| Eligibility |
Inclusion Criteria:
Inclusion criteria will be assessed within 28 days of starting study treatment:
1. Ability to provide signed informed consent.
2. Age = 18 years at time of study entry.
3. Willingness and ability to comply with the protocol for the duration of the study
including undergoing treatment, biopsy, and scheduled visits and examinations
including follow up.
4. Histology showing recurrent clear cell ovarian, peritoneal, or fallopian tube cancer.
5. Platinum resistant or refractory disease as defined by progression of disease on a
platinum- containing regimen or recurrence of disease within 180 days of previous
platinum treatment.
Have measurable disease based on modified RECIST 1.1. For the purposes of this study
measurable disease is defined at least one "target lesion" that can be accurately measured
in at least one dimension (longest dimension to be recorded). Each target lesion must be
>20 mm when measured by conventional techniques, including palpation, plain x-ray, computed
tomography (CT), and magnetic resonance imaging (MRI), or >10 mm when measured by spiral
CT. The target lesion must be distinct from other tumor areas selected for pre-treatment
biopsies. Pre- treatment imaging must be performed within 4 weeks of starting therapy. 7.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 8. Adequate normal
organ and marrow function as defined below.
1. Hemoglobin =9.0 g/dL.
2. Absolute neutrophil count (ANC) > 1500/mm3.
3. Platelet count =100 x 109/L (>75,000/mm3).
4. Serum bilirubin =1.5 x ULN. This will not apply to patients with confirmed Gilbert's
syndrome (persistent or recurrent hyperbilirubinemia that is predominantly
unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed
only in consultation with their physician.
5. AST (SGOT)/ALT (SGPT) =2.5 x ULN unless liver metastases are present, in which case it
must be
- 5x ULN.
6. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by
the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection
for determination of creatinine clearance: Creatinine CL (mL/min)
- Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) 9. Evidence of
post-menopausal status or negative serum pregnancy test for female pre-menopausal
patients.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months
without an alternative medical cause. The following age-specific requirements apply:
1. Women <50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post- menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).
2. Women =50 years of age would be considered post-menopausal if they have been
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 10.
Has primary central nervous system (CNS) malignancy or known unrelated/active CNS
metastases and/or carcinomatous meningitis.
1. Subjects with previously treated, asymptomatic brain metastases may participate
provided they meet the following criteria: clinically stable for at least 4 weeks and
have no evidence of new or enlarging brain metastases and are off steroids 14 days
prior to dosing with study medication. Stable brain metastases by this definition
should be established prior to the first dose of study drug.
2. Subjects with asymptomatic brain metastases (ie, no neurological symptoms, no
requirements for corticosteroids, and no lesion >1.5 cm) may participate but will
require regular imaging of the brain as a site of disease.
3. Subjects with CNS symptoms should undergo a computed tomography (CT) scan or magnetic
resonance imaging (MRI) of the brain to exclude new or progressive brain metastases.
Spinal cord metastasis is acceptable. However, subjects with spinal cord compression
must be excluded.
Exclusion Criteria:
Exclusion criteria will be assessed within 28 days of starting study treatment and is
listed below.
1. Participation in another clinical study with an investigational product during the
last 28 days.
2. Prior treatment with CD137 agonists, anti-TIGIT antibody, anti-CTLA-4 or anti-PDL1/PD1
antibodies.
3. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study.
4. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies) =28 days or 5 half-lives, whichever is shorter, prior to the first dose of
study drug. If sufficient wash-out time has not occurred due to the schedule or PK
properties of an agent, a longer wash-out period will be required, as agreed by study
sponsors and the investigator.
5. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria.
1. Patients with Grade =2 neuropathy will be evaluated on a case-by-case basis after
consultation with the primary investigator.
2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with investigational therapy may be included only after consultation
with the primary investigator.
6. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
7. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
first dose of IP. Note:
Local surgery of isolated lesions for palliative intent is acceptable.
8. History of allogenic organ transplantation.
9. Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
criteria.
a. Patients with vitiligo or alopecia. b. Patients with hypothyroidism (e.g.,
following Hashimoto syndrome) stable on hormone replacement.
c. Any chronic skin condition that does not require systemic therapy. d. Patients
without active disease in the last 5 years may be included but only after consultation
with the primary investigator. e. Patients with celiac disease controlled by diet
alone.
10. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent.
11. Any medical, social, or psychological condition that would interfere with evaluation
of study treatment or interpretation of patient safety or study results.
12. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
13. History of another primary malignancy except for the following histories.
1. Malignancy treated with curative intent and with no known active disease =5 years
before the first dose of IP and of low potential risk for recurrence.
2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
3. Adequately treated carcinoma in situ without evidence of disease.
14. History of leptomeningeal carcinomatosis.
15. Brain metastases or spinal cord compression. Patients with suspected brain metastases
at screening should have a MRI (preferred) or CT each preferably with intravenous (IV)
contrast of the brain prior to study entry.
16. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) =470 ms.
17. Current or prior use of immunosuppressive medication within 14 days before the first
dose of trial therapies. Listed below are the exceptions to this criterion.
1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent.
3. Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
90 days after the last dose of IP.
19. Female patients who are pregnant or breastfeeding or of reproductive potential who are
not willing to employ effective birth control from screening to 180 days after the
last dose of Nivolumab/Etigilimab combination therapy.
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
21. Unresolved partial or complete small or large bowel obstruction.
22. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements.
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