Clinical Trials /

Intratumoral Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors

NCT03684785

Description:

This is a phase 1b/2, open-label, two-part, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab or cemiplimab in patients with Merkel Cell Carcinoma, cutaneous squamous cell carcinoma, and advanced solid tumors. Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of cavrotolimod given with a fixed dose of pembrolizumab. The Phase 2 dose expansion part of the study will consist of two primary cohorts of patients: Merkel cell carcinoma and cutaneous squamous cell carcinoma. Patients in the Merkel Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the Cutaneous Squamous Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab. The Phase 2 dose expansion is designed to provide a preliminary estimate of efficacy in patients that have progressed on an anti-PD-(L)1 CPI.

Related Conditions:
  • Malignant Solid Tumor
  • Skin Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intratumoral Cavrotolimod Combined With Pembrolizumab or Cemiplimab in Patients With Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors
  • Official Title: Merkel Cell Carcinoma, Cutaneous Squamous Cell Carcinoma, or Other Advanced Solid Tumors: A Phase 1b/2 Study of Cavrotolimod Combined With Pembrolizumab or Cemiplimab

Clinical Trial IDs

  • ORG STUDY ID: AST-008-102
  • NCT ID: NCT03684785

Conditions

  • Advanced or Metastatic Merkel Cell Carcinoma
  • Advanced or Metastatic Cutaneous Squamous Cell Carcinoma
  • Advanced or Metastatic Melanoma
  • Advanced or Metastatic Head and Neck Squamous Cell Carcinoma
  • Advanced or Metastatic Solid Tumors

Interventions

DrugSynonymsArms
CavrotolimodDose Escalation Phase 1b
PembrolizumabDose Escalation Phase 1b
CemiplimabDose Expansion Phase 2, cutaneous squamous cell carcinoma
CavrotolimodExploratory Phase 2, Subcutaneous Dosing Cohort

Purpose

This is a phase 1b/2, open-label, two-part, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral cavrotolimod injections alone and in combination with intravenous pembrolizumab or cemiplimab in patients with Merkel Cell Carcinoma, cutaneous squamous cell carcinoma, and advanced solid tumors. Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of cavrotolimod given with a fixed dose of pembrolizumab. The Phase 2 dose expansion part of the study will consist of two primary cohorts of patients: Merkel cell carcinoma and cutaneous squamous cell carcinoma. Patients in the Merkel Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of pembrolizumab while the Cutaneous Squamous Cell Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of cemiplimab. The Phase 2 dose expansion is designed to provide a preliminary estimate of efficacy in patients that have progressed on an anti-PD-(L)1 CPI.

Detailed Description

      This study will be conducted in 2 phases. Phase 1 evaluates cavrotolimod given in combination
      with pembrolizumab in patients with advanced solid tumors in a classical 3+3 dose escalation
      design, with up to five ascending dose cohorts of cavrotolimod and enrollment of at least 3
      patients per cohort to identify an RP2D. Patients will be dosed twice with cavrotolimod as a
      monotherapy before adding pembrolizumab, which will be added starting at the second cycle.
      Once the MTD or highest escalation cohort has been reached, or notable efficacy has been
      observed at a given dose level, and a decision as to a RP2D has been made, a two 2-stage
      expansion cohort design will be initiated.

      Phase 2 will evaluate the RP2D of cavrotolimod given in combination with pembrolizumab or
      cemiplimab in two expansion cohorts following a modified Simon 2-stage optimal design
      comprised of patients with Merkel cell carcinoma or cutaneous squamous cell carcinoma. who
      previously received and have progressed on an anti-PD-(L)1 CPI. Patients in the Merkel Cell
      Carcinoma cohort will receive IT cavrotolimod combined with a fixed, standard dose of
      pembrolizumab while the Cutaneous Squamous Cell Carcinoma cohort will receive IT cavrotolimod
      combined with a fixed, standard dose of cemiplimab.

      Phase 2 will include an exploratory expansion cohort to evaluate cavrotolimod in combination
      with pembrolizumab in patients with other advanced solid tumors, including melanoma, who have
      progressed on anti-PD-(L)1 therapy.

      Exploratory expansion cohorts will evaluate patients with melanoma and additional patients
      with Merkel Cell Carcinoma who do not meet criteria for enrollment in the primary Merkel Cell
      Carcinoma cohort. In addition, two exploratory cohorts have been added to evaluate patients
      with advanced solid tumors and no superficial tumor accessible for IT injection using
      subcutaneously administered cavrotolimod or IT injection into liver metastases.

      A cohort of up to 10 evaluable patients with locally advanced or metastatic solid tumors with
      no superficial tumor lesions available for IT injection may be enrolled (inclusion criterion
      #4). The inclusion/exclusion criteria for this exploratory cohort will otherwise be the same
      as those used for the Phase 2 dose expansion cohorts except these patients will not be
      required to have a lesion accessible for biopsy (inclusion criterion #5). Patients will be
      dosed with cavrotolimod subcutaneously at a dose not to exceed the recommended Phase 2 dose,
      32 mg, in combination with pembrolizumab.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Phase 1bExperimentalDetermine the recommended Phase 2 dose of cavrotolimod in combination with pembrolizumab.
  • Cavrotolimod
  • Pembrolizumab
Dose Expansion Phase 2; Merkel cell carcinomaExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with advanced Merkel cell carcinoma that have progressed on an anti-PD-1 / anti-PD-L1 therapy.
  • Cavrotolimod
  • Pembrolizumab
Dose Expansion Phase 2, cutaneous squamous cell carcinomaExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and cemiplimab in patients with advanced cutaneous squamous cell carcinoma that have progressed on an anti-PD-1.
  • Cavrotolimod
  • Cemiplimab
Exploratory Phase 2, Merkel cell carinomaExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with advanced Merkel cell carcinoma that have progressed on anti-PD-1 / anti-PD-L1 therapy.
  • Cavrotolimod
  • Pembrolizumab
Exploratory Phase 2, Subcutaneous Dosing CohortExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with no superficial tumor lesion amenable that have progressed on anti-PD-1 / anti-PD-L1 therapy.
  • Pembrolizumab
  • Cavrotolimod
Exploratory Phase 2, MelanomaExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with locally Advanced or Metastatic Melanoma that have progressed on anti-PD-1 / anti-PD-L1 therapy.
  • Cavrotolimod
  • Pembrolizumab
Exploratory Phase 2, Liver LesionExperimentalDetermine the safety and preliminary efficacy of cavrotolimod and pembrolizumab in patients with metastatic solid tumors with liver metastases that have progressed on anti-PD-1 / anti-PD-L1 therapy.
  • Cavrotolimod
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent.

          2. Male or female ≥18 years of age.

          3. Must have an advanced inoperable histologically diagnosed solid tumor.

               -  Phase 2 Merkel Cell Carcinoma Dose Expansion Cohort: locally advanced or
                  metastatic Merkel cell caricinoma

               -  Phase 2 Cutaneous Squamous Cell Carcinoma Dose Expansion Cohort: locally advanced
                  or metastatic cutaneous squamous cell carcinoma

               -  Phase 2 Merkel Cell Carcinoma Exploratory Expansion Cohort: locally advanced or
                  metastatic Merkel cell carcinoma

               -  Phase 2 Melanoma Exploratory Expansion Cohort: Locally advanced or metastatic
                  melanoma

               -  Phase 2 Subcutaneous Dosing Exploratory Cohort: Locally advanced or metastatic
                  solid tumors

               -  Phase 2 Liver Lesion Exploratory Cohort: metastatic solid tumors with liver
                  metastases

          4. Phase 1b, Phase 2 Merkel Cell Carcinoma Dose Expansion Cohort, Phase 2 Cutaneous
             Squamous Cell Carcinoma Dose Expansion Cohort, Phase 2 Merkel Cell Carcinoma
             Exploratory Expansion Cohort, Phase 2 Melanoma Exploratory Expansion Cohort:

             At least one tumor lesion amenable to repeated IT injection via palpation or
             ultrasound. Injection of deep visceral lesions is not permitted.

             Patients enrolled in subcutaneous dosing cohort do not need lesions amenable to
             subcutaneous dosing.

          5. Phase 1b and Phase 2 Melanoma Exploratory Expansion Cohort:

             Agrees to provide a newly obtained biopsy of one or two lesions, and agrees to repeat
             biopsies, if applicable.

          6. Phase 1b:

             In the investigator's opinion the patient may derive clinical benefit from the
             treatment or is ineligible for a particular form of standard therapy due to
             tolerability, or the patient failed one or more established standard medical
             anti-cancer therapies. Exposure to anti-PD-(L)1 or anti-CTLA-4 antibody CPIs is
             permitted but not required.

             Phase 2 Merkel Cell Carcinoma Dose Expansion Cohort:

             i. At least a minimum number of cycles of avelumab, nivolumab, or pembrolizumab. Prior
             anti-CTLA-4 antibody therapy, including as most recent preceding therapy in
             combination with avelumab or pembrolizumab, is permitted but not required.

             ii. Confirmed progressive disease during treatment with avelumab or pembrolizumab
             therapy,

             Phase 2 Cutaneous Squamous Cell Carcinoma Dose Expansion Cohort

             i. At least a minimum number of cycles of cemiplimab, nivolumab, or pembrolizumab.
             Prior ipilimumab therapy, including as most recent preceding therapy in combination
             with cemiplimab, nivolumab, or pembrolizumab, is permitted but not required.

             ii. Confirmed progressive disease on cemiplimab or pembrolizumab therapy

             Phase 2 MCC and Melanoma Exploratory Expansion Cohort and Phase 2 Subcutaneous Dosing
             Exploratory Expansion Cohort:

             i. Treatment duration with anti-PD-(L)1 antibody ≥8 weeks as the most recent preceding
             therapy prior to being enrolled in this study with confirmed progression. Anti-PD-(L)1
             was administrated for metastatic or locally advanced Merkel Cell Carcinoma or
             melanoma. Prior ipilimumab therapy, including as most recent therapy in combination
             with anti-PD-(L)1 therapy, is permitted but not required.

             ii. Confirmed progressive disease on anti-PD-(L)1 antibody therapy

          7. Phase 1b and Phase 2 Melanoma Exploratory Expansion Cohort:

             Evaluable disease per RECIST 1.1 with at least two target lesions as defined by RECIST
             1.1. Both injectable and non-injectable target lesions should be chosen for efficacy
             evaluation.

          8. For the Phase 2 expansion portions of the study, a maximum of 4 prior lines of
             systemic treatment for locally advanced or metastatic disease.

               -  Phase 2 Merkel Cell Carcinoma and Melanoma Exploratory Expansion Cohorts and
                  Phase 2 Subcutaneous Dosing Exploratory Cohort

          9. For female patients of childbearing potential, defined as females who 1) have not
             undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy or 2)
             have not been postmenopausal for at least 12 consecutive months [i.e., have had menses
             at any time during the preceding 12 consecutive months]):

             • Willing to use one of the following effective methods of contraception for at least
             30 days before administration of cavrotolimod, during treatment with cavrotolimod,
             pembrolizumab, or cemiplimab, and for at least four months after the last dose of
             cavrotolimod, pembrolizumab, or cemiplimab:

             i. Total abstinence from sexual intercourse with a partner that may result in
             pregnancy

             ii. Hormonal contraception (oral, parenteral, or transdermal) used for at least 3
             consecutive months prior to the first dose of cavrotolimod

             iii. Intrauterine contraceptive device

             iiii. Barrier contraception (i.e., condom, cap, diaphragm, or sponge with spermicide)

             For male patients who have not had a vasectomy:

             • Willing to use one of the following effective methods of contraception for at least
             30 days before administration of cavrotolimod, during treatment with cavrotolimod,
             pembrolizumab, or cemiplimab, and for at least four months after the last dose of
             cavrotolimod, pembrolizumab, or cemiplimab:

             i. Total abstinence from sexual intercourse with a female partner of childbearing
             potential

             ii. Use by female partner of hormonal contraception (oral, parenteral, or transdermal)
             for at least 3 consecutive months prior to the first dose of cavrotolimod

             iii. Use by female partner of intrauterine contraceptive device

             iiii. Barrier contraception (i.e., condom, cap, diaphragm, or sponge with spermicide)

         10. Regarding history of CPI-related adverse events:

             i. Resolution of CPI-related AEs (including irAEs) to G0-1 and no corticosteroids for
             the amelioration of those irAEs for at least 4 weeks prior to the first dose of
             cavrotolimod. Controlled hypothyroidism and controlled adrenal insufficiency are
             exceptions to this criterion, provided doses do not exceed the threshold described in
             exclusion criterion #13.

             ii. No history of CTCAE G4 irAEs from CPI. iii. No history of CTCAE G3 irAEs from CPI.
             Patients with a history of CTCAE G3 irAEs from CPI requiring steroid treatment for no
             greater than 12 weeks may be considered at the discretion of the Investigator if
             supported by an assessment of risk-benefit and after discussion with the Medical
             Monitor.

         11. Adequate organ function.

         12. Able and willing to comply with the protocol and the restrictions and assessments
             therein.

        Exclusion Criteria:

          1. Small molecule or tyrosine kinase inhibitor within 2 weeks or 5 half-lives (whichever
             is longer) prior to the first dose of cavrotolimod, chemotherapy or biological cancer
             therapy within 3 weeks prior to the first dose of cavrotolimod, nitrosourea, or
             radioisotope within 6 weeks prior to first dose of cavrotolimod, or non-recovery to
             CTCAE G1 or better from the AEs due to cancer therapeutics administered more than 4
             weeks earlier.

          2. Known hypersensitivity to any phosphorothioate oligonucleotide, or previous exposure
             to a TLR9 agonist drug.

          3. Previous severe hypersensitivity reaction to treatment with pembrolizumab, cemiplimab
             or another anti-PD-(L)1 monoclonal antibody.

          4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) >1.

          5. Symptomatic ascites or pleural effusion. A patient with these conditions who has
             received treatment such as therapeutic thoracentesis or paracentesis and is clinically
             stable, defined as not requiring repeat drainage procedure within 2 weeks, may be
             considered after discussion with the Medical Monitor.

          6. Known active CNS metastases and/or carcinomatous meningitis. Patients with previously
             treated brain metastases may participate provided they are clinically stable for at
             least 4 weeks prior to the first dose of cavrotolimod, have no evidence of new or
             enlarging brain metastases and are off steroids for at least 14 days prior to the
             first dose of cavrotolimod.

          7. Known history of a hematologic malignancy, malignant primary brain tumor or malignant
             sarcoma, or of another malignant primary solid tumor (other than that under study),
             with the following exceptions: 1) patients who have undergone potentially curative
             therapy with no evidence of that disease for 3 years prior to the first dose of
             cavrotolimod; 2) patients who underwent successful definitive resection of basal cell
             carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the
             skin, in situ cervical cancer, or other in situ cancers; 3) stable chronic lymphocytic
             leukemia not requiring treatment within 3 years prior to the first dose of
             cavrotolimod.

          8. Significant autoimmune disease that requires or required systemic steroids or
             immunosuppressive agents within the last year. The following are not exclusionary: 1)
             vitiligo, resolved asthma/atopy, and limited eczema; 2) conidtions requiring
             intermittent use of bronchodilators or local steroid injections; 3) hypothyroidism or
             adrenal insufficiency that is stable on hormone replacement; or 4) irAEs related to
             checkpoint inhibitor therapy, provided inclusion criterion #10 and exclusion criterion
             #11 are met.

          9. Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15
             days or other immunosuppressive drugs within 30 days prior to the first dose of
             cavrotolimod. Inhaled and topical corticosteroids are permitted. Up to 10 mg/day
             prednisone or equivalent is permitted for hypothyroidism or adrenal insufficiency.

         10. Received an investigational product or been treated with an investigational device
             within 30 days prior to the first dose of cavrotolimod or will start any other
             investigational product or device study within 30 days after last study drug
             administration.

         11. History or clinical evidence of any surgical or medical condition which the
             Investigator judges as likely to interfere with the results of the study or pose an
             additional risk in participating e.g., rapidly progressive or uncontrolled disease
             involving a major organ system-vascular, cardiac, pulmonary, gastrointestinal,
             gynecologic, hematologic, neurologic, neoplastic, renal, endocrine or an
             immunodeficiency, or clinically significant active psychiatric or abuse disorders.

         12. Pregnant or breastfeeding or expecting to conceive or father children within the
             projected duration of the study through 4 months after the last dose of cavrotolimod,
             pembrolizumab, or cemiplimab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events of cavrotolimod alone and in combination with pembrolizumab or cemiplimab
Time Frame:Study day 36
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Secondary Outcome Measures

Measure:Recommended Phase 2 dose
Time Frame:12 months
Safety Issue:
Description:To recommend a dose of cavrotolimod and combination regimen for further development
Measure:Objective response rate (ORR) per RECIST v1.1
Time Frame:24 months
Safety Issue:
Description:ORR to be calculated overall and by cohort/subgroup using RECIST v1.1. Subgroups will be defined for the efficacy analyses based on prior exposure and response to immune checkpoint inhibitors.
Measure:Measure changes in correlative biomarkers including tumor-infiltrating lymphocytes, PD-L1 and other checkpoint expression at baseline, after cavrotolimod monotherapy, and after combination therapy of both cavrotolimod and pembrolizumab or cemiplimab.
Time Frame:Study day 36
Safety Issue:
Description:IHC on FFPE biopsies will be used to assess markers.
Measure:Measure changes in gene expression profiles at baseline, after cavrotolimod monotherapy, and after combination therapy of both cavrotolimod and pembrolizumab or cemiplimab.
Time Frame:Study day 36
Safety Issue:
Description:Selected gene-expression profiling on gene expression will be performed with nCounter (NanoString Technologies).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Exicure, Inc.

Trial Keywords

  • Advanced or Metastatic Merkel Cell Carcinoma
  • Advanced or Metastatic Cutaneous Squamous Cell Carcinoma
  • Advanced or Metastatic Head and Neck Squamous Cell Carcinoma
  • Advanced or Metastatic Melanoma
  • Advanced or Metastatic Solid Tumors
  • Head and Neck
  • Squamous Cell Carinoma
  • Cutaneous Squamous Cell Carcinoma
  • Merkel Cell Carcinoma
  • Melanoma
  • Skin Cancer

Last Updated

January 12, 2021