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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03684785
Recruitment Status : Recruiting
First Posted : September 26, 2018
Last Update Posted : February 21, 2020
Information provided by (Responsible Party):
Exicure, Inc.

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
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 Drug: AST-008 Biological: Pembrolizumab Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Study of AST-008 Combined With Pembrolizumab in Patients With Advanced Solid Tumors
Actual Study Start Date : December 13, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : April 1, 2021

Arm Intervention/treatment
Experimental: Dose Escalation Phase 1b
Determine the recommended Phase 2 dose of AST-008 in combination with pembrolizumab.
Drug: AST-008
Intratumorally dosed AST-008.

Biological: Pembrolizumab
Pembrolizumab dosing as per the US prescribing information.

Experimental: Dose Expansion Phase 2
Determine the safety and preliminary efficacy of AST-008 and pembrolizumab in anti-PD-1 / anti-PD-L1 therapy refractory patients.
Drug: AST-008
Intratumorally dosed AST-008.

Biological: Pembrolizumab
Pembrolizumab dosing as per the US prescribing information.

Primary Outcome Measures :
  1. Adverse events of AST-008 alone and in combination with pembrolizumab [ Time Frame: Study day 36 ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Secondary Outcome Measures :
  1. Recommended Phase 2 dose [ Time Frame: 12 months ]
    To recommend a dose of AST-008 and combination regimen for further development

  2. Disease assessment with RECIST 1.1 [ Time Frame: 24 months ]
    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

  3. Objective response rate (ORR) per RECIST v1.1 [ Time Frame: 24 months ]
    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.

  4. Further safety evaluation of AST-008 alone and in combination with pembrolizumab [ Time Frame: 24 months ]
    Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities.

  5. Duration of progression-free survival (PFS) and overall survival per RECIST v1.1 [ Time Frame: 24 months ]
    Progression-free and overall survival will be calculated using a Kaplan-Meier method for the analysis set overall and for appropriate subgroups and cohorts.

  6. Pharmacokinetic parameters of AST-008 [ Time Frame: Up to 1 week after dosing ]
    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.

  7. Disease control rate [ Time Frame: 24 months ]
    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).

  8. 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 ]
    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.

  9. 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 ]
    Selected gene-expression profiling on gene expression will be performed with nCounter (NanoString Technologies).

  10. 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 ]
    Summary statistics by cell type and timepoint, and summary statistics as a function of time will be assessed by subgroup and overall.

  11. 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 ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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:

      • At least 4 doses of q2w-administered, or 3 doses of q3w-administered, or 2 doses of q4w-administered anti-PD-(L)1 therapy. Prior anti-CTLA-4 antibody therapy is permitted but not required.
      • Progressive disease during therapy with an anti-PD-(L)1 antibody.
      • Last dose of anti-PD-(L)1 antibody therapy must be within 12 weeks of initiating study treatment.
      • Progressive disease on anti-PD-(L)1 antibody therapy defined as:

        • If treatment duration with the anti-PD-(L)1 antibody was ≥ 16 weeks: documented radiographic progression on a single radiographic scan per RECIST 1.1.
        • If treatment duration with anti-PD-(L)1 antibody therapy was greater than 8 but less than 16 weeks: documented radiographic progression per RECIST 1.1 on consecutive radiographic scans at least 4 weeks apart. However, if radiographic progression is accompanied with documented clinical progression, then a single scan assessment may be used.
        • If progression was only in a lymph node, biopsy confirmation of cancer in the lymph node is 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 6 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03684785

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Contact: Weston L Daniel, PhD 8476731715

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United States, California
John Wayne Cancer Institute / Providence St. John's Health Center Recruiting
Santa Monica, California, United States, 90401
Contact: Aleksandra Dubinchik    310-582-7455   
United States, Colorado
University of Colorado Cancer Center Not yet recruiting
Aurora, Colorado, United States, 80045
Contact: Victoria Nuanes    720-848-8845   
United States, Florida
Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Juan Salvador, CCRC    305-243-7358   
United States, Iowa
Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: Mimi McKay, RN BSN    319-467-5831   
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Kristina Kelley, RN   
United States, Ohio
University of Cincinnati Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Lisa Schmid    513-584-0502   
United States, Washington
University of Washington- Seattle Cancer Care Alliance Recruiting
Seattle, Washington, United States, 98109
Contact: Rosanna Hernandez    206-606-7614   
Sponsors and Collaborators
Exicure, Inc.
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Study Director: Exicure Inc. Exicure, Inc.

Additional Information:
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Responsible Party: Exicure, Inc. Identifier: NCT03684785    
Other Study ID Numbers: AST-008-102
First Posted: September 26, 2018    Key Record Dates
Last Update Posted: February 21, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in the article, after de-identification (text, tables, figures, and appendices) will be shared to researchers who provide a methodologically sound proposal and sign a data access agreement.
Supporting Materials: Study Protocol
Time Frame: Beginning 9 months and ending 36 months following article publication.
Access Criteria: Access will be considered to researchers who provide a methodologically sound proposal. Analysis must achieve the aims outlined in the approved proposal. Proposals should be directed to To gain access, data requestors will need to sign a data access agreement. Data are available for 36 months following article publication.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Tumor Virus Infections
Carcinoma, Neuroendocrine
Carcinoma, Merkel Cell
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents