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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03894215
Recruitment Status : Recruiting
First Posted : March 28, 2019
Last Update Posted : January 14, 2020
Sponsor:
Collaborator:
Gynecologic Oncology Group
Information provided by (Responsible Party):
Agenus Inc.

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.

Condition or disease Intervention/treatment Phase
Cervical Cancer Drug: AGEN2034 Drug: AGEN1884 Phase 2

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..

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : June 1, 2019
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cervical Cancer

Arm Intervention/treatment
Experimental: AGEN2034 + Placebo
AGEN2034 administered with placebo monotherapy: approximately 100 patients.
Drug: AGEN2034
PD-1 antibody

Experimental: AGEN2034 + AGEN1884
AGEN2034 administered in combination with AGEN1884 (combination therapy): approximately 100 patients.
Drug: AGEN2034
PD-1 antibody

Drug: AGEN1884
CTLA-4 antibody




Primary Outcome Measures :
  1. 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).


Secondary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. 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.

  5. Maximum observed drug concentration at steady state (Cmax-ss) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  6. Minimum observed drug concentration at steady-state (Cmin-ss) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  7. 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).

  8. 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).

  9. 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).

  10. Time to maximum drug concentration (tmax) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  11. Terminal disposition rate constant (λz) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  12. Terminal elimination half-life (t1/2) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  13. Systemic clearance (CL) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  14. Volume of distribution (Vd) [ Time Frame: 48 months ]
    To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).

  15. 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)

  16. Quality of Life Assessment per BPI [ Time Frame: 35 months ]
    To assess quality of life in the treated population using Brief Pain Inventory (BPI)



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:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Only female
Accepts Healthy Volunteers:   No
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.

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): NCT03894215


Contacts
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Contact: Kristin Johnston, BSN, RN 646-755-3663 kjohnston@massbio.io

Locations
Show Show 24 study locations
Sponsors and Collaborators
Agenus Inc.
Gynecologic Oncology Group

Publications of Results:
Bristol-Myers Squibb USA, 2017a. Opdivo® (nivolumab) package insert,
Bristol-Myers Squibb USA, 2017b. Yervoy® (ipilimumab) package insert,
Carlino, M.S. et al., 2017. KEYNOTE-029: Efficacy and safety of pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma. In ASCO Annual Meeting. Chicago.
Chand D, Savistky D, Gonzalez A,, et al. [Abstract]. J Immunother Cancer. 2017;5(Suppl2):P312.
Chung HC, Schellens JHM, Delord JP, et al. 2018. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. [ASCO abstract 5522]. J Clin Oncol. 36(15 suppl):5522.
Drescher, C., Moore, M.N., Liu, J., O'Malley, D.M., Wang, E.W., Wang, J.S-Z., Subbish, V., et al. Phase 1/2, Open-Label, Multiple Ascending Dose Trial of AGEN2034, an Anti-PD-1 Monoclonal Antibody, in Advanced Solid Malignancies: Results of Dose Escalation in Advanced Cancer and Expansion Cohorts in Subjects With Relapsed/Refractory Cervical Cancer. Poster presented at European Society for Medical Oncology. Poster presented at ESMO 2018 Congress; 19 - 23 Oct 2018; Munich, Germany; Poster 1158P. Ann Oncol 2018 Oct; 29(Suppl 8).
Food and Drug Administration. 2018. FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm610572.htm. Accessed 14 January 2019.
Frenel, J.-S. et al., 2017. Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study. Journal of Clinical Oncology, 34(suppl; abstr 5515).
Goldman, J.W. et al., 2017. Nivolumab (N) plus ipilimumab (I) as first-line (1L) treatment for advanced (adv) NSCLC: 2-yr OS and long-term outcomes from CheckMate 012. In ASCO Annual Meeting. Chicago.
Hellmann, M.D. et al., 2016. CheckMate 012: safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. In ASCO Annual Meeting. Chicago: Proc Am Soc Clin Oncol.
Hollebecque, A. et al., 2017. An open-label, multicohort, phase I/II study of nivolumab in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, vaginal, and vulvar cancers. Journal of Clinical Oncology, 35(suppl;abstr 5504).
Keytruda [package insert]. Whitehouse Station, NJ; Merck and Co, Inc; 2018.
Long, G.V. et al., 2016. Pembrolizumab (pembro) plus ipilimumab (ipi) for advanced melanoma: Results of the KEYNOTE-029 expansion cohort. Journal of Clinical Oncology, 34(15_suppl), pp.9506-9506.
National Comprehensive Cancer Network, 2016. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2017,
Oken, M.M. et al., 1982. Toxicity and response criteria of the Eastern Cooperative Oncology Group. American Journal of Clinical Oncology, 5(6), pp.649-655.Ott, P.A. et al., 2017. Combination immunotherapy: a road map. Journal for Immunotherapy of Cancer, 5(1), p.16.

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Responsible Party: Agenus Inc.
ClinicalTrials.gov Identifier: NCT03894215    
Other Study ID Numbers: C-750-01/GOG-3028
First Posted: March 28, 2019    Key Record Dates
Last Update Posted: January 14, 2020
Last Verified: January 2020
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
Additional relevant MeSH terms:
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Uterine Cervical Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female