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A Study of AK112, a PD-1/VEGF Bispecific Antibody, for Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT04047290
Recruitment Status : Not yet recruiting
First Posted : August 6, 2019
Last Update Posted : August 6, 2019
Sponsor:
Information provided by (Responsible Party):
Akeso ( Akesobio Australia Pty Ltd )

Brief Summary:
This study is to characterize the safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD) and anti-tumor activity of AK112, a PD-1/VEGF bispecific antibody, as a single agent in adult subjects with advanced solid tumor malignancies. The study consists of a dose escalation phase (Phase 1a) to determine the maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D) for AK112 as a single agent, and a dose expansion phase (Phase 1b) in subjects with specific tumor types which will characterize treatment of AK112 as a single agent at the MTD or RP2D.

Condition or disease Intervention/treatment Phase
Neoplasms Malignant Drug: AK112 Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 132 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1a/1b, Multicenter, Open-label, Dose-escalation and Dose-expansion Study to Evaluate the Safety, Pharmacokinetics, and Antitumor Activity of AK112 in Subjects With Advanced Solid Tumors
Estimated Study Start Date : August 15, 2019
Estimated Primary Completion Date : August 30, 2022
Estimated Study Completion Date : December 30, 2022

Arm Intervention/treatment
Experimental: AK112
AK112 IV every 2 weeks (q2w)
Drug: AK112
AK112 is a PD1/VEGF bispecific antibody.




Primary Outcome Measures :
  1. Number of participants with adverse events (AEs) [ Time Frame: From time ICF is signed until 90 days after last dose of AK112 ]
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product temporally associated with the use of study treatment, whether or not considered related to the study treatment.

  2. Number of participants with DLTs [ Time Frame: During the first four weeks of treatment ]
    DLTs will be assessed during the first 4 weeks of treatment for dose-escalation phase and are defined as toxicities that meet pre-defined severity criteria, and assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first cycle (4 weeks) of treatment.


Secondary Outcome Measures :
  1. Objective response rate (ORR) [ Time Frame: Up to 2 years ]
    The ORR is defined as the proportion of subjects with confirmed CR or confirmed PR, based on RECIST Version 1.1.

  2. Disease control rate (DCR) [ Time Frame: Up to 2 years ]
    The DCR is defined as the proportion of subjects with CR, PR, or SD (subjects achieving SD will be included in the DCR if they maintain SD for ≥8 weeks) based on RECIST Version 1.1.

  3. Progression-free survival (PFS) [ Time Frame: Up to 2 years ]
    Progression-free survival is defined as the time from the start of treatment with AK112 until the first documentation of disease progression or death due to any cause, whichever occurs first.

  4. Overall survival (OS) [ Time Frame: Up to 2 years ]
    Overall survival is defined as the time from the start of treatment with AK112 until death due to any cause.

  5. Area under the curve (AUC) of AK112 [ Time Frame: From first dose of AK112 through 90 days after last dose of AK112 ]
    The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration.

  6. Maximum observed concentration (Cmax) of AK112 [ Time Frame: From first dose of AK112 through 90 days after last dose of AK112 ]
    The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration.

  7. Minimum observed concentration (Cmin) of AK112 at steady state [ Time Frame: From first dose of AK112 through 90 days after last dose of AK112 ]
    The endpoints for assessment of PK of AK112 include serum concentrations of AK112 at different timepoints after AK112 administration.

  8. Number of subjects who develop detectable anti-drug antibodies (ADAs) [ Time Frame: From first dose of AK112 through 90 days after last dose of AK112 ]
    The immunogenicity of AK112 will be assessed by summarizing the number of subjects who develop detectable anti-drug antibodies (ADAs).



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Written and signed informed consent and any locally required authorization obtained from the subject/legal representative.
  • In dose-escalation cohorts (Phase 1a), histologically or cytologically documented advanced or metastatic solid tumor that is refractory/relapsed to standard therapies, or for which no effective standard therapy is available, or the subject refuses standard therapy.
  • In the dose-expansion cohorts (Phase 1b), histologically or cytologically confirmed selected advanced solid tumors.
  • Subject must have at least one measurable lesion according to RECIST Version1.1.
  • Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
  • Available archived tumor tissue sample to allow for correlative biomarker studies. In the setting where archival material is unavailable or unsuitable for use, the subject must consent and undergo fresh tumor biopsy.
  • Adequate organ function.
  • Subjects with central nervous system (CNS) metastases must have been treated, be asymptomatic.
  • Females of childbearing potential and non-sterilized males who are sexually active must use an effective method.
  • Adequate life expectancy

Exclusion Criteria:

  • History of severe hypersensitivity reactions to other mAbs.
  • For subjects enrolled in the dose escalation phase of the study (Phase 1a) who have received prior anti-PD-1, anti-PD-L1, anti-CTLA-4 or any other immunotherapy or immune-oncology (IO) agent:

