Clinical Trials /

Combination Therapy With GEN0101 and Pembrolizmub in Advanced Melanoma Patients PIb/PII

NCT03818893

Description:

This is a multi-center, open-labeled, non-randomized, single arm investigator-initiated trial to evaluate the safety and efficacy of GEN0101 and Pembrolizmub combination in patients with advanced melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Therapy With GEN0101 and Pembrolizmub in Advanced Melanoma Patients PIb/PII
  • Official Title: Phase Ib/II Investigator Initiated Safety and Efficacy Clinical Trial of Combination Therapy of Intracutaneous GEN0101 With Intravenous Pembrolizmub in Patients Who Have Advanced Melanoma

Clinical Trial IDs

  • ORG STUDY ID: GEN0101-JM005
  • NCT ID: NCT03818893

Conditions

  • Advanced Melanoma

Interventions

DrugSynonymsArms
Combination of GEN0101 and PembrolizmubNew Combination Immunotherapy

Purpose

This is a multi-center, open-labeled, non-randomized, single arm investigator-initiated trial to evaluate the safety and efficacy of GEN0101 and Pembrolizmub combination in patients with advanced melanoma.

Detailed Description

      1. Primary Objective & Hypothesis

        1. Objective: Efficacy of the combination therapy The combination therapy with
           intracutaneous injections of GEN0101 + intravenous infusions of Pembrolizumab is given
           to patients with confirmed SD or unconfirmed PD after anti-PD-1 antibody therapy. When
           the last subject completes Week 13 (Day 85th), the RECIST v1.1-based antitumor effect is
           assessed for all the subjects up to Week 17 (Day 113th) and then the ORR is calculated
           in both treatment groups, which are tested to examine the significant difference to
           historical data of KEYNOTE-002.

        2. Hypothesis: The antitumor effect and the induction of antitumor immunity of the
           combination therapy would be enhanced.

      2. Secondary Objectives & Hypothesises

        1. Objectives: Efficacy and safety of the combination therapy The combination therapy with
           intracutaneous injections of GEN0101 + intravenous infusions of Pembrolizumab is given
           to patients with confirmed SD or unconfirmed PD after anti-PD-1 antibody therapy.

           When the last subject completed Week 17 (Day 113th), antitumor effect in Week 13 (Day
           85th, unconfirmed) and Week 17 (Day 113th, confirmed) is assessed based on RECIST v1.1,
           irRC, and irRECIST for all subjects and then the ORR is calculated. Likewise, changes in
           individual tumor sizes in Week 13 (Day 85th, unconfirmed) and Week 17 (Day 113th,
           confirmed) are measured, and then percent changes in tumor sizes (percent tumor
           shrinkage or growth) are calculated. In each subject, the induction of antitumor
           immunity in Week 13 (Day 85th) is investigated with the index of activated NK cells in
           peripheral blood.

           When the last subject completed Week 53 (Day 365th), antitumor effect is assessed for
           all the subjects based on OS and RECIST v1.1, irRC, and irRECIST-based ORR, BOR and PFS,
           which are tested to examine significant difference to historical data of KEYNOTE-002.

           When the last subject completed Week 105 (Day 729th), antitumor effect is assessed for
           all the subjects based on OS and RECIST v1.1, irRC, and irRECIST-based ORR, BOR and PFS,
           which are tested to examine significant difference to historical data of KEYNOTE-002.

           On the basis of these results, the antitumor effect and the induction of antitumor
           immunity of the combination therapy is investigated. These are secondary objectives in
           the trial.

           As another secondary objective, AEs are investigated in all the subjects for safety
           evaluation of the combination therapy until the last subject completed Week 105 (Day
           729th).

        2. Hypothesis: The antitumor effect and the induction of antitumor immunity of the
           combination therapy would be enhanced and the safety would be acceptable.

