Clinical trial NCT03104699: Study of AGEN2034 in Advanced Tumors and Cervical Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Cancer
Cervical Cancer
Keywords: Antibodies
Immunologic effects
Physiological Effects of Drugs
Lead sponsor: Agenus Inc.
Sponsor class: INDUSTRY
First posted: 2017-04-07
Enrollment: 211
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

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 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.

Primary outcomes:
measure: Objective Response Rate (ORR), as determined by IERC, in the analysis population
timeFrame: Evaluated throughout the protocol, for the duration of the trial, up to 4 years
Secondary outcomes:
measure: Safety and Tolerability of AGEN2034
timeFrame: From the time of the first dose to the end of follow-up (up to 2 years after the last dose)
measure: Maximum drug concentration observed postdose at steady-state (Cmax-ss)
timeFrame: Pre-dose through 3 months after last dose
measure: Minimum observed concentration at steady-state (Cmin-ss)
timeFrame: Pre-dose through 3 months after last dose
measure: Area under the drug concentration-time curve within time span t1 to t2 at steady-state (AUC(τ1-τ2)-ss)
timeFrame: Pre-dose through 3 months after last dose
measure: 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-∞))
timeFrame: Pre-dose through 3 months after last dose
measure: Time to maximum observed concentration (tmax)
timeFrame: Pre-dose through 3 months after last dose
measure: Terminal disposition rate constant (λz)
timeFrame: Pre-dose through 3 months after last dose
measure: Terminal elimination half-life (t1/2)
timeFrame: Pre-dose through 3 months after last dose
measure: Systemic clearance (CL)
timeFrame: Pre-dose through 3 months after last dose
measure: Volume of distribution (Vd)
timeFrame: Pre-dose through 3 months after last dose
measure: Immunogenicity of AGEN2034
timeFrame: Pre-dose through 3 months after last dose
measure: Objective Response Rate (ORR), as determined by investigator
timeFrame: Evaluated throughout the protocol, for the duration of the trial, up to 4 years
measure: Duration of Response (DOR)
timeFrame: Time from first observation of response to first observation of documented disease progression, up to 4 years
measure: Disease Control Rate (DCR)
timeFrame: Duration of the trial, up to 4 years
measure: Duration of Stable Disease (SD)
timeFrame: Duration of the trial, up to 4 years
measure: Time to Response
timeFrame: Duration of the treatment phase of the trial, up to 2 years
measure: Progression-free Survival (PFS)
timeFrame: Duration of the trial, up to 4 years
measure: Overall Survival Rate (OS)
timeFrame: Duration of the trial, up to 4 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: HonorHealth Research Institute
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: Los Angeles
country: United States
facility: University of Southern California - Keck School of Medicine
state: California
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center
state: Florida
city: Sarasota
country: United States
facility: Florida Cancer Specialists & Research Institute
state: Florida
city: Augusta
country: United States
facility: Augusta Oncology
state: Georgia
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center of Northwestern University
state: Illinois
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: The University of Oklahoma Health Sciences Center
state: Oklahoma
city: Houston
country: United States
facility: The University of Texas MD Anderson Caner Center
state: Texas
city: Seattle
country: United States
facility: Swedish Medical Center-Cherry Hill Campus
state: Washington
city: Benowa
country: Australia
facility: Pindara Private Hospital
state: Queensland
city: North Adelaide
country: Australia
facility: Calvary North Adelaide Hospital
state: South Australia
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Recife
country: Brazil
facility: IMIP
state: PE
city: Rio De Janeiro
country: Brazil
facility: Instituto Nacional de Câncer
state: RJ
city: Ijui
country: Brazil
facility: Hospital de Caridade de Ijuí
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital Mãe de Deus
state: RS
city: São Paulo
country: Brazil
facility: Instituto do Cancer do Estado de São Paulo
state: SP
city: São Paulo
country: Brazil
facility: Hospital Amaral Carvalho
state: SP
city: Sao Jose do Rio Preto
country: Brazil
facility: Fundação Faculdade Regional de Medicina de São José do Rio Preto
city: Antofagasta
country: Chile
facility: Centro Oncológico del Norte
state: AN
city: Temuco
country: Chile
facility: Centro de Investigación Del Cáncer James Lind
state: AR
city: Santiago
country: Chile
facility: Fundación Arturo López Pérez
state: RM
city: Santiago
country: Chile
facility: Bradford Hill
state: RM
city: Tallinn
country: Estonia
facility: East-Tallinn Central Hospital
city: Tallinn
country: Estonia
facility: North Estonia Medical Centre Foundation
city: Bordeaux
country: France
facility: Institut Bergonié
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille Cedex 9
country: France
facility: L'Institut Paoli - Calmettes
city: Marseille
country: France
facility: CHU Hôpital de la Timone
city: Nice cedex 2
country: France
facility: Centre Antoine-Lacassagne
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Groupe Hospitalier Diaconesses Croix Saint-Simon - Hopital de la Croix Saint-Simon
city: Plérin
country: France
facility: Clinique Armoricaine de Radiologie
city: Saint-Herblain
country: France
facility: Institute de Cancerologie de l'Ouest (ICO) - René Gauducheau
city: Toulouse
country: France
facility: Institut Claudius Regaud
city: Villejuif Cedex
country: France
facility: Gustave Roussy
city: Kraków
country: Poland
facility: Szpital Swietego Rafala w Krakowie
state: MA
city: Gdynia
country: Poland
facility: Szpitale Pomorskie Sp. z o.o.
state: PM
city: Barcelona
country: Spain
facility: Vall d'Hebron Institut d'Oncologia
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Clínica Universidad de Navarra
Study officials:
affiliation: Agenus Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: