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Recurrent MelanomaPhase 1NCT01835184

Cabozantinib-S-Malate and Vemurafenib in Treating Patients With Solid Tumors or Melanoma That is Metastatic or That Cannot Be Removed By Surgery

A Phase 1 study testing cabozantinib-s-malate, vemurafenib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIIA Melanoma, run by National Cancer Institute (NCI) at 3 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This phase I trial studies the side effects and best dose of cabozantinib-s-malate when given together with vemurafenib in treating patients with solid tumors or melanoma that is metastatic or that cannot be removed by surgery. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
cabozantinib-s-malate, vemurafenib and laboratory biomarker analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
5 participants
Where
3 sitesUnited States
Study dates
May 2013to Sep 2014
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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 v-raf murine sarcoma viral oncogene homolog (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 [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%)
  • Leukocytes >= 3,000/mcL
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  • Absolute neutrophil count >= 1,000/mcL
  • Platelets >= 100,000/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 >= 60 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 >= lower limit of normal (LLN)
  • Serum magnesium >= LLN
  • Serum potassium >= 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
  • 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; 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

Who cannot join

  • 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, rash, and other non-clinically significant adverse events (AEs)
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  • 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 use of anti-convulsant medications are allowed only if these are non-enzyme inducing anti-epileptic agents (NEIAED) including but not limited to valproate, benzodiazepines, gabapentin, lamotrigine, levetiracetam, tiagabine and zonisamide
  • 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 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort); 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) ) family 1, subfamily A, polypeptide 2 (1A2), 3A4 and family 2, subfamily C, polypeptide 9 (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, meloxicam)
  • 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 cabozantinib
  • 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 treatment
  • 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 treatment:
  • Unstable angina pectoris
  • Clinically-significant cardiac arrhythmias
  • Stroke (including transient ischemic attack [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)
  • 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 treatment
  • 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 appendicitis
  • Malabsorption syndrome
  • Any of the following within 6 months before the first dose of study treatment:
  • 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) > 500 ms within 28 days before randomization
  • 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; breastfeeding should be discontinued if the mother is treated on this study
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Emory University/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02115

  • Virginia Commonwealth University

    Richmond, Virginia, 23298

Other trials in United States

About this study

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

This phase I trial studies the side effects and best dose of cabozantinib-s-malate when given together with vemurafenib in treating patients with solid tumors or melanoma that is metastatic or that cannot be removed by surgery. Cabozantinib-s-malate and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

  1. 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.

Being tested
cabozantinib-s-malate, vemurafenib, laboratory biomarker analysis, pharmacological study
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • cabozantinib-s-malateDrug

    Also called BMS-907351, Cometriq, XL184

    Given PO

  • vemurafenibDrug

    Also called BRAF(V600E) kinase inhibitor RO5185426, PLX4032, RG7204, RO5185426

    Given PO

  • laboratory biomarker analysisOther

    Correlative studies

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

Study groups in NCT01835184
Study groupRoleWhat they receive
Treatment (cabozantinib-s-malate, vemurafenib)ExperimentalPatients receive cabozantinib-s-malate PO QD and vemurafenib PO BID on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Drug: cabozantinib-s-malate; Drug: vemurafenib; Other: laboratory biomarker analysis; Other: pharmacological study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerable dose of cabozantinib-s-malate in combination with vemurafenib based on the incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute CTCAE version 4.0.

    DLT is defined as the occurrence of grade 4 hematologic toxicity, grade 3 or 4 non-hematologic toxicity including diarrhea, or nausea and vomiting.

    Measured: 28 days

Secondary outcomes (3)

  1. ORR (complete response [CR]+partial response [PR]) assessed using RECIST criteria

    Calculated and presented with 90% exact binomial confidence intervals.

    Measured: Up to 4 weeks after last dose of therapy

  2. DCR per RECIST version 1.1

    Rate will be calculated and presented with 90% exact binomial confidence intervals.

    Measured: Up to 4 weeks after last dose of therapy

  3. PFS per RECIST version 1.1

    Summarized using the method of Kaplan-Meier. Median PFS will be presented with 90% confidence intervals derived using log (-log [survival]) methodology.

    Measured: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 4 weeks after last dose of therapy

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2013 (estimated)
  2. Study startMay 2013
  3. Primary completionSep 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
5 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01835184
Sponsor's protocol ID
NCI-2013-00808
Other IDs
NCI-2013-00808, 13-017, 9287, U01CA062490, P30CA006516, UM1CA186709
Status last verified
Sep 2014
First submitted
16 Apr 2013
Last updated
25 Sep 2014
Results posted
No
Data monitoring committee
Yes

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing cabozantinib-s-malate, vemurafenib and laboratory biomarker analysis in people with Recurrent Melanoma and Stage IIIA Melanoma, run by National Cancer Institute (NCI) at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 64 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 25 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerable dose of cabozantinib-s-malate in combination with vemurafenib based on the incidence of dose-limiting toxicity (DLT) graded according to the National Cancer Institute CTCAE version 4.0. (time frame: 28 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01835184.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2014.

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