A Phase 2 Study of Mirvetuximab Soravtansine (IMGN853) and Pembrolizumab in Endometrial Cancer (EC)

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational drug to learn whether the drug works in treating a
specific disease. "Investigational" means that the drug is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved mirvetuximab soravtansine as
a treatment for any disease.

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this
specific disease but it has been approved for other uses.

In this research study, the investigators are studying the combination of mirvetuximab
soravtansine and pembrolizumab. Pembrolizumab is an immunotherapy that activates a patient's
own immune system to recognize and kill tumor cells. Pembrolizumab by itself may not be
enough to kill cancer cells in all people with cancer. In this study, all patients will
receive mirvetuximab soravtansine and pembrolizumab. Mirvetuximab soravtansine is an
antibody-drug conjugate. That is a type of agent that attaches a chemotherapy drug to a
molecule that binds a protein on the outside of cancer cells. The protein targeted by
mirvetuximab soravtansine is called folate receptor-alpha (FRα). FRα is expressed on the
surface of certain cancers, including endometrial cancer cells. Mirvetuximab soravtansine is
expected to kill cancer cells by delivering chemotherapy to cells that have high levels of
FRα. To participate in this study, a sample of your tumor was previously tested, and was
found to have high levels of FRα. Mirvetuximab soravtansine also may also active immune cells
and improve the response to immunotherapies like pembrolizumab.

In this study, the investigators expect to learn whether the combination of pembrolizumab and
mirvetuximab soravtansine can shrink endometrial cancers or prevent their growth for at least
6 months. The investigators will also learn more about the side effects patients experience
who receive this treatment. The investigators also plan to learn more about which patients
are likely to benefit from this treatment

Inclusion Criteria:

- Participants must have advanced or recurrent serous or endometrioid endometrial
cancer. In addition, the tumors must be:

- microsatellite stable (MSS) as documented by either intact immunohistochemical (IHC)
nuclear expression of the mismatch repair genes MSH2, MSH6, MLH1 and PMS2; or
microsatelitte stable by polymerase chain reaction (PCR), next generation sequencing,
or other CLIA-approved method;

AND

- FRα positive by central immunohistochemistry (IHC, Section 9.1). If archival tissue
does not meet FRα criteria, a fresh biopsy tumor sample may be submitted and used to
meet this criterium. If a fresh tumor biopsy cannot be done safely the patient will
not be allowed to enroll on this study.

- Participants must have measurable disease as defined by RECIST 1.1. Lesions
situated in a previously irradiated area are considered measurable if progression
has been demonstrated in such lesions.

- Prior therapy: Patients must have had one, but no more than two lines of
chemotherapeutic regimen for management of endometrial carcinoma in the recurrent
setting. Patients who have only received chemotherapy in the adjuvant setting
will not be eligible for the study.

- Prior hormonal therapy is allowed (no washout period is required after hormonal
therapy) and does not count as a prior line of therapy. Hormonal therapy in
combination with CDK4/6 inhibitors or mTOR or other PI3K-pathway inhibitors is allowed
and does not count as a line of prior therapy.

- Patients must NOT have received any class of drugs targeted to the PD-1/PD-L1 pathway
or folate receptor orthologs.

- Age 18 or greater years. Because insufficient dosing or adverse event data are
currently available on the use of mirvetuximab soravtansine and pembrolizumab in
participants <18 years of age, children are excluded. Endometrial cancer is rare
in the pediatric population.

- ECOG performance status 0 or 1

- Participants must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/mcL

- absolute neutrophil count ≥1,500/mcL

- platelets ≥100,000/mcL

- hemoglobin ≥ 9.0 g/dL

- total bilirubin ≤ 1.5 x institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine ≤ institutional upper limit of normal OR

- creatinine clearance ≥40 mL/min/1.73 m2 for participants with creatinine levels above
institutional normal.

-Time from prior therapy:

- Systemic anti-neoplastic therapy: 5 half-lives or 4 weeks, whichever is shorter.
Hormonal therapy is not considered anti-neoplastic therapy.

- Radiotherapy: wide-field radiotherapy (e.g. > 30% of marrow-bearing bones) completed
at least 4 weeks, or focal radiation completed at least 2 weeks, prior to starting
study treatment

- The effects of agents used in this study on the developing human fetus are
unknown. For this reason, women of child-bearing potential must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry, during study treatment, and for at least twelve weeks after
the last dose of study treatment. Should a woman become pregnant or suspect she
is pregnant while she is participating in this study, she should inform her
treating physician immediately.

- Women of child-bearing potential must have a negative serum pregnancy test within
3 days prior to the first dose of study treatment.

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

Exclusion Criteria:

- Participants who have had chemotherapy within 4 weeks or radiotherapy within 2 weeks
prior to entering the study. Participants must have recovered from all AEs due to
previous therapy to Grade 1 ≤ or baseline, except alopecia.

- Participants who are receiving any other investigational agents.

- Prior exposure to agents targeting the PD-1/PD-L1 pathway.

- Required use of folate-containing supplements (e.g. folate deficiency).

- Known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to monoclonal antibodies (including antibody drug-conjugates or checkpoint
inhibitors).

- Uncontrolled intercurrent illness including, but not limited to, any of the following
within 6 months of first study treatment: symptomatic congestive heart failure,
unstable angina pectoris, uncontrolled hypertension (≥ Grade 3), hypertensive crisis
or hypertensive encephalopathy, uncontrolled cardiac arrhythmias, thrombotic or
ischemic stroke, clinically-significant vascular disease (e.g. aortic aneurysm, or
dissecting aneurysm), severe aortic stenosis, clinically significant peripheral
vascular disease, or ≥ Grade 3 cardiac toxicity following prior chemotherapy, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Active or chronic corneal disorder, including but not limited to the following:
Sjogren's syndrome, Fuchs corneal dystrophy (requiring treatment), history of corneal
transplantation, active herpetic keratitis, and also active ocular conditions
requiring on-going treatment/monitoring such as wet age-related macular degeneration
requiring intravitreal injections, active diabetic retinopathy with macular edema,
presence of papilledema, and acquired monocular vision.

- Serious clinically-relevant active infection, including known HIV infection,
varicella-zoster virus, cytomegalovirus infection, has a known history of Hepatitis B
(defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C
virus (defined as HCV RNA is detected) or any other known concurrent infectious
disease requiring IV antibiotics with within 2 weeks of study enrollment are
ineligible because of the potential for immune side effects.

- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

- Current or prior use of immunosuppressive medication within 7 days prior to enrollment
with the following exceptions to this exclusion criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection);

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent;

- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent. Patients with diabetes type I, vitiligo, psoriasis, hypo-or hyperthyroid
disease not requiring immunosuppressive treatment are eligible.

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis.

- Pregnant or nursing women are excluded from this study because effects of agents used
in this study on infants or the developing human fetus are unknown

- Presence of other malignancies unless they are considered cured by patient's
oncologist