or all of the following:
computed tomography scan
blood and urine tests
electrocardiogram and echocardiogram
skin KS lesion biopsy
All participants will get NHS-IL12 every 4 weeks for up to 96 weeks (or 24cycles). It is
injected under the skin.
Some participants will also get M7824 every 2 weeks for up to 96 weeks (or 24cycles). It is
given through a plastic tube that is put in an arm vein.
Participants will complete questionnaires about how KS affects their quality of life. Their
KS lesions will be measured and photographed. They will repeat some of the screening tests.
They will give saliva samples or additional tissue samples. They will have a lung function
test. Their ability to perform their normal activities will be assessed. The treatment
duration is up to 96 weeks (or 24cycles) with an option to take NHS-IL12 and/or M7824 until
the KS tumors are not responding, or you develop unacceptable side effects.
Participants will have follow-up visits 7 and 30 days after treatment ends, then every 3 to 6
months for the next 18 months, then once a year for 3 years.
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
HIVassociated 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 Tcell
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
NHS-IL12 (M9241) 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
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- RII), 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
Currently, no clinical data exists for the combination of NHS-IL12 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 NHSIL12 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.
-Evaluate the safety, tolerability, and activity of single agent NHS-IL12 and the combination
of NHS-IL12 with M7824 in participants with advanced KS.
Age >18 years
Histologically confirmed Kaposi sarcoma (KS)
KS requiring systemic therapy, with a history of prior systemic therapy:
2 weeks from last chemotherapy
4 weeks from last immunotherapy
At least five measurable cutaneous KS lesions with no previous local radiation, surgical
or intralesional cytotoxic therapy to these measurable lesions.
ECOG Performance Status (PS) less than or equal to 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.
This is a Phase I/II study assessing the safety and efficacy of NHS-IL12 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 will receive NHS-IL12 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 has been planned to
investigate the activity of this single agent in 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 NHS-IL12 (MTD dose from the
monotherapy arm). The DLT period for this arm will be 6 weeks.
If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.
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