NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations

STATUS

Recruiting
End date

Sep 30, 2027
participants needed

49
sponsor

National Cancer Institute (NCI)

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Updated on 20 October 2022

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total body irradiation

lymphoma

absolute neutrophil count

metastatic disease

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tumor markers

cytokines

measurable disease

anticonvulsants

interferon

growth factor

pleural effusion

stem cell infusion

cns involvement

MRI

bone marrow procedure

glomerular filtration rate

hematopoietic growth factors

cytotoxic chemotherapy

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blood transfusion

cancer treatment

nitrosourea

tipifarnib

chemotherapeutic agents

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interleukins

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antineoplastic

solid tumor

blood count

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radiopharmaceutical therapy

antibody therapy

cns tumors

platelet transfusion

radiopharmaceutical

131i-mibg

iobenguane

autologous stem cell infusion

pegfilgrastim

myelosuppressive chemotherapy

donor lymphocyte infusion

cellular therapy

platelet transfusions

anti-cancer agents

seizure disorder

cns tumor

HRAS

pleural effusions

bone marrow infiltration

nervous system disorder

nervous system disorders

Summary

This phase II pediatric MATCH trial studies how well tipifarnib works in treating patients with solid tumors that have recurred or spread to other places in the body (advanced), lymphoma, or histiocytic disorders, that have a genetic alteration in the gene HRAS. Tipifarnib may block the growth of cancer cells that have specific genetic changes in a gene called HRAS and may reduce tumor size.

Description

PRIMARY OBJECTIVE:

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.

SECONDARY OBJECTIVES:

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.

EXPLORATORY OBJECTIVES:

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).

OUTLINE

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.

After completion of study treatment, patients are followed up at 30 days, then periodically thereafter.

Details

Condition	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
Treatment	Tipifarnib
Clinical Study Identifier	NCT04284774
Sponsor	National Cancer Institute (NCI)
Last Modified on	20 October 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	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 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
	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
	years of age. Note: Neurologic deficits in patients with CNS tumors must have
	Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive
	been relatively stable for at least 7 days prior to study enrollment. Patients
	>= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
	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
	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
	score
	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)
	Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
	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)
	reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after
	Autologous stem cell infusion including boost infusion: >= 42 days
	the last dose of agent
	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
	Patients must not have received prior exposure to tipifarnib
	Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
	Cellular therapy: >= 42 days after the completion of any type of cellular therapy
	Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
	(e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
	Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 (within 7 days prior to enrollment) or
	Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days
	A serum creatinine based on age/gender as follows (within 7 days prior to enrollment)
	after systemically administered radio-pharmaceutical therapy
	Age: Maximum serum creatinine (mg/dL)
	to < 2 years: male (0.6), female (0.6)
	to < 6 years: male (0.8), female (0.8)
	For patients with solid tumors without known bone marrow involvement (within 7 days
	prior to enrollment)
	to < 10 years: male (1), female (1)
	to < 13 years: male (1.2), female (1.2)
	For patients with solid tumors without known bone marrow involvement (within 7 days
	to < 16 years: male (1.5), female (1.4)
	prior to enrollment)
	>= 16 years: male (1.7), female (1.4)
	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)
	Patients with known bone marrow metastatic disease will be eligible for study provided
	Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
	they meet the blood counts (may receive transfusions provided they are not
	Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
	known to be refractory to red cell or platelet transfusions). These patients
	Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v] 5.0) resulting from prior therapy must be =< grade 2
	will not be evaluable for hematologic toxicity
	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
	Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
	age (within 7 days prior to enrollment)
Exclusion Criteria
	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

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pegfilgrastim

myelosuppressive chemotherapy

donor lymphocyte infusion

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platelet transfusions

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NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations