INCLUSION CRITERIA:
A patient must meet all of the following criteria to be eligible for enrollment (defined as
receiving the first trial treatment) in the trial:
1. Histologically or cytologically confirmed unresectable in-transit (stage IIIc) or
metastatic (stage IV) melanoma.
2. Must have at least 1 lesion that qualifies as a measurable (target) lesion per RECIST
v1.1. 3. Subjects must be willing to have blood draws for future biomarker testing as outlined
in Section 11.9 of the protocol.
4. The subject has an ECOG performance score of 12 weeks. 5. Aged 18 years and older.
6. The subject should not have received any treatment for advanced melanoma, EXCEPT, BRAF
and/or MEK inhibitor. (2 week washout)
7. The subjects who have received adjuvant therapy including anti- PD-1 can be included
in the study, if the last dose of the adjuvant treatment was >/= 6 months prior to
developing metastatic relapse.
8. The subject is capable of understanding and complying with the protocol requirements
and has signed the informed consent document.
9. Female patients of childbearing potential, must have a negative urine or serum
pregnancy test within 72 hours prior to taking the first dose of study medication, if.
• If the urine test is positive or cannot be confirmed as negative then a serum test
is required which must be negative for the patient to enroll.
• Women of childbearing potential (WOCBP) must be willing to use 2 medically
acceptable methods of contraceptive from Day 1 through 120 days after the last dose of
trial treatment. The 2 medically acceptable birth control methods can be either 2
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. The
following are considered adequate barrier methods of contraception: diaphragm, condom
(by the partner), copper intrauterine device, sponge, or spermicide as per local
regulations or guidelines. Appropriate hormonal contraceptives will include any
registered and marketed contraceptive agent that contains an estrogen and/or a
progestational agent (including oral, subcutaneous, intrauterine, or intramuscular
agents).
- - Male patients of reproductive potential must agree to use an adequate method of
contraception from Day 1 through 120 days after the last dose of trial treatment.
Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient.
10. Able to swallow pills.
11. The subject must have recovered to baseline or < Grade 1 CTCAE v 4 from toxicities
related to any prior treatments, unless AE(s) are clinically nonsignificant and /or
stable on supportive therapy.
EXCLUSION CRITERIA:
A patient meeting any of the following criteria is not eligible to participate in this
study:
1. Subject had prior treatment with any anti-PD-1, anti-PD-L1, or anti- PD-L2 agent for
the treatment of advanced melanoma (although prior use in adjuvant setting is allowed
if the last dose > 6 months prior developing metastatic disease).
2. Subjects with diagnosis of ocular and mucosal melanoma. 3. Subject had prior cabozantinib for any indication.
4. Subject who received any small molecule tyrosine kinase inhibitor within 2 weeks
before first dose of study treatment.
5. Subject who has had chemotherapy, radioactive, or biological cancer therapy within
four weeks prior to the first dose of study drug, or who has not recovered to CTCAE
Grade 1 or better from the AEs due to cancer therapeutics administered more than four
weeks earlier.
6. 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.
7. Patient is currently participating or has participated in a study of an
investigational agent or using an investigational device within 30 days of the first
dose of study drug. (A patient in the Survival Follow up phase of an investigational
agent where no further treatment is expected is eligible).Patient is expected to
require any other form of systemic or localized antineoplastic therapy while on study.
8. Patient is on any systemic corticosteroid therapy (more than 10 mg daily of prednisone
or equivalent) within one week before the planned date for first dose of randomized
treatment or on any other form of immunosuppressive medication.
9. Patient has a history of a malignancy (other than the disease under treatment in the
study) within 2 years prior to first study drug administration. This should exclude
adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin,
carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals
can be considered after discussion with Sponsor.
10. Patient has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are stable (without evidence of progression by MRI for at least four weeks prior
to the first dose of study drug), have no evidence of new or enlarging brain
metastases, neurologically asymptomatic and are off systemic steroids for at least two
weeks.
11. Patient previously had a severe hypersensitivity reaction to treatment with another
monoclonal antibody or small molecule tyrosine kinase inhibitor.
12. Patient has an active autoimmune disease or a documented history of autoimmune disease
or syndrome that requires systemic steroids or immunosuppressive agents. Patients with
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.
Patients that require intermittent use of bronchodilators or local steroid injections
would not be excluded from the study. Patients with hypothyroidism stable on hormone
replacement will not be excluded from the study.
13. Patient has an active infection requiring systemic therapy.
14. Patient has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies).
15. Patient has a known history of or is positive for Hepatitis B (HBsAg reactive) or
Hepatitis C (HCV RNA [qualitative] is detected). Patients will be tested for hepatitis
B or C infections during screening if they are considered by the investigator to be at
higher risk for these infections and have not been previously tested.
16. Patient has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.
17. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
18. Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.
19. Patient has received a live vaccine within 30 days prior to first dose.
20. Patient requires 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. 21. Patient has experienced any of the following within 3 months before the first dose of
study treatment:
a. clinically-significant hematemesis, hematuria or gastrointestinal bleeding b.
Clinically-significant hemoptysis of > or = 0.5 teaspoon (2.5ml) of red blood c. any other
signs indicative of pulmonary hemorrhage. 22. Present use or anticipated need for strong CYP3A4 inducers or inhibitors listed below.
Patients may not have received a strong CYP3A4 inducer within 12 days prior to registration
nor a strong CYP3A4 inhibitor within 7 days prior to registration. Because the lists of
these agents are constantly changing, it is important to regularly consult a comprehensive
list such as the one located at http://medicine.iupui.edu/clinpharm/ddis/.
- - Inducers - dexamethasone; phenytoin; carbamazepine; rifampin; rifabutin; rifapentin;
phenobarbital; St. John's Wort.
- - Inhibitors - Boceprevir; Conivaptan; Indinavir; Itraconazole; Nelfinavir;
Ketoconazole; Lopinavir/ritonavir; Mibefradil; Saquinavir; Nefazodone; Telaprevir;
Posaconazole; Ritonavir; Voriconazole; Clarithromycin; Telithromycin.
23. The subject has uncontrolled, significant intercurrent or recent illness
including, but not limited to, the following conditions:
a) Cardiovascular disorders including: i) Congestive heart failure (CHF): New York
Heart Association (NYHA) Class 3 (moderate) or Class 4 (severe) at the time of
screening.
ii) Concurrent uncontrolled hypertension defined as sustained BP > or = 150 mm Hg systolic
(grade 2), or > or = 90 mm Hg diastolic (grade 2) despite optimal antihypertensive
treatment. (Note: If there is any BP measurement that is performed within the screening
period that is < 150 mm Hg systolic and < 90 mm Hg diastolic, then BP does not meet
definition of sustained.) iii) Any congenital history of long QT syndrome. iv) Any of the
following within 6 months before the first dose of study treatment: v) unstable angina
pectoris.
- - clinically-significant cardiac arrhythmias.
- - stroke (including TIA, or other ischemic event)
- myocardial infarction.
- - thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a
venous filter (e.g. vena cava filter) are not eligible for this study vi) Cavitating
pulmonary lesions(s) or known endotracheal or endobronchial disease manifestation.
vii) Lesions invading or encasing any major blood vessels.
b) Gastrointestinal disorders particularly those associated with a high risk of perforation
or fistula formation including: i) Any of the following within 28 days before the first
dose of study treatment:
• intra-abdominal tumor/metastases invading GI mucosa (malignant abdominal ascites does not
constitute mucosal invasion)
- - active peptic ulcer disease,
- inflammatory bowel disease (including ulcerative colitis and Crohn's disease),
diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis.
- - malabsorption syndrome] ii) Any of the following within 6 months before the first dose
of study treatment:
- history of abdominal fistula.
- - gastrointestinal perforation.
- - bowel obstruction or gastric outlet obstruction.
- - intra-abdominal abscess.
Note: Complete resolution of an intra-abdominal abscess must
be confirmed prior to initiating treatment with cabozantinib even if the abscess
occurred more than 6 months ago.
iii) GI surgery (particularly when associated with delayed or incomplete healing) within 28
days. Note: Complete healing following abdominal surgery must be confirmed prior to
initiating treatment with cabozantinib even if surgery occurred more than 28 days ago.
c) Other disorders associated with a high risk of fistula formation including PEG tube
placement within 3 months before the first dose of study therapy or concurrent evidence of
intraluminal tumor involving the trachea and esophagus.
d) Moderate or severe hepatic impairment.
e) Other clinically significant disorders such as: i) active infection requiring systemic
treatment within 28 days before the first dose of study treatment ii) serious non-healing
wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii)
history of organ transplant iv) concurrent uncompensated hypothyroidism or thyroid
dysfunction within 7 days before the first dose of study treatment v) Major surgery (eg,
thoracotomy, removal or biopsy of brain metastasis) within 1 month before Week 1 Day 1,
minor surgery (eg, simple excision, tooth extraction) at least 10 days before Week 1 Day 1.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible. Subjects must have complete wound healing from major surgery or minor surgery
before first dose of study treatment.
24. The subject has organ and marrow function and laboratory values as follows:
Hematological:
- - Absolute neutrophil count (ANC) < 1,500/mm3/mcL.
- - White blood cell count < 2,500/mm3.
- - Platelets < 100,000/mm3/mcL.
- - Hemoglobin < 9 g/dL- transfusion of packed red blood cells allowed up to 7 days prior
to D1.
Renal:
- - Serum creatinine > 1.5 X upper limit of normal (ULN), GFR < 30 ml/min.
- - Serum electrolytes: Serum phosphorus, magnesium, and potassium < LLN after adequate
supplementation if necessary.
Hepatic:
- - Serum total bilirubin > 1.5 X ULN.
Patients with a total bilirubin > 1.5 X ULN will
not be excluded if Direct bilirubin
- AST (SGOT) and ALT (SGPT) > 2.5 X ULN.Coagulation • International Normalized Ratio (INR) or Prothrombin Time (PT) Activated
Partial Thromboplastin Time (aPTT) > 1.3 X ULN (Patients on oral anticoagulation are
excluded.)
Urine. • Urine protein/creatinine ratio (UPCR) > 1 (113.2 mg/mmol) creatinine or 24-hr urine
protein of >/= 1 g. 25. Cardiovascular: The subject has a corrected QT interval calculated by the Fridericia
formula (QTcF) >/= 500ms within 14 days before Cycle 1 Day 1. Ejection fraction on Echo or
MUGA /= 3. Note: If a single ECG show a QTcF with an absolute value
>/= 500 ms, two additional ECGs at intervals of at least 2 minutes must be performed within
30 minutes after the initial ECG, and the average of these three consecutive results for
QTcF will be used to determine eligibility.
