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Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03104699
Recruitment Status : Active, not recruiting
First Posted : April 7, 2017
Last Update Posted : October 19, 2020
Sponsor:
Information provided by (Responsible Party):
Agenus Inc.

Tracking Information
First Submitted Date  ICMJE March 27, 2017
First Posted Date  ICMJE April 7, 2017
Last Update Posted Date October 19, 2020
Actual Study Start Date  ICMJE April 11, 2017
Estimated Primary Completion Date April 16, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 23, 2019)
Objective Response Rate (ORR), as determined by IERC, in the analysis population [ Time Frame: Evaluated throughout the protocol, up to 2 years ]
per RECIST 1.1
Original Primary Outcome Measures  ICMJE
 (submitted: April 6, 2017)
  • Dose limiting toxicities (DLTs) of AGEN2034 [ Time Frame: 3 weeks ]
    Occurrence of DLTs during first 3 weeks of treatment in the dose escalation part of the study
  • Maximum tolerated dose (MTD) [ Time Frame: 1 year ]
    MTD for administration in the expansion part of the study
  • Best overall response (BOR) according to Response Evaluation Criteria in solid tumors (Phase 2 expansion) [ Time Frame: 1 year ]
    BOR confirmed per RECIST 1.1 and investigator assessment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 23, 2019)
  • Safety and Tolerability of AGEN2034 [ Time Frame: From the time of the first dose to the end of follow-up (up to 2 years after the last dose) ]
    Frequency, severity, and duration of TEAEs and laboratory abnormalities, using NCI CTCAE v4.03.
  • Maximum drug concentration observed postdose at steady-state (Cmax-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Minimum observed concentration at steady-state (Cmin-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Area under the drug concentration-time curve from time zero to time t (AUC(0-t)), area under the drug concentration-time curve from time zero to infinity (AUC(0-∞)) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Time to maximum observed concentration (tmax) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Terminal disposition rate constant (λz) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Terminal elimination half-life (t1/2) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Systemic clearance (CL) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Volume of distribution (Vd) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
  • Immunogenicity of AGEN2034 [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 ADA concentrations and serum AGEN2034 concentrations measured throughout the study
  • Objective Response Rate (ORR), as determined by investigator [ Time Frame: Evaluated throughout the protocol, up to 2 years ]
    per RECIST 1.1
  • Duration of Response (DOR) [ Time Frame: Time from first observation of response to first observation of documented disease progression, up to 3 years ]
    per RECIST 1.1, as determined by an IERC and investigator, defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks after last tumor assessment). Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
  • Disease Control Rate (DCR) [ Time Frame: Duration of the trial, up to 3 years ]
    defined as proportion of subjects with complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks
  • Duration of Stable Disease (SD) [ Time Frame: Duration of the trial, up to 3 years ]
    measured from the start of treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including baseline measurements.
  • Time to Response [ Time Frame: Duration of the treatment phase of the trial, up to 2 years ]
    defined as the time from the first dose date to first observation of confirmed response.
  • Progression-free Survival (PFS) [ Time Frame: Duration of the treatment phase of the trial, up to 2 years ]
    defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks after last tumor assessment), per RECIST 1.1, as determined by an IERC and investigator. Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
  • Overall Survival Rate (OS) [ Time Frame: Duration of the treatment phase of the trial, up to 2 years ]
    defined as time from start of treatment to death. For subjects who are still alive at time of data cutoff for trial analysis or who are lost to follow-up, survival will be censored at the last recorded date that the subject is known to be alive as of the cutoff date for analysis
Original Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2017)
  • Maximum Plasma Concentration (Cmax) of AGEN2034 [ Time Frame: 1 year ]
    Understanding PK
  • Area Under the Curve (AUC) of AGEN2034 [ Time Frame: 1 year ]
    Understanding PK
  • Progression-free survival (PFS) [ Time Frame: 1 year ]
    Time from first treatment to first observation of documented disease progression
  • Duration of response (DOR) [ Time Frame: 1 year ]
    Time from first observation of response to first observation of documented disease progression
  • Overall survival (OS) [ Time Frame: 1 year ]
    Time from first treatment to death
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1 / 2 Study of AGEN2034 in Advanced Tumors and Cervical Cancer
Official Title  ICMJE A Phase 1 / 2, Open-Label, Multiple Ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second Line Cervical Cancer
Brief Summary This is a 2-part trial: a Phase 1, open-label, dose-escalation study in subjects with metastatic or locally advanced solid tumors, with a consecutive Phase 2 expansion to evaluate efficacy in subjects with recurrent, unresectable, or metastatic (advanced) cervical cancer that has progressed after a platinum-based treatment regimen.
Detailed Description

Phase 1: Dose Escalation

Phase 1 will consist of a standard 3+3 dose escalation with the following escalating dose levels and schedules:

Part A1: 1, 3, and 10 mg/kg administered every 2 weeks Part A2: 6 and 10 mg/kg every 3 weeks Each subject will stay on the dose level and schedule assigned at trial entry. Subjects will receive AGEN2034 for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.

A Safety Monitoring Committee (SMC) will assess safety; decide on dose-escalation and opening of backfill enrollment; define the recommended Phase 2 dose (RP2D); and determine opening of the phase 2 cohorts.

In Part A1, the first subject of each cohort will be observed for 16 days (i.e., ≥ 48 hours after second dose) for occurrence of DLT before the second subject is administered trial medication. Thereafter, within each cohort, consecutively enrolled subjects may initiate treatment ≥ 48 hours after the prior enrolled subject initiated treatment. Dose escalation will continue until the maximum tolerated dose (MTD) is reached or the maximum planned dose level (10.0 mg/kg) is shown to be safe. The MTD is defined as the dose below which ≥ 2 DLTs are observed.

Once Part A1 is completed, enrollment to Part A2 will begin. If < 2 DLTs are observed in Part A1 at the maximum planned dose of 10 mg/kg every 2 weeks, open enrollment to Part A2 will begin with enrollment of 10 subjects at 6 mg/kg every 3 weeks, followed by open enrollment of 10 subjects at 10 mg/kg every 3 weeks. If ≥ 2 DLTs are observed in Part A1, at the maximum planned dose in Part A1, the standard 3+3 dose escalation will resume with Part A2 where consecutively enrolled subjects in dose escalation may initiate treatment ≥ 48 hours after the prior enrolled subject initiated treatment.

For cohorts in dose escalation, concurrent with the 3+3 dose escalation schema, additional subjects will be backfilled to lower dose levels to ensure that each cohort enrolls a total of 10 subjects. Subjects enrolled to backfill cohorts may be enrolled simultaneously, without sequential dosing (i.e., not required to wait 48 hours between 2 subjects). These additional subjects at each dose level will have the purpose of generating additional safety, PK, and receptor occupancy data, and will not undergo formal DLT observation.

Phase 2: Dose Expansion

To further characterize safety and efficacy, subjects with recurrent, unresectable, or metastatic cervical cancer will be enrolled in Phase 2 and receive the RP2D of AGEN2034 (3 mg/kg every 2 weeks) for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.

An SMC will assess safety, and an Independent Data Monitoring Committee (IDMC) will evaluate safety and efficacy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Cancer
  • Cervical Cancer
Intervention  ICMJE Drug: AGEN2034
Anti-PD-1 Monoclonal Antibody
Other Name: Anti-PD-1
Study Arms  ICMJE Experimental: Monotherapy
Dose of 3 mg/kg IV every 2 weeks for up to 24 months.
Intervention: Drug: AGEN2034
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 27, 2020)
211
Original Estimated Enrollment  ICMJE
 (submitted: April 6, 2017)
75
Estimated Study Completion Date  ICMJE May 14, 2022
Estimated Primary Completion Date April 16, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Voluntarily agree to participate by giving written informed consent. Participation in pharmacogenomics testing is optional.
  2. Be ≥ 18 years of age.
  3. Diagnosis and prior systemic treatment:

    1. Phase 1: Have a histologically or cytologically confirmed diagnosis of a metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
    2. Phase 2:

    I. Have (1) a histologically or cytologically confirmed diagnosis of squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix, and (2) metastatic, locally advanced, and/or unresectable disease at the time of enrollment. Histologic confirmation of the original primary tumor is required via pathology report.

    Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric type adenocarcinoma, clear cell carcinoma, and mesonephric carcinoma.

    II. Has cervical cancer and has relapsed after a platinum-based treatment (first line) regimen for advanced (recurrent, unresectable, or metastatic) disease; Note: Subjects who have received > 1 prior systemic treatment regimen for their advanced or metastatic disease will be eligible in the following cases: Subject receiving chemotherapy concurrently with primary radiation (e.g., weekly cisplatin) or subject receiving adjuvant chemotherapy following completion of radiation therapy (e.g., paclitaxel and carboplatin for ≤ 4 cycles) and progressed within 6 months after treatment completion.

  4. Measurable disease - based on investigator assessment

    1. Phase 1: Have objective evidence of disease; the presence of measurable disease is not required.
    2. Phase 2: Have measurable disease on imaging based on RECIST version 1.1. Note: Subjects must have at least one "target lesion" to be used to assess response, as defined by RECIST version 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.

    Note: Measurable disease by RECIST 1.1 must be confirmed by independent central radiologic review prior to first dose. Subjects without centrally confirmed measurable disease at baseline will not be eligible for this trial.

