Clinical trial NCT03894215: RaPiDS- A 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cervical Cancer
Lead sponsor: Agenus Inc.
Sponsor class: INDUSTRY
Collaborators: name: GOG Foundation
First posted: 2019-03-28
Enrollment: 212
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.
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.

Primary outcomes:
measure: Objective Response Rate
timeFrame: 48 months
Secondary outcomes:
measure: Frequency, severity and duration of treatment-emergent AEs
timeFrame: 48 months
measure: DOR per RECIST 1.1
timeFrame: 48 months
measure: Time to Confirmed Progression
timeFrame: 48 months
measure: Immunogenicity of AGEN2034
timeFrame: 48 months
measure: Maximum observed drug concentration at steady state (Cmax-ss)
timeFrame: 48 months
measure: Minimum observed drug concentration at steady-state (Cmin-ss)
timeFrame: 48 months
measure: Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss)
timeFrame: 48 months
measure: Area under the drug concentration-time curve from time zero to time t (AUC(0-t))
timeFrame: 48 months
measure: Area under the drug concentration-time curve from time zero to infinity (AUC(0-∞))
timeFrame: 48 months
measure: Time to maximum drug concentration (tmax)
timeFrame: 48 months
measure: Terminal disposition rate constant (λz)
timeFrame: 48 months
measure: Terminal elimination half-life (t1/2)
timeFrame: 48 months
measure: Systemic clearance (CL)
timeFrame: 48 months
measure: Volume of distribution (Vd)
timeFrame: 48 months
measure: Quality of Life Assessment per FACT-Cx
timeFrame: 35 months
measure: Quality of Life Assessment per BPI
timeFrame: 35 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama Mitchell Cancer Institute
state: Alabama
city: Phoenix
country: United States
facility: Arizona Oncology - Biltmore Cancer Center
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology - Tucson - Wilmot Road Location
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego (UCSD) - Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA- Women's Health Clinical Research Unit (WHCRU)
state: California
city: Newport
country: United States
facility: Gynecologic Oncology Associates
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: Jacksonville
country: United States
facility: Baptist MD Anderson Cancer Center
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Savannah
country: United States
facility: St Joseph's Hospital
state: Georgia
city: Indianapolis
country: United States
facility: Community Health Network - North Cancer Center
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Albert B. Chandler Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Camden
country: United States
facility: MD Anderson Cancer Center at Cooper
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Albert Einstein College of Medicine
state: New York
city: Lake Success
country: United States
facility: Northwell Health Monter Cancer Center
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Pinehurst
country: United States
facility: FirstHealth Outpatient Cancer Center
state: North Carolina
city: Cleveland
country: United States
facility: MetroHealth Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Columbus
country: United States
facility: Columbus NCORP
state: Ohio
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute, LLC
state: Oklahoma
city: Eugene
country: United States
facility: Willamette Valley Cancer Institute
state: Oregon
city: Portland
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Oregon
city: Philadelphia
country: United States
facility: Penn Medicine - Jordan Center for Gynecologic Cancer
state: Pennsylvania
city: York
country: United States
facility: WellSpan Gynecologic Oncology
state: Pennsylvania
city: Providence
country: United States
facility: Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Austin
country: United States
facility: Texas Oncology Surgical Specialists - Austin Central
state: Texas
city: Bedford
country: United States
facility: Texas Oncology - Bedford
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Dallas - Presbyterian Cancer Center
state: Texas
city: Dallas
country: United States
facility: The University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Texas Oncology - Fort Worth Cancer Center
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology - San Antonio Medical Center
state: Texas
city: The Woodlands
country: United States
facility: Texas Oncology - The Woodlands
state: Texas
city: Tyler
country: United States
facility: Texas Oncology
state: Texas
city: Fortaleza
country: Brazil
facility: CRIO - Centro Regional Integrado de Oncologia
state: Ceará
city: Vitória
country: Brazil
facility: Hospital Santa Rita
state: Espírito Santo
city: Recife
country: Brazil
facility: IMIP - Instituto de Medicina Integral Prof. Fernando Figueira
state: Pernambuco
city: Ijuí
country: Brazil
facility: ONCOSITE/Hospital de Caridade de Ijuí
state: Rio Grande Do Sul
city: Porto Alegre
country: Brazil
facility: Hospital Mãe de Deus
state: Rio Grande Do Sul
city: Boa Vista
country: Brazil
facility: CECOR - Centro Oncológico de Roraima
state: Roraima
city: Barretos
country: Brazil
facility: Hospital de CÃ¢ncer de Barretos
state: São Paulo
city: Rio De Janeiro
country: Brazil
facility: INCA - Instituto Nacional de Câncer
city: São Paulo
country: Brazil
facility: Instituto do Câncer do Estado de São Paulo
city: São Paulo
country: Brazil
facility: Perola Centro de Pesquisa em Oncologia
city: São Paulo
country: Brazil
facility: Hospital Amaral Carvalho
city: São Paulo
country: Brazil
facility: Fundação Antonio Prudente/AC Camargo Cancer Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University
city: Seoul
country: Korea, Republic of
facility: Gangnam Severence Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Mexico
country: Mexico
facility: COI Centro Oncológico Internacional S.A.P.I. de C.V.
state: Ciudad De Mexico
city: Monterrey
country: Mexico
facility: Christus Muguerza Hospital Vidriera
state: Nuevo Leon
city: Oaxaca
country: Mexico
facility: Oaxaca Site Management Organization (OSMO)
city: Queretaro
country: Mexico
facility: Cancerologia De Queretaro
city: Lima Lima
country: Peru
facility: Clinica MonteSur, Centro de Investigación Clínica Montesur RCI -259
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Mackay Memorial Hospital Taipei Branch
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital
city: Taipei
country: Taiwan
facility: Koo Foundation Sun Yat-Sen Cancer Center
city: Bangkok
country: Thailand
facility: King Chulalongkorn Memorial Hospital, Chulalongkorn University
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital, Mahidol University
Study officials:
affiliation: Agenus Inc.
name: Medical Director
role: STUDY_DIRECTOR
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