Inclusion Criteria
1. Written informed consent and HIPAA authorization for release of personal health
information.
2. Capable of understanding and complying with the protocol requirements.
3. Age ≥ 18 years at the time of consent.
4. Histological or serological evidence of germ cell tumor, including seminoma,
non-seminoma, and women with ovarian GCTs.
5. Must have progressed after first-line cisplatin based combination chemotherapy AND
demonstrated progression following at least one salvage regimen for advanced germ cell
and now considered incurable with standard therapies, including further chemotherapy
or surgery.
5.1. "Failure" of prior therapy is defined as: 5.1.1. A >25% increase in the products
of the perpendicular diameters of measurable tumor masses during prior therapy which
are not amenable to surgical resection.
5.1.2. The presence of new tumors that are not amenable to surgical resection 5.1.3.
An increase in AFP or beta-hcg (two separate determinations at least one week apart
are required if rising tumor markers are the only evidence of failure).
NOTE: Subjects with clinically growing teratoma (normal declining tumor markers and
radiographic or clinical progression) should be considered for surgery.
6. Subjects with relapsed primary mediastinal non-seminomatous germ cell tumor (PMNSGCT)
are eligible
7. Subjects with late relapse (>2 years from previous chemotherapy) not amenable to
resection are eligible if they have received first line platinum based chemotherapy
and are deemed not amenable to surgical resection (no need for 1 salvage regimen in
late relapse patients to be eligible).
8. Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
10. Adequate laboratory values obtained within 10 days prior to registration for protocol
therapy and as defined below:
10.1. Hemoglobin ≥9g/dL 10.2. WBC ≥2500/μL 10.3. Absolute neutrophil count ≥1500/mm3
10.4. Platelet count ≥100,000/mm3 10.5. Total bilirubin ≤1.5 X ULN except patients
with documented Gilbert's syndrome (≤3 X ULN) 10.6. Alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤3 X ULN; for
patients with hepatic metastases, ALT and AST ≤5 X ULN; ALP ≤5 X ULN with documented
bone metastases.
10.7. Serum albumin ≥ 2.8 g/dl 10.8. (PT)/INR or partial thromboplastin time (PTT)
test < 1.5x the laboratory ULN
- This applies only to patients who do not receive therapeutic anticoagulation;
patients receiving therapeutic anticoagulation (such as low-molecular-weight
heparin or direct factor Xa inhibitors) should be on a stable dose.
10.9. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30 mL/min (≥
0.5 mL/sec) using the Cockcroft-Gault equation:
a. Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) b. Females: [(140
- age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 10.10. Urine
protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol), or 24-h urine protein ≤ 1
g
11. Female patients of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required.
12. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.
13. Male patients should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.
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. Subjects who have not received ≥1 salvage treatment regimens (except late relapse) or
have further potentially curative treatment options.
4. Known brain metastases or cranial epidural disease unless adequately treated and
stable for at least 4 weeks prior to first dose of study treatment. Subjects must have
complete wound healing from major surgery or minor surgery before first dose of study
treatment. Eligible subjects must be neurologically asymptomatic at the time of first
dose of study treatment.
5. Radiation therapy for bone metastasis within 2 weeks, or any other radiation therapy
within 4 weeks prior to first dose of study treatment.
6. Expecting to father children within the projected duration of the trial, starting with
the pre-screening or screening visit through 120 days after the last dose of trial
treatment.
7. Treatment with investigational agent, any type of cytotoxic, biologic or other
systematic anticancer therapy within 28 days prior to registration for protocol
therapy.
8. Subjects with another active malignancy is not allowed except for adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason < Grade 7
prostate cancers, or other cancer for which the subject has not required therapy for
≥1 year.
9. History of psychiatric illness or social situations that would limit compliance with
study requirements.
10. The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
10.1 Cardiovascular disorders:
1. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina
pectoris, serious cardiac arrhythmias.
2. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment.
3. 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 of study treatment.
10.c.1 Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are
allowed if stable, asymptomatic, and treated with a stable dose of permitted
anticoagulation for at least 1 week before first dose of study treatment.
10.2 Gastrointestinal (GI) disorders associated with a high risk of perforation or fistula
formation:
1. The subject 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 Protocol Version
Date: 03/08/2022 Page 17 obstruction of the pancreatic duct or common bile duct, or
gastric outlet obstruction
2. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose of study treatment.
Note: Complete healing of an intra-abdominal abscess must be confirmed before first
dose of study treatment.
11. 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 of study treatment.
12. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
13. Lesions invading or encasing any major blood vessels. 14. Other clinically
significant disorders that would preclude safe study participation per the
investigator's opinion.
a. Serious non-healing wound/ulcer/bone fracture. b. Uncompensated/symptomatic
hypothyroidism. c. Moderate to severe hepatic impairment (Child-Pugh B or C). 15. 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.
16. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
electrocardiogram (ECG) within 14 days before first dose of study treatment.
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.
17. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, 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 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.
18. Pregnant or lactating females. 19. Inability to swallow tablets. 20. Previously
identified allergy or hypersensitivity to components of the study treatment
formulations.
Other Female Genital
Other Male Genital