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

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ClinicalTrials.gov Identifier: NCT04303117
Recruitment Status : Recruiting
First Posted : March 10, 2020
Last Update Posted : September 5, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE March 7, 2020
First Posted Date  ICMJE March 10, 2020
Last Update Posted Date September 5, 2021
Actual Study Start Date  ICMJE July 13, 2020
Estimated Primary Completion Date September 1, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 30, 2021)
safety and tolerability of NHS-IL12 alone or in combination with M7824 [ Time Frame: 24 cycles of treatment, until confirmed progression, unacceptable toxicity or trial withdrawal ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 7, 2020)
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 ]
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 7, 2020)
  • 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 ]
    Percentage of patients with the best overall response of CR or PR to therapy
  • 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 ]
    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
  • 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 ]
    duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma
Official Title  ICMJE Phase I/II of NHS-IL12 Monotherapy and in Combination With M7824 in Advanced Kaposi Sarcoma
Brief 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.

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, up to a total of 96 weeks, or 24 cycles.
  • 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Kaposi Sarcoma
Intervention  ICMJE
  • Drug: NHS-IL12
    An initial dose of 16.8 mcg/kg administered subcutaneously every 4 weeks and at an MTD dose with M7824 on day 1 of a 28-day cycle.
  • Drug: NHS-IL12+M7824
    1200 mg administered IV every two weeks while on NHS-IL12.
Study Arms  ICMJE
  • Experimental: Arm 1/Monotherapy
    Treatment with NHS-IL12 at de-escalating doses if necessary
    Intervention: Drug: NHS-IL12
  • Experimental: Arm 2/Combination therapy
    Treatment with NHS-IL12 at MTD and M7824 at a fixed dose
    Interventions:
    • Drug: NHS-IL12
    • Drug: NHS-IL12+M7824
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 7, 2020)
56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2025
Estimated Primary Completion Date September 1, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • 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 1,500/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 1.5 X institutional upper limit of normal
    • hemoglobin greater than or equal to 9g/dL
    • Creatinine within normal institutional limits OR creatinine clearance >30 mL/min/1.73m^2 as estimated by either Cockroft-Gault of 24- hour urine collection for patients with creatinine levels above institutional normal
  • Normal international normaoized ration (INR), PT less than or equal to 1.5 x ULN and activated partial thromboplastin time (aPTT) less than or equal to 1.5 x ULN
  • 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.
  • Subjects unwilling to accept blood products as medically indicated
  • 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 (with the exception of diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment) 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
  • Patients who have received or will receive a live vaccine within 30 days prior to the first administration of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. Locally approved COVID vaccines are permitted.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Irene Ekwede, R.N. (240) 760-6126 ekwedeib@mail.nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04303117
Other Study ID Numbers  ICMJE 200061
20-C-0061
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Ramya M Ramaswami, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date August 31, 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP