Clinical Trials /

Study of TLR9 Agonist CMP-001 in Combination With Nivolumab vs. Nivolumab

NCT04401995

Description:

The main goal of this research study is to determine how nivolumab and nivolumab/CMP-001 combination affect the likelihood of destroying melanoma involving lymph node and/or in-transit/satellite areas. The main goal of the PET/CT scan with 18F]F-AraG is to evaluate how [18F]F-AraG uptake changes before and after administration of either nivolumab or nivolumab/CMP-001 combination.

Related Conditions:
  • Melanoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of TLR9 Agonist CMP-001 in Combination With Nivolumab vs. Nivolumab
  • Official Title: Randomized Neoadjuvant Pilot Phase II Study of TLR9 Agonist CMP-001 in Combination With Nivolumab vs. Nivolumab in Stage IIIB/C/D Melanoma Patients With an Integrated Imaging Biomarker

Clinical Trial IDs

  • ORG STUDY ID: 20-049
  • NCT ID: NCT04401995

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
CMP-001Nivolumab and CMP-001 Combination with [18F]F-AraG PET/CT
NivolumabNivolumab and CMP-001 Combination with [18F]F-AraG PET/CT

Purpose

The main goal of this research study is to determine how nivolumab and nivolumab/CMP-001 combination affect the likelihood of destroying melanoma involving lymph node and/or in-transit/satellite areas. The main goal of the PET/CT scan with 18F]F-AraG is to evaluate how [18F]F-AraG uptake changes before and after administration of either nivolumab or nivolumab/CMP-001 combination.

Detailed Description

      This is a phase II pilot study comparing MPR rate between two neoadjuvant. This study is
      designed to evaluate a neoadjuvant regimen [nivolumab in combination with Toll-like receptor
      9 (TLR9) agonist CMP-001] of 20 patients as compared against nivolumab monotherapy. This
      study includes an integrated [18F]F-AraG imaging biomarker that aims assess the imaging
      biomarker in patients receiving either neoadjuvant CMP-001/nivolumab or neoadjuvant
      nivolumab.

      Patients with stage IIIB-IIID cutaneous (or unknown primary) melanoma with palpable nodal
      disease and/or in-transit disease who have yet to undergo definitive surgery are eligible to
      enroll. Patients with nodal and/or in-transit relapse including those who have received prior
      adjuvant IFN and/or ipilimumab are eligible to enroll.

      Suitable patients will be identified pre-operatively. Patients will undergo a 28 day
      screening evaluation including surgical assessment, clinical assessment, systemic/CNS staging
      scans, and laboratory studies to confirm suitability. Biopsies will occur pre-treatment, W4-5
      and the injected lesion(s) will be resected at the time of surgery.

      Eligible patients will be randomized 1:1 to receive Arm A (neoadjuvant Nivolumab/CMP) vs. Arm
      B (neoadjuvant Nivolumab) during the (Prime Phase) pre-operatively for 6-7 weeks. Patients
      randomized to Arm A will receive: Nivolumab 240mg IV q2 x3 and CMP-001 5mg SC 1st dose then
      10mg IT 2nd-7th doses (7 weeks). Patients randomized to Arm B will receive: Nivolumab 240mg
      IV q2 x3 (6 weeks). In the Prime Phase, CMP-001 will be administered weekly via sub-cutaneous
      injection (5mg SC; week 1) then intra-tumorally (10mg IT; weeks 2-7).

      [18F]F-AraG PET-CT scan (18-F PET) is an integrated biomarker and will be performed at 2
      imaging time-points: pre-treatment (pre-W1) and on-treatment (W4). At each imaging timepoint,
      [18F]F-AraG will be administered by a licensed nuclear medicine technologist under the
      supervision of a nuclear medicine physician on an outpatient basis. Each patient will receive
      a single bolus injection of 5 mCi [18F]F-AraG IV into a hand or arm vein. At pre-W1/W4
      imaging timepoints, following [18F]F-AraG injection, a 30-min static PET-CT scan will be
      performed covering the brain to the upper legs.

      Following the Prime Phase and restaging systemic scans, patients will undergo surgical
      resection.

