RaPiDS- A Phase 2 Study of Anti-PD-1 Independently or in Combination With Anti-CTLA-4 in Second-Line Cervical Cancer
18 Years and older, Female
C-750-01/GOG-3028 (primary)
NCI-2019-04431
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.
Objectives
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
- 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.
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts...
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