    1. Subjects have received anti-PD-1, anti-PD-L1, anti-CTLA-4 or any other immunotherapy or IO agent within 28 days of commencing treatment with investigational product.
    2. Subjects have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. Subjects have experienced a ≥ Grade 3 irAE or a neurologic or ocular AE of any grade while receiving prior immunotherapy.
    3. All AEs while receiving prior immunotherapy have not completely resolved or resolved to Grade 1 prior to screening for this study.
    4. Subjects have required the use of additional immunosuppression other than corticosteroids for the management of an AE, or have experienced recurrence of an AE if re-challenged with corticosteroids while receiving prior immunotherapy.
  • For dose-expansion phase (Phase 1b), prior exposure to any anti-PD-1, anti-PD-L1, anti-CTL4 antibody or any other antibody or drug targeting T-cell costimulation or checkpoint pathways such as ICOS, or agonists such as CD40, CD137, GITR, OX40 etc.
  • Receipt of any immunotherapy, any conventional or investigational systemic anticancer therapy within 4 weeks prior to the first dose of AK112 except for treatment with small-molecule tyrosine kinase-targeted agents within 2 weeks prior to the first dose of AK112.
  • Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer related conditions is acceptable.
  • History or concurrent gastrointestinal perforation, surgery and wound healing complications, hemorrhage events.
  • Subjects with clinically significant cardiovascular disease
  • Subjects with a condition requiring systemic treatment with either corticosteroid (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
  • Current or recent (within 10 days of the first dose of investigational product) use of aspirin (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol.
  • Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for > 2 weeks prior to the first dose of AK112
  • Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects with vitiligo, alopecia, Grave's disease, type I diabetes mellitus, hypothyroidism (e.g., following Hashimoto syndrome) only requiring hormone replacement on a stable dose, psoriasis or eczema not requiring systemic treatment (within the past 2 years), or conditions not expected to recur in the absence of an external trigger are not excluded.
  • Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
  • History of primary immunodeficiency.
  • History of organ transplant or hematopoietic stem cell that requires use of immunosuppressives.
  • Known allergy or reaction to any component of the AK112 formulation.
  • History of interstitial lung disease or non-infectious pneumonitis except for those induced by radiation therapies.
  • Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v5.0 Grade 0 or 1, or to levels dictated in the inclusion/exclusion criteria.
  • Major surgical procedure within 30 days prior to the first dose of AK112 or still recovering from prior surgery.
  • Known history of tuberculosis.
  • Known history of HIV.
  • Known active hepatitis B or C infections. Note: Subjects with HCC and positive HBsAg result are eligible if the subjects were treated with antiviral therapy and HBV viral load less than 500 IU/mL prior to first dose of AK112. Subjects positive for HCV antibody are eligible only if quantitative HCV RNA results less than the lower limits of detection of the assay.
  • An active infection requiring systemic therapy 25. with the exception of anti-viral therapy for hepatitis as specified by the protocol.
  • Receipt of live attenuated vaccination within 30 days prior to the first dose of AK112.
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results.

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 ClinicalTrials.gov identifier (NCT number): NCT04047290


Contacts
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Contact: Xiaoping Jin, PhD +86 (0760) 8987 3999 clinicaltrials@akesobio.com

Locations
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Australia, New South Wales
Scientia Clinical Research Ltd Not yet recruiting
Randwick, New South Wales, Australia, 2031
Contact    +61 2 9382 5811      
Principal Investigator: Charlotte Lemech, MBBS         
Australia, Queensland
ICON Cancer Foundation Not yet recruiting
South Brisbane, Queensland, Australia, 4101
Contact    +61 3737 4500      
Principal Investigator: Jermain Coward, MBBS         
Australia, South Australia
Adelaide Cancer Centre Not yet recruiting
Kurralta Park, South Australia, Australia, 5037
Contact    +61 8 8292 2220      
Principal Investigator: Dusan Kotasek, MBBS         
Australia, Victoria
Monash Health Not yet recruiting
Clayton, Victoria, Australia, 3168
Contact    +61 3 8572 2429      
Principal Investigator: Ben Markman, MBBS         
Sponsors and Collaborators
Akesobio Australia Pty Ltd

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Responsible Party: Akesobio Australia Pty Ltd
ClinicalTrials.gov Identifier: NCT04047290     History of Changes
Other Study ID Numbers: AK112-101
First Posted: August 6, 2019    Key Record Dates
Last Update Posted: August 6, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Akeso ( Akesobio Australia Pty Ltd ):
anti-PD-1/VEGF bispecific antibody
immunotherapy
immuno-oncology
advanced solid tumors
bispecific
PD-1/VEGF
Additional relevant MeSH terms:
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Neoplasms
Antibodies
Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs