Clinical Trials /

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

NCT04284774

Description:

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.

Related Conditions:
  • Histiocytosis
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
  • Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of Tipifarnib in Patients With Tumors Harboring HRAS Genomic Alterations

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01015
  • SECONDARY ID: NCI-2020-01015
  • SECONDARY ID: APEC1621M
  • SECONDARY ID: APEC1621M
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT04284774

Conditions

  • 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 II 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 II Glioma

Interventions

DrugSynonymsArms
TipifarnibR115777, ZarnestraTreatment (tipifarnib)

Purpose

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.

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tipifarnib)ExperimentalPatients 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.
  • Tipifarnib

Eligibility Criteria

        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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.
Measure:Percentage of patients experiencing grade 3 or higher adverse events
Time Frame:From enrollment to the end of treatment, up to 2 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 19, 2021