Clinical Trials /

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

NCT04303117

Description:

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 24 weeks. It is injected under the skin. Some participants will also get M7824 every 2 weeks for 24 weeks. 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 24 weeks with an option to take NHS-IL12 and/or M7824 for an extra 24 weeks. 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....

Related Conditions:
  • Kaposi Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II of NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma
  • Official Title: Phase I/II of NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 200061
  • SECONDARY ID: 20-C-0061
  • NCT ID: NCT04303117

Conditions

  • Kaposi Sarcoma

Interventions

DrugSynonymsArms
NHS-IL12Arm 1/Monotherapy
M7824Arm 2/Combination therapy

Purpose

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 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 advanced KS. - 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 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- 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 infection. - 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. Objectives: -Evaluate the safety and tolerability of single agent NHS-IL12 and the combination of NHSIL12 with M7824 in patients with advanced KS. Eligibility: - 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 - Patient must be willing to give informed consent. - Patients can be HIV positive or negative. - Antiretroviral therapy (ART) for HIV+ patients 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. - Patients 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 NHS-IL12 alone or in combination with M7824 in patients with advanced KS. Patients will receive therapy until optimal tumor response, unacceptable toxicity, the patient s request to discontinue therapy, PI decision, or 24 weeks of treatment. Patients on both arms will have the option of an additional 24 weeks of treatment, if they are deriving clinical benefit - Monotherapy: Patients will receive NHS-IL12 alone with a 3+3 design applicable to the first 3-6 patients 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. - Combination Therapy: The combination arm will open following accrual and completion of the the DLT period for patients in the monotherapy arm. Up to 28 patients 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.

Detailed 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
           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
           advanced KS.

        -  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
           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- 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
           infection.

        -  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.

      Objectives:

      -Evaluate the safety and tolerability of single agent NHS-IL12 and the combination of NHSIL12
      with M7824 in patients with advanced KS.

      Eligibility:

        -  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

        -  Patient must be willing to give informed consent.

        -  Patients can be HIV positive or negative.

        -  Antiretroviral therapy (ART) for HIV+ patients 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.

        -  Patients 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 NHS-IL12 alone or in
           combination with M7824 in patients with advanced KS. Patients will receive therapy until
           optimal tumor response, unacceptable toxicity, the patient s request to discontinue
           therapy, PI decision, or 24 weeks of treatment. Patients on both arms will have the
           option of an additional 24 weeks of treatment, if they are deriving clinical benefit

        -  Monotherapy: Patients will receive NHS-IL12 alone with a 3+3 design applicable to the
           first 3-6 patients 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.

        -  Combination Therapy: The combination arm will open following accrual and completion of
           the the DLT period for patients in the monotherapy arm. Up to 28 patients 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1/MonotherapyExperimentalTreatment with NHSIL12 at deescalating doses if necessary
  • NHS-IL12
Arm 2/Combination therapyExperimentalTreatment with NHSIL12 at MTD and M7824 at a fixed dose
  • NHS-IL12
  • M7824

Eligibility Criteria

        -  INCLUSION CRITERIA:

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

          -  KS requiring systemic therapy, with a history of prior therapy:

               -  T1 KS or T0 KS sufficiently widespread that systemic therapy is advisable, or KS

        affecting quality-of-life due to local symptoms or psychological distress OR

          -  KS patients with an inadequate response to liposomal doxorubicin, paclitaxel, other
             systemic chemotherapy (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 weeks
                  from last immunotherapy, other systemic treatment with a biologic agent, or
                  monoclonal antibody therapy will be required.

               -  Resolution of toxicity from prior therapy to less than or equal to Grade 1.

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

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

               -  Patients can be HIV positive or negative.

               -  ART for HIV+ patients for 8 or more weeks prior to entry with an HIV viral load
                  of <400 copies/ml at screening and CD4+ T cell count of >50 cells/ (NotEqual)L as
                  this may be expected if patients have received several courses of chemotherapy.

               -  Age greater than or equal to18 years.

               -  ECOG performance status less than or equal to 2 (Karnofsky greater than or equal
                  to 60%).

