NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma

Last updated: March 12, 2025
Sponsor: National Cancer Institute (NCI)
Overall Status: Active - Recruiting

Phase

1/2

Condition

Sarcoma

Soft Tissue Sarcoma

Kaposi's Sarcoma

Treatment

M7824

NHS-IL12

Clinical Study ID

NCT04303117
200061
20-C-0061
  • Ages > 18
  • All Genders

Study Summary

Background:

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.

Objective:

To learn if giving NHS-IL12 alone or with M7824 could help the immune system fight KS tumors.

Eligibility:

People 18 and older with KS that has been treated with chemotherapy or immunotherapy

Design:

Participants will be screened with some or all of the following:

medical history

physical exam

chest X-ray

computed tomography scan

blood and urine tests

electrocardiogram and echocardiogram

skin KS lesion biopsy

lung exam

gastrointestinal exam

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.

Eligibility Criteria

Inclusion

  • INCLUSION CRITERIA:

  • Individuals with biopsy proven (confirmed in the Laboratory of Pathology, CCR)Kaposi sarcoma (KS)

  • KS requiring systemic therapy, with or without history of prior KS therapy:

  • T1 KS or T0 KS sufficiently widespread that systemic therapy is advisable, orKS affecting quality-of-life due to local symptoms or psychological distress

OR,

  • KS with an inadequate response to liposomal doxorubicin, paclitaxel, other systemicchemotherapy (either progressive disease or stable disease after 3 or more cycles)or immunotherapy (progressive disease)

  • A wash-out period off treatment of 2 weeks from last chemotherapy and 4 weeksfrom last immunotherapy, other systemic treatment with a biologic agent, ormonoclonal antibody therapy will be required in individuals with prior KStherapy.

  • Resolution of toxicity from prior therapy to <= Grade 1.

  • At least five measurable cutaneous KS lesions with no previous local radiation,surgical or intralesional cytotoxic therapy that would prevent responseassessment for that lesion.

  • Measurable disease by the criteria proposed by the AIDS Clinical Trials Group (ACTG) Oncology Committee for KS

  • HIV positive or negative.

  • ART for HIV+ individuals for 8 or more weeks prior to entry with an HIV viralload of <400 copies/ml at screening and CD4+ T cell count of >= 50cells/microliter as this may be expected if individuals have received severalcourses of chemotherapy.

  • Age >=18 years.

  • ECOG performance status <=2 (Karnofsky >=60%).

  • Adequate organ and marrow function as defined below:

  • Absolute neutrophil count >=1,000/mcL

  • Platelets >=100,000/mcL

  • Total bilirubin within normal institutional limits; OR <3x institutional ULN forGilbert s syndrome or HIV protease inhibitors; OR <5x ULN and direct bilirubin < 0.7mg/dL for individuals on atazanavir-containing HIV regimen

  • AST(SGOT)/ALT(SGPT) <=1.5 X institutional upper limit of normal

  • Hemoglobin >= 9g/dL

  • Creatinine within normal institutional limits OR creatinine clearance >30mL/min/1.73m^2 as estimated by either Cockroft-Gault of 24- hour urine collection ifcreatinine levels above institutional normal

  • Normal international normalized ratio (INR), PT<=1.5 x ULN and activatedpartial thromboplastin time (aPTT) <= 1.5 x ULN

  • The effects of PDS01ADC and M7824 on the developing human fetus are unknown.For this reason, individuals of child-bearing potential (IOCBP) and individualsable to father a child must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry, duringtreatment and for at least 4 months after the last dose of treatment and agreeto inform the treating physician immediately if they become pregnant. Also,there is unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with M7824 and/or PDS01ADC, thereforeIOCBP must agree to discontinue nursing if treated with these agents.

  • Ability of individual to understand and the willingness to sign a writteninformed consent document.

Exclusion

EXCLUSION CRITERIA:

  • Receiving any other investigational agents.

  • Pregnant individuals are excluded from this study as the effects of PDS01ADC andM7824 have potential teratogenic or abortifacient effects.

  • Severe KS (such as symptomatic pulmonary KS) that could be life threatening if itprogressed over 2-4 weeks

  • Actively bleeding sites caused by visceral KS.

  • Unwilling to accept blood products as medically indicated

  • Actively bleeding and/or requiring transfusions in the 2 weeks preceding studyentry.

  • History of bleeding, diathesis, or recent major bleeding events within a period of 4weeks considered by the investigator as high risk for investigational drugtreatment.

  • Any active or recent history (symptomatic in the last 3 months) of a known orsuspected autoimmune disease (with the exception of diabetes type I, vitiligo,psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressivetreatment) or recent history of a syndrome that required systemic corticosteroids (10mg daily prednisone or equivalent) or immunosuppressive medications exceptinhaled steroids and adrenal replacement steroids doses up to 10mg daily prednisoneequivalents are permitted in the absence of active autoimmune disease.

  • Uncontrolled opportunistic infections

  • Active multicentric Castleman disease

  • Individuals with primary effusion lymphoma

  • History of malignant tumors other than KS, unless:

  • In complete remission for >= 3 years from the time complete remission was firstdocumented or

  • Resected basal cell or squamous cell carcinoma of the skin or

  • In situ cervical or anal dysplasia

  • History of allergic reactions attributed to compounds of similar chemical orbiologic composition to PDS01ADC and/or M7824 investigational agents used in study.

  • Active tuberculosis (TB):

  • Individuals who are undergoing first month of therapy (RIPE or equivalent) foractive TB or

  • Individuals with TB immune reconstitution syndrome (IRIS) requiringcorticosteroids

  • Received or will receive a live vaccine within 30 days prior to the firstadministration of study intervention. Seasonal flu vaccines that do not contain alive virus are permitted. Locally approved COVID vaccines are permitted.

  • Uncontrolled substantial intercurrent illness including, but not limited to, ongoingor active severe infection, symptomatic congestive heart failure, unstable anginapectoris, cardiac arrhythmia, that would limit compliance with study requirements.

  • Medical or psychiatric illness or social situation that would, in the opinion of theinvestigator, preclude participation in the study or the ability of individuals toprovide informed consent for themselves.

  • Uncontrolled HBV infection, defined as plasma HBV DNA detectable by PCR

Note: the following will NOT be exclusionary:

  • A positive hepatitis B serology indicative of previous immunization (i.e. HbsAbpositive and HbcAb negative), or a fully resolved acute HBV infection

  • Chronic HBV suppressed by appropriate antiretroviral therapy with activity againstHBV, as outlined in DHHS guidelines.

  • Uncontrolled HCV infection, defined as plasma HCV DNA detectable by PCR

Note: the following will NOT be exclusionary:

  • Positive HCV serology but no detectable HCV RNA, indicative of spontaneously clearedHCV infection

  • Successfully treated for HCV as long as therapy for HCV has been completed.

-Individuals will be excluded from the combination therapy arm if:

  • they have discontinued prior PD1/L1 blocking agent due to immune mediated adverseevent(s) OR

  • they have active non-infectious pneumonitis or a history of steroid requiringnon-infectious pneumonitis.

Study Design

Total Participants: 80
Treatment Group(s): 2
Primary Treatment: M7824
Phase: 1/2
Study Start date:
July 13, 2020
Estimated Completion Date:
December 01, 2028

Study Description

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.

  • 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.

Connect with a study center

  • National Institutes of Health Clinical Center

    Bethesda, Maryland 20892
    United States

    Active - Recruiting

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