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.
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.
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-child
bearing 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.
