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

Cervical Cancer Clinical Trial

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03894215
• Other study ID #: C-750-01/GOG-3028
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 1, 2019
• Est. completion date: September 2026

Study information

• Verified date: March 2024
• Source: Agenus Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 212
• Est. completion date: September 2026
• Est. primary completion date: August 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cervical Cancer
• Uterine Cervical Neoplasms

Intervention

Drug:
• AGEN2034
PD-1 antibody
• AGEN1884
CTLA-4 antibody

Locations

Country	Name	City	State
Brazil	Hospital de Câncer de Barretos	Barretos	São Paulo
Brazil	CECOR - Centro Oncológico de Roraima	Boa Vista	Roraima
Brazil	CRIO - Centro Regional Integrado de Oncologia	Fortaleza	Ceará
Brazil	ONCOSITE/Hospital de Caridade de Ijuí	Ijuí	Rio Grande Do Sul
Brazil	Hospital Mãe de Deus	Porto Alegre	Rio Grande Do Sul
Brazil	IMIP - Instituto de Medicina Integral Prof. Fernando Figueira	Recife	Pernambuco
Brazil	INCA - Instituto Nacional de Câncer	Rio De Janeiro
Brazil	Fundação Antonio Prudente/AC Camargo Cancer Center	São Paulo
Brazil	Hospital Amaral Carvalho	São Paulo
Brazil	Instituto do Câncer do Estado de São Paulo	São Paulo
Brazil	Perola Centro de Pesquisa em Oncologia	São Paulo
Brazil	Hospital Santa Rita	Vitória	Espírito Santo
Korea, Republic of	Gangnam Severence Hospital	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University	Seoul
Mexico	COI Centro Oncológico Internacional S.A.P.I. de C.V.	Mexico	Ciudad De Mexico
Mexico	Christus Muguerza Hospital Vidriera	Monterrey	Nuevo Leon
Mexico	Oaxaca Site Management Organization (OSMO)	Oaxaca
Mexico	Cancerologia De Queretaro	Queretaro
Peru	Clinica MonteSur, Centro de Investigación Clínica Montesur RCI -259	Lima Lima
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	Koo Foundation Sun Yat-Sen Cancer Center	Taipei
Taiwan	Mackay Memorial Hospital Taipei Branch	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Thailand	King Chulalongkorn Memorial Hospital, Chulalongkorn University	Bangkok
Thailand	Ramathibodi Hospital, Mahidol University	Bangkok
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Northside Hospital	Atlanta	Georgia
United States	Texas Oncology Surgical Specialists - Austin Central	Austin	Texas
United States	Texas Oncology - Bedford	Bedford	Texas
United States	University of Alabama at Birmingham School of Medicine	Birmingham	Alabama
United States	Albert Einstein College of Medicine	Bronx	New York
United States	MD Anderson Cancer Center at Cooper	Camden	New Jersey
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	MetroHealth Medical Center	Cleveland	Ohio
United States	Columbus NCORP	Columbus	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Texas Oncology - Dallas - Presbyterian Cancer Center	Dallas	Texas
United States	The University of Texas Southwestern Medical Center	Dallas	Texas
United States	Willamette Valley Cancer Institute	Eugene	Oregon
United States	Texas Oncology - Fort Worth Cancer Center	Fort Worth	Texas
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 Diego (UCSD) - Moores Cancer Center	La Jolla	California
United States	Northwell Health Monter Cancer Center	Lake Success	New York
United States	University of Kentucky Albert B. Chandler Hospital	Lexington	Kentucky
United States	UCLA- Women's Health Clinical Research Unit (WHCRU)	Los Angeles	California
United States	University of South Alabama Mitchell Cancer Institute	Mobile	Alabama
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York
United States	Gynecologic Oncology Associates	Newport	California
United States	Stephenson Cancer Center	Oklahoma City	Oklahoma
United States	Penn Medicine - Jordan Center for Gynecologic Cancer	Philadelphia	Pennsylvania
United States	Arizona Oncology - Biltmore Cancer Center	Phoenix	Arizona
United States	FirstHealth Outpatient Cancer Center	Pinehurst	North Carolina
United States	Northwest Cancer Specialists, P.C.	Portland	Oregon
United States	Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	Texas Oncology - San Antonio Medical Center	San Antonio	Texas
United States	California Pacific Medical Center	San Francisco	California
United States	University of California, San Francisco Medical Center	San Francisco	California
United States	St Joseph's Hospital	Savannah	Georgia
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	Texas Oncology - The Woodlands	The Woodlands	Texas
United States	Arizona Oncology - Tucson - Wilmot Road Location	Tucson	Arizona
United States	Oklahoma Cancer Specialists and Research Institute, LLC	Tulsa	Oklahoma
United States	Texas Oncology	Tyler	Texas
United States	WellSpan Gynecologic Oncology	York	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Agenus Inc.	GOG Foundation

Countries where clinical trial is conducted

United States,  Brazil,  Korea, Republic of,  Mexico,  Peru,  Taiwan,  Thailand, 

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* Note: There are 45 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Objective Response Rate	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).	48 months
Secondary	Frequency, severity and duration of treatment-emergent AEs	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.	48 months
Secondary	DOR per RECIST 1.1	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).	48 months
Secondary	Time to Confirmed Progression	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).	48 months
Secondary	Immunogenicity of AGEN2034	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.	48 months
Secondary	Maximum observed drug concentration at steady state (Cmax-ss)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Minimum observed drug concentration at steady-state (Cmin-ss)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Area under the concentration-time curve within time span t1 to t2 at steady-state (AUC(t1-t2)-ss)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Area under the drug concentration-time curve from time zero to time t (AUC(0-t))	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Area under the drug concentration-time curve from time zero to infinity (AUC(0-8))	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Time to maximum drug concentration (tmax)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Terminal disposition rate constant (?z)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Terminal elimination half-life (t1/2)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Systemic clearance (CL)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Volume of distribution (Vd)	To characterize AGEN2034 and AGEN1884 pharmacokinetics (PK).	48 months
Secondary	Quality of Life Assessment per FACT-Cx	To assess quality of life in the treated population using the Functional Assessment of Cancer Therapy - Cervical Cancer Trial Outcome Index (FACT-Cx)	35 months
Secondary	Quality of Life Assessment per BPI	To assess quality of life in the treated population using Brief Pain Inventory (BPI)	35 months