Clinical Trials /

Pembrolizumab TX-naive Distant Mets Melanoma and Use of AMT (PET) at Baseline as Imaging Biomarker

NCT03089606

Description:

Explore association between intensity of C11-AMT PET at baseline, as measured by mean standardized uptake value (SUVmax at each lesion), total tumor metabolic volume, measurement of intra-tumoral and inter-lesional heterogeneity), with objective response rate (ORR) at 12 weeks (as defined via RECIST 1.1) to pembrolizumab in patients with treatment-naïve metastatic melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab TX-naive Distant Mets Melanoma and Use of AMT (PET) at Baseline as Imaging Biomarker
  • Official Title: Pembrolizumab in Systemic Treatment-Naïve Distant Metastatic Melanoma and Exploration of Use of 11Cmethyl-L-tryptophan (AMT) PET at Baseline as a Predictive Imaging Biomarker of Response

Clinical Trial IDs

  • ORG STUDY ID: LCCC 1531
  • NCT ID: NCT03089606

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaC11-AMT PET

Purpose

Explore association between intensity of C11-AMT PET at baseline, as measured by mean standardized uptake value (SUVmax at each lesion), total tumor metabolic volume, measurement of intra-tumoral and inter-lesional heterogeneity), with objective response rate (ORR) at 12 weeks (as defined via RECIST 1.1) to pembrolizumab in patients with treatment-naïve metastatic melanoma.

Detailed Description

      Objectives:

      Primary Objective

      Explore association between intensity of C11-AMT PET at baseline, as measured by mean
      standardized uptake value (SUVmax at each lesion), total tumor metabolic volume, measurement
      of intra-tumoral and inter-lesional heterogeneity), with objective response rate (ORR) at 12
      weeks as defined via RECIST 1.1 to pembrolizumab in patients with Programmed Death (PD)-1
      inhibitor-naïve unresectable stage III or distant metastatic (AJCC stage IV) melanoma.

      Secondary Objectives

      Estimate ORR (CR + PR) by RECIST 1.1 at 12 weeks to pembrolizumab in patients with PD-1
      inhibitor-naïve unresectable stage III or distant metastatic metastatic melanoma (AJCC stage
      III/IV).

      Estimate progression-free survival (PFS) in patients with unresectable stage III or distant
      metastatic melanoma treated with pembrolizumab as front-line therapy.

      Explore associations in SUVmax and other PET parameters (e.g. total tumor metabolic volume,
      measurement of intra-tumoral and inter-lesional heterogeneity) between C11-AMT PET and
      fluorodeoxyglucose (FDG)-PET at baseline.

      Explore associations between SUVmax, and other PET parameters (e.g. total tumor metabolic
      volume, measurement of intra-tumoral and inter-lesional heterogeneity) identified at baseline
      C11-AMT PET imaging with expression of components of the Indoleamine-pyrrole 2,3-dioxygenase
      (IDO) pathway detected by immunohistochemistry (IHC) or immunofluorescence (LAT1, IDO, TPH1),
      lymphocyte subtypes (CD4, cluster of differentiation 8 (CD8), FoxP3, MDSC), PD-1/PD-L1, and
      other immune checkpoint pathways (LAG3, glucocorticoid-induced tumor necrosis factor receptor
      (GITR), TIM3) in freshly acquired tumor specimens prior to treatment with pembrolizumab.

      Assess metabolic changes at week 12 (or earlier, if patient progresses) following treatment
      with pembrolizumab using baseline and week 12 FDG PET.

      Outline:

      Screening:

      Physical exam, medical history, and laboratory tests, as per standard of care. Brain MRI and
      Whole body FDG PET/CT scan with IV contrast will be performed at least 24 hours before
      C11-AMT PET scanning. Although, the FDG PET/CT scan with IV contrast is preferred the
      following baseline measurements may be used if they have occurred within the below specified
      windows:

        1. Whole body FDG PET/CT scan without IV contrast, will be accepted for study purposes
           (i.e. correlation between baseline FDG PET scan and baseline C11-AMT scan) if it has
           occurred within 28 days before the C11-AMT PET scan. In this case, the patient will only
           be required to have a baseline CT scan of the chest, abdomen, and pelvis (also neck, if
           applicable) with IV contrast within 28 days of starting pembrolizumab.

        2. CT scan with IV contrast will be accepted for study purposes (i.e. baseline tumor
           assessment) if it has occurred within 28 days of starting pembrolizumab. In this case,
           the patient will only be required to have a baseline PET scan without CT coregistration
           28 days prior to C11-AMT. This is to correlate baseline FDG PET with baseline C11-AMT
           PET parameters.

      If eligibility criteria are met, patients will proceed to Study Related Scans and Biopsy:

      C11-AMT PET will be performed at least 24 hours before pembrolizumab treatment and at least
      24 hours after FDG PET/CT scan. A research biopsy will be performed before pembrolizumab
      treatment.

      After screening and study related scans and biopsy, treatment will consist of the following:

      Pembrolizumab 200mg IV flat dose will be administered over 30 minutes on Day 1; Pembrolizumab
      dosing will be repeated every 3 weeks until progression or subject withdrawal for other
      reasons.

      At the end of treatment:

      Whole body FDG PET/CT scan with IV contrast.

      Projected Accrual:

      Up to 25 subjects who have not received prior therapy for their recent diagnosis of distant
      metastatic melanoma.
    

Trial Arms

NameTypeDescriptionInterventions
C11-AMT PETOtherWhole body FDG PET/CT scan with IV contrast will be performed at least 24 hours before C11-AMT PET scanning, as per standard of care. C11-AMT PET will be performed at least 24 hours before pembrolizumab treatment and at least 24 hours after FDG PET/CT scan. Pembrolizumab 200mg by IV flat dose will be administered over 30 minutes on Day 1; Pembrolizumab dosing will be repeated every 3 weeks until progression or subject withdrawal for other reasons. Whole body FDG PET/CT scan with IV contrast at end of treatment.
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Sign written informed consent and HIPAA authorization for release of personal health
             information. Note: HIPAA authorization may be included in the informed consent or
             obtained separately.

          2. Subject must be 18 years of age or more on the day of signing informed consent.

          3. Have histologic or cytologic biopsy-proven diagnosis of unresectable stage III or
             distant metastatic melanoma, irrespective of histologic type (i.e. cutaneous, unknown
             primary, mucosal, or ocular). Patients with resectable bulky stage IIIB or stage IIIC
             melanoma (for example at least 2.5-cm in shortest diameter for lymph nodes infiltrated
             by tumor and at least 2-cm in longest diameter for non-lymph nodes infiltrated by
             tumor) can also be entered into the study at the discretion of the Principal
             Investigator.

          4. Have measurable disease based on RECIST v1.1. for solid tumors

          5. Be willing to undergo fresh tumor tissue biopsy of an accessible tumor lesion prior to
             pembrolizumab. A mandatory fresh biopsy will be collected following C11-AMT PET
             imaging. Subjects for whom fresh samples cannot be provided (e.g. inaccessible or
             subject safety concern) or do not agree to this fresh tumor research biopsy of
             accessible tumor will be deemed ineligible for study participation. Exception to the
             mandatory tumor tissue collection are patients with metastatic lung lesions as the
             only site of metastatic disease. Fresh biopsy collection from these subjects will be
             optional, due to high risk of pneumothorax.

          6. Be willing to allow for investigators to collect archival tumor tissues from surgical
             procedures that may have been performed before or after enrollment into this trial for
             research purposes (in-house cases and/or outside cases). These samples will be
             obtained by study staff as long as subject continues on follow-up. Blocks of tissue
             will be requested, and if blocks are not able to be obtained, 5micron slides (10-15)
             will be sufficient.

          7. Be willing to be injected with 11C-methyl-L-tryptophan (C11-AMT)

          8. Have a performance status of 0 - 2 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          9. Has not received prior therapy with cytotoxic T lymphocyte antigen (CTLA)-4,
             PD-1/PD-L1 inhibitors, other co-stimulatory or co-inhibitory immune checkpoint
             antibody therapies (e.g. LAG3, TIM3, cluster of differentiation (CD) 137, Killer
             immunoglobulin-like receptor (KIR3DL), cluster of differentiation (CD) 70, and CD27)
             for distant metastatic melanoma. Patients who have received mitogen-activated protein
             kinase (MAPK) inhibitors are allowed on condition that they have recovered from
             adverse events to at most Grade 1 by CTCAE v4.03 and at least 15 days have elapsed
             between last dose of MAPK inhibitors and C11-AMT imaging. Patients who have previously
             received CTLA-4 inhibitors in the adjuvant setting are allowed to participate as long
             as they discontinued CTLA-4 treatment at least 30 days ago and meet criteria outlined
             in inclusion #14. Patients who have previously received adjuvant PD-1 inhibitors are
             excluded.

         10. Demonstrate adequate organ function as defined in below; all screening labs to be
             obtained within 14 days prior to C11-AMT PET scan:

             Hematological:

             Hemoglobin (Hgb) - ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin
             (EPO) dependency (within 7 days of Hgb) Absolute Neutrophil Count (ANC) - ≥ 1,500/mm3
             Platelets - ≥ 100,000/mm3

             Renal:

             Serum Creatinine OR Measured or calculated creatinine clearance (GFR can also be used
             in place of creatinine or CrCl) - ≤1.5 x ULN OR ≥ 60 mL/min using the Cockcroft-Gault
             formula for subject with creatinine levels > 1.5 X institutional upper limits of
             normal (ULN)

             Hepatic:

             Serum Total Bilirubin - ≤ 1.5 X ULN Aspartate aminotransferase (AST) - ≤ 2.5 X ULN OR
             < 5 X ULN for subjects with liver metastases Alanine aminotransferase (ALT) - ≤ 2.5 X
             ULN OR < 5 X ULN for subjects with liver metastases Albumin - ≥ 2.5 mg/dL

             Coagulation:

             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

         11. Female subjects of childbearing potential should have a negative urine or serum
             pregnancy within 14 days prior to C11-AMT PET scan. If the urine test is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required.

         12. Female subjects of childbearing potential must be willing to use adequate methods of
             contraception as outlined - Contraception for the course of the study through 120 days
             after the last dose of study medication. Subjects of childbearing potential are those
             who have not been surgically sterilized or have not been free from menses for > 1
             year.

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

             Male subjects should agree to use an adequate method of contraception as outlined -
             Contraception starting with the first dose of study therapy through 120 days after the
             last dose of study therapy.

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

         13. Patients who have received prior adjuvant high dose interferon are allowed to
             participate as long as the last injection was given at least 30 days prior to the
             C11-AMT PET scan and they have fully recovered from side effects (i.e., Grade ≤1 or
             permanent side effects that require hormone replacement therapy).

         14. Patients on adjuvant ipilimumab are allowed to participate at least 30 days from drug
             discontinuation as long as they have at most Grade 1 adverse events (or grade 2 if
             they have to received hormone replacement therapy for their otherwise grade 1
             ipilimumab-induced autoimmune endocrinopathies).

        Exclusion Criteria:

          1. Is currently participating and receiving study therapy for his/her advanced melanoma
             or has participated in a study of an investigational agent and received study therapy
             in the advanced melanoma setting.

          2. Has received prior treatment with PD-1/PD-L1 pathway inhibitors in the adjuvant
             setting.

          3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to C11-AMT PET Scan

          4. Has a known history of active tuberculosis (Bacillus Tuberculosis)

          5. Hypersensitivity to pembrolizumab or any of its excipients described

          6. Has had prior monoclonal antibody (mAb) targeting immune checkpoint proteins, for
             distant metastatic melanoma and have progressed or have developed intolerable side
             effect.

          7. Adjuvant anticancer treatments are allowed at least 30 days has elapsed between the
             infusion/injection and C11-AMT PET scan as part of this study.

          8. Prior radiation therapy for metastatic melanoma is allowed as long as the patient
             bears measurable actively growing disease outside the previously irradiated field.
             Note: If subject received major surgery, they must have recovered adequately from the
             toxicity (i.e., all symptoms ≤ grade 1) and/or complications from the intervention
             prior to starting therapy.

          9. History of prior malignancy, with the exception of the following:

               -  Non-melanoma skin cancers, non-invasive bladder cancer, and carcinoma in situ of
                  the cervix,

               -  Prior history of prostate provided patient not under active systemic treatment
                  other than hormonal therapy and with documented undetectable prostate-specific
                  antigen (PSA) (<0.2ng/mL),

               -  Chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) provided
                  patient has isolated lymphocytosis (Rai stage 0), and does not require systemic
                  treatment [for "B" symptoms, Richter's transformation, lymphocyte doubling time
                  (<6 months), lymphadenopathy or hepatosplenomegaly],

               -  Lymphoma or any type or hairy-cell leukemia provided patient is not on active
                  systemic treatment and is in complete remission, as evidenced by PET/CT scans and
                  bone marrow biopsies for at least 3 months,

               -  Papillary thyroid cancer. Since this malignancy very infrequently metastasizes
                  distantly, patients with concurrent metastatic melanoma can be enrolled even if
                  patients may: A) have just completed thyroidectomy within the last 2 years, B)
                  have not received adjuvant radioactive iodine therapy, C) were only recently
                  diagnosed with asymptomatic papillary thyroid cancer and their surgery is
                  pending.

               -  History of malignancy provided patient has completed therapy and is free of
                  disease for ≥ 2 years. If patient had other malignancy within the last 2 years
                  from which he may have been completely cured by surgery alone, he may considered
                  to be enrolled on condition that the risk of development of distant metastatic
                  disease based on AJCC staging system is less than 30%.

         10. Has known active parenchymal central nervous system (CNS) metastases that are
             symptomatic, and/or more than one lesions, and/or their largest diameter is > 5-mm
             and/or require antiepileptic drugs or corticosteroids. Patients with carcinomatous
             meningitis are also excluded. Exceptions are: subjects with previously treated brain
             metastases provided they are stable (without evidence of progression by imaging) for
             at least 2 weeks prior to C11-AMT and any neurologic symptoms have returned to
             baseline, have no evidence of new or enlarging brain metastases, and are not using
             ongoing steroids for at least 7 days prior to C11-AMT. Patients with active (i.e. not
             treated with stereotactive radiosurgery), single, asymptomatic, up to 5-mm in largest
             diameter brain metastases (measured either by brain MRI with IV contrast or head CT
             with IV contrast measured within 2 weeks prior to C11-AMT) are allowed.

         11. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease-modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

         12. Has known history of (non-infectious) pneumonitis that required steroids, or any
             evidence of current pneumonitis.

         13. Has an active infection requiring systemic therapy.

         14. 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.

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

         16. 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 120 days after the last dose of trial treatment.

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

         18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C virus (HCV) (e.g.,
             HCV RNA [qualitative] is detected).

         19. Has received a live vaccine within 14 days of C11-AMT PET scan. Note: Seasonal
             influenza vaccines for injection are generally inactivated flu vaccines and are
             allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated
             vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Association of SUVmax with Objective Response Rate
Time Frame:12 weeks
Safety Issue:
Description:Association between intensity of C11-AMT PET at baseline, as measured by mean standardized uptake value (SUVmax at each lesion), total tumor metabolic volume, measurement of intra-tumoral and inter-lesional heterogeneity), with objective response rate (ORR) at 12 weeks (as defined via RECIST 1.1) to pembrolizumab in patients with PD-1 inhibitor-naïve unresectable stage III or distant metastatic (AJCC stage IV) melanoma.

Secondary Outcome Measures

Measure:Objective Response Rate
Time Frame:12 Weeks
Safety Issue:
Description:Objective Response Rate (Complete Response + Partial Response) by RECIST 1.1 at 12 weeks to pembrolizumab in patients with PD-1 inhibitor-naïve unresectable stage III or distant metastatic metastatic melanoma (AJCC stage III/IV).
Measure:Progression-Free Survival
Time Frame:3 years
Safety Issue:
Description:Progression-free survival (PFS) in patients with unresectable stage III or distant metastatic melanoma treated with pembrolizumab as front-line therapy.
Measure:PET parameters
Time Frame:28 Days
Safety Issue:
Description:Associations in SUVmax and other PET parameters (e.g. total tumor metabolic volume, measurement of intra-tumoral and inter-lesional heterogeneity), using C11-AMT PET co-between C11-AMT PET and FDG-PET at baseline.
Measure:PET parameters and IDO pathway
Time Frame:12 weeks
Safety Issue:
Description:Associations between SUVmax and other PET parameters (e.g. total tumor metabolic volume, measurement of intra-tumoral and inter-lesional heterogeneity) identified at baseline C11-AMT PET imaging with expression of components of the IDO pathway detected by immunohistochemistry (IHC) or immunofluorescence (LAT1, IDO, TPH1), lymphocyte subtypes (CD4, CD8, FoxP3, MDSC), PD-1/PD-L1, and other immune checkpoint pathways (LAG3, GITR, TIM3) in freshly acquired tumor specimens prior to treatment with pembrolizumab.
Measure:Metabolic changes
Time Frame:12 weeks
Safety Issue:
Description:Assess metabolic changes at week 12 (or earlier, if patient progresses) following treatment with pembrolizumab using baseline and week 12 FDG PET.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:UNC Lineberger Comprehensive Cancer Center

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