Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Melanoma of the Eye

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01835145
First received: April 16, 2013
Last updated: August 19, 2014
Last verified: April 2014

April 16, 2013
August 19, 2014
July 2013
November 2015   (final data collection date for primary outcome measure)
PFS4 [ Time Frame: At 4 months ] [ Designated as safety issue: No ]
A patient will be declared a PFS4 success if they are on study and progression free for at least 4 months. This study will be declared promising if a one-sided chi-squared test for a difference in PFS4 rates yields a p-value of less than 0.10.
Progression-free survival (PFS) [ Time Frame: 4 months ] [ Designated as safety issue: No ]
This study will be declared promising if a one-sided chi-squared test for a difference in PFS4 rates yields a p-value of less than 0.10.
Complete list of historical versions of study NCT01835145 on ClinicalTrials.gov Archive Site
  • PFS [ Time Frame: Number of days from registration until disease progression (or death), assessed up to 2 years ] [ Designated as safety issue: No ]
    The distribution of PFS time will be estimated using the method of Kaplan Meier.
  • Overall survival (OS) [ Time Frame: Number of days from registration until death, assessed up to 2 years ] [ Designated as safety issue: No ]
    The distribution of OS time will be estimated using the method of Kaplan Meier.
  • Confirmed response rate as determined by the RECIST criteria (version 1.1) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    The confirmed response rates will be estimated by dividing the number of confirmed responders by the number of evaluable patients. 95% confidence intervals will be calculated.
  • Maximum grade for each type of adverse event, graded according to the NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    Frequency tables will be created to look for patterns.
  • PFS [ Time Frame: Number of days from registration until disease progression (or death), assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated using the method of Kaplan Meier.
  • Overall survival (OS) [ Time Frame: Number of days from registration until death, assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated using the method of Kaplan Meier.
  • Confirmed response rates by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    95% confidence intervals will be calculated.
Not Provided
Not Provided
 
Cabozantinib-S-Malate Compared With Temozolomide or Dacarbazine in Treating Patients With Melanoma of the Eye
Randomized Phase II Study Comparing the MET Inhibitor Cabozantinib to Temozolomide/Dacarbazine in Ocular Melanoma

This randomized phase II trial studies how well cabozantinib-s-malate works compared with temozolomide or dacarbazine in treating patients with melanoma of the eye. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and dacarbazine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

PRIMARY OBJECTIVES:

I. Compare the progression-free survival rate at 4 months (PFS4) of patients with ocular melanoma treated with cabozantinib (cabozantinib-s-malate) or temozolomide (or dacarbazine).

SECONDARY OBJECTIVES:

I. Estimate the distribution of progression-free survival (PFS) times. II. Estimate the distribution of overall survival (OS) times. III. Estimate the confirmed response rate as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.

IV. Assess the safety of these agents by examining the toxicity profile. V. Correlate the response of mesenchymal-epithelial transition factor (MET) molecular status.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

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

ARM II: Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine intravenously (IV) over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. At the time of progression patients may cross-over to Arm I.

After completion of study treatment, patients are followed up every 12 weeks for 2 years.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Ciliary Body and Choroid Melanoma, Medium/Large Size
  • Ciliary Body and Choroid Melanoma, Small Size
  • Iris Melanoma
  • Metastatic Intraocular Melanoma
  • Recurrent Intraocular Melanoma
  • Stage IIIA Intraocular Melanoma
  • Stage IIIB Intraocular Melanoma
  • Stage IIIC Intraocular Melanoma
  • Stage IV Intraocular Melanoma
  • Drug: cabozantinib-s-malate
    Given PO
    Other Names:
    • BMS-907351
    • Cometriq
    • XL184
  • Drug: temozolomide
    Given PO
    Other Names:
    • SCH 52365
    • Temodal
    • Temodar
    • TMZ
  • Drug: dacarbazine
    Given IV
    Other Names:
    • DIC
    • DTIC
    • DTIC-Dome
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (cabozantinib-s-malate)
    Patients receive cabozantinib-s-malate PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: cabozantinib-s-malate
    • Other: laboratory biomarker analysis
  • Experimental: Arm II (temozolomide or dacarbazine)
    Patients receive temozolomide PO daily on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If temozolomide is not available, patients receive dacarbazine IV over 15-60 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. At the time of progression patients may cross-over to Arm I.
    Interventions:
    • Drug: temozolomide
    • Drug: dacarbazine
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
69
Not Provided
November 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically confirmed uveal melanoma that is metastatic or unresectable; if histologic or cytologic confirmation of the primary is not available, confirmation of the primary diagnosis of uveal melanoma by the treating investigator can be clinically obtained, as per standard practice for uveal melanoma; pathologic confirmation of diagnosis will be performed at the participating site
  • Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan or magnetic resonance imaging (MRI)
  • Prior therapies allowed, except for those treatments directed toward, or with activity against, c-Met or vascular endothelial growth factor/receptor (VEGF/R), and the chemotherapy agents temozolomide and dacarbazine; prior treatment must have been no earlier than 3 weeks prior to starting treatment with cabozantinib with exceptions noted and the following: at least 4 weeks since prior hepatic infusion or at least 2 weeks since radiation therapy
  • No cytotoxic chemotherapy including investigational cytotoxic chemotherapy or biologic agents (e.g., cytokines or antibodies) within the last 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment; at least 6 weeks must have elapsed if the last regimen included an anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody; patients must have experienced disease progression on their prior therapy in the opinion of the treating investigator
  • No prior radiation therapy within the last 4 weeks, except as below

