NHS-IL12 + M7824 for Kaposi Sarcoma
Recruiting in Palo Alto (17 mi)
Overseen byRamya M Ramaswami, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must be taking: ART
Must not be taking: Corticosteroids, Immunosuppressives
Disqualifiers: Severe KS, Autoimmune disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial requires a washout period (time without taking certain medications) of 2 weeks from the last chemotherapy and 4 weeks from the last immunotherapy or other systemic treatments before starting the study. This means you may need to stop some current medications before participating.
What data supports the effectiveness of the drug NHS-IL12 + M7824 for Kaposi Sarcoma?
Research shows that interleukin-12 (IL-12), a component of the treatment, has shown promising results in treating AIDS-related Kaposi's sarcoma, with a significant number of patients experiencing partial or complete responses. This suggests that IL-12 may be effective in managing this condition.
12345Is the treatment NHS-IL12 + M7824 generally safe for humans?
Interleukin-12 (IL-12), a component of the treatment, has been tested in humans with AIDS-related Kaposi sarcoma and was generally well tolerated, with some side effects like flu-like symptoms, changes in liver enzymes, low white blood cell counts, anemia, and depression. These studies suggest that IL-12 has acceptable safety in humans, but specific safety data for the combination with M7824 (Bintrafusp alfa) is not provided in the available research.
12345What makes the drug NHS-IL12 unique for treating Kaposi Sarcoma?
NHS-IL12 is unique because it uses interleukin-12 (IL-12), a protein that boosts the immune system and has shown promise in treating Kaposi Sarcoma by enhancing immune responses and reducing blood vessel growth in tumors. This approach is different from standard treatments, as it specifically targets the immune system to fight the cancer.
12346Eligibility Criteria
Adults over 18 with Kaposi Sarcoma (KS) who've had prior treatments that didn't work well can join. This includes those living with HIV, provided they meet certain viral load and immune cell count criteria. Participants need measurable KS lesions and good organ/marrow function. They must not be pregnant or breastfeeding and agree to use contraception.Inclusion Criteria
You have a specific type of measurable disease according to the AIDS Clinical Trials Group (ACTG) Oncology Committee criteria for KS.
My organs and bone marrow are functioning well.
I have not had chemotherapy in the last 2 weeks or immunotherapy in the last 4 weeks.
+10 more
Exclusion Criteria
I do not have any untreated serious infections.
I have been diagnosed with active multicentric Castleman disease.
I have had cancer other than Kaposi's sarcoma, but under certain conditions.
+16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive NHS-IL12 every 4 weeks for up to 96 weeks, with some also receiving M7824 every 2 weeks
96 weeks
24 visits (in-person) for NHS-IL12, 48 visits (in-person) for M7824
Follow-up
Participants are monitored for safety and effectiveness after treatment
3 years
Follow-up visits 7 and 30 days after treatment ends, then every 3 to 6 months for 18 months, then annually
Participant Groups
The trial is testing NHS-IL12 alone or combined with M7824 in treating KS. NHS-IL12 boosts the immune system against tumors, while M7824 blocks cancer pathways that inhibit the immune response. The drugs are given via injections under the skin or through a vein for up to 96 weeks.
3Treatment groups
Experimental Treatment
Group I: Arm 2/Combination therapyExperimental Treatment2 Interventions
Treatment with NHS-IL12 at MTD and M7824 at a fixed dose
Group II: Arm 1a/Monotherapy ExpansionExperimental Treatment1 Intervention
Treatment with NHS-IL12 at MTD
Group III: Arm 1/MonotherapyExperimental Treatment1 Intervention
Treatment with NHS-IL12 at de-escalating doses if necessary
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Treatment of AIDS-related Kaposi's sarcoma with interleukin-12: rationale and preliminary evidence of clinical activity. [2019]In this article, we review the preliminary evidence for the activity of interleukin-12 (IL-12) against Kaposi's sarcoma (KS) and discuss these results in the context of the biology of IL-12 and KS. IL-12 is a cytokine that enhances type 1 immunity, induces production of interferon gamma (IFN-gamma), and mediates antiangiogenic effects. In addition, it can downregulate a constitutively active G protein coupled receptor that is encoded by Kaposi's sarcoma-associated herpesvirus, the causative agent of KS. These factors suggested that IL-12 might be worth exploring as a potential anti-KS agent. In an initial phase I pilot study, IL-12 was found to have anti-KS activity when used alone in patients with AIDS-associated KS who were on a stable regimen of antiretroviral therapy. In preliminary results from a subsequent study of the combination of IL-12 plus liposomal doxorubicin along with highly active antiretroviral therapy, remissions were obtained in a substantial percentage of patients with advanced AIDS-associated KS. IL-12 has also been found active in patients with certain lymphomas. These results suggest that IL-12 may be worth exploring further as a potential antitumor agent in selected tumors.
Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma. [2021]Interleukin-12 (IL-12) enhances Th1-type T-cell responses and exerts antiangiogenic effects. We initiated a phase 1 pilot study of IL-12 in 32 patients with acquired immunodeficiency syndrome (AIDS)-related Kaposi sarcoma (KS) whose KS was progressing while on antiretroviral therapy. Fifteen patients had poor prognosis T(1)S(1) disease. IL-12 was administered subcutaneously twice weekly at doses from 100 to 625 ng/kg. The maximum tolerated dose was 500 ng/kg, and the principal toxicities were flulike symptoms, transaminase or bilirubin elevations, neutropenia, hemolytic anemia, and depression. No tumor responses were seen at the lowest dose (100 ng/kg), but 17 of 24 evaluable patients at the higher doses had partial or complete responses (response rate, 71%; 95% confidence interval, 48%-89%). Only 3 of 17 patients had a change in antiretroviral therapy before responding, and there were no significant differences between responders and nonresponders with regard to changes in CD4 counts or viral loads. Patients had increases in their serum IL-12, interferon-gamma, and inducible protein-10 (IP-10) after the first dose, and increases above baseline persisted after week 4. These results provide preliminary evidence that IL-12 has substantial activity against AIDS-related KS with acceptable toxicity and warrants further investigation for this indication.
Exacerbation of epidemic Kaposi's sarcoma with a combination of interleukin-2 and beta-interferon: results of a phase 2 study. [2015]Epidemic Kaposi's sarcoma (EKS) is the most common neoplastic manifestation of acquired immune deficiency syndrome (AIDS). The underlying immune deficiency can be partially reversed in vitro with interleukin-2 (IL-2). The type 1 interferons (IFN), alpha and beta, inhibit the growth of the etiologic agent of AIDS, the human immunodeficiency virus, have antitumor activity against Kaposi's sarcoma, and are synergistic with IL-2 in stimulating natural killer cell activity. Four patients with EKS were treated three times weekly with simultaneous intravenous injections of recombinant IL-2 (5 X 10(6) Cetus units/m2) and recombinant IFN-beta (6 X 10(6) units/m2). All patients had generalized disease, were without systemic symptoms, had no prior opportunistic infection, and had stable disease at the initiation of therapy. No patient had an objective response. Three patients exhibited rapid disease progression within 2-4 weeks of starting treatment, necessitating discontinuation of therapy and early closure of the study. This adverse result may have resulted from the significant levels of gamma-interferon (IFN-gamma) that can be generated with this dose and schedule of IL-2. Investigators using IL-2 should monitor IFN-gamma levels and avoid intermediate to high-dose bolus IL-2 therapy in patients with EKS.
Phase 2 study of pegylated liposomal doxorubicin in combination with interleukin-12 for AIDS-related Kaposi sarcoma. [2021]Thirty-six patients with AIDS-associated Kaposi sarcoma (KS) requiring chemotherapy were treated for six 3-week cycles of pegylated liposomal doxorubicin (20 mg/m(2)) plus interleukin-12 (IL-12; 300 ng/kg subcutaneously twice weekly), followed by 500 ng/kg subcutaneous IL-12 twice weekly for up to 3 years. All received highly active antiretroviral therapy (HAART). Twenty-two had poor-prognosis KS (T(1)S(1)). Thirty patients had a major response, including 9 with complete response, yielding an 83.3% major response rate (95% confidence interval: 67.2%-93.6%). Median time to first response was 2 cycles. Median progression was not reached at median potential follow-up of 46.9 months. Of 27 patients with residual disease when starting maintenance IL-12, 15 had a new major response compared with this new baseline. The regimen was overall well tolerated; principal toxicities were neutropenia, anemia, transaminitis, and neuropsychiatric toxicity. Patients had increases in serum IL-12, interferon gamma, and inducible protein-10 (IP-10), and these remained increased at weeks 18 and 34. The regimen of IL-12 plus liposomal doxorubicin yielded rapid tumor responses and a high response rate in patients with AIDS-KS receiving HAART, and responses were sustained on IL-12 maintenance therapy. A randomized trial of IL-12 in this setting may be warranted. This study is registered at (http://www.clinicaltrials.gov) as no. NCT00020449.
Interleukin-4 in the treatment of AIDS-related Kaposi's sarcoma. [2020]To define the safety and toxicity of interleukin-4 (IL-4) when administered subcutaneously in patients with AIDS-related Kaposi's sarcoma (AIDS-KS); to evaluate the effect of IL-4 on immunologic and virologic parameters; and to preliminarily assess the response rate of IL-4 in AIDS-KS.
Sarcoma IL-12 overexpression facilitates NK cell immunomodulation. [2021]Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.