      3. Exploratory Objective Objective: Storage and use of samples for future exploratory
      evaluation
    

Trial Arms

NameTypeDescriptionInterventions
New Combination ImmunotherapyExperimentalPatients will receive Pembrolizumab once every 3 weeks and a maximum of 35 doses over 105 weeks . The patients should be inpatient during treatment with GEN0101 in each treatment cycle and may be outpatient during off-treatment period with GEN0101, observation period, follow-up period with Pembrolizumab. GEN0101 in a vial will be reconstituted with 1 mL of sterile distilled water and then will be injected intracutaneously (including skin tumor site). Nonetheless, it will not be deemed as deviation if an injection has been given subcutaneously unintentionally, e.g., leakage around the peri-injection sites. A dose will be 60,000 mNAU in total, and 1 mL per injection site should be administered to 6 injection sites in total. For a patient, the total dose in a treatment cycle will be 360,000 mNAU (360 NAU), and the total dose over 2 treatment cycles will be 720,000 mNAU (720 NAU).
  • Combination of GEN0101 and Pembrolizmub

Eligibility Criteria

        Inclusion Criteria:

        Patient will be eligible for this trial if all the following apply:

          1. Patient has given written informed consent by themselves

          2. Patient aged 20 to 85 years at the time of informed consent

          3. Patient has histologically- or cytologically-confirmed melanoma

          4. Patient with a diagnosis of incurable and unresectable, Stage IIIC, IIID or Stage IV
             advanced melanoma, showing confirmed SD or unconfirmed PD over 12-week treatment with
             an anti-PD-1 antibody such as nivolumab or Pembrolizumab. To be assigned a status of
             SD, changes in tumor measurements must be confirmed by consecutive repeat evaluations
             that should be performed in 4 to 6 weeks after the criteria for response are first met
             over 12-week of an anti-PD-1 antibody treatment.

          5. Patient has a measurable tumor

          6. Patient has life expectancy of at least 12 weeks after the first dose of
             investigational product

          7. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
             at screening

          8. Patient has met the following criteria of clinical laboratory tests at screening
             (1)White blood cell (WBC) count over 3,000/μL and neutrophil count over 1,500/μL
             (2)Platelet count over over 75,000/μL (3)Hemoglobin over 8.0 g/dL (4)AST and ALT ≤ 2.5
             × upper limit of normal (ULN) (5)Total bilirubin ≤ 2 × ULN (6)Serum creatinine ≤ 2 ×
             ULN

          9. LDH is not higher than the 2-fold of the upper limit of the institutional reference.

         10. A female patient of childbearing potential (a premenopausal woman, a woman with
             medically or drug-induced amenorrhea, and a woman with no history of sterilization),
             who has agreed to use appropriate contraception, e.g., the barrier method and a total
             abstinence, during the trial treatment until 3 months passed after completion of the
             trial treatment. A male patient who has agreed to use appropriate contraception, e.g.,
             the barrier method and a total abstinence, during the above period.

        Exclusion Criteria:

        Patient will be excluded from participation if any of the following apply:

          1. Patient has brain metastases. Patients with previously treated brain metastases may
             participate provided they are radiologically stable, i.e. without evidence of
             progression for at least 4 weeks by repeat imaging* (note that the repeat imaging
             should be performed during study screening), clinically stable and without requirement
             of steroid treatment for at least 14 days prior to first dose of study treatment.

          2. Patient has showed positive reaction in a prick testing for GEN0101

          3. A patient who has the mutant BRAF gene in a tumor biopsy.

          4. A patient who has current pneumonitis.

          5. Patient concurrently has an active infection requiring systemic therapy.

          6. Patient has received other systemic anticancer therapy than an anti-PD-1 antibody
             therapy such as nivolumab, Pembrolizumab, or local IFN-beta therapy within 3 weeks
             before the time of informed consent (or within 6 weeks before the time of the informed
             consent for a patient who received nitrosourea or mitomycin C)

          7. Patient has received another unapproved drug other than anti-PD-L1 antibody within 4
             weeks before the time of informed consent

          8. Patient has intraocular (uveal) melanoma

          9. Patient has or had another malignant tumor than melanoma. However, this criterion does
             not apply to a patient who has experienced neither recurrence nor metastasis for at
             least 5 years at the time of informed consent.

         10. Patient has received systemic corticosteroid or systemic immunosuppressant within 1
             week before the first dose of investigational product. However, this criterion does
             not apply to a patient who has been on long-term (>6-month) treatment at a low dose
             (equivalent to oral prednisolone under 10 mg/day) or who received prophylactic
             immunosuppressant against contrast media allergy.

         11. Patient has received a live vaccine within 30 days before registration

         12. Patient has enrolled in another clinical trial and received an investigational product
             within 4 months before the first dose of investigational product, or patient has
             intended to be enrolled in another clinical trial in parallel with this clinical trial

         13. A patient who has an active TB infection.

         14. Female patient is pregnant (including one with positive results from a pregnancy test
             at screening), lactating, or intending to become pregnant during participation in this
             trial and before 3 months have passed after completion of this trial. However, this
             criterion does not apply to a patient who will stop lactating (from the date of
             informed consent until 30 days passed after the last treatment). Of note, female
             patients should undergo a beta-HCG test to demonstrate pregnancy status. Male patient
             who does not agree to use appropriate contraception such as the barrier method and a
             total abstinence during this trial until 3 months passed after the completion of this
             trial. (Detailed method is described in 5.7 Contraception)

         15. Patient has psychiatric disease considered to be a potential concern from the
             viewpoints of follow-up and protocol adherence

         16. Patient had given autografting or allografting of organ or tissue (receiving an
             immunosuppressant)

         17. Patient has over 10%-shorter prothrombin time (PT) compared to lower limit of normal
             (LLN) or over 1.5-fold longer activated partial thromboplastin time (APTT) compared to
             ULN at screening

         18. Patient has showed positive reaction to any of HBs antigen, HCV antibody, HIV-1
             antibody, or HIV-2 antibody at screening. However, even if it is positive for HCV
             antibody, it should not be excluded when HCV RNA test is negative.

         19. Patient is considered ineligible for this trial by the investigator or the
             sub-investigators
      
Maximum Eligible Age:85 Years
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR), central review
Time Frame:until Week17 (Day113th)
Safety Issue:
Description:As overall tumor response in all the tumors in each subject, the ORR is calculated based on the assessment results in Week 9 (Day 57th), Week 13 (Day 85th) and Week 17 (Day 113th) as confirmatory assessment.

Secondary Outcome Measures

Measure:Overall response rate (ORR) and Best overall response (BOR), investigator assessment and central review
Time Frame:until Week 105 (Day 729th)
Safety Issue:
Description:In all the tumors in each subject, the RECIST v1.1-based, the irRC-based and the irRECIST-based overall tumor response is assessed by the site investigator until Week 105 (Day 729th). Then, based on the assessment results, the ORR and BOR are calculated.
Measure:Percent change in individual tumor sizes
Time Frame:Until Week 105 (Day 729th)
Safety Issue:
Description:Until Week 105 (Day 729th) in each subject, the size of each tumor is calculated by the longest diameter the perpendicular diameter of each tumor, and then percent changes in individual tumor sizes (percent shrinkage or growth) and the local Response Rates are calculated
Measure:Progression free survival (PFS)
Time Frame:Until Week 105 (Day 729th)
Safety Issue:
Description:When the last subject completed Week 22 (Day 148th) (and Week 26 as confirmatory assessment of PD) and Week 53 (Day 365th) and Week 105 (Day 729th) of GEN0101, the RECIST v1.1-based PFS is assessed for all the subjects, where the assessment results in Week 8 should not be used and the central assessment results since Week 13 (Day 85th) only are used for all the subjects.
Measure:Overall survival (OS)
Time Frame:Until Week 105 (Day 729th)
Safety Issue:
Description:When the last subject completes Week 22 (Day 148th) and Week 53 (Day 365th) and Week 105 (Day 729th) of GEN0101, OS is calculated for all the subjects.
Measure:Induction of antitumor immunity
Time Frame:Week 13 (Day 85th)
Safety Issue:
Description:In Week 9 (Day 57th) and Week 13 (Day 85th) of GEN0101 in each subject, the induction of antitumor immunity after the combination therapy is investigated with the index of peripheral blood activated NK cells.
Measure:Adverse Events
Time Frame:up to Week 105 (Day 729th)
Safety Issue:
Description:AEs occurring in each subject up to Week 105 (Day 729th) of GEN0101 are evaluated with CTCAE v4.03

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Osaka University

Trial Keywords

  • Cancer immunotherapy

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