    • To the thoracic cavity, abdomen, or pelvis within 12 weeks before the first dose of study treatment, or has ongoing complications, or is without complete recovery to < grade 1 toxicity
    • To bone or brain metastasis within 14 days before the first dose of study treatment
    • To any other site(s) within 28 days before the first dose of study treatment
    • Prior radiation treatment may have included no more than 3000 centigray (cGy) to fields including substantial bone marrow
  • No prior radionuclide treatment within 6 weeks of the first dose of study treatment
  • No prior treatment with a small molecule kinase inhibitor or a hormonal therapy within 14 days or 5 half-lives (whichever is longer)
  • No concomitant anti-cancer therapy within 28 days of the first dose of study treatment, including other investigational agents; palliative radiation therapy will not be allowed while on protocol
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • A corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 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 patient meets eligibility in this regard
  • Common Terminology Criteria for Adverse Events (CTCAE) recovered to baseline or CTCAE =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
  • No active brain metastases or epidural disease; patients with brain metastases previously treated with whole brain radiation or radiosurgery or patients with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible; neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 12 weeks before starting study treatment; baseline brain imaging with contrast-enhanced CT or MRI scans for patients with known brain metastases is required to confirm eligibility
  • No clinically significant gastrointestinal bleeding within 24 weeks before the first dose of study treatment
  • No hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 12 weeks before the first dose of study treatment
  • No signs indicative of pulmonary hemorrhage within 12 weeks before the first dose of study treatment
  • No prior radiographic evidence of cavitating pulmonary lesion(s)
  • No tumor in contact with, invading or encasing any major blood vessels
  • No 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 treatment
  • The patient may not have 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
      • Any of the following within 24 weeks 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: patients 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 24 weeks before the first dose of study treatment:

        • Abdominal fistula
        • Gastrointestinal perforation
        • 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 that 24 weeks before the first dose of study treatment
        • Bowel obstruction or gastric outlet obstruction
    • Other clinically significant disorders such as:

      • 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 in past 6 weeks of the first dose of cabozantinib if there were no wound healing complications or within 24 weeks of the first dose of cabozantinib if there were wound complications
        • Minor surgery within 4 weeks of the first dose of cabozantinib if there were no wound healing complications or within 12 weeks 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
      • Active infection requiring systemic treatment within 28 days before the first dose of study treatment as per the protocol template
  • No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or factor 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; please note that drugs that strongly induce or inhibit cytochrome P450 3A4 (CYP3A4) or are associated with a risk of Torsades are not allowed; chronic concomitant treatment of CYP3A4 inducers is not allowed (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; the following drugs are strong inhibitors of CYP3A4 and are not allowed during the treatment with cabozantinib:

    • Boceprevir
    • Indinavir
    • Nelfinavir
    • Lopinavir/ritonavir
    • Saquinavir
    • Telaprevir
    • Ritonavir
    • Clarithromycin
    • Conivaptan
    • Itraconazole
    • Ketoconazole
    • Mibefradil
    • Nefazodone
    • Posaconazole
    • Voriconazole
    • Telithromycin
    • Drugs with possible or conditional risk of torsades should be used with caution knowing that cabozantinib could prolong the QT interval
  • Patients who are pregnant or nursing are not eligible; women of child bearing potential must have a negative serum or urine pregnancy test within 16 days prior to registration; women of child-bearing potential include:

    • Any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12 consecutive months)
    • Women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level > 35m IU/mL
    • Women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy)
  • No history of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib, temozolomide and dacarbazine
  • Absolute neutrophil count >= 1,500/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]) =< 5.0 × institutional upper limit of normal (for patients with metastases); AST (SGOT)/ALT (SGPT) =< 2.5 × institutional upper limit of normal (for patients without metastases)
  • Serum creatinine =< 1.5 × ULN, OR calculated creatinine clearance >= 30 mL/minute (modified Cockroft and Gault formula)
  • Hemoglobin >= 9 g/dL
  • Serum albumin >= 2.8 g/dL
  • Urine protein/creatinine ratio (UPCR) =< 1; if urine/protein creatinine (UPC) >= 1, then a 24-hour urine protein must be assessed; eligible patients must have a 24-hour urine protein value < 1 g
  • Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL
  • No clinical or radiographic evidence of pancreatitis
Both
18 Years and older
No
Contact: NCI CTRP 866-319-4357 ncictro@mail.nih.gov
United States
 
NCT01835145
NCI-2013-00821, NCI-2013-00821, CALGB-A091201, A091201, A091201, U10CA031946, U10CA180821
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Jason Luke Cancer and Leukemia Group B
National Cancer Institute (NCI)
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP