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Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)

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ClinicalTrials.gov Identifier: NCT03220035
Recruitment Status : Recruiting
First Posted : July 18, 2017
Last Update Posted : September 12, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II Pediatric MATCH trial studies how well vemurafenib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with BRAF V600 mutations that have spread to other places in the body and have come back or do not respond to treatment. Vemurafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma BRAF NP_004324.2:p.V600X Ependymoma Ewing Sarcoma Hepatoblastoma Histiocytosis Langerhans Cell Histiocytosis Malignant Germ Cell Tumor Malignant Glioma Osteosarcoma Peripheral Primitive Neuroectodermal Tumor Recurrent Childhood Central Nervous System Neoplasm Recurrent Childhood Non-Hodgkin Lymphoma Recurrent Malignant Solid Neoplasm Recurrent Neuroblastoma Refractory Central Nervous System Neoplasm Refractory Malignant Solid Neoplasm Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Rhabdoid Tumor Rhabdomyosarcoma Soft Tissue Sarcoma Wilms Tumor Other: Laboratory Biomarker Analysis Drug: Vemurafenib Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with vemurafenib with advanced solid tumors (including central nervous system [CNS] tumors), lymphomas or histiocytic disorders that harbor activating BRAF V600 mutations.

SECONDARY OBJECTIVES:

I. To estimate the progression free survival in pediatric patients treated with vemurafenib with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating BRAF V600 mutations.

II. To obtain information about the tolerability of vemurafenib in children with relapsed or refractory cancer.

TERTIARY OBJECTIVES:

I. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).

OUTLINE:

Patients receive vemurafenib orally (PO) twice daily (BID) on day 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Vemurafenib in Patients With Tumors Harboring Braf V600 Mutations
Actual Study Start Date : July 24, 2017
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Treatment (vemurafenib)
Patients receive vemurafenib PO BID on day 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Vemurafenib
Given PO
Other Names:
  • BRAF (V600E) kinase inhibitor RO5185426
  • BRAF(V600E) Kinase Inhibitor RO5185426
  • PLX-4032
  • PLX4032
  • RG 7204
  • RG7204
  • RO 5185426
  • Zelboraf




Primary Outcome Measures :
  1. Overall response rate (ORR) [ Time Frame: Up to 4.5 years ]
    ORR defined as complete response + partial response determined by Response Evaluation Criteria in Solid Tumors. Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.


Secondary Outcome Measures :
  1. Progress free survival (PFS) [ Time Frame: From the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 4.5 years ]
    PFS along with the confidence intervals will be estimated using the Kaplan-Meier method. Patients with local calls of disease progression (i.e. calls made by the treating institution), will be counted as having had an event, even if the central review does not declare progression.

  2. Incidence of adverse events evaluated according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days after last dose ]
    Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.


Other Outcome Measures:
  1. Changes in tumor genomics [ Time Frame: Baseline up to 4.5 years ]
    Will explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid. Will be summarized with simple summary statistics and will be descriptive in nature.



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Ages Eligible for Study:   12 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621G based on the presence of a BRAF V600 mutation
  • Patients must have a body surface area >= 0.37 m^2 at enrollment while the 120 mg strength tablet supply is available; patients < 0.73 m^2 must follow the dosing nomogram; patients >= 0.73 m^2 at enrollment must follow the dosing nomogram
  • Patients enrolled after the drug supply of the 120 mg strength has been exhausted must have a body surface area >= 0.73 m^2 at enrollment and follow the dosing nomogram
  • Patients must have radiographically measurable disease at the time of study enrollment; patients with neuroblastoma who do not have measurable disease but have metaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible; measurable disease in patients with CNS involvement is defined as tumor that is measurable in two perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than one slice; Note: The following do not qualify as measurable disease:

    • Malignant fluid collections (e.g., ascites, pleural effusions)
    • Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
    • Lesions only detected by nuclear medicine studies (e.g., bone, gallium or positron emission tomography [PET] scans) except as noted for neuroblastoma
    • Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
    • Previously radiated lesions that have not demonstrated clear progression post radiation
    • Leptomeningeal lesions that do not meet the measurement requirements for Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment; patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

    • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

      • >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
    • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
    • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
    • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
    • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for growth factors that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
    • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)
    • Stem cell Infusions (with or without total-body irradiation [TBI]):

      • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
      • Autologous stem cell infusion including boost infusion: >= 42 days
    • Cellular therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
    • Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation; Note: Radiation may not be delivered to "measurable disease" tumor site(s) being used to follow response to subprotocol treatment
    • Radiopharmaceutical therapy (e.g., radiolabeled antibody, iobenguane I-131 [131I-MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
    • Patients must not have received prior exposure to a BRAF inhibitor (e.g. vemurafenib, dabrafenib or encorafenib)
  • For patients with solid tumors without known bone marrow involvement:

    • Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
    • Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts in above criteria (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

    • Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6
    • Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8
    • Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1
    • Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2
    • Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4
    • Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
  • Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)
  • Serum albumin >= 2 g/dL
  • Corrected QT (QTc) interval =< 480 milliseconds; Note: Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
  • Patients must be able to swallow intact tablets
  • All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines

Exclusion Criteria:

  • Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method, for the duration of study treatment and for 6 months after the last dose of vemurafenib
  • Patients receiving corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Patients who are currently receiving another investigational drug are not eligible
  • Patients who are currently receiving other anti-cancer agents are not eligible
  • Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
  • Patients who are currently receiving drugs that are moderate to strong inducers or inhibitors of CYP3A4 are not eligible; moderate to strong inducers or inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study; Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
  • Patients who are currently receiving drugs that are inhibitors or inducers of p-glycoprotein (P-gp) or adenosine triphosphate (ATP)-binding cassette, subfamily G, member 2 (ABCG2 [BCRP]) are not eligible
  • Patients with known active cutaneous squamous cell carcinoma (includes keratoacanthoma or mixed keratoacanthoma subtype) are not eligible; patients who have fully excised lesions with dermatologic confirmation of absence of disease are eligible
  • Patients with low grade glioma patients (World Health Organization [WHO] grades I and II) are not eligible
  • Patients who have an uncontrolled infection are not eligible
  • Patients who have received a prior solid organ transplantation are not eligible
  • Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03220035


  Show 85 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: AeRang Kim Children's Oncology Group

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03220035     History of Changes
Other Study ID Numbers: NCI-2017-01244
NCI-2017-01244 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
APEC1621G
APEC1621G ( Other Identifier: Childrens Oncology Group )
APEC1621G ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Posted: July 18, 2017    Key Record Dates
Last Update Posted: September 12, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Sarcoma
Lymphoma, Non-Hodgkin
Neuroblastoma
Neoplasms, Germ Cell and Embryonal
Glioma
Osteosarcoma
Rhabdomyosarcoma
Ependymoma
Sarcoma, Ewing
Neuroectodermal Tumors
Neuroectodermal Tumors, Primitive
Wilms Tumor
Neuroectodermal Tumors, Primitive, Peripheral
Histiocytosis
Rhabdoid Tumor
Histiocytosis, Langerhans-Cell
Nervous System Neoplasms
Central Nervous System Neoplasms
Hepatoblastoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Connective and Soft Tissue
Neoplasms, Neuroepithelial
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue