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RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line 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: NCT03894215
Recruitment Status : Active, not recruiting
First Posted : March 28, 2019
Last Update Posted : December 7, 2022
Sponsor:
Collaborator:
GOG Foundation
Information provided by (Responsible Party):
Agenus Inc.

Tracking Information
First Submitted Date  ICMJE March 19, 2019
First Posted Date  ICMJE March 28, 2019
Last Update Posted Date December 7, 2022
Actual Study Start Date  ICMJE June 1, 2019
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 27, 2019)		 Objective Response Rate [ Time Frame: 48 months ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2019)
  • Frequency, severity and duration of treatment-emergent AEs [ Time Frame: 48 months ]
    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.
  • DOR per RECIST 1.1 [ Time Frame: 48 months ]
    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).
  • Time to Confirmed Progression [ Time Frame: 48 months ]
    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).
  • Immunogenicity of AGEN2034 [ Time Frame: 48 months ]
    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.
  • Maximum observed drug concentration at steady state (Cmax-ss) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Minimum observed drug concentration at steady-state (Cmin-ss) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Area under the drug concentration-time curve from time zero to time t (AUC(0-t)) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Area under the drug concentration-time curve from time zero to infinity (AUC(0-∞)) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Time to maximum drug concentration (tmax) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Terminal disposition rate constant (λz) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Terminal elimination half-life (t1/2) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Systemic clearance (CL) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Volume of distribution (Vd) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
  • Quality of Life Assessment per FACT-Cx [ Time Frame: 35 months ]
    To assess quality of life in the treated population using the Functional Assessment of Cancer Therapy - Cervical Cancer Trial Outcome Index (FACT-Cx)
  • Quality of Life Assessment per BPI [ Time Frame: 35 months ]
    To assess quality of life in the treated population using Brief Pain Inventory (BPI)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer
Official Title  ICMJE 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
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Cervical Cancer
Intervention  ICMJE
  • Drug: AGEN2034
    PD-1 antibody
  • Drug: AGEN1884
    CTLA-4 antibody
Study Arms  ICMJE
  • Experimental: AGEN2034 + Placebo
    AGEN2034 administered with placebo monotherapy: approximately 100 patients.
    Intervention: Drug: AGEN2034
  • Experimental: AGEN2034 + AGEN1884
    AGEN2034 administered in combination with AGEN1884 (combination therapy): approximately 100 patients.
    Interventions:
    • Drug: AGEN2034
    • Drug: AGEN1884
Publications *

*   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
Estimated Enrollment  ICMJE
 (submitted: March 27, 2019)		 200
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2026
Estimated Primary Completion Date August 2024   (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:

    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.

  4. Measurable Disease:

    a. Have measurable disease on imaging based on RECIST version 1.1 by Investigator assessments and independent central radiologic review.

    Note: Patients without centrally confirmed measurable disease at baseline will not be eligible for this trial.

    Note: Patients must have at least 1 "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 creatinine ≤ 1.5 × upper limit of normal (ULN) OR measured or calculated creatinine clearance ≥ 40 mL/minute per Institutional standard. Assessment methods should be recorded.
    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. Has no history of another primary malignancy, with the exception of:

    1. Malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of study drug and of low potential risk for recurrence.
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease and superficial bladder cancer.

  8. Patients must provide a sufficient and adequate 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. Archival tumor tissue must be ≤ 3 years old. If no tumor tissue is available, a fresh biopsy will be required (See Section 7.2.3.1 for details).

    Note: Tissue from core biopsy 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-childbearing 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.
  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.
  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 the study drug.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Only 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 Brazil,   Korea, Republic of,   Mexico,   Peru,   Taiwan,   Thailand,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03894215
Other Study ID Numbers  ICMJE C-750-01/GOG-3028
Has Data Monitoring Committee Not Provided
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
Current Responsible Party Agenus Inc.
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Agenus Inc.
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE GOG Foundation
Investigators  ICMJE
Study Director: Medical Director Agenus Inc.
PRS Account Agenus Inc.
Verification Date December 2022

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