Clinical Trials /

Neoadjuvant Use of Talimogene Laherparepvec and BRAF/MEK Inhibitor for Advanced Nodal BRAF Mutant Melanoma

NCT03972046

Description:

This study will investigate whether the use of talimogene laherparepvec (T-VEC) in combination with BRAF/MEK inhibitor will result in durable regional and distant recurrence free survival in the neoadjuvant setting for treatment of advanced nodal BRAF mutant melanoma.

Related Conditions:
  • Cutaneous Melanoma
  • Melanoma of Unknown Primary
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant Use of Talimogene Laherparepvec and BRAF/MEK Inhibitor for Advanced Nodal BRAF Mutant Melanoma
  • Official Title: Neoadjuvant Use of Talimogene Laherparepvec and BRAF/MEK Inhibitor for Advanced Nodal BRAF Mutant Melanoma: A Pilot Study

Clinical Trial IDs

  • ORG STUDY ID: 17-086
  • SECONDARY ID: 20187504
  • NCT ID: NCT03972046

Conditions

  • Melanoma (Skin)
  • Melanoma Stage IIIb-IVM1B
  • Metastasis Skin
  • Tumor Skin
  • BRAF Gene Mutation

Interventions

DrugSynonymsArms
T-Vec + BRAF/MEK InhibitorT-Vec + BRAF/MEK

Purpose

This study will investigate whether the use of talimogene laherparepvec (T-VEC) in combination with BRAF/MEK inhibitor will result in durable regional and distant recurrence free survival in the neoadjuvant setting for treatment of advanced nodal BRAF mutant melanoma.

Detailed Description

      This is a prospective, non-randomized, open-label, single-center interventional study looking
      at the response rate when using talimogene laherparepvec (T-VEC) in combination with BRAF/MEK
      inhibitor in neoadjuvant setting for treatment of advanced nodal BRAF mutant melanoma. For
      this pilot study, a sample size of 20 participants, over 18 years of age will be included.
    

Trial Arms

NameTypeDescriptionInterventions
T-Vec + BRAF/MEKExperimentalParticipants will begin taking the following 3 medications: BRAF Inhibitor dabrafenib 150 mg by mouth twice a day; MEK inhibitor trametinib 2 mg by mouth once a day; Talimogene laherparepvec up to 4mL subcutaneous injection (Dose #1: 10^6 PFU/mL; Dose #2: 10^8 PFU/mL 21 (+3) days after first dose; Subsequent doses: 10^8 PFU/mL every 14 (+/-3) days). Dosing to continue for at least 3 months, or up to 6 months if no plateau in response. May stop earlier than 3 months at physician discretion depending on side effects and response. Ultrasound of tumor nodal basin(s) monthly. Labs every 4 weeks: CBC with differential, CMP, LDH CT of chest/abdomen/pelvis every 3 months. PET CT or brain MRI as needed at discretion of the investigator. Manual tumor measurement in office prior to each injection.
  • T-Vec + BRAF/MEK Inhibitor

Eligibility Criteria

        Inclusion

          -  Age ≥ 18

          -  Malignant melanoma Stage IIIb-IVM1B patients.

          -  Primary or recurrent disease.

          -  Cutaneous primary melanoma or unknown primary.

          -  Measurable disease as evidenced by:

               -  At least one lesion measuring greater than or equal to 10 mm on CT, ultrasound,
                  or physical exam

               -  A conglomerate of superficial lesions measuring which in aggregate have a total
                  diameter of 10 mm

          -  Injectable disease

          -  Palpable regional metastasis at the time of initial presentation or with regional
             recurrence

          -  Tumor(s) with BRAF mutation

          -  ECOG 0,1,2

          -  Life expectancy > 2 years in the opinion of the investigator

          -  Able to provide written informed consent

          -  Adequate organ function based on most recent labs (according to investigator
             discretion), defined as follows:

               -  Hematological: Absolute neutrophil count ≥ 1500/mm3 (1.5x109/L); Platelet count ≥
                  75,000/mm3 (7.5x109/L); Hemoglobin ≥ 8 g/dL (without need for hematopoietic
                  growth factor or transfusion support)

               -  Renal: Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour
                  creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN.
                  (Note: Creatinine clearance need not be determined if the baseline serum
                  creatinine is ≤ 1.5 x ULN. . Creatinine clearance should be determined per
                  institutional standard).