               -  Patients must have adequate organ and marrow function as defined below:

          -  absolute neutrophil count greater than or equal to 1,000/mcL

          -  platelets greater than or equal to 100,000/mcL

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

          -  AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal

          -  hemoglobin greater than or equal to 9g/dL

          -  Creatinine within normal institutional limits OR creatinine clearance >45
             mL/min/1.73m^2 as estimated by either Cockroft-Gault of 24- hour urine collection for
             patients with creatinine levels above institutional normal

               -  The effects of NHS-IL12 and M7824 on the developing human fetus are unknown. For
                  this reason, women of child-bearing potential and men must agree to use adequate
                  contraception (hormonal or barrier method of birth control; abstinence) prior to
                  study entry, during treatment and for at least 4 months after the last dose of
                  treatment and agree to inform the treating physician immediately if they become
                  pregnant. Also, there is unknown but potential risk for adverse events in nursing
                  infants secondary to treatment of the mother with M7824 and/or NHS-IL12,
                  therefore female patients must agree to discontinue breastfeeding if treated with
                  these agents.

               -  Ability of subject to understand and the willingness to sign a written informed
                  consent document.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Pregnant women are excluded from this study as the effects of NHS-IL12 and M7824 have
             potential teratogenic or abortifacient effects.

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

          -  Actively bleeding sites caused by visceral KS.

          -  Patients who are actively bleeding and/or requiring transfusions in the 2 weeks
             preceding study entry.

          -  Patients with history of bleeding, diathesis, or recent major bleeding events within a
             period of 4 weeks considered by the investigator as high risk for investigational drug
             treatment.

          -  Patients with any active or recent history (symptomatic in the last 3 months) of a
             known or suspected autoimmune disease or recent history of a syndrome that required
             systemic corticosteroids (10mg daily prednisone or equivalent) or immunosuppressive
             medications except inhaled steroids and adrenal replacement steroids doses up to 10mg
             daily prednisone equivalents are permitted in the absence of active autoimmune
             disease.Uncontrolled opportunistic infections

          -  Active multicentric Castleman disease

          -  Patients with primary effusion lymphoma

          -  History of malignant tumors other than KS, unless:

               -  In complete remission for greater than or equal to 3 years from the time complete
                  remission was first documented 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 or biologic
             composition to NHS-IL12 and/or M7824 investigational agents used in study.

          -  Active tuberculosis (TB):

               -  Patients who are undergoing first month of therapy (RIPE or equivalent) for
                  active TB or

               -  Patients with TB immune reconstitution syndrome (IRIS) requiring corticosteroids

          -  Uncontrolled substantial intercurrent illness including, but not limited to, ongoing
             or active severe infection, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, that would limit compliance with study requirements.

          -  Medical or psychiatric illness or social situation that would, in the opinion of the
             investigator, preclude participation in the study or the ability of patients to
             provide 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. HBsAb
             positive and HBcAb negative), or a fully resolved acute HBV infection

          -  Patients with chronic HBV suppressed by appropriate antiretroviral therapy with
             activity against HBV, 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 cleared
             HCV infection

          -  Patients who have been successfully treated for HCV as long as therapy for HCV has
             been completed.

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

          -  they have discontinued prior PD1/L1 blocking agent due to immune mediated adverse
             event(s) OR

          -  they have active non-infectious pneumonitis or a history of steroid requiring
             non-infectious pneumonitis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:safety and tolerability of NHSIL12 alone or in combination with M7824
Time Frame:24 weeks of treatment, until confirmed progression, unacceptable toxicity or trial withdrawal
Safety Issue:
Description:The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified. Maximum tolerated dose will also be reported.

Secondary Outcome Measures

Measure:objective response rates
Time Frame:every 3 months for the first 6 months after completion of therapy, then every six months for the next 18 months, and then annually for a total of 3 years
Safety Issue:
Description:Percentage of patients with the best overall response of CR or PR to therapy
Measure:duration of response
Time Frame:every 3 months for the first 6 months after completion of therapy, then every six months for the next 18 months, and then annually for a total of 3 years
Safety Issue:
Description:the time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR
Measure:progression free survival
Time Frame:every 3 months for the first 6 months after completion of therapy, then every six months for the next 18 months, and then annually for a total of 3 years
Safety Issue:
Description:duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immune Therapy
  • AIDS
  • HIV
  • Immunocytokine

Last Updated

March 7, 2020