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

 -  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 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 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

 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