Trial Title:
Cabozantinib and Dostarlimab in Recurrent Gynecologic Carcinosarcoma
NCT ID:
NCT05559879
Condition:
Gynecologic Cancer
Carcinoma
Uterine Cancer
Endometrial Cancer
Conditions: Official terms:
Endometrial Neoplasms
Uterine Neoplasms
Carcinosarcoma
Mixed Tumor, Mullerian
Dostarlimab
Conditions: Keywords:
Gynecologic Cancer
Carcinoma
Uterine Cancer
Endometrial Cancer
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
This is a phase Ib/II, single-arm, combination therapy of the safety and efficacy of
therapy involving a tyrosine kinase inhibitor along with immunotherapy in the setting of
recurrent carcinosarcoma.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Cabo + Dostarlimab
Description:
Combination of standard dose of cabozantinib and 500 mg dostarlimab for first 4 cycles
followed by standard dose of cabozantinib and 1000 mg of dostarlimab until 2 years of
treatment
Arm group label:
Cabo + Dostarlimab
Summary:
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.
Criteria for eligibility:
Criteria:
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
Gender:
Female
Gender based:
Yes
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
O'Neal Comprehensive Cancer Center at UAB
Address:
City:
Birmingham
Zip:
35294
Country:
United States
Status:
Recruiting
Contact:
Last name:
Pamela Hardwick, CRNP
Phone:
205-975-5387
Email:
pamdixon@uab.edu
Investigator:
Last name:
Rebecca Arend, MD, MSPH
Email:
Principal Investigator
Start date:
August 20, 2023
Completion date:
December 2025
Lead sponsor:
Agency:
University of Alabama at Birmingham
Agency class:
Other
Source:
University of Alabama at Birmingham
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05559879
