Primary Objectives:
• To estimate the proportion of patients with recurrent carcinosarcoma, who survive
progression-free for at least 6 months, treated with cabozantinib + nivolumab + ipilimumab in
the second-line and beyond setting (per iRECIST).
Secondary Objectives:
- To evaluate time to progression (Time Frame: From the date the patient received the
first study treatment dose until the date of first documented progression, assessed up
to 2 years). Progression Free Survival (PFS) according to iRECIST.
- To determine the nature and degree of toxicity of cabozantinib + nivolumab + ipilimumab
in this cohort of patients. Toxicity according to CTCAE v4.03
- To estimate the overall survival (OS) of patients with carcinosarcoma treated with
cabozantinib + nivolumab + ipilimumab
Exploratory Objectives:
- To determine expression of biomarkers, which will include PD-L1 and MET expression by
IHC, MSI status by NGS, and other relevant potential biomarkers.
- To determine whether these marker expression levels alone or in combination are
associated with response, PFS, and/or overall survival.
Inclusion Criteria:
1. Histologically confirmed diagnosis of carcinosarcoma (independent of organ of 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 v4 from toxicities related to any prior
treatments, unless AE(s) are clinically non-significant and/or stable on supportive
therapy.
5. Karnofsky performance status greater than or equal to 70% or ECOG PS = 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 subjects 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
9. 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 subjects and their
partners must agree to use medically accepted methods of contraception (eg, 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 subjects of childbearing potential must not be pregnant at screening. Females
of childbearing potential are defined as premenopausal females capable of becoming
pregnant (ie, females who have had any evidence of menses in the past 12 months, with
the exception of those who had 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 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. Subjects 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 subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment.
6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin
and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel). Allowed
anticoagulants are the following:
1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is
permitted.
2. Low-dose low molecular weight heparins (LMWH) are permitted.
3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without
known brain metastases who are on a stable dose of LMWH for at least 6 weeks
before first dose of study treatment, and who have had no clinically significant
hemorrhagic complications from the anticoagulation regimen or the tumor.
7. The subject 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 subject 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) > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
or other ischemic event, or thromboembolic event (eg, 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 subject has evidence of tumor invading the GI
tract, active peptic ulcer disease, inflammatory bowel disease (eg, 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 (eg, 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. iii. Moderate to severe hepatic impairment (Child-Pugh B or C).
9. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (eg, simple excision,
tooth extraction) at least 10 days before first dose. 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.
