A Phase II Trial of Belzutifan in Patients with Recurrent or Persistent Clear Cell Carcinoma of the Ovary or Clear Cell Carcinoma of other Gynecologic Origin

The purpose of this research study is to see if the study drug Belzutifan is effective
and safe for participants with clear cell gynecologic malignancy, including but not
limited to, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar
cancer, or endometriosis-related cancer.

The name of the study drug involved in this study is:

- Belzutifan (a type of Hypoxia-Inducible Factor-2 alpha (HIF-2a) inhibitor)

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed recurrent or
persistent clear cell carcinoma of the ovary (CCOC) or clear cell carcinoma of other
gynecologic origin (e.g., endometrial, cervical, vaginal, vulvar,
endometriosis-related). If mixed histology, then ≥50% clear cell component.

- Participants must have measurable disease, defined as at least one lesion that can
be accurately measured per Response Evaluation Criteria in Solid Tumors (RECIST)
v1.1 criteria. Lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions.

- Participants must have received at least one prior platinum-based chemotherapeutic
regimen for primary management of disease.

- Prior bevacizumab is allowed.

- Prior use of immunotherapy is allowed.

- Unlimited prior lines for the treatment of recurrent or persistent disease are
allowed.

- Age ≥18 years. Because no dosing or adverse event data are currently available on
the use of Belzutifan in participants <18 years of age, children are excluded from
this study.

- ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1 (Karnofsky
performance scale ≥70%, see Appendix A).

- Participants must meet the following organ and marrow function as defined below:

- Absolute neutrophil count ≥ 1,500/mcL

- Hemoglobin ≥ 10.0 g/dL (without use of erythropoietin; without packed red blood
cell (RBC) transfusion within preceding 2 weeks)

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) OR direct
bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 ULN

- AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (ULN) (in the
absence of liver metastases) or ≤ 5 x institutional ULN (in the presence of
liver metastases)

- Creatinine ≤ 1.5 x institutional upper limit of normal (ULN) OR estimated
creatinine clearance (CrCl) by the Cockcroft-Gault formula

≥51mL/min if creatinine > 1.5 x institutional ULN or institutional standard
method

- INR OR PT and PTT ≤1.5 × institutional ULN unless participant is receiving
anticoagulant therapy and PT/INR or PTT are within therapeutic range of that
anticoagulation

- Participants with known brain metastases are eligible if they have completed primary
CNS-directed therapy (such as surgical resection or radiotherapy) and if they have
remained clinically stable, asymptomatic, radiologically stable without evidence of
progression for at least 4 weeks by repeat imaging and have been off of steroids for
at least 4 weeks prior to starting study treatment.

- Participants with a prior or concurrent malignancy whose natural history or
treatment does not have the potential to interfere with the safety or efficacy
assessment of the Belzutifan, as determined after discussion with the
Sponsor-Investigator, are eligible for this trial.

- Archival tumor tissue must be available as 17 (15 unstained + 2 H&E) freshly
serially cut slides from formalin-fixed, paraffin-embedded (FFPE) tissue blocks. The
most recent available tissue is preferred to archived tissue. If fewer than 17
slides are available, the participant may still be eligible pending discussion with
the Sponsor-Investigator.

- The effects of Belzutifan on the developing human fetus are unknown. For this
reason, women of child-bearing potential* must have a negative serum or urine
pregnancy test at the Screening and Cycle 1 Day 1 visits. A negative serum or urine
pregnancy test must be obtained within 24 hours before the first dose of study
intervention in order to start receiving the study drug. Women of child-bearing
potential and men must agree to use adequate contraception (see Appendix D) prior to
study entry, for the duration of study participation, and for at least 30 days after
last receipt of study therapy. Additionally, should a woman become pregnant or
suspect she is pregnant while she is participating in this study, she should inform
her treating physician immediately.

--Female participants who do not meet the definition of women of child-bearing
potential must meet either criteria:

- Post-menopausal, defined as amenorrheic for at least 12 consecutive months
within the appropriate age group and without an alternative medical cause OR

- Surgically sterilized (i.e. bilateral oophorectomy, bilateral tubal ligation or
salpingectomy, or total hysterectomy)

- Ability to swallow orally administered medications.

