Clinical Trials /

Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer

NCT03894215

Description:

This is a randomized, blinded, non-comparative, two-arm Phase 2 clinical trial to assess the efficacy and safety of AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy) for treatment of patients with advanced cervical cancer who relapsed or progressed after receiving first-line platinum-based chemotherapy. The study is not intended to compare the efficacy of the 2 experimental arms. Rather, the efficacy of each arm will be evaluated against its relevant historical controls as appropriate.

Related Conditions:
  • Cervical Adenocarcinoma
  • Cervical Adenosquamous Carcinoma
  • Cervical Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer
  • Official Title: A Two-arm, Randomized, Non-comparative, Phase 2 Trial of AGEN2034 (Anti-PD-1) as a Monotherapy or Combination Therapy With AGEN1884 (Anti-CTLA4) or With Placebo in Women With Recurrent Cervical Cancer (Second Line) - RaPiDS

Clinical Trial IDs

  • ORG STUDY ID: C-750-01/GOG-3028
  • NCT ID: NCT03894215

Conditions

  • Cervical Cancer

Interventions

DrugSynonymsArms
AGEN2034AGEN2034 + Placebo
AGEN1884AGEN2034 + AGEN1884

Purpose

This is a randomized, blinded, non-comparative, two-arm Phase 2 clinical trial to assess the efficacy and safety of AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy) for treatment of patients with advanced cervical cancer who relapsed or progressed after receiving first-line platinum-based chemotherapy. The study is not intended to compare the efficacy of the 2 experimental arms. Rather, the efficacy of each arm will be evaluated against its relevant historical controls as appropriate.

Detailed Description

      This is a randomized, blinded, non-comparative, two-arm Phase 2 clinical trial to assess the
      efficacy and safety of AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or
      with AGEN1884 (Treatment Arm 2 - combination therapy) for treatment of patients with advanced
      cervical cancer who relapsed or progressed after receiving first-line platinum-based
      chemotherapy. The study is not intended to compare the efficacy of the 2 experimental arms.
      Rather, the efficacy of each arm will be evaluated against its relevant historical controls
      as appropriate Patients will receive AGEN2034 with placebo as a monotherapy or with AGEN1884
      as combination therapy for a maximum of 24 months or until confirmed progression,
      unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the
      trial occurs. Placebo administration in Treatment Arm 1 (AGEN 2034 monotherapy) of the study
      is intended to preserve the integrity of the investigators' interpretation of the efficacy
      and safety data by eliminating biases in disease assessment monitoring, declaration of
      disease progression, and assessment of toxicities. Therefore, it is understood that
      investigators, patients, and research personnel will not know whether patients have received
      AGEN2034/placebo (Treatment Arm 1) or AGEN2034/AGEN1884 (Treatment Arm 2).

      An Independent Data Monitoring Committee (IDMC) will evaluate safety and efficacy. An IRRC
      will be established to adjudicate tumor response..
    

Trial Arms

NameTypeDescriptionInterventions
AGEN2034 + PlaceboExperimentalAGEN2034 administered with placebo monotherapy: approximately 100 patients.
  • AGEN2034
AGEN2034 + AGEN1884ExperimentalAGEN2034 administered in combination with AGEN1884 (combination therapy): approximately 100 patients.
  • AGEN2034
  • AGEN1884

Eligibility Criteria

        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:

               1. 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.

               2. Has cervical cancer and has relapsed after a platinum-based treatment (first
                  line) regimen for advanced (recurrent, unresectable, or metastatic) disease;

             Note: Patient receiving chemotherapy concurrently with primary radiation (e.g., weekly
             cisplatin) or patient receiving adjuvant chemotherapy following completion of
             radiation therapy (e.g., paclitaxel and carboplatin for ≤ 4 cycles) and progressed
             within 6 months after treatment completion will be eligible as this systemic therapy
             will be considered as first-line treatment.

          4. Measurable Disease

             a) Have measurable disease on imaging based on RECIST version 1.1 by investigator
             assessments.

             Note: Patients 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.

          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 10^9/L, platelet count > 100 x 10^9/L, and hemoglobin >8 g/dL (without
                  transfusions within 1 week of first dose).

               2. Adequate hepatic function based by a total bilirubin level ≤ 1.5 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 IULN and albumin ≥3.0 mg/dL.

               3. Adequate renal function defined as calculated creatinine clearance >50 mL/min
                  (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 patient is receiving anticoagulant
                  therapy); and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless
                  the patient is receiving anticoagulant therapy)

          7. 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, and has
             undergone potentially curative therapy with no evidence of that disease recurrence for
             5 years since initiation of that therapy.

