Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial

Inclusion Criteria:

• Patient must have enrolled onto APEC1621SC (NCT03155620) and must have been given atreatment assignment to MATCH to APEC1621M based on the presence of an actionablemutation 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 studyenrollment. Patients with neuroblastoma who do not have measurable disease but havemetaiodobenzylguanidine (MIBG) positive (+) evaluable disease are eligible.Measurable disease in patients with CNS involvement is defined as any lesion that isat minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) orcomputed 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 forneuroblastoma

• Lesions only detected by nuclear medicine studies (e.g., bone, gallium orpositron emission tomography [PET] scans) except as noted forneuroblastoma

• Elevated tumor markers in plasma or cerebral spinal fluid (CSF)

• Previously radiated lesions that have not demonstrated clear progressionpost radiation

• Leptomeningeal lesions that do not meet the measurement requirements forResponse Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Karnofsky >= 50 for patients > 16 years of age and Lansky >= 50 for patients =< 16years of age. Note: Neurologic deficits in patients with CNS tumors must have beenrelatively stable for at least 7 days prior to study enrollment. Patients who areunable to walk because of paralysis, but who are up in a wheelchair, will beconsidered ambulatory for the purpose of assessing the performance score

• Patients must have fully recovered from the acute toxic effects of all prioranti-cancer therapy and must meet the following minimum duration from prioranti-cancer directed therapy prior to enrollment. If after the required timeframe,the numerical eligibility criteria are met, e.g. blood count criteria, the patientis 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 myelosuppressivechemotherapy (42 days if prior nitrosourea)

• Anti-cancer agents not known to be myelosuppressive (e.g. not associated withreduced platelet or absolute neutrophil count [ANC] counts): >= 7 days afterthe last dose of agent

• Antibodies: >= 21 days must have elapsed from infusion of last dose ofantibody, and toxicity related to prior antibody therapy must be recovered tograde =< 1

• Corticosteroids: If used to modify immune adverse events related to priortherapy, >= 14 days must have elapsed since last dose of corticosteroid

• Hematopoietic growth factors: >= 14 days after the last dose of a long-actinggrowth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor.For growth factors that have known adverse events occurring beyond 7 days afteradministration, this period must be extended beyond the time during whichadverse events are known to occur. The duration of this interval must bediscussed with the study chair and the study-assigned research coordinator

• Interleukins, interferons and cytokines (other than hematopoietic growthfactors): >= 21 days after the completion of interleukins, interferon orcytokines (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 anystem cell infusion including donor lymphocyte infusion (DLI) or boostinfusion: >= 84 days after infusion and no evidence of graft versus hostdisease (GVHD)

• Autologous stem cell infusion including boost infusion: >= 42 days

• Cellular therapy: >= 42 days after the completion of any type of cellulartherapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells,etc.)

• Radiation therapy (XRT)/external beam irradiation including protons: >= 14 daysafter 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): >= 42days 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 daysprior to enrollment):

• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

• For patients with solid tumors without known bone marrow involvement (within 7 daysprior to enrollment):

• Platelet count >= 100,000/mm^3 (transfusion independent, defined as notreceiving platelet transfusions for at least 7 days prior to enrollment)

• Patients with known bone marrow metastatic disease will be eligible for studyprovided they meet the blood counts (may receive transfusions provided they are notknown to be refractory to red cell or platelet transfusions). These patients willnot be evaluable for hematologic toxicity

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70ml/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 toenrollment):

• 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]) =< 135U/L. (For the purpose of this study, the ULN for SGPT is 45 U/L.) (within 7 daysprior to enrollment)

• Serum albumin >= 2 g/dL (within 7 days prior to enrollment)

• Patients with seizure disorder may be enrolled if on anticonvulsants and wellcontrolled

• 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, proteinshake, or a dietary supplement drink (such as Ensure). Percutaneous endoscopicgastrostomy (PEG)-tube or nasogastric tube administration is permitted

• All patients and/or their parents or legally authorized representatives must sign awritten informed consent. Assent, when appropriate, will be obtained according toinstitutional guidelines

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks offetal and teratogenic adverse events as seen in animal/human studies. Pregnancytests must be obtained in girls who are post-menarchal. Males or females ofreproductive potential may not participate unless they have agreed to use twoeffective contraceptive methods for the duration of study treatment. Both femalesubjects and male subjects with female partners of child-bearing potential mustagree to use a highly effective method of contraception for 2 weeks prior toprotocol therapy, during, and at least 4 weeks after last dose of tipifarnib. Inaddition, since tipifarnib could induce toxicity of male reproductive organs andcause impairment of fertility, sperm cryopreservation should be recommended for malesubjects wishing to preserve their fertility following tipifarnib treatment

• Patients receiving corticosteroids who have not been on a stable or decreasing doseof corticosteroid for at least 7 days prior to enrollment are not eligible. If usedto modify immune adverse events related to prior therapy, >= 14 days must haveelapsed 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 preventgraft-versus-host disease post bone marrow transplant are not eligible for thistrial

• Patients who are currently receiving drugs that are strong inducers or inhibitors ofCYP3A4/5 or UGT are not eligible. Strong inducers or inhibitors of CYP3A4/5 or UGTshould be avoided from 14 days prior to the 1st dose of tipifarnib to the end of thestudy. In addition, patients receiving agents that are sensitive or narrowtherapeutic range substrates of CYP3A4/5 are not eligible. Note: CYP3A4/5 inducinganti-epileptic drugs and dexamethasone for CNS tumors or metastases, on a stabledose, are allowed

• Patients with known hypersensitivity to tipifarnib or any components of the tabletare 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 thesafety monitoring requirements of the study are not eligible