Clinical Trials /

Phase II Multicenter Study of Talimogene Laherparepvec in Classic or Endemic Kaposi Sarcoma

NCT04065152

Description:

Kaposi Sarcoma (KS) is a lymphangioproliferation associated with human herpes virus 8 (HHV8) promoted by immunosuppression. HIV-related KS and iatrogenic posttransplantation KS are treated by immune restoration, in association with local or systemic therapies as chemotherapies if required. Conversely in classic and endemic KS, the underlying relative immunosuppression cannot be directly targeted. Treatment is poorly codified, mostly based on surgery or radiotherapy for localized KS. Most aggressive forms with visceral involvement are treated with chemotherapies or interferon, which give at best 30-60% of transient responses and may not be well tolerated in elderly patients. Talimogene laherparepvec is the first oncolytic immunotherapy approved by the FDA, in metastatic or unresectable melanoma with injectable nodal or cutaneous lesions. It is designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In Merkel cell carcinoma (MCC), another virus-induced tumor, treatment with PD-1/PD-L1 axis inhibitors have proven efficacy, thus providing a proof of principle that immunotherapy could be effective in virus-induced tumors. Two cases of metastatic MCC successfully treated with talimogene laherparepvec were recently reported, suggesting that talimogene laherparepvec may also be an effective therapeutic option. Considering the high immunogenicity of viral epitopes in KS tumors, the role of the immune evasion in the development of KS, and the cutaneous manifestations (>90% of patients) that can be easily injected, classic and endemic KS is a good tumor model to be targeted with talimogene laherparepvec. The main objective is to assess whether talimogene laherparepvec is clinically inactive (partial+complete response probability π0<10%) or truly active (partial+complete response probability π1>40%) in classic and endemic Kaposi sarcoma.

Related Conditions:
  • Kaposi Sarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Multicenter Study of Talimogene Laherparepvec in Classic or Endemic Kaposi Sarcoma
  • Official Title: Phase II Multicenter Study of Talimogene Laherparepvec in Classic or Endemic Kaposi Sarcoma - KAPVEC

Clinical Trial IDs

  • ORG STUDY ID: P17072019
  • NCT ID: NCT04065152

Conditions

  • Kaposi Sarcoma

Interventions

DrugSynonymsArms
Talimogene laherparepveconcolytic immunotherapy

Purpose

Kaposi Sarcoma (KS) is a lymphangioproliferation associated with human herpes virus 8 (HHV8) promoted by immunosuppression. HIV-related KS and iatrogenic posttransplantation KS are treated by immune restoration, in association with local or systemic therapies as chemotherapies if required. Conversely in classic and endemic KS, the underlying relative immunosuppression cannot be directly targeted. Treatment is poorly codified, mostly based on surgery or radiotherapy for localized KS. Most aggressive forms with visceral involvement are treated with chemotherapies or interferon, which give at best 30-60% of transient responses and may not be well tolerated in elderly patients. Talimogene laherparepvec is the first oncolytic immunotherapy approved by the FDA, in metastatic or unresectable melanoma with injectable nodal or cutaneous lesions. It is designed to induce tumor regression of injected lesions through direct lytic effects, and of uninjected lesions through induction of systemic antitumor immunity. In Merkel cell carcinoma (MCC), another virus-induced tumor, treatment with PD-1/PD-L1 axis inhibitors have proven efficacy, thus providing a proof of principle that immunotherapy could be effective in virus-induced tumors. Two cases of metastatic MCC successfully treated with talimogene laherparepvec were recently reported, suggesting that talimogene laherparepvec may also be an effective therapeutic option. Considering the high immunogenicity of viral epitopes in KS tumors, the role of the immune evasion in the development of KS, and the cutaneous manifestations (>90% of patients) that can be easily injected, classic and endemic KS is a good tumor model to be targeted with talimogene laherparepvec. The main objective is to assess whether talimogene laherparepvec is clinically inactive (partial+complete response probability π0<10%) or truly active (partial+complete response probability π1>40%) in classic and endemic Kaposi sarcoma.

Trial Arms

NameTypeDescriptionInterventions
oncolytic immunotherapyExperimentalTalimogene laherparepvec Dose: 10^6 pfu/ml at week 1 then 10^8/ml at week 4 and every 2 weeks (up to 4ml for each injection) Route: intralesional injection Duration of treatment: 6 months (12 cycles)
  • Talimogene laherparepvec

Eligibility Criteria

        Inclusion Criteria:

          -  Classic or endemic histologically confirmed Kaposi Sarcoma (KS) that is progressive,
             but does not require a systemic therapy ;

          -  Injectable and measurable disease, defined as:

               -  At least 2 cutaneous lesion ≥10mm in its largest diameter, in a not previously
                  irradiated field;

               -  At least 2 other cutaneous lesion ≥10mm in their largest diameter available for
                  repeated cutaneous biopsies, in a not previously irradiated field.

               -  Clusters of small lesions with edge to edge distance <2 mm, if the biggest
                  diameter of each cluster meet the 2 previous criteria.