          8. Patients 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. Patients must have a negative serum pregnancy test at screening (within 72 hours of
             first dose of study medication) 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 had menses for greater than 1 year,

               2. Amenorrheic ≥ 2 years without a hysterectomy and oophorectomy and a
                  follicle-stimulating hormone (FSH) value in the postmenopausal range upon
                  pretrial (screening) evaluation,

               3. History of hysterectomy, oophorectomy or tubal ligation.

               4. Definitive pelvic radiation for the treatment of cervical cancer.

         10. If of childbearing potential, female patients must be willing to use 2 adequate
             barrier methods 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 patient.

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

        Exclusion Criteria:

        The patient must be excluded from participating in the trial if the patient:

          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 of 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. More than 1 systemic treatment regimen for the advanced (recurrent, unresectable,
                  or metastatic) cervical cancer for which the patient is considered for the study.

          4. Has persisting toxicity related to prior therapy of National Cancer Institute Common
             Terminology Criteria for Adverse Events version 5.0 (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
             (NCI-CTCAE Grade ≥3), any history of anaphylaxis, or uncontrolled asthma.(i.e., ≥3
             features of partly controlled asthma).

          7. Has received systemic corticosteroid therapy ≤ 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 (AE),
             and/or a premedication for IV contrast allergies/reactions is allowed). Patients who
             are receiving daily corticosteroid replacement therapy are an exception to this rule.
             Daily prednisone at doses of up to 5 mg or equivalent hydrocortisone dose are examples
             of permitted replacement therapy.

          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: Patients 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 immunosuppressive
             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
             immunosuppressive systemic treatment.

             Note: Patients 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 (IV) systemic therapy.

         13. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         14. Has known active Hepatitis B (HBV), Hepatitis C (HCV), 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 ribonucleic acid (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 of enrollment, unstable
             angina, congestive heart failure (New York Heart Association class ≥II), or serious
             uncontrolled cardiac arrhythmia requiring medication or intervention.

         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 patient's
             participation for the full duration of the trial, or is not in the best interest of
             the patient 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). Medicinal marijuana use is not considered "illicit" and is
             allowed to be utilized prior to and during enrollment.

         19. Is legally incapacitated or has limited legal capacity.

         20. Is pregnant or breastfeeding or expecting to conceive within the projected duration of
             the trial, starting with the screening visit through 120 days after the last dose of
             AGEN2034 and/or AGEN1884.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate
Time Frame:48 months
Safety Issue:
Description:To assess the Objective Response Rate (ORR) to the treatment of AGEN2034 (anti-PD-1) administered with placebo (Treatment Arm 1 - monotherapy), or with AGEN1884 (anti-CTLA4) (Treatment Arm 2 - combination therapy), defined as the binomial proportion of intent to treat (ITT) patients with best overall response (BOR) of complete response (CR) or partial response (PR), in women with recurrent/persistent/metastatic cervical cancer who have progressed following first-line therapy. BOR will be determined by the Independent Radiology Review Committee (IRRC), according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

Secondary Outcome Measures

Measure:Frequency, severity and duration of treatment-emergent AEs
Time Frame:48 months
Safety Issue:
Description:To confirm the safety and tolerability of AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy) in patients with recurrent, progressive second-line cervical cancer.
Measure:DOR per RECIST 1.1
Time Frame:48 months
Safety Issue:
Description:To assess duration of response (DOR), stable disease (SD), duration of stable disease and disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) per RECIST 1.1 for AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy).
Measure:Time to Confirmed Progression
Time Frame:48 months
Safety Issue:
Description:To estimate the time to confirmed progression by the investigator per iRECIST for AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy).
Measure:Immunogenicity of AGEN2034
Time Frame:48 months
Safety Issue:
Description:To evaluate the immunogenicity of AGEN2034 administered with placebo (Treatment Arm 1 - monotherapy) or with AGEN1884 (Treatment Arm 2 - combination therapy) and to correlate it to exposure and biological activity.
Measure:Maximum observed drug concentration at steady state (Cmax-ss)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Minimum observed drug concentration at steady-state (Cmin-ss)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Area under the drug concentration-time curve from time zero to time t (AUC(0-t))
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Area under the drug concentration-time curve from time zero to infinity (AUC(0-∞))
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Time to maximum drug concentration (tmax)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Terminal disposition rate constant (λz)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Terminal elimination half-life (t1/2)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Systemic clearance (CL)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Volume of distribution (Vd)
Time Frame:48 months
Safety Issue:
Description:To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Measure:Quality of Life Assessment per FACT-Cx
Time Frame:35 months
Safety Issue:
Description:To assess quality of life in the treated population using the Functional Assessment of Cancer Therapy - Cervical Cancer Trial Outcome Index (FACT-Cx)
Measure:Quality of Life Assessment per BPI
Time Frame:35 months
Safety Issue:
Description:To assess quality of life in the treated population using Brief Pain Inventory (BPI)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Agenus Inc.

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