Clinical Trials /

Intratumoral AST-008 Combined With Pembrolizumab or Cemiplimab in Patients With Advanced Solid Tumors

NCT03684785

Description:

This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral AST-008 injections alone and in combination with intravenous pembrolizumab or cemiplimab in patients with advanced solid tumors. Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of AST-008 given with a fixed dose of pembrolizumab. The Phase 2 dose expansion part of the study will consist of two cohorts of patients: Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (CSCC). Patients in the MCC cohort will receive IT AST-008 combined with a fixed, standard dose of pembrolizumab while the CSCC cohort will receive IT AST-008 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 or are otherwise refractory to CPI therapy.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Intratumoral AST-008 Combined With Pembrolizumab in Patients With Advanced Solid Tumors
  • Official Title: A Phase 1b/2 Study of AST-008 Combined With Pembrolizumab in Patients With Advanced Solid Tumors

Clinical Trial IDs

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

Conditions

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

Interventions

DrugSynonymsArms
AST-008Dose Escalation Phase 1b
PembrolizumabDose Escalation Phase 1b

Purpose

This is a phase 1b/2, open-label, multicenter trial designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary efficacy of intratumoral AST-008 injections alone and in combination with intravenous pembrolizumab in patients with advanced solid tumors. Phase 1b of this trial is a 3+3 dose escalation study evaluating escalating or intermediate dose levels of AST-008 given with a fixed dose of pembrolizumab. Phase 2 is an expansion cohort to further evaluate AST-008 given in combination with pembrolizumab in a specific population to provide a preliminary estimate of efficacy in patients who have previously received and not responded to anti-PD-1 or anti-PD-L1 antibody therapy.

Detailed Description

      This study will be conducted in 2 phases. Phase 1 evaluates AST-008 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 AST-008 and enrollment of 3 patients per
      cohort to identify an RP2D. Patients will be dosed twice with AST-008 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-stage expansion cohort will be
      initiated.

      Phase 2 will evaluate the RP2D of AST-008 given in combination with pembrolizumab in an
      expansion cohort following a modified Simon 2-stage optimal design comprised of patients with
      a specific indication who previously received and did not responded anti-PD-1 or anti-PD-L1
      antibody therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation Phase 1bExperimentalDetermine the recommended Phase 2 dose of AST-008 in combination with pembrolizumab.
  • AST-008
  • Pembrolizumab
Dose Expansion Phase 2ExperimentalDetermine the safety and preliminary efficacy of AST-008 and pembrolizumab in anti-PD-1 / anti-PD-L1 therapy refractory patients.
  • AST-008
  • 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.

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

          5. Agrees to provide a newly obtained biopsy of injected and witness lesions (if they can
             be biopsied based on the investigator's assessment) prior to start of study treatment,
             and to repeat biopsies twice during study treatment, and to providing the acquired
             tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously
             irradiated, but a new or progressing lesion in the radiation field is acceptable.

          6. In the investigator's opinion the patient may derive clinical benefit from the
             treatment or is ineligible for a particular form of standard therapy on medical
             grounds, or the patient failed or did not tolerate one or more established standard
             medical anti-cancer therapies, including:

               1. In the dose escalation phase, exposure to anti-PD-(L)1 or anti-CTLA-4 antibody
                  CPIs is permitted but not required.

               2. In the dose expansion phase, stable or progressive disease after 12 weeks of
                  therapy with an anti-PD(L)1 antibody. Prior anti-CTLA-4 antibody therapy is
                  permitted but not required.

          7. For expansion cohorts only: lack of response on/after the most recent treatment
             regimen.

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

          9. For the expansion portion of the study, a maximum of 3 prior lines of systemic
             treatment for locally advanced or metastatic disease.

         10. If not menopausal or surgically sterile, willing to practice at least one of the
             following highly effective methods of birth control for at least a (partner's)
             menstrual cycle before and for four months after AST-008 and pembrolizumab
             administration: (1) Total abstinence from sexual intercourse with a member of the
             opposite sex; (2) Sexual intercourse with vasectomized male/sterilized female partner;
             (3) Hormonal female contraceptive (oral, parenteral, or transdermal) for at least 3
             consecutive months prior to investigational product administration; (4) Other
             acceptable forms of birth control (condoms, contraceptive sponge, diaphragm or vaginal
             ring with spermicide or cream); (5) Use of an intrauterine contraceptive device.

         11. Full resolution to G0 or baseline of CPI-related adverse effects (including irAEs) and
             no treatment for these AEs for at least 4 weeks prior to the time of enrollment. See
             Criterion 12 for more details on severe irAEs.

         12. For phase 1b escalation phase: No history of irAEs from a CPI (defined as any CTCAE G4
             or G3 requiring treatment for >4 weeks).

             For phase 2 expansion phase:

               1. Resolution of CPI-related AEs (including irAEs) back to G0-1 and no
                  corticosteroids for the amelioration of those irAEs for at least four weeks prior
                  to first dose of study drug.

               2. No history of life-threatening irAEs (CTCAE G4) from CPI requiring steroid
                  treatment.

               3. No history of CTCAE G3 irAEs from CPI requiring steroid treatment (>10 mg/day
                  prednisone or equivalent dose) for >12 weeks.

         13. Adequate organ function.

         14. 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 study drug, chemotherapy or biological cancer
             therapy within 3 weeks prior to the first dose of study therapy, nitrosurea, or
             radioisotope within 6 weeks prior to first dose, 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 or another
             anti-PD(L)1 monoclonal antibody.

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

          5. Baseline QTc > 480 msec using Fredericia's formula.

          6. Risk factors for bowel obstruction or bowel perforation (examples include but are not
             limited to a recent medical history of acute diverticulitis or other infective
             abdominal condition, or a diagnosis of abdominal carcinomatosis) that could confound
             interpretation of GI AEs.

          7. Symptomatic ascites or pleural effusion. A patient who is clinically stable following
             treatment for these conditions (including therapeutic thoraco- or paracentesis) is
             eligible.

          8. 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 study entry, have no evidence of new or enlarging brain
             metastases and are off steroids for at least 14 days prior to first dose of study
             drug.

          9. 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),
             unless the patient has undergone potentially curative therapy with no evidence of that
             disease for 3 years.

             Note: The time requirement for no evidence of disease for 3 years does not apply to
             the tumor for which a patient is enrolled in the study. The time requirement also does
             not apply to 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.

         10. History of pneumonitis or interstitial lung disease or evidence of such as determined
             by HRCT at baseline.

         11. Known infection with HIV-1, HIV-2, hepatitis B (surface antigen), or hepatitis C.
             Baseline testing is not required for patient enrollment.

         12. Active autoimmune disease or a documented history of autoimmune disease or syndrome
             that requires systemic steroids or immunosuppressive agents. Vitiligo or resolved
             childhood asthma/atopy are exceptions to this rule. Patients requiring intermittent
             use of bronchodilators or local steroid injections would not be excluded from the
             study. Patients with hypothyroidism that is stable on hormone replacement will not be
             excluded from the study.

         13. Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15
             days or other immunosuppressive drugs within 30 days prior to start of the study.
             Inhaled and topical corticosteroids are permitted. Up to 10 mg/day prednisone or
             equivalent is permitted as replacement therapy for adrenal insufficiency only.

         14. Active infection requiring therapy.

         15. Therapeutic anticoagulation, meaning any thromboembolic event within the last 12
             months or anticoagulation with therapeutic (non-prophylactic) intent.

         16. Patients who have received prior thoracic radiation with a dose >30 Gy within 26 weeks
             of the first dose of study drug.

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

         18. 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.

         19. At the time of signing informed consent is a regular user (including "recreational
             use") of any illicit drugs or had a recent history (within the last year) of substance
             abuse (including alcohol).

         20. Pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse events of AST-008 alone and in combination with pembrolizumab
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 AST-008 and combination regimen for further development
Measure:Disease assessment with RECIST 1.1
Time Frame:24 months
Safety Issue:
Description:To provide a preliminary estimate of change in the number and size of tumor lesions per RECIST 1.1 after dosing with AST-008 and pembrolizumab
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:Further safety evaluation of AST-008 alone and in combination with pembrolizumab
Time Frame:24 months
Safety Issue:
Description:Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities.
Measure:Duration of progression-free survival (PFS) and overall survival per RECIST v1.1
Time Frame:24 months
Safety Issue:
Description:Progression-free and overall survival will be calculated using a Kaplan-Meier method for the analysis set overall and for appropriate subgroups and cohorts.
Measure:Pharmacokinetic parameters of AST-008
Time Frame:Up to 1 week after dosing
Safety Issue:
Description:Plasma concentration and time data from all eligible patients will be subjected to non-compartmental assessment. The parameters will be stratified by dose group and summary statistics will be generated.
Measure:Disease control rate
Time Frame:24 months
Safety Issue:
Description:The disease control rate will be defined as the percentage of patients with a complete response (CR), partial response (PR), or stable disease (SD) for at least 2 consecutive tumor assessments (i.e., confirmed CR, PR, or SD for at least 12 weeks).
Measure:Measure changes in correlative biomarkers including tumor-infiltrating lymphocytes, PD-L1 and other checkpoint expression at baseline, after AST-008 monotherapy, and after combination therapy of both AST-008 and pembrolizumab.
Time Frame:Study day 36
Safety Issue:
Description:IHC on FFPE biopsies will be used to assess markers including PD-L1, CD3+ T-cells, and CD8+ T-cells. Other markers, including TIM3, LAG3, and IDO1 expression as well as cytotoxic cells, NK cells, Th-1 cells, or other immune cell markers in the injected and uninjected tumor microenvironments will be evaluated.
Measure:Measure changes in gene expression profiles at baseline, after AST-008 monotherapy, and after combination therapy of both AST-008 and pembrolizumab.
Time Frame:Study day 36
Safety Issue:
Description:Selected gene-expression profiling on gene expression will be performed with nCounter (NanoString Technologies).
Measure:Measure changes in activation of circulating lymphocytes, NK-cells, monocytes, pDCs, mDCs by flow cytometry and immunofluorescence at baseline, after AST-008 monotherapy, and after combination therapy of both AST-008 and pembrolizumab.
Time Frame:Study day 36
Safety Issue:
Description:Summary statistics by cell type and timepoint, and summary statistics as a function of time will be assessed by subgroup and overall.
Measure:Measure changes in levels of serum cytokine/chemokine markers at baseline, after AST-008 monotherapy, and after combination therapy of both AST-008 and pembrolizumab.
Time Frame:Study day 36
Safety Issue:
Description:The mechanism of action-related cytokine and chemokine markers that will be studied are IFN-α, IFN-γ, IL-10, IL-12p40, IL-1β, IL-1RA, IL-2, IL-6, IL-8, IP-10, MCP-1, and TNF-α. Summary statistics by cytokine/chemokine, timepoint and summary statistics as a function of time will be assessed by subgroup and overall.

Details

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

Last Updated