Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
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|ClinicalTrials.gov Identifier: NCT04284774|
Recruitment Status : Recruiting
First Posted : February 26, 2020
Last Update Posted : March 10, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Malignant Solid Neoplasm Recurrent Adrenal Gland Pheochromocytoma Recurrent Ectomesenchymoma Recurrent Ependymoma Recurrent Ewing Sarcoma Recurrent Hepatoblastoma Recurrent Kidney Wilms Tumor Recurrent Langerhans Cell Histiocytosis Recurrent Malignant Germ Cell Tumor Recurrent Malignant Glioma Recurrent Medulloblastoma Recurrent Melanoma Recurrent Neuroblastoma Recurrent Non-Hodgkin Lymphoma Recurrent Osteosarcoma Recurrent Peripheral Primitive Neuroectodermal Tumor Recurrent Rhabdoid Tumor Recurrent Rhabdoid Tumor of the Kidney Recurrent Rhabdomyosarcoma Recurrent Soft Tissue Sarcoma Recurrent Thyroid Gland Carcinoma Recurrent WHO Grade 2 Glioma Refractory Adrenal Gland Pheochromocytoma Refractory Ependymoma Refractory Ewing Sarcoma Refractory Hepatoblastoma Refractory Langerhans Cell Histiocytosis Refractory Malignant Germ Cell Tumor Refractory Malignant Glioma Refractory Medulloblastoma Refractory Melanoma Refractory Neuroblastoma Refractory Non-Hodgkin Lymphoma Refractory Osteosarcoma Refractory Peripheral Primitive Neuroectodermal Tumor Refractory Rhabdoid Tumor Refractory Rhabdoid Tumor of the Kidney Refractory Rhabdomyosarcoma Refractory Soft Tissue Sarcoma Refractory Thyroid Gland Carcinoma Refractory WHO Grade 2 Glioma||Procedure: Biospecimen Collection Procedure: Bone Marrow Aspiration and Biopsy Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Procedure: Positron Emission Tomography Procedure: Radionuclide Imaging Drug: Tipifarnib||Phase 2|
I. To determine the objective response rate (ORR; complete response + partial response) in pediatric patients treated with tipifarnib with advanced solid tumors (including central nervous system [CNS] tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS.
I. To estimate the progression free survival in pediatric patients treated with tipifarnib with advanced solid tumors (including CNS tumors), lymphomas or histiocytic disorders that harbor activating genetic alterations in HRAS.
II. To obtain information about the tolerability of tipifarnib in children and adolescents with relapsed or refractory cancer.
I. To evaluate other biomarkers as predictors of response to tipifarnib and specifically, whether tumors that harbor different missense mutations or variant allele frequency will demonstrate differential response to tipifarnib treatment.
II. To explore approaches to profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid (DNA).
Patients receive tipifarnib orally (PO) or via nasogastric or gastric tube twice daily (BID) on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with positron emission tomography (PET) scan, computed tomography (CT) scan, magnetic resonance imaging (MRI), or meta-iodobenzylguanidine (MIBG) scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||49 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations|
|Actual Study Start Date :||July 13, 2020|
|Estimated Primary Completion Date :||September 30, 2027|
|Estimated Study Completion Date :||September 30, 2027|
Experimental: Treatment (tipifarnib)
Patients receive tipifarnib PO or via nasogastric or gastric tube BID on days 1-7 and 15-21. Treatment repeats every 28 days for up to 26 cycles (2 years) in the absence of disease progression or unacceptable toxicity. Patients undergo tumor disease evaluation with PET scan, CT scan, MRI, or MIBG scintigraphy throughout the trial. Patients may undergo bone marrow aspiration or biopsy at baseline, or if there is suspicion of bone marrow metastasis, or when a complete or partial response is identified, or if there is disease progression in the marrow suspected. Patients may undergo blood specimen collections throughout the trial.
Procedure: Biospecimen Collection
Undergo blood sample collection
Procedure: Bone Marrow Aspiration and Biopsy
Undergo bone marrow aspiration or biopsy
Procedure: Computed Tomography
Undergo a CT scan
Procedure: Magnetic Resonance Imaging
Procedure: Positron Emission Tomography
Undergo a PET scan
Procedure: Radionuclide Imaging
Undergo a MIBG scintigraphy scan
Given PO or via nasogastric or gastric tube
- Objective response rate (complete response + partial response) in pediatric patients treated with tipifarnib [ Time Frame: From enrollment to the end of treatment, up to 2 years ]A responder is defined as a patient who achieves a best response of partial response or complete response on the study. 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.
- Progression free survival (PFS) [ Time Frame: From the initiation of subprotocol treatment, until disease progression or disease recurrence or death from any cause, assessed up to 7 years ]PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
- Percentage of patients experiencing grade 3 or higher adverse events [ Time Frame: From enrollment to the end of treatment, up to 2 years ]Percentage of patients experiencing grade 3 or higher adverse events will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All patients who receive at least one dose of protocol therapy will be considered in the evaluation of toxicity.
- Biomarker analysis [ Time Frame: Up to 7 years ]Will evaluate other biomarkers as predictors of response to tipifarnib and whether tumors that harbor different missense mutations or fusions will demonstrate differential response to treatment.
- Profiling changes in tumor genomics [ Time Frame: Baseline, assessed up to 7 years ]Will explore approaches to the profiling changes in tumor genomics over time through evaluation of circulating tumor deoxyribonucleic acid.
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
|Ages Eligible for Study:||12 Months to 21 Years (Child, Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Patient must have enrolled onto APEC1621SC and must have been given a treatment assignment to MATCH to APEC1621M based on the presence of an actionable mutation as defined in APEC1621SC
- Patients must be >=12 months and =< 21 years of age at the time of study enrollment
- Patients must have a body surface area >= 0.29 m^2 at enrollment
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 any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
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 cerebral spinal 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 relatively 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, 131I-MIBG): >= 42 days after systemically administered radio-pharmaceutical therapy
- Patients must not have received prior exposure to tipifarnib
For patients with solid tumors without known bone marrow involvement (within 7 days prior to enrollment):
- Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
For patients with solid tumors without known bone marrow involvement (within 7 days prior to enrollment):
- 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 (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 (within 7 days prior to enrollment) or
A serum creatinine based on age/gender as follows (within 7 days prior to enrollment):
Age: Maximum serum creatinine (mg/dL)
- 1 to < 2 years: male (0.6), female (0.6)
- 2 to < 6 years: male (0.8), female (0.8)
- 6 to < 10 years: male (1), female (1)
- 10 to < 13 years: male (1.2), female (1.2)
- 13 to < 16 years: male (1.5), female (1.4)
- >= 16 years: male (1.7), female (1.4)
- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
- 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.) (within 7 days prior to enrollment)
- Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
- Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
- Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) resulting from prior therapy must be =< grade 2
- Patients must be able to swallow intact tablets or crushed tablets mixed in water, orange juice, apple juice, tomato juice, ginger ale, applesauce, yogurt, protein shake, or a dietary supplement drink (such as Ensure). Percutaneous endoscopic gastrostomy (PEG)-tube or nasogastric tube administration is permitted
- 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
- Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies. 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 two effective contraceptive methods for the duration of study treatment. Both female subjects and male subjects with female partners of child-bearing potential must agree to use a highly effective method of contraception for 2 weeks prior to protocol therapy, during, and at least 4 weeks after last dose of tipifarnib. In addition, since tipifarnib could induce toxicity of male reproductive organs and cause impairment of fertility, sperm cryopreservation should be recommended for male subjects wishing to preserve their fertility following tipifarnib treatment
- 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 strong inducers or inhibitors of CYP3A4/5 or UGT are not eligible. Strong inducers or inhibitors of CYP3A4/5 or UGT should be avoided from 14 days prior to the 1st dose of tipifarnib to the end of the study. In addition, patients receiving agents that are sensitive or narrow therapeutic range substrates of CYP3A4/5 are not eligible. Note: CYP3A4/5 inducing anti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stable dose, are allowed
- Patients with known hypersensitivity to tipifarnib or any components of the tablet are not eligible
- Patients with hypersensitivity to imidazoles, such as clotrimazole, ketoconazole, miconazole and others in this drug class 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
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): NCT04284774
|Principal Investigator:||Christine A Pratilas||Children's Oncology Group|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2020-01015 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
APEC1621M ( Other Identifier: Children's Oncology Group )
APEC1621M ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
|First Posted:||February 26, 2020 Key Record Dates|
|Last Update Posted:||March 10, 2023|
|Last Verified:||December 2022|
|Individual Participant Data (IPD) Sharing Statement:|
|Plan to Share IPD:||Yes|
|Plan Description:||NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Neoplasms, Germ Cell and Embryonal
Neuroectodermal Tumors, Primitive
Neuroectodermal Tumors, Primitive, Peripheral
Neoplasms by Histologic Type