RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer
- Registration Number
- NCT03894215
- Lead Sponsor
- 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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- Female
- Target Recruitment
- 212
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Voluntarily agree to participate by giving written informed consent. (Participation in pharmacogenomics testing is optional).
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Be ≥18 years of age.
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Diagnosis:
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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.
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Has cervical cancer and has relapsed after a platinum- based treatment (first line) regimen for advanced (recurrent, unresectable, or metastatic) disease.
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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.
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Have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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Have adequate organ function as indicated by the following laboratory values:
- 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).
- 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.
- 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.
- 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)
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Has no history of another primary malignancy, with the exception of:
- 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.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease and superficial bladder cancer.
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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.
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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):
- ≥45 years of age and has not had menses for greater than 1 year,
- Amenorrheic ≥ 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
- History of hysterectomy, oophorectomy or tubal ligation.
- Definitive pelvic radiation for the treatment of cervical cancer.
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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.
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Is willing and able to comply with the requirements of the protocol.
The patient must be excluded from participating in the trial if the patient:
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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.
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Has an inadequate washout period prior to first dose of study drug defined as:
- Received systemic cytotoxic chemotherapy or biological therapy within 3 weeks before first dose,
- Received radiation therapy within 3 weeks before first dose, or
- Had major surgery within 4 weeks before first dose.
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Has received prior therapy with:
- 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
- More than 1 systemic treatment regimen for the advanced (recurrent, unresectable, or metastatic) cervical cancer for which the patient is considered for the study.
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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.
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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).
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Has known severe hypersensitivity reactions to fully human monoclonal antibodies (NCI-CTCAE Grade ≥3), any history of anaphylaxis, or uncontrolled asthma.
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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.
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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.
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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.
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Has had an allogeneic tissue/solid organ transplant.
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Has or had interstitial lung disease (ILD) OR has had a history of pneumonitis that has required oral or IV corticosteroids.
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Has an active infection requiring intravenous (IV) systemic therapy.
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Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
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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.
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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.
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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.
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Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
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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.
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Is legally incapacitated or has limited legal capacity.
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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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description AGEN2034 + Placebo AGEN2034 AGEN2034 administered with placebo monotherapy: approximately 100 patients. AGEN2034 + AGEN1884 AGEN2034 AGEN2034 administered in combination with AGEN1884 (combination therapy): approximately 100 patients. AGEN2034 + AGEN1884 AGEN1884 AGEN2034 administered in combination with AGEN1884 (combination therapy): approximately 100 patients.
- Primary Outcome Measures
Name Time Method Objective Response Rate 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
Name Time Method DOR per RECIST 1.1 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 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).
Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss) 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)) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Area under the drug concentration-time curve from time zero to infinity (AUC(0-∞)) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Frequency, severity and duration of treatment-emergent AEs 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.
Immunogenicity of AGEN2034 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) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Minimum observed drug concentration at steady-state (Cmin-ss) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Time to maximum drug concentration (tmax) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Terminal disposition rate constant (λz) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Terminal elimination half-life (t1/2) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Systemic clearance (CL) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Volume of distribution (Vd) 48 months To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).
Quality of Life Assessment per FACT-Cx 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 35 months To assess quality of life in the treated population using Brief Pain Inventory (BPI)
Trial Locations
- Locations (68)
UCLA- Women's Health Clinical Research Unit (WHCRU)
🇺🇸Los Angeles, California, United States
The Ohio State University Wexner Medical Center
🇺🇸Columbus, Ohio, United States
Columbus NCORP
🇺🇸Columbus, Ohio, United States
ONCOSITE/Hospital de Caridade de Ijuí
🇧🇷Ijuí, Rio Grande Do Sul, Brazil
Hospital Santa Rita
🇧🇷Vitória, Espírito Santo, Brazil
California Pacific Medical Center
🇺🇸San Francisco, California, United States
Northside Hospital
🇺🇸Atlanta, Georgia, United States
Community Health Network - North Cancer Center
🇺🇸Indianapolis, Indiana, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
University of California, San Francisco Medical Center
🇺🇸San Francisco, California, United States
Gynecologic Oncology Associates
🇺🇸Newport, California, United States
Texas Oncology - Bedford
🇺🇸Bedford, Texas, United States
Texas Oncology - Dallas - Presbyterian Cancer Center
🇺🇸Dallas, Texas, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
Texas Oncology - San Antonio Medical Center
🇺🇸San Antonio, Texas, United States
Oklahoma Cancer Specialists and Research Institute, LLC
🇺🇸Tulsa, Oklahoma, United States
Perola Centro de Pesquisa em Oncologia
🇧🇷São Paulo, Brazil
CECOR - Centro Oncológico de Roraima
🇧🇷Boa Vista, Roraima, Brazil
Gangnam Severence Hospital
🇰🇷Seoul, Korea, Republic of
Hospital de Câncer de Barretos
🇧🇷Barretos, São Paulo, Brazil
Christus Muguerza Hospital Vidriera
🇲🇽Monterrey, Nuevo Leon, Mexico
Hospital Mãe de Deus
🇧🇷Porto Alegre, Rio Grande Do Sul, Brazil
Seoul National University
🇰🇷Seoul, Korea, Republic of
INCA - Instituto Nacional de Câncer
🇧🇷Rio De Janeiro, Brazil
Instituto do Câncer do Estado de São Paulo
🇧🇷São Paulo, Brazil
Fundação Antonio Prudente/AC Camargo Cancer Center
🇧🇷São Paulo, Brazil
University of Alabama at Birmingham School of Medicine
🇺🇸Birmingham, Alabama, United States
Arizona Oncology - Biltmore Cancer Center
🇺🇸Phoenix, Arizona, United States
Moffitt Cancer Center
🇺🇸Tampa, Florida, United States
Stephenson Cancer Center
🇺🇸Oklahoma City, Oklahoma, United States
Northwest Cancer Specialists, P.C.
