Overview

Immunotherapy has gained a significant amount of attention recently, but its efficacy as a single agent in gynecological cancers has been disappointing. Pre-clinical evidence supports the combination of using Vascular Endothelial Growth Factors (VEGF) inhibitors with immunotherapy. VEGF inhibitors suppress the activation of tumor-associated macrophages (TAMs) and VEGF has been shown to affect the functional maturation of dendritic cells; therefore, VEGF inhibitors could improve the function of antigen presentation. In this study, Cabozantinib (VEGF inhibitor) and Dostarlimab (immunotherapeutic drug) will be admnistered as a combination to patients with recurrent gynecologic carcinosarcoma.

Eligibility

Inclusion Criteria:

1. Histologically confirmed diagnosis of carcinosarcoma (independent of organ of gynecologic 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 prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
5. ECOG Performance Status of 0-2
6. Age ≥ 18 years
7. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
   1. Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support.
   2. White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L).
   3. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion.
   4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
   5. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documented bone metastases.
   6. Total bilirubin ≤ 1.5 x ULN (for patients with Gilbert's disease ≤ 3 x ULN).
   7. Serum albumin ≥ 2.8 g/dl.
   8. 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. Urine
             protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol).
          8. Capable of understanding and complying with the protocol requirements and must have
             signed the informed consent document.
          9. Women of childbearing potential (WOCBP) ie. sexually active fertile patients and their
             partners must agree to use medically accepted methods of contraception (e.g., barrier
             methods, including male condom, female condom, or diaphragm with spermicidal gel)
             during the course of the study and for 5 months after the last dose of study
             treatment.
         10. Females should not breastfeed while receiving treatment on trial.
         11. Female patients of childbearing potential must not be pregnant at screening. Females
             of childbearing potential are defined as premenopausal females capable of becoming
             pregnant (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 have
             been amenorrheic for 12 or more months are still considered to be of childbearing
             potential 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 investigational
             kinase inhibitor) within 2 weeks or 5 half-lives (whichever is longer) before first
             dose 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 therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before the first dose of study treatment. Patients with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible.
          5. Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
             before first dose of study treatment. Eligible patients must be neurologically
             asymptomatic and without corticosteroid treatment at the time of first dose of study
             treatment.
          6. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
             inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixabin, or platelet
             inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
               1. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
                  guidelines) and low-dose low molecular weight heparins (LMWH).
               2. Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
                  rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
                  are on a stable dose of the anticoagulant for at least 1 week before first dose
                  of study treatment without clinically significant hemorrhagic complications from
                  the anticoagulation regimen or the tumor.
          7. 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.
          8. 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 Association
             Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
             ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
             systolic 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 of
             perforation or fistula formation: i. The patient has evidence of tumor invading the GI
             tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's
             disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis,
             acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or
             gastric outlet obstruction.
             ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
             within 6 months before first dose.
             Note: Complete healing of an intra-abdominal abscess must be confirmed before first
             dose.
             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., pulmonary
             hemorrhage) within 12 weeks before first dose.
             d. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
             manifestation.
             e. Lesions invading or encasing any major blood vessels. f. Other clinically
             significant disorders that would preclude safe study participation.
             i. Serious non-healing wound/ulcer/bone fracture ii. Uncompensated/symptomatic
             hypothyroidism (i.e. inadequately treated hypothyroidism) iii. Moderate to severe
             hepatic impairment (Child-Pugh B or C)
          9. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
             metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
             within 10 days before first dose of study treatment. Subjects must have complete wound
             healing from major surgery or minor surgery before first dose of study treatment.
             Subjects with clinically relevant ongoing complications from prior surgery are not
             eligible.
         10. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
             electrocardiogram (ECG) within 28 days before first dose of study treatment [add
             reference for Fridericia formula].
             Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional
             ECGs at intervals of approximately 3 min must be performed within 30 min after the
             initial ECG, and the average of these three consecutive results for QTcF will be used
             to determine eligibility.
         11. Inability to swallow tablets.
         12. Previously identified allergy or hypersensitivity to components of the study treatment
             formulations.
         13. 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 and
             not treated with systemic therapy.
         14. Patients with concurrent cytotoxic chemotherapy or radiation therapy are excluded.
         15. Patients with a serious chronic or acute illness, such as cardiac disease (NYHA class
             III or IV), hepatic disease, or other illness considered by the Principal Investigator
             as unwarranted high risk for investigational drug treatment.
         16. Patients with a medical or psychological impediment to probable compliance with the
             protocol should be excluded.
         17. Presence of a known active acute or chronic infection including: a urinary tract
             infection, HIV or viral hepatitis; however, it is acceptable to treat an acute
             infection and then re-screen or re-evaluate eligibility.
         18. Administration of a live, attenuated vaccine within 30 days prior to first dose of
             study treatment
         19. Other clinically significant disorders:
               1. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
                  pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on
                  screening chest CT scan.
               2. Active, known, or suspected autoimmune disease (exceptions: type 1 diabetes
                  mellitus, hypothyroidism, skin disorders, conditions not expected to recur in the
                  absence of an external trigger)
               3. Malabsorption syndrome
               4. Requirement for hemodialysis or peritoneal dialysis
               5. History of solid organ or allogenic stem cell transplant