- Ability to understand and the willingness to sign a written informed consent
document.

Exclusion Criteria:

- Prior use of Belzutifan or another HIF-2a inhibitor.

- Participant has any of the following:

- Pulse oximeter reading <92% at rest, or

- Requires intermittent supplemental oxygen, or

- Requires chronic supplemental oxygen

- Anti-cancer treatment (chemotherapy, radiotherapy, or other investigational therapy)
within 4 weeks prior to entering the study (6 weeks prior to study entry for
nitrosoureas or mitomycin C).

- Prior small molecule kinase inhibitor (including investigational kinase inhibitor) ≤
2 weeks prior to entering the study.

- Prior radiation therapy within 2 weeks of start of study drugs. Participants must
have recovered from all radiation-related toxicities and must not require steroids.
Participants must not have had radiation pneumonitis. Palliative radiation (≤2 weeks
of radiotherapy) to non-CNS (central nervous system) disease is permitted, provided
there is at least a 1-week washout prior to start of study drugs.

- Use of herbal supplements, including but not limited to: cannabis, St. John's wort,
gingko biloba, ginseng, saw palmetto, and ephedra. Herbal supplements must be
stopped at least 1 week prior to beginning study treatment.

- Participants who are known to require concomitant therapy with moderate or strong
CYP3A4 inducers. Due to potential drug interactions, concomitant use of these
medications is not permitted for the duration of treatment on trial. Participants
are eligible for study entry if an appropriate substitution is made prior the first
dose of study medication.

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks before the first dose of
study intervention. Note: Participants who have entered the follow-up phase of an
investigational study may participate as long as it has been 4 weeks after the last
dose of the previous investigational agent.

- Participants who have AEs due to previous anticancer therapies must have recovered
to

- Grade 1 or baseline with the exception of alopecia. Participants with
endocrine-related AEs who are adequately treated with hormone replacement or
participants who have

- Grade 2 neuropathy are eligible.

- Has received a live or live-attenuated vaccine within 30 days prior to the first
dose of study drug. Administration of killed vaccines are allowed.

Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country
is allowed in the study as long as they are mRNA vaccines, replication-incompetent
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any
other concomitant therapy.

- Major surgical procedures within 4 weeks of beginning study treatment are not
allowed. Minor surgical procedures (with the exception of port placement) within 1
week of beginning study treatment are not allowed.

- Any gastrointestinal disorder that would interfere with the passage or absorption of
oral medications. Participants must be able to swallow oral medications.
Participants with an enteric tube (e.g., gastrostomy or jejunostomy tube), receiving
total parenteral nutrition (TPN), or dependent on IV fluid support are ineligible.

- Participants with significant cardiovascular impairment, including uncontrolled
hypertension, congestive heart failure of New York Heart Association Grade II or
above, unstable angina, myocardial infarction within the past 6 months, or serious
cardiac arrhythmia within the past 6 months.

- Has moderate to severe hepatic impairment (Child-Pugh B or C).

- Has received colony-stimulating factors (e.g., G-CSF, GM-CSF, or recombinant EPO)

≤28 days prior to the first dose of study intervention.

- Has a diagnosis of immunodeficiency.

- Is known to be positive for Human Immunodeficiency Virus (HIV). Subjects with HIV,
including those on antiretroviral therapy, are excluded due to risk of
immunodeficiency and risk of overlapping toxicity.

- Is known to be positive for Hepatitis B virus (HBV) or Hepatitis C virus (HCV).
Participants are eligible if they have a history of HCV infection that has been
treated and cured, with an undetectable viral load.

- Participants with uncontrolled intercurrent illness, including but not limited to
active infection and serious non-healing wounds or ulcers.

- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.

- Participants with a history of allergic reactions or hypersensitivity attributed to
compounds of similar chemical or biological composition to belzutifan.

- Pregnant women are excluded from this study. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with belzutifan, breastfeeding participants are excluded from this study.

- History or current evidence of any condition, therapy, laboratory abnormality, or
other circumstance that might confound the results of the study, interfere with the
participant's participation for the full duration of the study, such that it is not
in the best interest of the participant to participate, in the opinion of the
treating investigator.