🇺🇸Portland, Oregon, United States
Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
The University of Texas Southwestern Medical Center
🇺🇸Dallas, Texas, United States
Texas Oncology
🇺🇸Tyler, Texas, United States
St Joseph's Hospital
🇺🇸Savannah, Georgia, United States
Texas Oncology - Fort Worth Cancer Center
🇺🇸Fort Worth, Texas, United States
Hospital Amaral Carvalho
🇧🇷São Paulo, Brazil
FirstHealth Outpatient Cancer Center
🇺🇸Pinehurst, North Carolina, United States
University of South Alabama Mitchell Cancer Institute
🇺🇸Mobile, Alabama, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone
🇺🇸New York, New York, United States
Northwell Health Monter Cancer Center
🇺🇸Lake Success, New York, United States
WellSpan Gynecologic Oncology
🇺🇸York, Pennsylvania, United States
Willamette Valley Cancer Institute
🇺🇸Eugene, Oregon, United States
Women & Infants Hospital of Rhode Island
🇺🇸Providence, Rhode Island, United States
Penn Medicine - Jordan Center for Gynecologic Cancer
🇺🇸Philadelphia, Pennsylvania, United States
Texas Oncology - The Woodlands
🇺🇸The Woodlands, Texas, United States
CRIO - Centro Regional Integrado de Oncologia
🇧🇷Fortaleza, Ceará, Brazil
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Koo Foundation Sun Yat-Sen Cancer Center
🇨🇳Taipei, Taiwan
COI Centro Oncológico Internacional S.A.P.I. de C.V.
🇲🇽Mexico, Ciudad De Mexico, Mexico
Oaxaca Site Management Organization (OSMO)
🇲🇽Oaxaca, Mexico
IMIP - Instituto de Medicina Integral Prof. Fernando Figueira
🇧🇷Recife, Pernambuco, Brazil
MetroHealth Medical Center
🇺🇸Cleveland, Ohio, United States
King Chulalongkorn Memorial Hospital, Chulalongkorn University
🇹🇭Bangkok, Thailand
Arizona Oncology - Tucson - Wilmot Road Location
🇺🇸Tucson, Arizona, United States
Clinica MonteSur, Centro de Investigación Clínica Montesur RCI -259
🇵🇪Lima Lima, Peru
Taipei Veterans General Hospital
🇨🇳Taipei, Taiwan
Cancerologia De Queretaro
🇲🇽Queretaro, Mexico
Taichung Veterans General Hospital
🇨🇳Taichung, Taiwan
Ramathibodi Hospital, Mahidol University
🇹🇭Bangkok, Thailand
Ochsner Clinic Foundation
🇺🇸New Orleans, Louisiana, United States
Albert Einstein College of Medicine
🇺🇸Bronx, New York, United States
Texas Oncology Surgical Specialists - Austin Central
🇺🇸Austin, Texas, United States
University of Kentucky Albert B. Chandler Hospital
🇺🇸Lexington, Kentucky, United States
University of New Mexico Cancer Center
🇺🇸Albuquerque, New Mexico, United States
University of California, San Diego (UCSD) - Moores Cancer Center
🇺🇸La Jolla, California, United States
MD Anderson Cancer Center at Cooper
🇺🇸Camden, New Jersey, United States
Mackay Memorial Hospital Taipei Branch
🇨🇳Taipei, Taiwan