Study of AGEN2034 in Advanced Tumors and Cervical Cancer

• ClinicalTrials.gov Identifier: NCT03104699
• Recruitment Status: Completed
• First Posted: April 7, 2017
• Last Update Posted: June 5, 2023
• Sponsor: Agenus Inc.
• Information provided by (Responsible Party): Agenus Inc.

Study Description

Brief Summary:

This is a 2-part trial: a Phase 1, open-label, dose-escalation study in subjects with metastatic or locally advanced solid tumors, with a consecutive Phase 2 expansion to evaluate efficacy in subjects with recurrent, unresectable, or metastatic (advanced) cervical cancer that has progressed after a platinum-based treatment regimen.

Condition or disease	Intervention/treatment	Phase
Advanced Cancer; Cervical Cancer	Drug: AGEN2034	Phase 1; Phase 2

Detailed Description:

Phase 1: Dose Escalation

Phase 1 will consist of a standard 3+3 dose escalation with the following escalating dose levels and schedules:

Part A1: 1, 3, and 10 mg/kg administered every 2 weeks Part A2: 6 and 10 mg/kg every 3 weeks Each subject will stay on the dose level and schedule assigned at trial entry. Subjects will receive AGEN2034 for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.

A Safety Monitoring Committee (SMC) will assess safety; decide on dose-escalation and opening of backfill enrollment; define the recommended Phase 2 dose (RP2D); and determine opening of the phase 2 cohorts.

In Part A1, the first subject of each cohort will be observed for 16 days (i.e., ≥ 48 hours after second dose) for occurrence of DLT before the second subject is administered trial medication. Thereafter, within each cohort, consecutively enrolled subjects may initiate treatment ≥ 48 hours after the prior enrolled subject initiated treatment. Dose escalation will continue until the maximum tolerated dose (MTD) is reached or the maximum planned dose level (10.0 mg/kg) is shown to be safe. The MTD is defined as the dose below which ≥ 2 DLTs are observed.

Once Part A1 is completed, enrollment to Part A2 will begin. If < 2 DLTs are observed in Part A1 at the maximum planned dose of 10 mg/kg every 2 weeks, open enrollment to Part A2 will begin with enrollment of 10 subjects at 6 mg/kg every 3 weeks, followed by open enrollment of 10 subjects at 10 mg/kg every 3 weeks. If ≥ 2 DLTs are observed in Part A1, at the maximum planned dose in Part A1, the standard 3+3 dose escalation will resume with Part A2 where consecutively enrolled subjects in dose escalation may initiate treatment ≥ 48 hours after the prior enrolled subject initiated treatment.

For cohorts in dose escalation, concurrent with the 3+3 dose escalation schema, additional subjects will be backfilled to lower dose levels to ensure that each cohort enrolls a total of 10 subjects. Subjects enrolled to backfill cohorts may be enrolled simultaneously, without sequential dosing (i.e., not required to wait 48 hours between 2 subjects). These additional subjects at each dose level will have the purpose of generating additional safety, PK, and receptor occupancy data, and will not undergo formal DLT observation.

Phase 2: Dose Expansion

To further characterize safety and efficacy, subjects with recurrent, unresectable, or metastatic cervical cancer will be enrolled in Phase 2 and receive the RP2D of AGEN2034 (3 mg/kg every 2 weeks) for a maximum of 2 years or until confirmed progression, unacceptable toxicity, or any criterion for stopping the study drug or withdrawal from the trial occurs.

An SMC will assess safety, and an Independent Data Monitoring Committee (IDMC) will evaluate safety and efficacy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 211 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 / 2, Open-Label, Multiple Ascending Dose Trial to Investigate the Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second Line Cervical Cancer
• Actual Study Start Date: April 11, 2017
• Actual Primary Completion Date: June 15, 2022
• Actual Study Completion Date: June 15, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Monotherapy; Dose of 3 mg/kg IV every 2 weeks for up to 24 months.	Drug: AGEN2034; Anti-PD-1 Monoclonal Antibody; Other Name: Anti-PD-1

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR), as determined by IERC, in the analysis population [ Time Frame: Evaluated throughout the protocol, for the duration of the trial, up to 4 years ]
   per RECIST 1.1

Secondary Outcome Measures :

1. Safety and Tolerability of AGEN2034 [ Time Frame: From the time of the first dose to the end of follow-up (up to 2 years after the last dose) ]
   Frequency, severity, and duration of TEAEs and laboratory abnormalities, using NCI CTCAE v4.03.
2. Maximum drug concentration observed postdose at steady-state (Cmax-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
3. Minimum observed concentration at steady-state (Cmin-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
4. Area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
5. Area under the drug concentration-time curve from time zero to time t (AUC(0-t)), area under the drug concentration-time curve from time zero to infinity (AUC(0-∞)) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
6. Time to maximum observed concentration (tmax) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
7. Terminal disposition rate constant (λz) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
8. Terminal elimination half-life (t1/2) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
9. Systemic clearance (CL) [ Time Frame: Pre-dose through 3 months after last dose ]
   Serum AGEN2034 concentrations measured throughout the study
10. Volume of distribution (Vd) [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 concentrations measured throughout the study
11. Immunogenicity of AGEN2034 [ Time Frame: Pre-dose through 3 months after last dose ]
    Serum AGEN2034 ADA concentrations and serum AGEN2034 concentrations measured throughout the study
12. Objective Response Rate (ORR), as determined by investigator [ Time Frame: Evaluated throughout the protocol, for the duration of the trial, up to 4 years ]
    per RECIST 1.1
13. Duration of Response (DOR) [ Time Frame: Time from first observation of response to first observation of documented disease progression, up to 4 years ]
    per RECIST 1.1, as determined by an IERC and investigator, defined as time from first observation of response to first observation of documented disease progression (or death within 12 weeks after last tumor assessment). Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
14. Disease Control Rate (DCR) [ Time Frame: Duration of the trial, up to 4 years ]
    defined as proportion of subjects with complete response (CR), partial response (PR), or stable disease (SD) for at least 12 weeks
15. Duration of Stable Disease (SD) [ Time Frame: Duration of the trial, up to 4 years ]
    measured from the start of treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including baseline measurements.
16. Time to Response [ Time Frame: Duration of the treatment phase of the trial, up to 2 years ]
    defined as the time from the first dose date to first observation of confirmed response.
17. Progression-free Survival (PFS) [ Time Frame: Duration of the trial, up to 4 years ]
    defined as time from first treatment administration to first observation of documented disease progression (or death within 12 weeks after last tumor assessment), per RECIST 1.1, as determined by an IERC and investigator. Subjects without an event at analysis cutoff date will be censored on date of last tumor assessment.
18. Overall Survival Rate (OS) [ Time Frame: Duration of the trial, up to 4 years ]
    defined as time from start of treatment to death. For subjects who are still alive at time of data cutoff for trial analysis or who are lost to follow-up, survival will be censored at the last recorded date that the subject is known to be alive as of the cutoff date for analysis

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: 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 and prior systemic treatment:

   1. Phase 1: Have a histologically or cytologically confirmed diagnosis of a metastatic or locally advanced solid tumor for which no standard therapy is available or standard therapy has failed.
   2. Phase 2:

   I. 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.

   II. Has cervical cancer and has relapsed after a platinum-based treatment (first line) regimen for advanced (recurrent, unresectable, or metastatic) disease; Note: Subjects who have received > 1 prior systemic treatment regimen for their advanced or metastatic disease will be eligible in the following cases: Subject receiving chemotherapy concurrently with primary radiation (e.g., weekly cisplatin) or subject receiving adjuvant chemotherapy following completion of radiation therapy (e.g., paclitaxel and carboplatin for ≤ 4 cycles) and progressed within 6 months after treatment completion.

4. Measurable disease - based on investigator assessment

   1. Phase 1: Have objective evidence of disease; the presence of measurable disease is not required.
   2. Phase 2: Have measurable disease on imaging based on RECIST version 1.1. Note: Subjects 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.

   Note: Measurable disease by RECIST 1.1 must be confirmed by independent central radiologic review prior to first dose. Subjects without centrally confirmed measurable disease at baseline will not be eligible for this trial.

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 109/L, platelet count ≥ 100 x 109/L, and stable hemoglobin ≥ 8 g/dL (without transfusions within 1 week before first dose).
   2. Adequate hepatic function based by a total bilirubin level ≤ 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 x IULN.
   3. Adequate renal function defined as creatinine ≤ 1.5 x IULN OR calculated creatinine clearance ≥ 50 mL/min for subjects with creatinine levels > 1.5 x IULN (if no local guideline is available, 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 subject is receiving anticoagulant therapy); and activated partial thromboplastin time (aPTT) ≤ 1.5 x IULN (unless the subject is receiving anticoagulant therapy)
7. Other than the cancer for which the subject is enrolled, 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, or has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.

8. In Phase 2, subjects 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. Female subjects must have a negative serum pregnancy test at screening (within 72 hours before first dose of study drug) 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 menstruated for greater than 1 year,
   2. Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone (FSH) value in the postmenopausal range upon pretrial (screening) evaluation,
   3. Whose status is post hysterectomy, oophorectomy or tubal ligation.

10. If of childbearing potential, female subjects must be willing to use 2 highly effective methods (defined in the informed consent form [ICF]) 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 subject.

11. Male subjects with a female partner(s) of child-bearing potential must agree to use 2 highly effective methods (defined in the ICF) throughout the trial starting with the screening visit through 120 days after the last dose of study treatment is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

    Note: Abstinence is acceptable if this is the established and preferred contraception for the subject.

12. Is willing and able to comply with the requirements of the protocol.

Exclusion Criteria:

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 before 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. For Phase 2: > 1 systemic treatment regimen for the advanced (recurrent, unresectable, or metastatic) cervical cancer for which the subject is considered for the study Note: In Phase 1, prior treatment with a CTLA-4 antibody is permissible for subjects with metastatic melanoma.

