Canadian clinical trial registry

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Study Description

This is a multi-center, open-label, international study to evaluate the dose, safety and tolerability, antitumor activity, pharmacokinetic and pharmacodynamics of avelumab in pediatric subjects 0 to less than 18 years of age with refractory or relapsed malignant solid tumors (including central nervous system tumors) and lymphoma for which no standard therapy is available or for which the subject is not eligible for the existing therapy.

Inclusion Criteria

• Male or female subjects 0 to less than 18 years of age at the time of first treatment dose with histologically or cytologically confirmed solid malignant tumors (including CNS tumors) or lymphoma for which no standard therapy is available
• Confirmed progression on or refractory to standard therapy or no standard therapy available.
• Availability of archival formalin-fixed, paraffin-embedded block containing tumor tissue, or slides, or a fresh/recent tumor biopsy prior to avelumab treatment for subjects in Phase 2
• Adequate bone marrow, kidney, and liver function
• Other protocol defined inclusion criteria could apply

Exclusion Criteria

• Prior therapy with any antibody or drug targeting T-cell coregulatory proteins
• Concurrent anticancer treatment or immunosuppressive agents
• Prior organ transplantation
• Significant acute or chronic infections
• Other significant diseases or conditions that might impair the subject's tolerance of trial treatment
• Other protocol defined exclusion criteria could apply

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Centres

Study Description

This Is a Multicenter, Randomized, Open-Label, Parallel-Group, Phase 2 Study to Compare the Efficacy and Safety of Lenvatinib in Combination with Ifosfamide and Etoposide Versus Ifosfamide and Etoposide in Children, Adolescents, and Young Adults with Relapsed or Refractory Osteosarcoma.

Inclusion Criteria

1. Histologically or cytologically confirmed diagnosis of high grade osteosarcoma
2. Refractory or relapsed osteosarcoma after 1 to 2 prior lines of systemic treatments
3. Measurable or evaluable disease per RECIST 1.1.
4. Life expectancy of 12 weeks or more
5. Lansky play score greater than or equal to (>=) 50 Percent (%) or Karnofsky Performance Status score >=50%. Use Karnofsky for participants >=16 years of age and Lansky for participants less than (<)16 years of age. Participants who are unable to walk because of paralysis, but who are able to perform activities of daily living while wheelchair bound, will be considered ambulatory for the purpose of assessing the performance score
6. Adequate organ function per blood work
7. Adequate cardiac function as evidenced by left ventricular ejection fraction (LVEF) >=50% at baseline as determined by echocardiography or multigated acquisition (MUGA) scan

8. Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as:

   BP <95th percentile for sex, age, and height/length at screening (as per National Heart Lung and Blood Institute guidelines) and no change in antihypertensive medications within 1 week prior to Cycle 1 Day 1. Participants >18 years of age should have BP less than or equal to (<=) 150/90 millimeters of Mercury at screening and no change in antihypertensive therapy within 1 week prior to Cycle 1 Day 1

9. Washout before Cycle 1 Day 1 of 3 weeks in case of prior chemotherapy, 6 weeks if treatment included nitrosoureas; 4 weeks for definitive radiotherapy, 2 weeks for palliative radiotherapy; and 3 months from high-dose chemotherapy and stem cell rescue. For all other anti-cancer therapies, washout before Cycle 1 Day 1 of at least 5 half-lives (or at least 28 days, whichever is shorter). Participants must have recovered [to Grade <=1, except for alopecia, ototoxicity, and Grade <=2 peripheral neuropathy, per common terminology criteria for adverse events (CTCAE) v5.0] from the acute toxic effects of all prior anticancer therapy before Cycle 1 Day 1
10. Must have no prior history of lenvatinib treatment

Eligibility for optional lenvatinib crossover:

1. Disease progression per RECIST 1.1 (as confirmed by IIR for all participants who crossover prior to the study data-cut)
2. No new systemic anti-cancer medication administered after the last dose of study drugs
3. Meets all safety parameters listed in the inclusion criteria and none listed in the exclusion criteria
4. Study is ongoing

Exclusion Criteria

1. Any active infection or infectious illness unless fully recovered prior to Cycle 1 Day 1 (that is, no longer requiring systemic treatment)
2. Participants with central nervous system metastases are not eligible, unless they have completed local therapy (example, whole brain radiation therapy, surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 2 weeks before Cycle 1 Day 1
3. Active second malignancy within 2 years prior to enrollment ([in addition to osteosarcoma], but not including definitively treated superficial melanoma, carcinoma-in-situ, basal or squamous cell carcinoma of the skin)
4. Has had major surgery within 3 weeks prior to Cycle 1 Day 1. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
5. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolonged QT or corrected QT (QTc) interval (example, a repeated demonstration of a QTc interval greater than [>] 480 millisecond [msec])
6. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability. Note: Medically controlled arrhythmia would be permitted
7. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that in the opinion of the investigator might affect the absorption of lenvatinib
8. Pre-existing Grade >=3 gastrointestinal or non-gastrointestinal fistula
9. Gastrointestinal bleeding or active hemoptysis (bright red blood of at least 1 divided [/] by 2 teaspoon) within 3 weeks prior to Cycle 1 Day 1
10. Radiographic evidence of intratumoral cavitation, encasement, or invasion of a major blood vessel. Additionally, the degree of proximity to major blood vessels should be considered for exclusion because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis after lenvatinib therapy
11. History of ifosfamide-related Grade >=3 nephrotoxicity or encephalopathy
12. Known to be human immunodeficiency virus (HIV) positive
13. Known active Hepatitis B (example, Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (example, hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected). Note: Testing for Hepatitis B or Hepatitis C is required at screening only when mandated by local health authority

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Centres

Study Description

Phase 1 of this study, utilizing a rolling 6 design, will be conducted to determine a maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and to describe the toxicities of lenvatinib administered in combination with everolimus once daily to pediatric participants with recurrent/refractory solid tumors [phase 1 has been completed]

Phase 2, utilizing Simon's optimal 2-stage design, will be conducted to estimate the antitumor activity of lenvatinib in combination with everolimus in pediatric participants with selected recurrent/refractory solid tumors including Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), rhabdomyosarcoma, and high grade glioma (HGG) using objective response rate (ORR) at Week 16 as the outcome measure.

Inclusion Criteria

• ≥2 years and <18 years of age for enrolment in Phase 1 or ≥2 years and ≤21 years of age for enrolment in Phase 2.

• Recurrent or refractory solid tumors

  • Phase 1: All solid tumors (measurable or evaluable disease), including primary central nervous system (CNS) tumors; exclusion of hepatoblastoma and lymphomas. Participants with diffuse intrinsic pontine glioma, optic pathway glioma, or pineal tumors with elevated tumor markers (alpha-fetoprotein [AFP] and beta-human chorionic gonadotropin [ß-hCG][or human chorionic gonadotropin [hCG])do not require histological or cytological confirmation of diagnosis
  • Phase 2: Ewing sarcoma/peripheral primitive neuroectodermal tumor (pPNET), Rhabdomyosarcoma, High Grade Glioma (HGG) (all must have measurable disease); exclusion of Diffuse Intrinsic Pontine Glioma
• Histologically or cytologically confirmed diagnosis

• Measurable disease that meets the following criteria (Phase 2):

  1. RECIST 1.1 (for all tumor types except HGG): At least 1 lesion of ≥1.0 cm in the longest diameter for a non lymph node or ≥1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computed tomography /magnetic resonance imaging (CT/MRI)
  2. Response Assessment in Neuro-Oncology (RANO) for high grade glioma (HGG): At least one lesion must be measurable as defined as a bi dimensionally contrast enhancing lesion with clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are preferably at most 5 mm apart with 0 mm skip

Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as radiofrequency (RF) ablation must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion

• Karnofsky performance score ≥50 for participants>16 year of age and Lansky play score ≥50 for participants ≤16 years of age. Neurologic deficits in participants with CNS tumors must have been relatively stable for at least 7 days prior to study enrollment. Participants 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

