EPOCH: Eribulin and Pembrolizumab in Ovarian/Uterine Carcinosarcoma

Inclusion Criteria:

1. Provision of written informed consent prior to any study specific procedures and theability to comply with the protocol for the duration of the study, includingundergoing treatment and scheduled visits and examinations.

2. Patients > 18 years old who have a histologically confirmed tubo-ovariancarcinosarcoma or uterine carcinosarcoma with evidence of recurrence or progression.The component of sarcoma in the diagnostic pathology sample must be equal to or > 5%of tumour.

3. Must have Positron Emission Tomography (PET), Computerized Tomography CT, orMagnetic Resonance Imaging (MRI) -proven relapsed disease after completion of atleast one line and not more than two lines of chemotherapy.

4. Must have at least one evaluable measurable lesion (other than the lesion that willbe used for biopsy) using standard techniques according to the Response EvaluationCriteria in Solid Tumours (RECIST v1.1) guidelines (Appendix 1).

5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Appendix 5). Evaluation of ECOG is to be performed within 28 days prior to thefirst dose of the study intervention.

6. Have adequate organ function as defined below (refer also Appendix 6).

• Absolute neutrophil count (ANC) ≥1.5 x 109/L

• Platelets ≥100 x 109/L

• Haemoglobin (Hb) ≥90 g/L or ≥5.6 mmol/L (criteria must be met withouterythropoietin dependency and without packed red blood cell (pRBC) transfusionwithin last 2 weeks).

• Creatinine ≤ 1.5 x Upper Limit Normal (ULN); OR Creatinine Clearance (CrCl) ≥ 30 mL/min (calculated per institutional standard) for participants withcreatinine levels >1.5 ULN (glomerular filtration rate, GFR, can also be usedin place of creatinine or CrCl). (Patients with moderate renal impairment (CrCl 30-49ml/min) will receive a 25% reduced dose of eribulin).

• Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with totalbilirubin levels >1.5 × ULN

• Alkaline phosphatase (ALP), Aspartate aminotransferase (AST) and alanineaminotransferase (ALT) ≤2.5 × ULN (≤5 × ULN for participants with livermetastases)

• International normalized ratio (INR) OR prothrombin time (PT), Activatedpartial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receivinganticoagulant therapy as long as PT or aPTT is within therapeutic range ofintended use of anticoagulants Biological specimens must be collected within 28days prior to the first dose of the study intervention (within 7 days, whereindicated in the SoA).

7. Available formalin fixed, paraffin embedded (FFPE) tumour sample from the primarycancer and/or metastatic tumour from the up-front or secondary debulking surgerywith adequate neoplastic cell content (>30%).

8. Must have disease amenable to biopsy and must be willing to undergo a paired biopsyfor additional correlative analyses (the first biopsy to be performed within 28 daysprior to the start of the study intervention and the second biopsy in the five-daywindow prior to Cycle 2 (post Cycle 1)). For patients that experience progression oftheir disease whilst on study, separate patient consent will be sought foradditional biopsies of their tumour for research.

9. Willing to have blood samples collected for translational research

10. Must not be pregnant, not breastfeeding, and at least one of the followingconditions applies:

11. Not a person of childbearing potential (POCBP). OR

12. A POCBP who agrees to follow the contraceptive guidance during the treatmentperiod and for at least 4 months (120 days) after the last dose of the studytreatment.

Exclusion Criteria:

1. Prior line of treatment involving immunotherapy with an anti-PD-1, anti-PD-L1, oranti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitoryT-cell receptor. This criteria is applicable for both intervention arms as patientsmay cross-over from the non-immunotherapy arm during their study participation.

2. Prior treatment with eribulin for any malignancy.

3. Absence of a second disease site suitable for biopsy

4. Has received prior systemic anti-cancer therapy including investigational agentswithin 4 weeks prior to the first dose of the study intervention.

5. Has active autoimmune disease (such as Systemic Lupus Erythematosus) that hasrequired systemic treatment in the past 2 years (i.e., with use of disease modifyingagents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g.,thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal orpituitary insufficiency, etc.) is not considered a form of systemic treatment and isallowed.

6. A POCBP who has a positive urine pregnancy test within 7 days prior to the firstdose of the study intervention (see Appendix 7). If the urine pregnancy test ispositive or cannot be confirmed as negative, a serum pregnancy test will berequired.

7. Has received prior radiotherapy within 2 weeks of the start of the studyintervention. Patients must have recovered from all radiation-related toxicities,not require corticosteroids, and not have had radiation pneumonitis. A 1-weekwashout is permitted for palliative radiation (≤2 weeks of radiotherapy) tonon-central nervous system disease.

8. Known central nervous system malignancy or metastasis, including leptomeningealmetastasis or carcinomatous meningitis, unless adequately treated and patients areneurologically stable for at least one month prior to enrolment. Patients must beeither off corticosteroids or on stable or decreasing dose of < /=10 mg dailyprednisone (or equivalent) within 28 days prior to the first dose of the studyintervention. In the case of short-term use of systemic corticosteroids (less than 24 hours within 28 days) of greater than 10 mg daily of prednisone or an equivalentcorticosteroid, the required washout period prior to starting the first dose of thestudy intervention is 7 days. Anticonvulsants are allowed to be continued except forthose which interfere with the study interventions or are associated with livertoxicity. However, patients receiving anticonvulsants must be discussed with StudyChair or Acting Chair of Trial Management Committee (TMC) prior to their enrolmentto the study.

9. Symptomatic or clinically significant inflammatory bowel disease (Crohn's disease orulcerative colitis).

10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of the studyintervention.

11. Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of the study intervention. Live vaccine or live-attenuated vaccine cannotbe administered during treatment with the study intervention and for 30 days postdiscontinuation of the study intervention. Administration of killed vaccines isallowed.

12. Has an active infection requiring systemic therapy.

13. Has had an allogenic tissue/solid organ transplant.

14. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of itsexcipients.

15. Has a history of (non-infectious) pneumonitis/interstitial lung disease thatrequired steroids or has current pneumonitis/interstitial lung disease.

16. Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: notesting for HIV is required unless mandated by local health authority.

17. 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 > 25 internationalunits/mL is detected) infection. Note: no testing for Hepatitis B and Hepatitis C isrequired unless mandated by local health authority.

18. Has a known additional active malignancy that is likely to interfere with assessmentof response or tolerance to the study intervention.

19. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the study, interfere with thepatients' participation for the full duration of the study, or is not in the bestinterest of the patient to participate, in the opinion of the treating Investigator.

20. Inability to attend or comply with treatment or follow-up scheduling.