  5. Have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  6. Have adequate organ function as indicated by the following laboratory values:

    1. Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and stable hemoglobin ≥ 8 g/dL (without transfusions within 1 week before first dose).
    2. Adequate hepatic function based by a total bilirubin level ≤ the institutional upper limit of normal (IULN), aspartate aminotransferase (AST) level ≤ 2.5 x IULN, alanine aminotransferase (ALT) level ≤ 2.5 x IULN, and alkaline phosphatase ≤ 2.5 x IULN.
    3. Adequate renal function defined as creatinine ≤ 1.5 x IULN OR calculated creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 1.5 x IULN (if no local guideline is available, creatinine clearance should be calculated using the Cockcroft-Gault Method).
    4. Adequate coagulation defined by international normalized ratio (INR) or prothrombin time ≤ 1.5 x IULN (unless the subject is receiving anticoagulant therapy); and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless the subject is receiving anticoagulant therapy)
  7. Other than the cancer for which the subject is enrolled, have no history of prior malignancy, with the exception of basal cell carcinoma of the skin, superficial bladder cancer, squamous-cell carcinoma of the skin, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
  8. In Phase 2, subjects must provide a sufficient and adequate formalin fixed paraffin embedded (FFPE) tumor tissue sample preferably from the most recent biopsy of a tumor lesion, collected either at the time of or after the diagnosis of advanced or metastatic disease has been made AND from a site not previously irradiated. If no tumor tissue is available, a fresh biopsy will be required.

    Note: Tissue from needle or excisional biopsy or from resection is required.

  9. Female subjects must have a negative serum pregnancy test at screening (within 72 hours before first dose of study drug) if of childbearing potential or be of non-child bearing potential. Non-childbearing potential is defined as (by other than medical reasons):

    1. ≥ 45 years of age and has not menstruated for greater than 1 year,
    2. Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
    3. Whose status is post hysterectomy, oophorectomy or tubal ligation.
  10. If of childbearing potential, female subjects must be willing to use 2 highly effective methods (defined in the informed consent form [ICF]) throughout the study, starting with the screening visit through 120 days after the last dose of study treatment.

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

  11. Male subjects with a female partner(s) of child-bearing potential must agree to use 2 highly effective methods (defined in the ICF) throughout the trial starting with the screening visit through 120 days after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

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

  12. Is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks before the first dose of treatment.
  2. Has an inadequate washout period prior to first dose of study drug defined as:

    1. Received systemic cytotoxic chemotherapy or biological therapy within 3 weeks before first dose,
    2. Received radiation therapy within 3 weeks before first dose, or
    3. Had major surgery within 4 weeks before first dose.
  3. Has received prior therapy with:

    1. Any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies
    2. For Phase 2: > 1 systemic treatment regimen for the advanced (recurrent, unresectable, or metastatic) cervical cancer for which the subject is considered for the study Note: In Phase 1, prior treatment with a CTLA-4 antibody is permissible for subjects with metastatic melanoma.
  4. Has persisting toxicity related to prior therapy of NCI CTCAE Grade > 1 severity.

    Note: Sensory neuropathy or alopecia of Grade ≤ 2 is acceptable.

  5. Is expected to require any other form of systemic or localized antineoplastic therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection).
  6. Has known severe hypersensitivity reactions to fully human monoclonal antibodies (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [NCI CTCAE] Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.
  7. Is receiving systemic corticosteroid ≤ 7 days prior to the first dose of trial treatment or receiving any other form of systemic immunosuppressive medication (corticosteroid use on study for management of immune-related adverse events, and/or a premedication for IV contrast allergies/reactions is allowed). Subjects who are receiving daily corticosteroid replacement therapy are an exception to this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid therapy administered by topical, intraocular, intranasal, and/or inhalation routes.
  8. Has a central nervous system (CNS) tumor, metastasis(es), and/or carcinomatous meningitis identified either on the baseline brain imaging obtained during the screening period OR identified prior to consent.

    Note: Subjects with history of brain metastases that have been treated may participate provided they show evidence of stable supra-tentorial lesions at screening (based on 2 sets of brain images, performed ≥ 4 weeks apart, and obtained after the brain metastases treatment). In addition, any neurologic symptoms that developed either as a result of the brain metastases or their treatment must have resolved or be minimal and be expected as sequelae from treated lesions. For individuals who received steroids as part of brain metastases treatment, steroids must be discontinued ≥ 7 days prior to first dose of study drug.

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

    Note: Subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

  10. Has had an allogeneic tissue/solid organ transplant.
  11. Has or had interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV corticosteroids.
  12. Has an active infection requiring intravenous systemic therapy.
  13. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  14. Has known active Hepatitis B, Hepatitis C or tuberculosis. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay.
  15. Has clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months before enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ II), or serious uncontrolled cardiac arrhythmia requiring medication.
  16. 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.
  17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  18. Is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
  19. Is legally incapacitated or has limited legal capacity.
  20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Belgium,   Brazil,   Chile,   Estonia,   France,   Poland,   Spain,   United States
Removed Location Countries Georgia,   Lithuania,   Moldova, Republic of,   Romania,   Ukraine
 
Administrative Information
NCT Number  ICMJE NCT03104699
Other Study ID Numbers  ICMJE C-700-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Agenus Inc.
Study Sponsor  ICMJE Agenus Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Agenus Inc.
PRS Account Agenus Inc.
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP