The purpose of this study is to characterize the safety and tolerability, identify a
recommended dose for expansion (RDE) / recommended phase II dose (RP2D), pharmacodynamics,
and antitumor activity of Oregovomab vaccination in combination with Nivolumab as a novel
combinatorial immunotherapeutic strategy in in female patients with recurrent epithelial
ovarian cancer (EOC) who progressed after two or more prior lines of cytotoxic chemotherapy.
This study tests the hypothesis that the combination of Oregovomab and Nivolumab will improve
intracellular Cancer Antigen (CA) 125 antigen processing and elicit a stronger systemic CA
125-specific T cell response; in a manner that is synergistic, safe, and clinically
efficacious in patients with relapsed EOC.
This is an open-label, single-arm, phase Ib/IIa, single-center study with dose finding and
dose expansion parts.
In the phase Ib part, clinically recommended doses as monotherapy for Oregovomab (IV 2 mg
Q4W, dose level 1) and Nivolumab (IV 240 mg Q2W) will be the starting doses for their
A modified "3+3" dose finding design will be employed, with 2 lower dosages of Oregovomab
(dose level -1 at 1 mg Q4W; level -2 at 0.5 mg Q4W) specified in case of excessive toxicity
(defined as ≥ 2 dose limiting toxicities (DLTs) out of first 3 patients, or all 6 patients)
encountered at dose level 1. Three patients will be initially enrolled into dose level 1. If
0 or 1 DLT is observed, another 3 patients will be enrolled into the same dose level;
otherwise de-escalate and enroll 3 patients at dose level -1. If ≤ 1 DLT is observed among
the 6 patients, dose level 1 will be the RDE/RP2D of Oregovomab to be combined with
Nivolumab. Likewise, in the event of de-escalation, if 0 or 1 DLT is observed at a lower dose
level, a further 3 patients will be enrolled for that level; if ≤ 1 DLT is observed out of
the 6 patients, that dose level will be the RDE/RP2D.
A minimum of 6 and a maximum of 18 patients will be enrolled in the dose finding part.
Approximately 14 patients are to enroll in the dose expansion part wherein they will receive
Oregovomab at RDE/RP2D, combined with Nivolumab. In total, 20 patients from the dose finding
and dose expansion cohorts will be treated at RDE/RP2D, and be included in the phase IIa
Patients will be followed up for survival and post-progression treatment(s) over a duration
of up to 36 months from the time of treatment initiation (i.e., Week 0 until up to 36
1. Signed Written Informed Consent
- Able to understand and voluntarily sign the Informed Consent Form (ICF). Written
informed consent must be obtained before any study specific procedures that are
not part of standard of care.
- Willing and able to comply with scheduled visits, treatment schedule, laboratory
test, and other protocol requirements
2. Age and Target Population
• Age ≥ 21 years old
- Histologically and/or cytologically confirmed diagnosis of epithelial ovarian
carcinoma (serous, clear cell, endometrioid, mucinous, mixed, and others),
fallopian tube and primary peritoneal carcinoma
- Serum CA 125 level at enrollment must be at least twice the upper limit of normal
(ULN) using local laboratory ranges
- Objective evidence of disease recurrence following initial curative-intent
treatment, and of progression after at least 2 prior lines of cytotoxic
chemotherapy (including platinum and taxane) for advanced stage disease. Patients
may have received prior treatment with Bevacizumab.
- Presence of:
(a) measurable disease as defined by RECIST v1.1 AND a pre-treatment serum CA 125
level ≥ 2 x ULN on 1 occasion, OR (b) non-measurable but evaluable disease such
as ascites and pleural effusions attributable to disease or radiologic
abnormalities that do not meet RECIST v1.1 criteria AND a pre-treatment serum CA
125 level ≥ 2 x ULN on 2 occasions at least 1 week apart, OR (c) non-evaluable,
non-measurable disease as defined by RECIST v1.1 AND pre-treatment CA 125 level ≥
2 x ULN on 2 occasions at least 1 week apart
- Estimated life expectancy greater than 3 months
- Performance status Eastern Cooperative Oncology Group (ECOG) 0 or 1
- Adequate hematologic and end organ function, defined by the following local
laboratory results obtained within 14 days before study entry:
1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 109/L (without granulocyte
colony-stimulating factor support within 2 weeks of laboratory test used to
2. White Blood Cells (WBC) count ≥ 2.0 × 109/L
3. Platelet count ≥ 100 × 109/L (without transfusion within 2 weeks of
laboratory test used to determine eligibility)
4. Hemoglobin ≥ 9.0 g/dL (Patients may be transfused or receive erythropoietic
treatment to meet this criterion)
5. Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 30 ml/min
according to Cockcroft-Gault formula below:
Female CrCl = [(140 - age in years) x weight in kg x 1.04]/serum creatinine
Male CrCl = [(140 - age in years) x weight in kg x 1.23]/ serum creatinine
6. AST and ALT ≤ 3 × ULN (or ≤ 5 × ULN in patients with liver metastases)
7. Serum bilirubin ≤ 1.5 × ULN (except patients with known Gilbert's disease
who have serum bilirubin level ≤ 3 × ULN)
- Recovery of acute AEs of prior anticancer therapies, including surgery and
radiotherapy, to baseline or CTCAE grade ≤ 1 before study entry.
- Patients with toxicities attributed to prior anticancer therapy that either
are not expected to resolve and/or can result in long-lasting sequelae, such
as peripheral neuropathy and ototoxicity of CTCAE grade ≤ 2 after
platinum-based therapy, or are not expected to interfere with treatment on
study, such as alopecia, are eligible.
3. Reproductive Status
- Women of childbearing potential (WOCBP) must have a negative urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of hCG) within 14 days before
- No breastfeeding
- WOCBP must agree to observe abstinence from heterosexual sexual intercourse, or
use contraceptive methods that results in a failure rate of < 1% per year during
the treatment period and for 5 half-lives of Nivolumab (half-life up to 25 days)
plus 30 days (duration of ovulatory cycle) for a total of 23 weeks after the last
IP administration. The investigator or a designated associate is requested to
advise the subject on how to achieve adequate birth control.
- A woman is considered to be of childbearing potential if she has not reached
a postmenopausal state (≥ 12 consecutive months of amenorrhea with no
identified cause other than menopause), and has not undergone surgical
sterilization (bilateral oophorectomy with or without hysterectomy, or
bilateral tubal ligation).
- Examples of contraceptive methods with a failure rate of < 1% per year
include bilateral tubal ligation, male sterilization, properly used hormonal
contraceptives that inhibit ovulation (stable on the same pill for minimum
of 3 months before study entry), hormone-releasing intrauterine devices, and
copper intrauterine devices.
1. Cancer-specific Exclusions
• Non-epithelial ovarian tumors, including malignant mixed Müllerian tumors
(carcinosarcoma), or ovarian tumors with low malignant potential (i.e., borderline
- Active symptomatic central nervous system (CNS) metastases. Patients with
previous CNS metastases are eligible provided that they underwent CNS
irradiation, are asymptomatic, do not require treatment with radiation therapy or
anticonvulsants, and have stable disease at the screening tumor assessment. In
addition, these patients must have been either off corticosteroids, or on a
stable or decreasing dose of ≤ 10 mg daily prednisolone (or equivalent).
- Spinal cord compression not definitively treated with surgery and/or radiation.
Patients with previously diagnosed and treated spinal cord compression are
eligible provided that they have stable disease at the screening tumor
assessment. In addition, these patients must have been either off
corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisolone
- Leptomeningeal carcinomatosis
- Uncontrolled pleural effusion(s), pericardial effusion, or ascites requiring
recurrent drainage procedures
o Patients with functioning pleural and/or peritoneal drainage catheters/devices
in situ at time of study entry may be eligible.
- Previous malignancies (except non-melanoma skin cancers, and the following in
situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma,
or breast) unless a complete remission was achieved at least 2 years before study
entry AND no additional therapy is required, or anticipated to be required,
during the study period.
2. General Medical Exclusions
- Pregnant or lactating women
- Evidence of significant uncontrolled concomitant disease that could affect
compliance with the protocol or interpretation of results, including significant
liver disease such as cirrhosis, uncontrolled major seizure disorder, or superior
vena cava syndrome
- Significant cardiovascular disease, such as New York Heart Association cardiac
disease (Class II or greater), myocardial infarction within 3 months before study
entry, unstable arrhythmias/heart block, or unstable angina
o Patients with a known left ventricular ejection fraction (LVEF) < 40% or
pre-existing poorly controlled hypertension (systolic blood pressure > 160 mmHg
or diastolic pressure > 90 mmHg despite optimal medical management) will be
- Patients with known coronary artery disease, congestive heart failure not
meeting the above criteria, or LVEF < 50% must be on a stable medical
regimen that is optimized in the opinion of the treating physician, in
consultation with a cardiologist if appropriate.
- Patients with stable cardiac arrhythmia requiring stable dose(s) of
anti-arrhythmic therapy may be eligible.
- Severe infections within 4 weeks before study entry including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
- Significant traumatic injury, or major surgical procedure within 4 weeks before
study entry, or anticipation of need for a major surgical procedure during the
course of the study other than for diagnosis
- History of abdominal fistula, history of gastrointestinal perforation, and signs
or symptoms of bowel obstruction
- Symptoms or radiological evidence of active bowel obstruction
- Non-healing wound or ulcer, or bone fracture within 3 months before study entry.
- Systemic anticancer therapy during the study, or before study entry as follows:
(a) Cytotoxic chemotherapy: greater than the duration of the most recent cycle of
the previous regimen, with a minimum of 6 weeks for nitrosoureas and mitomycin-C
and a minimum of 2 weeks for all others
(b) Biologic therapy (e.g., antibodies): up to 2 weeks
(c) Endocrine therapy: Fulvestrant 4 weeks; Tamoxifen 2 weeks; aromatase
inhibitors 2 weeks
(d) Continuous or intermittent small molecule therapeutic: 5 times the half-life
(if known), with a minimum of 2 weeks
(e) Immunostimulatory agent (including but not limited to interferons,
interleukin-2 or other cytokines): 4 weeks or 5 times the half-life (if known),
whichever is shorter
- Patients who have not recovered from therapy-related toxicities, except
alopecia, peripheral neuropathy and ototoxicity (CTCAE grade ≤ 2), to
baseline or CTCAE grade ≤ 1 are also excluded.
- Extended field radiotherapy within 4 weeks, or limited field radiotherapy within
2 weeks before study entry. Patients who have not recovered from therapy-related
toxicities to baseline or CTCAE grade ≤ 1 are also excluded. The site of previous
radiotherapy should have evidence of progressive disease if this is the only site
- Seizure disorder requiring anti-epileptic medication
- Renal failure requiring hemo- or peritoneal dialysis
- Known medical condition that, in the investigator's opinion, would increase the
risk associated with study participation or administration of Investigational
Products (IPs), or interfere with the interpretation of safety results
- Substance abuse, medical, psychological or social conditions that may interfere
with the patient's participation in the study or evaluation of the study results
3. Exclusions Related to Investigational Products
• Other concurrent/ongoing systemic investigational agents
- Previous assignment to treatment during this study. Subjects permanently
withdrawn from study treatment participation will not be allowed to re-enter the
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
murine or humanized antibodies or fusion protein
- Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese
hamster ovary cell products or any component of the IPs
- Prior therapy with anti-CA 125 cancer vaccine, or anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including any other antibody or
immunotherapeutic drug specifically targeting T cell co-stimulation or checkpoint
- Active, known or suspected autoimmune disease including but not limited to
myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus,
rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated
with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
Subjects with an autoimmune paraneoplastic syndrome requiring concurrent
immunosuppressive treatment are excluded.
- Patients with controlled Type 1 diabetes mellitus, autoimmune thyroid
disorders who are currently euthyroid or with residual hypothyroidism only
requiring hormone replacement, skin disorders (e.g., vitiligo, psoriasis or
alopecia) not requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger may be eligible.
- Active use of systemic corticosteroids (≥ 10mg/day prednisolone or equivalent) or
other systemic immunosuppressive agents (including but not limited to
prednisolone, dexamethasone, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks before
study entry, or anticipated requirement for systemic immunosuppressive
medications during the study.
- Patients who have received acute, low dose, corticosteroid medications
(e.g., a one-time dose of dexamethasone for nausea) may be eligible.
Replacement-dose steroids in the setting of adrenocortical insufficiency
(provided this is ≤ 10mg/day prednisolone or equivalent) is permitted.
- The use of topical, inhaled, nasal and ophthalmic corticosteroids and
systemic mineralocorticoids (e.g., fludrocortisone) is allowed.
- History of solid organ allograft or allogeneic hematopoietic stem cell
- Pre-existing Human Immunodeficiency Virus (HIV) infection, Acquired Human
Immunodeficiency Syndrome (AIDS) or chronic hepatitis C infection. Patients with
past hepatitis B virus (HBV) infection or resolved HBV infection (defined as
having a negative hepatitis B surface antigen [HBsAg] test and a positive
antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible.
Patients with hepatitis B (HBV) infection (defined as having a positive HBsAg
test) AND undetectable HBV DNA titer are also eligible.
o HBV DNA must be obtained in these patients before study entry. The use of
antiviral therapy to attain virological response (i.e., undetectable HBV DNA
titer) in HBV-infected patients is permitted.
- Active tuberculosis
- Administration of a live, attenuated vaccine within 4 weeks before study entry,
or anticipation that such a live attenuated vaccine will be required during the
- Interstitial lung disease that is symptomatic or may interfere with the detection
and management of suspected drug-related pulmonary toxicity.
4. Other Exclusions Criteria
- Inability to attend or comply with treatment of follow-up scheduling