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

NCT01835184 | Terminated Phase 1 DMC

• 6 other identifiers: NCI-2013-0080813-0179287U01CA062490P30CA006516UM1CA186709
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 3

Brief 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. Cabozantinib-s-malate and vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conditions

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

Outcome Measures

Primary Outcomes (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.

  28 days

Secondary Outcomes (3)

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

  Up to 4 weeks after last dose of therapy

• DCR per RECIST version 1.1

  Up to 4 weeks after last dose of therapy

• PFS per RECIST version 1.1

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

Other Outcomes (3)

• Change in met proto-oncogene (MET) expression by immunohistochemistry (IHC)

  Baseline and after 4 weeks of therapy

• Change in serum levels of hepatocyte growth factor (HGF) by IHC

  Baseline to up to 8 weeks

• Clinical benefit (CR, PR, or stable disease), assessed according to RECIST

  Up to 4 weeks after last dose of therapy

Study Arms (1)

Treatment (cabozantinib-s-malate, vemurafenib)

EXPERIMENTAL

Patients 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.

Drug: cabozantinib-s-malate; Drug: vemurafenib; Other: laboratory biomarker analysis; Other: pharmacological study

Interventions

cabozantinib-s-malate DRUG

Given PO

Also known as: BMS-907351, Cometriq, XL184

Treatment (cabozantinib-s-malate, vemurafenib)

vemurafenib DRUG

Given PO

Also known as: BRAF(V600E) kinase inhibitor RO5185426, PLX4032, RG7204, RO5185426

Treatment (cabozantinib-s-malate, vemurafenib)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (cabozantinib-s-malate, vemurafenib)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (cabozantinib-s-malate, vemurafenib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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)
• 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)

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Emory University/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Virginia Commonwealth University

Richmond, Virginia, 23298, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

cabozantinib; Vemurafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Jason Luke

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2013
• First Posted: April 18, 2013
• Study Start: May 1, 2013
• Primary Completion: September 1, 2014
• Last Updated: September 25, 2014

Record last verified: 2014-09

Locations

US (3)