Cabozantinib and Dostarlimab in Recurrent Gynecologic Carcinosarcoma

Inclusion Criteria:

1. Histologically confirmed diagnosis of carcinosarcoma (independent of organ ofgynecologic origin)

2. Received at least one prior chemotherapy regimen for their cancer

3. Must have measurable or evaluable lesion defined by iRECIST

4. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any priortreatments, unless AE(s) are clinically nonsignificant and/or stable on supportivetherapy

5. ECOG Performance Status of 0-2

6. Age ≥ 18 years

7. Adequate organ and marrow function, based upon meeting all of the followinglaboratory criteria within 14 days before first dose of study treatment:

8. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocytecolony-stimulating factor support.

9. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).

10. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion.

11. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).

12. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN withdocumented bone metastases.

13. Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's disease ≤ 3 x ULN).

14. Serum albumin ≥ 2.8 g/dl.

15. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation:

[(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 i. Urineprotein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).

8. Capable of understanding and complying with the protocol requirements and must havesigned the informed consent document.

9. Women of childbearing potential (WOCBP) ie. sexually active fertile patients andtheir partners must agree to use medically accepted methods of contraception (e.g.,barrier methods, including male condom, female condom, or diaphragm with spermicidalgel) during the course of the study and for 5 months after the last dose of studytreatment.

10. Females should not breastfeed while receiving treatment on trial.

11. Female patients of childbearing potential must not be pregnant at screening. Femalesof childbearing potential are defined as premenopausal females capable of becomingpregnant (i.e., females who have had any evidence of menses in the past 12 months,with the exception of those who had a prior hysterectomy). However, women who havebeen amenorrheic for 12 or more months are still considered to be of childbearingpotential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens,low body weight, ovarian suppression, or other reasons.

Exclusion Criteria:

1. Prior treatment with cabozantinib.

2. Receipt of any type of small molecule kinase inhibitor (including investigationalkinase inhibitor) within 2 weeks or 5 half-lives (whichever is longer) before firstdose of study treatment.

3. Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.

4. Radiation therapy for bone metastasis within 2 weeks, any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before the first dose of study treatment. Patients withclinically relevant ongoing complications from prior radiation therapy are noteligible.

5. Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksbefore first dose of study treatment. Eligible patients must be neurologicallyasymptomatic and without corticosteroid treatment at the time of first dose of studytreatment.

6. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombininhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixabin, or plateletinhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

7. Prophylactic use of low-dose aspirin for cardio-protection (per localapplicable guidelines) and low-dose low molecular weight heparins (LMWH).

8. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitorsrivaroxaban, edoxaban, or apixaban in subjects without known brain metastaseswho are on a stable dose of the anticoagulant for at least 1 week before firstdose of study treatment without clinically significant hemorrhagiccomplications from the anticoagulation regimen or the tumor.

9. The patient has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 X the laboratory ULN within 7 days before the first dose of study treatment.

10. The patient has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions: a. Cardiovascular disorders: i. Congestive heart failure New York Heart AssociationClass 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hgsystolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,pulmonary embolism) within 6 months before first dose. b. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation: i. The patient has evidence of tumor invading theGI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn'sdisease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, orgastric outlet obstruction. ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscesswithin 6 months before first dose. Note: Complete healing of an intra-abdominal abscess must be confirmed before firstdose. c. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history of significant bleeding (e.g., pulmonaryhemorrhage) within 12 weeks before first dose. d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial diseasemanifestation. e. Lesions invading or encasing any major blood vessels. f. Other clinicallysignificant disorders that would preclude safe study participation. i. Serious non-healing wound/ulcer/bone fracture ii. Uncompensated/symptomatichypothyroidism (i.e. inadequately treated hypothyroidism) iii. Moderate to severehepatic impairment (Child-Pugh B or C)

11. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy ofbrain metastasis) within 2 weeks before first dose of study treatment. Minorsurgeries within 10 days before first dose of study treatment. Subjects must havecomplete wound healing from major surgery or minor surgery before first dose ofstudy treatment. Subjects with clinically relevant ongoing complications from priorsurgery are not eligible.

12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 28 days before first dose of study treatment [addreference for Fridericia formula]. Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additionalECGs at intervals of approximately 3 min must be performed within 30 min after theinitial ECG, and the average of these three consecutive results for QTcF will beused to determine eligibility.

13. Inability to swallow tablets.

14. Previously identified allergy or hypersensitivity to components of the studytreatment formulations.

15. Diagnosis of another malignancy within 2 years before first dose of study treatment,except for superficial skin cancers, or localized, low-grade tumors deemed cured andnot treated with systemic therapy.

16. Patients with concurrent cytotoxic chemotherapy or radiation therapy are excluded.

17. Patients with a serious chronic or acute illness, such as cardiac disease (NYHAclass III or IV), hepatic disease, or other illness considered by the PrincipalInvestigator as unwarranted high risk for investigational drug treatment.

18. Patients with a medical or psychological impediment to probable compliance with theprotocol should be excluded.

19. Presence of a known active acute or chronic infection including: a urinary tractinfection, HIV or viral hepatitis; however, it is acceptable to treat an acuteinfection and then re-screen or re-evaluate eligibility.

20. Administration of a live, attenuated vaccine within 30 days prior to first dose ofstudy treatment

21. Other clinically significant disorders:

22. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-inducedpneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis onscreening chest CT scan.

23. Active, known, or suspected autoimmune disease (exceptions: type 1 diabetesmellitus, hypothyroidism, skin disorders, conditions not expected to recur inthe absence of an external trigger)

24. Malabsorption syndrome

25. Requirement for hemodialysis or peritoneal dialysis

26. History of solid organ or allogenic stem cell transplant