A Phase 2, Open Label Study of PEmigatinib and REtifanlimab in Advanced Dedifferentiated LIposarcoma (PERELI)

Inclusion Criteria:

Participants will be eligible for the study if all of the following criteria are met:

1. Be 18 years of age or above, on day of signing informed consent.

2. Must be willing and able to provide written informed consent. Written informedconsent must be signed and dated before the start of specific protocol procedures.

3. Must be willing and able to conform to and comply with all protocol requirements,including, all scheduled visits, protocol procedures, and the ability to swalloworal tablets.

4. Histologically confirmed DDLPS*. Written pathology report indicating the diagnosisof DDLPS with positive MDM2 immunohistochemistry or MDM2 amplification asdemonstrated by fluorescence in situ hybridization, polymerase chain reaction (PCR)or sequencing-based methods must be available.

5. Have the presence of at least 1 measurable lesion by CT per RECIST v1.1 that isconsidered non amenable to surgery or other curative treatments or procedures. Tumorlesions located in a previously irradiated area or in an area subjected to otherloco-regional therapy are considered measurable if progression has been demonstratedin the lesion.

6. Disease relapse or radiological progression, as determined by the Investigator,within the last 6 months after at least one line of systemic treatment. a. Patients considered to be medically unfit for chemotherapy, as assessed by thesarcoma centre in charge of the patient's treatment, can be considered for the trialafter discussion with the trial steering committee.

7. Be willing to provide tissue by core or excisional biopsy of a tumor lesion at thetime points specified in the Trial Flow Chart. Archival tumor tissue can be usedinstead of pre-treatment biopsy. Biopsy will only be performed if the risk ofcomplication is considered acceptable for the patient.

8. Have a performance status of 0-2 on the ECOG Performance Scale.

9. Patient must have adequate organ function as indicated by laboratory values obtainedwithin 14 days of receiving the first dose of study drug (see study protocol)

10. Female patients of childbearing potential should have a negative urine or serumpregnancy test within 72 hours prior to receiving the first dose of studymedication. If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.

11. Female patients of childbearing potential must be willing to use a highly effectivemethod of contraception, for the course of the study through 180 days after the lastdose of study medication. Please refer to Section 5.3 for list of highly effectivecontraception.

12. Male patients must agree to use an highly effective method of contraception startingwith the first dose of study therapy through 180 days after the last dose of studytherapy.

Exclusion Criteria:

1. Patient has received anticancer therapy within 28 days of the first administrationof study treatment, with the exception of localized radiotherapy given to a lesionnot considered for RECIST measurements.

2. Toxicity of prior therapy that has not recovered to ≤ Grade 1 with the exception of

3. Alopecia

4. Peripheral neuropathy

5. Anemia not requiring transfusional support

6. Other toxicities may be considered acceptable (not an exclusion criteria) upondiscussion with the Sponsor.

7. Is currently participating and receiving study therapy or has participated in astudy of an investigational agent and received study therapy or used aninvestigational device within 4 weeks of the first dose of treatment.

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

9. Hypersensitivity to pemigatinib or retifanlimab or any of its excipients. 6.Patients with a prior or concurrent malignant disease whose natural history ortreatment have the potential to interfere with the safety or efficacy assessment ofthis clinical trial are not eligible. Exceptions include, but are not limited to,patients with a history of breast cancer, requiring continued hormonal treatment (e.g. anti-estrogen or an aromatase inhibitor), patients with a history of prostatecancer, requiring continued support with luteinizing hormone- releasing hormone (LHRH) agonists, with or without androgens, basal cell carcinoma of the skin orsquamous cell carcinoma of the skin that has undergone potentially curative therapyor in situ cervical cancer.

10. Has known active central nervous system (CNS) metastases and/or sarcomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for at leastfour weeks prior to the first dose of trial treatment and any neurologic symptomshave returned to baseline), have no evidence of new or enlarging brain metastases,and are not using steroids for at least 7 days prior to trial treatment. Thisexception does not include sarcomatous meningitis which is excluded regardless ofclinical stability.

11. Has an active autoimmune disease requiring systemic immunosuppression withcorticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugswithin 14 days before the first dose of study treatment.

12. Receiving chronic systemic corticosteroids (> 10 mg/day of prednisone orequivalent):

Notes:

1. Physiologic corticosteroid replacement therapy at doses > 10 mg daily of prednisoneor equivalent for adrenal or pituitary insufficiency and in the absence of activeautoimmune disease is permitted.

2. Participants with a condition that requires intermittent use bronchodilators,inhaled steroids, or local steroid injections may be admitted (eg, asthma or chronicobstructive pulmonary disease exacerbation).

3. Participants using topical, ocular, intra-articular, or intranasal steroids (withminimal systemic absorption) may be admitted.

4. Brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or studytreatment-related standard premedication is permitted.

5. Has a history of organ transplant, including allogeneic stem celltransplantation.

6. Has an active infection requiring systemic antibiotics or antifungal orantiviral treatment within 7 days before first dose of study treatment.

7. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in thebest interest of the subject to participate, in the opinion of the treatingInvestigator.

8. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.

9. Is pregnant or breastfeeding or expecting to conceive or father children withinthe projected duration of the trial, starting with the pre-screening orscreening visit through 180 days after the last dose of trial treatment.

10. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

11. Has received prior therapy with a selective FGFR inhibitor. 17. Has a knownhistory of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

12. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCVRNA [qualitative] is detected).

13. Has received a live vaccine within 30 days of planned start of study therapy.

a. Note: COVID-19 vaccines are allowed. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

20. Has a history of calcium or phosphate homeostasis disorder or systemic mineralimbalance with ectopic calcification of soft tissues (exception: commonly observedcalcifications in soft tissues such as the skin, kidney tendon, or vessel due toinjury, disease, or aging in the absence of systemic mineral imbalance).

21. Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug.

22. Has current evidence of clinically significant corneal (including, but not limitedto, bullous/band keratopathy, corneal abrasion, inflammation/ulceration,keratoconjunctivitis) or retinal disorder (including, but not limited to,macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmedby ophthalmologic examination 23. Has a history of hypovitaminosis D currentlyrequiring supraphysiologic doses (eg, 50,000 UI/weekly) to replenish the deficiency.Vitamin D supplements are allowed.