4. Has persisting toxicity related to prior therapy of 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 (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 [NCI CTCAE] Grade ≥ 3), any history of anaphylaxis, or uncontrolled asthma.
7. Is receiving systemic corticosteroid ≤ 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, and/or a premedication for IV contrast allergies/reactions is allowed). Subjects who are receiving daily corticosteroid replacement therapy are an exception to this rule. Examples of permitted therapy are daily prednisone at doses of 5 to 7.5 mg or equivalent hydrocortisone dose, and steroid therapy administered by topical, intraocular, intranasal, and/or inhalation routes.

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: Subjects 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 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 systemic treatment.

   Note: Subjects 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 systemic therapy.
13. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. Has known active Hepatitis B, Hepatitis C 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 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 before 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 subject's participation for the full duration of the trial, or is not in the best interest of the subject 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).
19. Is legally incapacitated or has limited legal capacity.
20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study treatment.

Contacts and Locations

Locations

United States, Arizona

HonorHealth Research Institute

Scottsdale, Arizona, United States, 85258

United States, California

City of Hope

Duarte, California, United States, 91010

University of Southern California - Keck School of Medicine

Los Angeles, California, United States, 90033

United States, Florida

Sylvester Comprehensive Cancer Center

Miami, Florida, United States, 33136

Florida Cancer Specialists & Research Institute

Sarasota, Florida, United States, 34232

United States, Georgia

Augusta Oncology

Augusta, Georgia, United States, 30912

United States, Illinois

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Chicago, Illinois, United States, 60611

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Ohio

The Ohio State University Comprehensive Cancer Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

The University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73104

United States, Texas

The University of Texas MD Anderson Caner Center

Houston, Texas, United States, 77030

United States, Washington

Swedish Medical Center-Cherry Hill Campus

Seattle, Washington, United States, 98104

Australia, Queensland

Pindara Private Hospital

Benowa, Queensland, Australia, 4217

Australia, South Australia

Calvary North Adelaide Hospital

North Adelaide, South Australia, Australia, 5006

Belgium

Cliniques Universitaires Saint-Luc

Brussels, Belgium, 1200

Brazil

IMIP

Recife, PE, Brazil, 50070-550

Instituto Nacional de Câncer

Rio De Janeiro, RJ, Brazil, 20220-410

Hospital de Caridade de Ijuí

Ijui, RS, Brazil, 98700-000

Hospital Mãe de Deus

Porto Alegre, RS, Brazil, 90110-270

Instituto do Cancer do Estado de São Paulo

São Paulo, SP, Brazil, 01246-000

Hospital Amaral Carvalho

São Paulo, SP, Brazil, 03162-065

Fundação Faculdade Regional de Medicina de São José do Rio Preto

Sao Jose do Rio Preto, Brazil, 15090-000

Chile

Centro Oncológico del Norte

Antofagasta, AN, Chile, 1240000

Centro de Investigación Del Cáncer James Lind

Temuco, AR, Chile, 4800827

Fundación Arturo López Pérez

Santiago, RM, Chile, 7500918

Bradford Hill

Santiago, RM, Chile, 8420323

Estonia

East-Tallinn Central Hospital

Tallinn, Estonia, 1131

North Estonia Medical Centre Foundation

Tallinn, Estonia, 13419

France

Institut Bergonié

Bordeaux, France, 33076

Centre Léon Bérard

Lyon, France, 69008

L'Institut Paoli - Calmettes

Marseille Cedex 9, France, 13273

CHU Hôpital de la Timone

Marseille, France, 13385

Centre Antoine-Lacassagne

Nice cedex 2, France, 6189

Hôpital Cochin

Paris, France, 75014

Groupe Hospitalier Diaconesses Croix Saint-Simon - Hopital de la Croix Saint-Simon

Paris, France, 75020

Clinique Armoricaine de Radiologie

Plérin, France, 22190

Institute de Cancerologie de l'Ouest (ICO) - René Gauducheau

Saint-Herblain, France, 44805

Institut Claudius Regaud

Toulouse, France, 31100

Gustave Roussy

Villejuif Cedex, France, 94800

Poland

Szpital Swietego Rafala w Krakowie

Kraków, MA, Poland, 30-693

Szpitale Pomorskie Sp. z o.o.

Gdynia, PM, Poland, 81-519

Spain

Vall d'Hebron Institut d'Oncologia

Barcelona, Spain, 8035

Hospital Clínic de Barcelona

Barcelona, Spain, 8036

Clínica Universidad de Navarra

Madrid, Spain, 28027

Sponsors and Collaborators

Agenus Inc.

Investigators

• Study Director: Medical Director; Agenus Inc.

More Information

• Responsible Party: Agenus Inc.
• ClinicalTrials.gov Identifier: NCT03104699
• Other Study ID Numbers: C-700-01
• First Posted: April 7, 2017
• Last Update Posted: June 5, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Agenus Inc.:

Antibodies; Immunologic effects; Physiological Effects of Drugs

Additional relevant MeSH terms:

Uterine Cervical Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases