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Phase I Dose Escalation of the MET Inhibitor XL184 and the BRAF Inhibitor Vemurafenib

Phase 1
18 Years
Not Enrolling
Recurrent Melanoma, Stage IIIA Melanoma, Stage IIIB Melanoma, Stage IIIC Melanoma, Stage IV Melanoma, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Dose Escalation of the MET Inhibitor XL184 and the BRAF Inhibitor Vemurafenib


I. To determine a tolerable dose of XL184 (cabozantinib-s-malate) in combination with


I. To determine the Objective Response Rate (ORR) and Disease Control Rate (DCR) per
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

II. To determine the progression-free survival (PFS). III. To determine the response rate
according to the molecular phenotype.

OUTLINE: This is a dose-escalation study of cabozantinib-s-malate.

Patients receive cabozantinib-s-malate orally (PO) once daily (QD) and vemurafenib PO twice
daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients entered on the dose-escalation portion of the trial must have a
histologically confirmed solid tumor malignancy that is metastatic or unresectable
and molecularly confirmed to harbor a mutation in BRAF at V600

- Patients entered on the dose expansion portion of the study must have histologically
and molecularly confirmed malignant melanoma that is metastatic or unresectable and
found to be harbor a mutation in BRAF at V600

- Patients in the dose escalation portion of the study may have had none or any number
of prior therapies

- Patients in the dose expansion portion may have any number of prior therapies but
must have been treated with a selective BRAF inhibitor (including but not necessarily
limited to vemurafenib, trametinib, Raf kinase inhibitor LGX818) as their prior line
of therapy, and had documented stable disease for at least 4 months or disease
progression, as interpreted by the accruing investigator; there is no minimum period
of treatment with a BRAF inhibitor required prior to determination of progression;
documentation of progression on a selective BRAF inhibitor may not have taken place
more than 1 month prior to enrollment on this study

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,000/mcL

- Platelets >= 75,000/mcL

- Total bilirubin =< 1.5 × upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 × institutional upper limit of normal

- Creatinine =< 1.5 × ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.5 g/dL

- Lipase < 2.0 × ULN and no radiologic or clinical evidence of pancreatitis

- Urine protein/creatinine ratio (UPCR) =< 1

- Serum phosphorus calcium, magnesium and potassium >= lower limit of normal (LLN)

- Women of childbearing potential must have a negative pregnancy test at screening;
women of childbearing potential include women who have experienced menarche and who
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are not postmenopausal; post-menopause is
defined as amenorrhea >= 12 consecutive months; note: 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, anti-estrogens, ovarian suppression
or any other reversible reason

- The effects of XL184 on the developing human fetus are unknown; for this reason and
because both serine-threonine and tyrosine kinase inhibitor agents are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception prior to study entry and for the duration of study participation;
should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately;
men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of XL184 administration; sexually active subjects (men and
women) must agree to use medically accepted barrier methods of contraception (e.g.,
male or female condom) during the course of the study and for 4 months after the last
dose of study drug(s), even if oral contraceptives are also used; all subjects of
reproductive potential must agree to use both a barrier method and a second method of
birth control during the course of the study and for 4 months after the last dose of
study drug(s)

- Patients to be enrolled in the maximum tolerated dose (MTD) dose expansion portion of
the study must have progressive measurable disease (excluding central nervous system
[CNS]-only based disease) prior to the administration of study treatment

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior treatment with XL184 (cabozantinib) or other mesenchymal-epithelial transition
(MET) directed therapy

- The subject has received radiation therapy:

- To the thoracic cavity, abdomen, or pelvis within 3 months before the first dose
of study treatment, or has ongoing complications, or is without complete
recovery and healing from prior radiation therapy

- To bone metastasis within 14 days before the first dose of study treatment

- The subject has received radionuclide treatment within 6 weeks of the first dose of
study treatment

- The subject has not recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia
and other non-clinically significant adverse events (AEs)

- The subject has unstable brain metastases or epidural disease; subjects with brain
metastases who are treated with whole brain radiation or radiosurgery or subjects
with epidural disease previously treated with radiation or surgery who are
asymptomatic following treatment and do not require steroid treatment for 2 weeks
before starting study treatment are eligible (BRAF inhibitor should be continued
through this period if possible); neurosurgical resection of brain metastases or
brain biopsy is permitted if completed at least 3 months before starting study
treatment; baseline brain imaging with contrast-enhanced computed tomography (CT) or
magnetic resonance imaging (MRI) scans for subjects with known brain metastases is
required to confirm eligibility

- The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the
first dose of study treatment

- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or factor xabans (Xa)
inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81
mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight
heparin (LMWH) are permitted

- The subject requires chronic concomitant treatment of strong cytochrome P450 3A4
(CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentin, phenobarbital, and St. John's Wort); because the lists of
these agents are constantly changing, it is important to regularly consult a
frequently-updated list such as; medical
reference texts such as the Physicians' Desk Reference may also provide this
information; as part of the enrollment/informed consent procedures, the patient will
be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product; concomitant medications that are
primarily metabolized by the cytochrome P450 (CYP450) 1A2, 3A4 and 2C9 as well as
those that strongly inhibit or induce CYP3A4 should be used with caution with
vemurafenib; the categories of drugs listed below if used, should be monitored with
caution for potential alterations in drug exposure and toxicity

- Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, diclofenac,

- Oral hypoglycemic agents (e.g., tolbutamide, glipizide, glyburide, glimepiride)

- Antihypertensives (e.g., losartan, irbesartan, torsemide)

- Anticonvulsants (e.g., phenytoin)

- Anticoagulants (e.g., warfarin)

- Lipid lowering drugs (e.g., statins)

- Caution should be taken when vemurafenib is co-administered with drugs that
cause corrected QT interval (QTc) prolongation or cardiac arrhythmia, and
when patients have a pre-existing cardiac disease or electrocardiogram
(ECG) abnormality that may predispose them to cardiac dysrhythmia

- Investigators should closely monitor patients who are on medications and/or
supplements that may affect QT interval prolongation; such agents include,
but are not limited to terfenadine, quinidine, procainamide, disopyramide,
sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and other
drugs with dysrhythmic potential

- The subject has experienced any of the following:

- Clinically-significant gastrointestinal bleeding within 6 months before the
first dose of study treatment

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the
first dose of study treatment

- Any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment

- The subject has radiographic evidence of cavitating pulmonary lesion(s)

- The subject has tumor in contact with, invading or encasing any major blood vessels

- The subject has evidence of tumor invading the gastrointestinal (GI) tract
(esophagus, stomach, small or large bowel, rectum or anus), or any evidence of
endotracheal or endobronchial tumor within 28 days before the first dose of

- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

- Cardiovascular disorders including:

- Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening

- Concurrent uncontrolled hypertension defined as sustained blood pressure
(BP) > 140 mmHg systolic, or > 90 mmHg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study

- Any history of congenital long QT syndrome or active treatment with drugs
with dysrhythmic potential

- Any of the following within 6 months before the first dose of study

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

- Stroke (including transient ischemic attack [TIA], or other ischemic

- Myocardial infarction

- Thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter (e.g. vena cava filter) are not eligible
for this study)

- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following within 28 days before the first dose of study

- Intra-abdominal tumor/metastases invading GI mucosa

- Active peptic ulcer disease

- Inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or

- Malabsorption syndrome

- Any of the following within 6 months before the first dose of study

- 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 before the first dose of study treatment.

- Other disorders associated with a high risk of fistula formation including
percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before
the first dose of study therapy

- Other clinically significant disorders such as:

- Active infection requiring systemic treatment within 28 days before the
first dose of study treatment

- Serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7
days before the first dose of study treatment

- History of major surgery as follows:

- Major surgery within 3 months of the first dose of cabozantinib if there
were no wound healing complications or within 6 months of the first dose of
cabozantinib if there were wound complications

- Minor surgery within 1 months of the first dose of cabozantinib if there
were no wound healing complications or within 3 months of the first dose of
cabozantinib if there were wound complications

- In addition, complete wound healing from prior surgery must be confirmed at
least 28 days before the first dose of cabozantinib irrespective of the time
from surgery

- The subject is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
450 ms within 28 days before randomization; note: if initial QTcF is found to be >
500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes
should be performed; if the average of these three consecutive results for QTcF is =<
500 ms, the subject meets eligibility in this regard

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee

- For disease specific studies: the subject has had evidence within 2 years of the
start of study treatment of another malignancy which required systemic treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to XL184 or vemurafenib

- Pregnant women are excluded from this study because XL184, as a tyrosine kinase
inhibitor, and vemurafenib, as a serine-threonine inhibitor, have the potential for
teratogenic or abortifacient effects; because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with these
agents, breastfeeding should be discontinued if the mother is treated on this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
XL184; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerable dose of cabozantinib-s-malate in combination with vemurafenib

Outcome Description:

Dose limiting toxicity (DLT) is defined as the occurrence of Grade 4 hematologic toxicity, Grade 3 or 4 non-hematologic toxicity including diarrhea, or nausea and vomiting. Graded according to the National Cancer Institute Common Toxicity Criteria, version 3.0.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Jason Luke

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

December 2013

Completion Date:

Related Keywords:

  • Recurrent Melanoma
  • Stage IIIA Melanoma
  • Stage IIIB Melanoma
  • Stage IIIC Melanoma
  • Stage IV Melanoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Melanoma



Dana-Farber Cancer InstituteBoston, Massachusetts  02115