          -  Be willing to provide tissue from cutaneous biopsy;

          -  At least 4 weeks washout for all KS specific therapies including topical treatment,
             chemotherapy, radiotherapy and immunotherapy including interferon;

          -  Provide written, informed consent prior to the performance of any study specific
             procedures;

          -  Be more than 18 years of age on day of signing informed consent.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Demonstrate adequate organ function:

               -  Haematological : Absolute neutrophil count (ANC) ≥1500/mm3; Platelets ≥100
                  000/mm3; haemoglobin≥ 8 g/dL;

               -  Renal: Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR calculated
                  creatinine clearance ≥ 40mL/min for subject with creatinine levels > 1.5 x ULN.

               -  Hepatic: AST (SGOT) and ALT (SGPT) ≤ 2.5xULN, serum total bilirubin ≤ 1.5xULN OR
                  direct bilirubin ≤ ULN for subjects with total bilirubin levels >1.5xULN.

               -  PT≤1.5; PTT (TCA) ≤1.5

          -  Female subject of childbearing potential should have a negative serum pregnancy within
             72 hours prior to receiving the first dose of study medication

          -  Have a health insurance.

        Exclusion Criteria:

          -  Known history of organ transplantation or HIV (HIV 1/2 antibodies detected at
             selection);

          -  Symptomatic visceral involvement of KS including brain metastases;

          -  Active autoimmune disease that requires systemic treatment (i.e. with use of disease
             modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy
             (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for
             adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
             treatment. Patients with vitiligo, type I diabetes mellitus, hypothyroidism, psoriasis
             non requiring systemic treatment are permitted to enrol;

          -  Evidence of clinically significant immunosuppression such as the following: primary
             immunodeficiency state such as Severe Combined Immunodeficiency Disease; concurrent
             opportunistic infection;

          -  Receiving systemic immunosuppressive therapy including oral steroid doses > 10 mg/day
             of prednisone or equivalent within 7 days prior to enrolment;

          -  Active herpetic skin lesions or prior complications of HSV-1 infection (eg, herpetic
             keratitis or encephalitis);

          -  Intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic
             drug (eg, acyclovir), other than intermittent topical use;

          -  Previous treatment with talimogene laherparepvec or any other oncolytic virus;

          -  Prior radiotherapy in which the fields overlap the injection sites;

          -  Prior immunosuppressive, chemotherapy, radiotherapy, biological cancer therapy, or
             major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1
             or better from adverse event due to KS therapy administered more than 28 days prior to
             enrollment.

          -  Prior therapy with tumor vaccine;

          -  Received live vaccine within 28 days prior to enrolment;

          -  Currently treatment with another investigational device or drug study, or less than 28
             days since ending treatment with another investigational device or drug study(s);

          -  Acute or chronic active hepatitis B (HbS Ag detected) or C infection (HCV RNA
             detected) at inclusion;

          -  Known additional malignancy that is currently progressing or requires active treatment
             within the last 3 years. Exceptions include basal cell carcinoma of the skin or
             squamous cell carcinoma of the skin that has undergone potentially curative therapy or
             in situ cervical cancer;

          -  Sensitivity to any of the products or components to be administered ;

          -  Psychiatric or substance abuse disorders that would interfere with cooperation with
             the requirements of the trial;

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial and 3 months after the last dose of talimogene
             laherparepvec;

          -  Subjects who are unwilling to minimize exposure with his/her blood or other body
             fluids to individuals who are at higher risks for HSV-1 induced complications such as
             immunosuppressed individuals, individuals known to have HIV infection, pregnant women,
             or infants under the age of 3 months, during talimogene laherparepvec treatment and
             through 30 days after the last dose of talimogene laherparepvec.

          -  Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial.

          -  Female subject of childbearing potential who are unwilling to use acceptable method(s)
             of effective contraception during study treatment and through 3 months after the last
             dose of talimogene laherparepvec.

          -  Sexually active subjects and their partners unwilling to use male or female latex
             condom to avoid potential viral transmission during sexual contact while on treatment
             and within 30 days after treatment with talimogene laherparepvec.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Best overall response
Time Frame:6 months
Safety Issue:
Description:Best overall response rate (BORR) defined by the occurrence of complete response or partial response of the injected lesions following PGA criteria (PGA 0 to 4) recorded from the start of treatment until 6 months or the beginning of any other specific therapy for Kaposi sarcoma if it occurs before 6 months. PGA score: Score and category Description 0: completely clear Complete relief of symptoms; 100% of improvement almost clear Marked improvement of all clinical symptoms as compared with baseline with residual signs (≥90% and <100%) marked improvement Significant improvement of symptoms (≥75% and <90%) moderate improvement Moderate improvement between score 2 and 4. slight improvement Improvement of signs and symptoms as compared with baseline (<50% and ≥25%) but remaining signs of active KS no change Clinical signs and symptoms unchanged from baseline (+-25%) worse Clinical signs and symptoms deteriorated from baseline (≥25% of deterioration)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Assistance Publique - Hôpitaux de Paris

Last Updated

August 22, 2019