      Post-operatively, patients will continue to receive maintenance therapy (Boost Phase) per
      randomization. In the Boost Phase, patients randomized to Arm A (neoadjuvant Nivolumab/CMP)
      will receive Nivolumab and CMP (480mg IV q4 x12; CMP-001 5mg SC q4 x12; 48 weeks); while
      patients randomized to Arm B (neoadjuvant Nivolumab) will receive Nivolumab (480mg IV q4 x12;
      48 weeks). In the post-operative period, CMP-001 will be administered subcutaneously.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab and CMP-001 Combination with [18F]F-AraG PET/CTExperimentalPrime Phase - Nivolumab 240mg IV, every 2 weeks starting with Cycle 2 (Cycles 2,4,6) for 6 weeks in combination with CMP-001 5mg subcutaneous 1st dose, and the remaining injections, 10mg intra-tumorally will be administered Weeks 2-7. [18F]F-AraG PET/CT, single bolus injection of 5 (±10%) mCi IV into a vein, Screening and at Week 5. Boost Phase - Nivolumab 480mg IV, every 4 weeks and CMP-001 5mg subcutaneous every 4 weeks up to 48 weeks.
  • CMP-001
  • Nivolumab
Nivolumab with [18F]F-AraG PET/CTExperimentalPrime Phase - Nivolumab 240mg IV, every 2 weeks starting with Cycle 2 (Cycles 2, 4, 6) for 6 weeks. [18F]F-AraG PET/CT, single bolus injection of 5 (±10%) mCi IV into a vein, Screening and at Week 5. Boost Phase - Nivolumab 480mg IV, every 4 weeks starting from the time of surgery recovery for up to 48 weeks.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the study.

          2. Be ≥ 18 years of age on day of signing informed consent.

          3. Willingness to undergo [18F]F‑AraG PET imaging at pre- and week 5 timepoints.

          4. Diagnosis of histologically or cytologically confirmed diagnosis of cutaneous melanoma
             belonging to one of the following AJCC TNM stages:

               1. Tx or T1-4 and

               2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c and

               3. M0

             Patients are eligible for this trial either at presentation for primary melanoma with
             concurrent regional nodal and/or in-transit metastasis; or at the time of clinical
             detected nodal and/or in-transit recurrence; and may belong to any of the following
             groups:

               -  Primary cutaneous melanoma with clinically apparent regional lymph node
                  metastases.

               -  Clinically detected recurrent melanoma at the proximal regional lymph node(s)
                  basin.

               -  Clinically detected primary cutaneous melanoma involving multiple regional nodal
                  groups.

               -  Clinical detected nodal melanoma (if single site) arising from an unknown
                  primary.

               -  In-transit and/or satellite metastases with or without regional lymph node
                  involved permitted if considered potentially surgically resectable at baseline.

               -  NOTE: Determination of potential resectability must be made at baseline to be
                  eligible for this neoadjuvant study.

               -  NOTE: Patients with mucosal and/or uveal melanoma are not permitted to enroll.
                  Patients with melanomas of unknown primary may be enrolled at the discretion of
                  the treating investigator in discussion with Principal Investigator.

          5. Presence of injectable and measurable disease based on RECIST 1.1.

          6. Willing to undergo tumor biopsy (core, punch, incisional or excisional). Patients must
             undergo biopsy (core, punch) or open biopsy (incisional, excisional) within 4 weeks of
             registration on the study and at W4-5.

          7. Performance status of 0 or 1 on the ECOG Performance Scale.

          8. Demonstrate adequate organ function as defined below performed on screening labs
             obtained within 4 weeks of registration.

               -  Absolute neutrophil count (ANC) ≥1,500 /mcL

               -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L

               -  Platelets ≥100,000 / mcL

               -  Serum creatinine or Measured or calculated creatinine clearance (GFR can also be
                  used in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60
                  mL/min for subject with creatinine levels > 1.5 X institutional ULN.

               -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with
                  total bilirubin levels > 1.5 ULN.

               -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN.

               -  International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
                  subject is receiving anticoagulant therapy as long as PT or PTT is within
                  therapeutic range of intended use of anticoagulants.

               -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is
                  receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
                  of intended use of anticoagulants.

          9. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

         10. Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 26 weeks after the last dose of study medication (Section 5.7.2).
             Subjects of childbearing potential are those who have not been surgically sterilized
             or have not been free from menses for > 1 year.

         11. Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 26 weeks after the last dose of study therapy.

        Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
        for the subject.

        Exclusion Criteria:

          1. History of uveal or mucosal melanoma.

          2. Is currently participating in or has participated in a study of an investigational
             agent or using an investigational device within 4 weeks of the first dose of
             treatment.

          3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting
                  therapy.

               -  Note: Subjects with autoimmune disorders of Grade 4 while on prior immunotherapy
                  will be excluded. Subjects who developed autoimmune disorders of Grade ≤ 3 may
                  enroll if the disorder has resolved to Grade ≤1 and the subject has been off
                  systemic steroids at doses >10 mg/d for at least 2 weeks.

          5. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.

          6. Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
             skin, or in situ cervical cancer that has undergone potentially curative therapy.

          7. Has a systemic disease that requires systemic pharmacologic doses of corticosteroids
             greater than 10mg daily prednisone (or equivalent). Subjects who are currently
             receiving steroids at a dose of ≤10mg daily do not need to discontinue steroids prior
             to enrollment Subjects that require topical, ophthalmologic and inhalational steroids
             would not be excluded from the study. Subjects with hypothyroidism stable on hormone
             replacement or Sjogren's syndrome will not be excluded from the study. Subjects who
             require active immunosuppression (greater than steroid dose discussed above) for any
             reason are excluded.

          8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.

          9. Has an active infection requiring systemic therapy.

         10. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         11. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         12. Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 26 weeks after the last dose of trial treatment.

         13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or
             BRAF/MEK inhibitor. Prior treatment with ipilimumab or interferon alfa is allowed.
             Patients with history of allergic or hypersensitivity reaction to interferon alfa or
             ipilimumab are also excluded.

         14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected. Patients with treated Hepatitis B/C with no evidence of
             active infection may be enrolled.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Immune-related Major Pathologic Response rate (MPR rate)
Time Frame:At the time of surgery (Week 8-10)
Safety Issue:
Description:A ratio of responders (to treatment) to total number of tumors (responders plus non-responders to treatment). Immune-related pathologic response rate based on the percent (%) of residual volume of tumor (RVT). Pathologic No Response (pNR) is defined as %RVT>50%; Partial Pathologic Response (pPR) is defined as 10%< %RVT<50% (at least 10%, up to 49%); Major Pathologic Response (MPR) is defined as %RVT≤10%; Pathologic Complete Response (pCR) is defined as %RVT=0%.

Secondary Outcome Measures

Measure:Tumor PET response via [18F]F-AraG
Time Frame:At Week 1 (baseline) and Week 5
Safety Issue:
Description:[18F]F-AraG is an experimental PET imaging agent. Tumor PET response will be assessed via standard uptake values (SUV) measured as SUVmax, SUVpeak, SUVmean, and SUVtotal.The max, peak, mean and total values for each patient will be used to determine the average standard uptake values for the study population. The possible range of SUV values is between 0 - 100. Higher SUV correlates with greater malignancy.
Measure:Relapse-Free Survival (RFS)
Time Frame:At 6-months, 12-months, 1-year, 2-year, 3-year, 5-year; up to 5 years
Safety Issue:
Description:The length of time from initiation of treatment until melanoma relapse or death.
Measure:Overall Survival (OS)
Time Frame:At 6-month, 12-months, 1-year, 2-year, 3-year, 5-year; up to 5 years
Safety Issue:
Description:The length of (survival) time from the start of treatment until death from any cause.
Measure:Adverse Events at Least Possibly Related to Study Treatment
Time Frame:Up to 5 years
Safety Issue:
Description:Toxicities defined by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 are adverse events classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded and the frequency of toxicities will be tabulated for the study population.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Diwakar Davar

Trial Keywords

  • residual volume of tumor (RVT)
  • standard uptake value (SUV)

Last Updated

May 20, 2020