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

Inclusion Criteria:

• Participants must have advanced or recurrent serous endometrial cancer. Patientswith mixed histologies/tumors are eligible if the serous component is the dominanthistological subtype. 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; ormicrosatelitte stable by polymerase chain reaction (PCR), next generationsequencing, or other CLIA-approved method;

AND

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

• Participants must have measurable disease as defined by RECIST 1.1. Lesionssituated in a previously irradiated area are considered measurable ifprogression has been demonstrated in such lesions.

• Prior therapy: Patients must have had one, but no more than three lines ofchemotherapy for endometrial carcinoma.

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

• Prior IO therapy targeted to the PD-1/PD-L1 pathway is allowed in up to 19 patientsof the total cohort.

• Patients must NOT have received prior therapy with any folate receptor orthologagents.

• Age 18 or greater years. Because insufficient dosing or adverse event data arecurrently available on the use of mirvetuximab soravtansine and pembrolizumabin participants <18 years of age, children are excluded. Endometrial cancer israre 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 levelsabove 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) completedat least 4 weeks, or focal radiation completed at least 2 weeks, prior to startingstudy treatment

• The effects of agents used in this study on the developing human fetus areunknown. For this reason, women of child-bearing potential must agree to useadequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry, during study treatment, and for at leasttwelve weeks after the last dose of study treatment. Should a woman becomepregnant 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 testwithin 3 days prior to the first dose of study treatment.

• Ability to understand and the willingness to sign a written informed consentdocument

Exclusion Criteria:

• Participants who have had chemotherapy within 5 half-lives or 4 weeks (whichever isshorter) or radiotherapy within 2 weeks prior to entering the study. Patientscompleting wide-field radiotherapy (e.g. >30% of marrow-bearing bones) must not havehad treatment within 4 weeks prior to entering study. Participants must haverecovered from all AEs due to previous therapy to Grade 1 ≤ or baseline, exceptalopecia. Participants with endocrine-related AEs who are adequately treated withhormone replacement are eligible.

• Participants who are receiving any other investigational agents.

• Participants with prior exposure to IO agents targeting the PD-1/PD-L1 pathway whodiscontinued therapy due to treatment-related toxicity deemed to be specificallyrelated to IO therapy.

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

• Known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, 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 daysprior to first dose of study treatment.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to monoclonal antibodies (including antibody drug-conjugates orcheckpoint inhibitors).

• Uncontrolled intercurrent illness including, but not limited to, any of thefollowing within 6 months of first study treatment: symptomatic congestive heartfailure, unstable angina pectoris, uncontrolled hypertension (≥ Grade 3),hypertensive crisis or hypertensive encephalopathy, uncontrolled cardiacarrhythmias, thrombotic or ischemic stroke, clinically-significant vascular disease (e.g. aortic aneurysm, or dissecting aneurysm), severe aortic stenosis, clinicallysignificant peripheral vascular disease, or ≥ Grade 3 cardiac toxicity followingprior chemotherapy, cardiac arrhythmia, or psychiatric illness/social situationsthat 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 ofcorneal transplantation, active herpetic keratitis, and also active ocularconditions requiring on-going treatment/monitoring such as wet age-related maculardegeneration requiring intravitreal injections, active diabetic retinopathy withmacular 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 HepatitisB (defined as Hepatitis B surface antigen [HBsAg] reactive) or known activeHepatitis C virus (defined as HCV RNA is detected) or any other known concurrentinfectious disease requiring IV antibiotics with within 2 weeks of study enrollmentare 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, BacillusCalmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines forinjection are generally killed virus vaccines and are allowed; however, intranasalinfluenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

• Current or prior use of immunosuppressive medication within 7 days prior toenrollment 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 ofprednisone or equivalent;

• Steroids as premedication for hypersensitivity reactions (eg, CT scanpremedication).

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

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

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

• Presence of other malignancies unless they are considered cured by patient'soncologist