               -  Hepatic: Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with
                  total bilirubin level > 1.5 x ULN; Aspartate aminotransferase (AST) ≤ 2.5 x ULN
                  OR ≤ 5 x ULN, if liver metastases present and injection does not involve a
                  visceral lesion; Alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN, if
                  liver metastases present and injection does not involve a visceral lesion

               -  Coagulation: International normalization ratio (INR) or prothrombin time (PT) ≤
                  1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case
                  PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within
                  therapeutic range of intended use of anticoagulants; PTT or aPTT ≤ 1.5 x ULN,
                  unless the subject is receiving anticoagulant therapy as long as PT and PTT/aPTT
                  is within therapeutic range of intended use of anticoagulants.

               -  Female subjects of childbearing potential should have a negative urine or serum
                  pregnancy test within 72 hours prior to enrollment. If urine test is positive or
                  cannot be confirmed as negative, a serum pregnancy test will be required.

        Exclusion

          -  BRAF wild type tumor

          -  M1C disease

          -  Clinically active cerebral metastases, bony metastases, visceral metastases

          -  Mucosal or ocular primary disease

          -  Known active central nervous system (CNS) metastases. Subjects with previously treated
             brain metastases may participate provided they are stable (without evidence of
             progression by imaging for at least four weeks prior to the first dose of trial
             treatment and any neurologic symptoms have returned to baseline), have no evidence of
             new or enlarging brain metastases, and are not using steroids >10 mg/day of prednisone
             or equivalent. The exception does not include carcinomatosus meningitis which is
             excluded regardless of clinical stability.

          -  History or evidence of active autoimmune disease that requires systemic treatment (ie,
             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.

          -  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 (> 2 weeks) including oral steroid
                  doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment.

          -  Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic
             keratitis or encephalitis).

          -  Requires intermittent or chronic systemic (intravenous or oral) treatment with an
             antiherpetic drug (e.g., acyclovir), other than intermittent topical use.

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

          -  Previous treatment with a BRAF or MEK inhibitor

          -  Prior therapy with tumor vaccine.

          -  Received live vaccine within 28 days prior to enrollment.

          -  Prior immunosuppressive, chemotherapy, radiotherapy (in which the field encompassed a
             planned injection site), 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 cancer therapy administered more than 28 days prior to enrollment. Adjuvant
             hormonal therapy is allowed if appropriate for planned study.

          -  Prior radiotherapy in which the field does not overlap the injection sites or
             non-immunosuppressive targeted therapy within 14 days prior to enrollment or has not
             recovered to CTCAE grade 1 or better from adverse event due to cancer therapy
             administered more than 14 days prior to enrollment

          -  Currently receiving treatment with another investigational device or drug study, or <
             28 days since ending treatment with another investigational device or drug study(s).

          -  Other investigational procedures while participating in this study are excluded.

          -  Known to have acute or chronic active hepatitis B infection.

          -  Known to have acute or chronic active hepatitis C infection.

          -  Known to have human immunodeficiency virus (HIV) infection.

          -  History of other malignancy within the past 5 years with the following exceptions:

               -  Adequately treated non melanoma skin cancer without evidence of disease at the
                  time of enrollment

               -  Adequately treated cervical carcinoma in situ without evidence of disease at the
                  time of enrollment

               -  Adequately treated breast ductal carcinoma in situ without evidence of disease at
                  the time of enrollment

               -  Prostatic intraepithelial neoplasia without evidence of prostate cancer at the
                  time of enrollment.

          -  Subject has known sensitivity to talimogene laherparepvec or any of its components to
             be administered during dosing.

          -  Female subject is pregnant or breast-feeding, or planning to become pregnant 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.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recurrence-free survival
Time Frame:1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Melanoma specific survival
Time Frame:1 year
Safety Issue:
Description:
Measure:Melanoma specific survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Melanoma specific survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Distant metastatic free survival
Time Frame:1 year
Safety Issue:
Description:
Measure:Distant metastatic free survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Distant metastatic free survival
Time Frame:3 years
Safety Issue:
Description:
Measure:Tumor response rate to therapy according to RECIST criteria
Time Frame:3 months
Safety Issue:
Description:
Measure:Tumor response rate to therapy according to RECIST criteria
Time Frame:6 months
Safety Issue:
Description:
Measure:Pathological response in the surgical specimen
Time Frame:3 months
Safety Issue:
Description:
Measure:Pathological response in the surgical specimen
Time Frame:6 months
Safety Issue:
Description:
Measure:Incidence of all adverse events (AEs)
Time Frame:1 month
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:2 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:3 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:4 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:5 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:6 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs
Measure:Incidence of all adverse events (AEs)
Time Frame:7 months
Safety Issue:
Description:includes treatment-related AEs, serious AEs, and fatal AEs

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Angela N Fellner PhD CCRP

Trial Keywords

  • T-VEC
  • BRAF/MEK inhibition
  • Melanoma
  • Nodal metastasis
  • Neoadjuvant treatment
  • BRAF mutant

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