• Prior Therapy

  • Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy
  • Cytotoxic chemotherapy or other chemotherapy 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 (eg, not associated with reduced platelet or absolute neutrophil counts): ≥7 days after the last dose of agent
  • Monoclonal antibodies: ≥21 days or 3 half-lives (whichever is shorter) of the antibody must have elapsed after the last dose of a monoclonal antibody (including checkpoint inhibitors). 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. Participants 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
  • Hematopoietic growth factors: ≥14 days after the last dose of a long-acting growth factor or 7 days for short-acting growth factor. For agents 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
  • Interleukins, interferons, and cytokines (other than hematopoietic growth factors): ≥21 days after the completion of interleukins, interferons or cytokines (other than hematopoietic growth factors)
  • Stem cell infusions (with or without total body irradiation): Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor leukocytes infusion or boost infusion: ≥84 days after infusion and no evidence of graft versus host disease; Autologous stem cell infusion including boost infusion: ≥42 days
  • Cellular Therapy: ≥42 days after the completion of any type of cellular therapy (eg, modified T cells, natural killer cells, dendritic cells, etc)
  • Radiotherapy (XRT)/External Beam Irradiation including Protons: ≥14 days after local XRT; ≥150 days after total body irradiation, craniospinal XRT or if radiation to ≥50% of the pelvis; ≥42 days if other substantial bone marrow radiation.
  • Radiopharmaceutical therapy: ≥42 days after systemically administered therapy.
  • Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted or mammalian target of rapamycin (mTOR)-targeted therapies: Must not have received prior exposure to lenvatinib; May have previously progressed on an mTOR inhibitor; No more than 2 prior VEGF/VEGFR-targeted therapies (For Phase 2 only); Must not have received prior VEGF/VEGFR-targeted therapy in combination with an mTOR inhibitor (For Phase 2 only)
• Adequate bone marrow function for participants with solid tumors without known bone marrow involvement
• Adequate bone marrow function for participants with known bone marrow metastatic disease
• Adequate renal function
• Adequate liver function
• Adequate cardiac function
• Adequate neurologic function
• Adequate blood pressure (BP) control with or without antihypertensive medications
• Adequate coagulation
• Adequate pancreatic function
• Participants must have a minimum body surface area (BSA) of 0.6 m^2 at study entry.

Exclusion Criteria

• Participants who have had or are planning to have the following invasive procedures

  • Major surgical procedure, laparoscopic procedure, open biopsy or significant traumatic injury within 28 days prior to enrolment
  • Central line placement or subcutaneous port placement is not considered major surgery. External central lines must be placed at least 3 days prior to enrollment and subcutaneous ports must be placed at least 7 days prior to enrollment
  • Fine needle aspirate within 7 days prior to enrolment
  • Surgical or other wounds must be adequately healed prior to enrolment
  • For purposes of this study, bone marrow aspirate and biopsy are not considered surgical procedures and therefore are permitted within 14 days prior to start of protocol therapy
• Participants who have non-healing wound, unhealed or incompletely healed fracture, or a compound (open) bone fracture at the time of enrolment
• Clinical evidence of nephrotic syndrome prior to enrolment
• Gastrointestinal bleeding or active hemoptysis (bright red blood of at least half teaspoon) within 21 days prior to enrolment
• Thrombotic/ thromboembolic event requiring systemic anticoagulation within 90 days prior to enrollment
• Evidence of new intracranial hemorrhage of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment for Participants with HGG
• Diagnosis of lymphoma
• Radiographic evidence of major blood vessel invasion/infiltration.
• Evidence of untreated CNS metastases (exception: participants with primary CNS tumors and leptomeningeal disease)
• Participants who are currently receiving enzyme-inducing anticonvulsants
• Participants chronically receiving strong cytochrome P450 3A4 (CYP3A4)/P-glycoprotein (P-gp) inhibitors or inducers within 7 days prior to study enrollment
• Females who are breastfeeding or pregnant. For females of childbearing potential, a negative screening pregnancy test must be obtained within 72 hours before the first dose of study drug

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Centres

Study Description

Brief Summary:

Many pediatric brain and solid tumors have altered epigenetic landscapes, and altered DNA methylation. As such this study is a Phase I/Ib study of combined 5'Azacitidine with an escalating dose of carboplatin for all recurrent/refractory pediatric brain and solid tumors. The phase I component will establish with maximum tolerated dose of carboplatin with azacytidine. An expansion cohort will be recruited of up to 30 patients will follow consisting of 20 recurrent posterior fossa ependymoma and 10 recurrent supratentorial ependymoma.

Detailed Description:

Aberrant DNA methylation is frequently observed in many pediatric solid tumors, but in particularly several entities such as ependymoma, medulloblastoma, embryonal tumor with multilayered rosettes, atypical/teratoid rhabdoid tumor, neuroblastoma and wilm's tumor have promoter hypermethylation. Treatment with DNMTi (DNA methyltransferase inhibitors) agents such as 5-azacytidine has been shown to be safe and efficacious in adult myelodysplastic syndromes, causing significant decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. However, monotherapy with DNMTi has been shown to result in resistance in leukamia's and efficacy in solid tumours is limited. Synergy between DNMTi and platinum agents has shown promise in pre-clinical models including pediatric ependymoma, and in addition, the combination of demethylating agents with carboplatin has provided promising results in platinum resistant ovarian cancers. However, this approach has not been applied to pediatric solid malignancies, which are attractive targets due to their frequent epigenetic dysregulation.

Platinums are the backbone of therapy for most pediatric solid tumors, and as such it is an attractive hypothesis that part of the reason for resistance to upfront therapies is platinum resistance. Specifically, ependymoma's are highly chemoresistant tumors and studies in preclinical models of ependymoma support that this chemoresistance can be overcome with DNMTi.

There is a clear medical need for new therapies, particularly for relapsed solid tumors, specifically brain tumors. Although pre-clinical data from our group and others suggests DNA demethylase inhibitors to be promising therapies for high risk ependymoma, medulloblastoma and ETMR (embryonal tumor with multilayered rosettes), 5'azacitidine monotherapy has been disappointing in clinical studies of adult solid tumours. Previous studies have suggested that platinum therapy can be effectively combined with azacitidine therapy and based on adult studies, maximum demethylation occurs approximately 5-10 days after treatment with 5'azacitidine. As such combination of azacitidine and carboplatin is a rationale therapy for several pediatric brain tumours, particularly those with a hypermethylated phenotype.

Two phases of the study will be conducted. The Phase I will establish the maximum tolerated dose of carboplatin and 5'azacytidine in a rolling 6 design. 5'azacytidine will be administered on Days 1-7 followed by Carboplatin on Day 15. The initial dose level will be 5'Azacytidine 75mg/m2/day for 7 days with Carboplatin administered on Day 15 at AUC (Area under curve) 4. Carboplatin will be dose escalated to a maximum of AUC 6, or de-escalated to AUC 3. The Phase Ib will be an ependymoma specific expansion cohort at the established MTD (maximum tolerated dose), to determine the feasibility and initial efficacy of the combination of carboplatin and 5'azacytidine in patients with recurrent/refractory posterior fossa and supratentorial ependymoma.

Inclusion Criteria

1. Greater than the age of 1 year and under age 18 at the time of study enrolment
2. Recurrent or refractory solid tumor (Phase I), or recurrent or refractory ependymoma (Phase Ib)
3. Tissue from diagnosis or resection prior to registration must be available (either flash frozen tissue or an FFPE (formalin fixed paraffin embedded) block)
4. Previous therapy with carboplatin will be permitted
5. Failed first line treatment (surgery, radiation therapy or chemotherapy) and should not be eligible for treatment with curative potential.
6. Be at least 4 weeks from the completion of myelosuppressive chemotherapy and/or biologic agents before starting day 1 of this study treatment
7. Be at least 14 days from the completion of radiation therapy and MIBG before starting day 1 of this study treatment
8. Be at least 3 months post hematopoetic stem cell rescue following myeloablative therapy before starting day 1 of this study treatment
9. Must have visible disease on imaging. Resection of visible disease is permitted while on study after two cycles including achievement of a gross total resection. If a resection is performed while on study, fresh frozen tissue should be submitted for analysis.
10. Concurrent medications will be limited to supportive medications including anti-emetics, steroids, analgesics and non-enzyme inducing anticonvulsants. Inducers of the P450 system will not be permitted. Other concurrent medications require approval of the study sponsor.
11. Ability of the parent and/or child to understand and the willingness to sign a written informed consent document
12. Karnofsky ≥ 50 for patients > 16 years of age and Lansky ≥ 50 for patients ≤ 16 years of age (See Appendix I for the Karnofsky-Lansky Scores). 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 with posterior fossa syndrome/cerebellar mutism demonstrating clear improvement post-surgically can be enrolled based on physician discretion.

13. Adequate hepatic, renal, marrow and cardiac function as defined below within 14 days prior to cycle 1 day 1:

    • Serum creatinine within normal institutional limits or creatinine clearance greater than 60mL/min
    • Serum bilirubin <1.5 times upper limit of institutional normal. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis
    • AST, ALT and Alkaline Phosphatase <2.5 times upper limit of institutional normal. If liver metastases are present, then <5 times upper limit of normal is permitted.
    • Normal QTc interval at screening ECG (baseline echocardiogram is not required)

    • Adequate marrow function defined below within 14 days prior to cycle 1 day 1:

      • Leukocytes greater than or equal to 3000 x10E6/L
      • Absolute neutrophil count greater than or equal to 0.75x10E9/L
      • Platelets greater than or equal to 75x10E9/L
      • Hemoglobin greater than or equal to 10g/dL (may be transfused).

Exclusion Criteria

1. Female patient who is pregnant or breast feeding (Lactating females must agree not to breast feed while taking azacitidine) or with childbearing potential and not willing to use a double method of contraception up to 3 months after the end of study treatment. Male patient who is not willing to use a barrier method of contraception up to 6 months after the end of study treatment.
2. Patients may not be receiving any other investigational agents within 30 days prior to day 1 of protocol treatment
3. Prior therapy with a DNA demethylase inhibitor
4. Evidence of cardiac toxicity (shortening fraction below 28%; shortening fraction measures and ratios the change in the diameter of the left ventricle between the contracted and relaxed states)
5. Abnormal coagulation parameters (PT >15 seconds, PTT>40 seconds, and/or INR >1.5)
6. Significant active cardiac disease within the previous 6 months including:
   • NYHA class 3 or 4 CHF
   • Unstable angina
   • Myocardial infarction
7. Known or suspected hypersensitivity to azacitidine or mannitol carboplatin
8. Previous carboplatin exposure is not an exclusion criteria but previous allergic reaction to carboplatin will exclude enrolment.
9. Patient must not require use of enzyme inducing anticonvulsants; patients who are receiving an enzyme inducing anticonvulsant must be able to switch to a non-enzyme inducing anticonvulsant such as Levetiracetam, Clobazam, Lacosamide, Valproate or Topiramate at least 2 weeks prior to study enrolment.
10. Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment)
11. Active viral infection with HIV or hepatitis type B or C Patients with advanced malignant hepatic tumors
12. Patients with advanced malignant hepatic tumors

Publications

Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stütz AM, Wang X, Gallo M, Garzia L, Zayne K, Zhang X, Ramaswamy V, Jäger N, Jones DT, Sill M, Pugh TJ, Ryzhova M, Wani KM, Shih DJ, Head R, Remke M, Bailey SD, Zichner T, Faria CC, Barszczyk M, Stark S, Seker-Cin H, Hutter S, Johann P, Bender S, Hovestadt V, Tzaridis T, Dubuc AM, Northcott PA, Peacock J, Bertrand KC, Agnihotri S, Cavalli FM, Clarke I, Nethery-Brokx K, Creasy CL, Verma SK, Koster J, Wu X, Yao Y, Milde T, Sin-Chan P, Zuccaro J, Lau L, Pereira S, Castelo-Branco P, Hirst M, Marra MA, Roberts SS, Fults D, Massimi L, Cho YJ, Van Meter T, Grajkowska W, Lach B, Kulozik AE, von Deimling A, Witt O, Scherer SW, Fan X, Muraszko KM, Kool M, Pomeroy SL, Gupta N, Phillips J, Huang A, Tabori U, Hawkins C, Malkin D, Kongkham PN, Weiss WA, Jabado N, Rutka JT, Bouffet E, Korbel JO, Lupien M, Aldape KD, Bader GD, Eils R, Lichter P, Dirks PB, Pfister SM, Korshunov A, Taylor MD. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature. 2014 Feb 27;506(7489):445-50. doi: 10.1038/nature13108. Epub 2014 Feb 19.

Ramaswamy V, Hielscher T, Mack SC, Lassaletta A, Lin T, Pajtler KW, Jones DT, Luu B, Cavalli FM, Aldape K, Remke M, Mynarek M, Rutkowski S, Gururangan S, McLendon RE, Lipp ES, Dunham C, Hukin J, Eisenstat DD, Fulton D, van Landeghem FK, Santi M, van Veelen ML, Van Meir EG, Osuka S, Fan X, Muraszko KM, Tirapelli DP, Oba-Shinjo SM, Marie SK, Carlotti CG, Lee JY, Rao AA, Giannini C, Faria CC, Nunes S, Mora J, Hamilton RL, Hauser P, Jabado N, Petrecca K, Jung S, Massimi L, Zollo M, Cinalli G, Bognár L, Klekner A, Hortobágyi T, Leary S, Ermoian RP, Olson JM, Leonard JR, Gardner C, Grajkowska WA, Chambless LB, Cain J, Eberhart CG, Ahsan S, Massimino M, Giangaspero F, Buttarelli FR, Packer RJ, Emery L, Yong WH, Soto H, Liau LM, Everson R, Grossbach A, Shalaby T, Grotzer M, Karajannis MA, Zagzag D, Wheeler H, von Hoff K, Alonso MM, Tuñon T, Schüller U, Zitterbart K, Sterba J, Chan JA, Guzman M, Elbabaa SK, Colman H, Dhall G, Fisher PG, Fouladi M, Gajjar A, Goldman S, Hwang E, Kool M, Ladha H, Vera-Bolanos E, Wani K, Lieberman F, Mikkelsen T, Omuro AM, Pollack IF, Prados M, Robins HI, Soffietti R, Wu J, Metellus P, Tabori U, Bartels U, Bouffet E, Hawkins CE, Rutka JT, Dirks P, Pfister SM, Merchant TE, Gilbert MR, Armstrong TS, Korshunov A, Ellison DW, Taylor MD. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol. 2016 Jul 20;34(21):2468-77. doi: 10.1200/JCO.2015.65.7825. Epub 2016 Jun 6.

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Centres

Study Description

This is a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors.

Part A is a repeat dose, dose escalation monotherapy study that will identify the recommended phase II dose (RP2D) on the continuous dosing schedule using a 3 + 3 dose- escalation procedure.

Part B will evaluate the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Each cohort will enroll at least 10 response-evaluable subjects (evaluable for response is defined as a subject with a pre-dose and at least 1 post-dose disease assessment or clinical assessment of progression of disease).

Part C is will be a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part C will enroll up to 24 subjects.

Part D will evaluate the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects diagnosed with LGG and LCH. LGG cohort will enroll approximately 20 response-evaluable subjects and the LCH cohort will enroll approximately 10 response-evaluable subjects.

The overall goal of this trial is to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

This study is currently open for LCH and neuroblastoma only.

Inclusion Criteria

General Eligibility Criteria (All Parts)

• Written informed consent - a signed informed consent and/or assent (as age appropriate) for study participation including PK sampling will be obtained according to institutional guidelines.
• Male or female between one month and <18 years of age (inclusive) at the time of signing the informed consent form (Part C and Part D between 12 months and <18 years of age, inclusive).
• Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or must have a current disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.
• Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1] with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. All subjects must have recovered to grade <=1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy includes; myelosuppressive chemotherapy, differentiating agents/ biologic response modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent), non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem cell transplantation or infusion, number of prior treatment regimens, colony stimulating factors, corticosteroids.
• Performance score of >=50% according to the Karnofsky/Lansky performance status scale.
• Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs, throughout treatment period and for 4 months after last dose of study drugs.
• Must have adequate organ function as defined by the following values: renal function - 24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square (mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.
• Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube) administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for age, height, and gender.
• French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Specific Eligibility Criteria, Part A

• Subjects must meet general eligibility criteria.
• For the initial dose escalation to identify the maximum tolerable or PK target dose, age between 2 years and <18 years (inclusive) at the time of signing the informed consent form. Children < 2 years of age will be enrolled once the age specific expansion cohorts are open.
• Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the requirement for histological confirmation can be waived if a biopsy was not performed. For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiological findings, but should be considered if malignant degeneration of a PN is clinically suspected.
• Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is only detected by bone marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid (HVA/VMA) are not eligible.
• Adequate bone marrow function defined as absolute neutrophil count (ANC) >=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).

Specific Eligibility Criteria, Part B

• Subjects must meet general eligibility criteria. The specific eligibility criteria listed here will apply to subjects enrolling to different cohorts of Part B.
• Tumor tissue (archived or fresh) is required and must be available to be shipped to GSK or site specific laboratory.
• Solid tumor cohort (B1) specific criteria
  • B1: Refractory or relapsed neuroblastoma
  • B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion
  • B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant.
  • B4: BRAF V600 mutant tumors.

Specific Eligibility Criteria, Part C - Subjects must meet general eligibility criteria.

• Tumors that have been documented by CLIA or equivalent certified laboratory test to harbor BRAF V600 mutation at diagnosis or relapse
• Measurable or evaluable disease
• Adequate bone marrow function

Specific Eligibility Criteria, Part D - Subjects must meet general eligibility criteria

• Measurable or evaluable disease
• Recurrent or refractory BRAFV600 mutant LGG or LCH tumors
• Adequate bone marrow function

Exclusion Criteria

• Lactating or pregnant female.
• History of another malignancy including resected non-melanomatous skin cancer.
• Subjects with NF-1 associated optic pathway tumors are excluded if they are actively receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant solid tumor.
• Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).
• Subjects with NF-1 actively receiving therapy for the optic pathway tumor.
• Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis (only applicable to Part B).
• Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
• Any prohibited medication(s), currently used or expected to be required.
• Any medications for treatment of left ventricular systolic dysfunction.
• Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4. Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy, as determined by the investigator.
• Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment or excipients that contraindicate their participation.
• Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or liver metastases).
• History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 3 months.
• History of heparin-induced thrombocytopenia.
• History of interstitial lung disease or pneumonitis.
• History of or current evidence of retinal vein occlusion (RVO).
• For subjects with solid tumors that are not primary central nervous system (CNS) tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded. NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and are not currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at least 7 days prior to enrolment are permitted.
• A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.
• Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia.
• Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption of drugs.
• A history or evidence of cardiovascular risk including: a QT interval corrected for heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of current clinically significant uncontrolled arrhythmias (clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible); a history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; a history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators; abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. Subjects with prosthetic valves can be considered eligible provided they meet the criteria as stated above; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or above 95th age-specific percentile listed in protocol), which cannot be controlled by anti-hypertensive therapy.

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Study Description

This is a Phase I, open-label, dose escalation and dose expansion study with BID (suspension) and TID (tablet) oral dose of tazemetostat. Subjects will be screened for eligibility within 14 days of the planned first dose of tazemetostat. A treatment cycle will be 28 days. Response assessment will be evaluated after 8 weeks of treatment and subsequently every 8 weeks while on study.

The study has two parts: Dose Escalation and Dose Expansion.

Dose escalation for subjects with the following relapsed/refractory malignancies:

• Rhabdoid tumors:
• Atypical teratoid rhabdoid tumor (ATRT)
• Malignant rhabdoid tumor (MRT)
• Rhabdoid tumor of kidney (RTK)
• Selected tumors with rhabdoid features
• INI1-negative tumors:
• Epithelioid sarcoma
• Epithelioid malignant peripheral nerve sheath tumor
• Extraskeletal myxoid chondrosarcoma
• Myoepithelial carcinoma
• Renal medullary carcinoma
• Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) (with Sponsor approval)
• Synovial Sarcoma with a SS18-SSX rearrangement

Dose Expansion at the MTD or the RP2D

• Cohort 1 -(closed to enrollment) ATRT
• Cohort 2 - (closed to enrollment) MRT/RTK/selected tumors with rhabdoid features
• Cohort 3 - INI-negative tumors:
  • Epithelioid sarcoma
  • Epithelioid malignant peripheral nerve sheath tumor
  • Extraskeletal myxoid chondrosarcoma
  • Myoepithelial carcinoma
  • Renal medullary carcinoma
  • Chordoma (poorly differentiated or de-differentiated)
  • Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval
• Cohort 4 -(closed to enrollment) Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement

Inclusion Criteria

1. Age (at the time of consent/assent): ≥6 months to <18 years

   - Cohort 4 only: ≥10 years to <18 years

2. Performance Status:

   • If <12 years of age: Lanksy Performance Status >50%
   • If ≥12 years of age: Karnofsky Performance Status >50% NOTE: If subject is unable to walk due to paralysis, but is mobile in a wheelchair, subject is considered to be ambulatory for the purpose of assessing their performance status.
3. Has provided signed written informed consent/assent
4. Has a life expectancy of >3 months
5. Has relapsed or refractory disease and no standard treatment options as determined by locally or regionally available standards of care and treating physician's discretion
6. Is ineligible or inappropriate for other treatment regimens known to have effective potential
7. Has a documented local diagnostic pathology of original biopsy confirmed by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) or equivalent laboratory certification
8. Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade 1 per CTCAE, version 4.03 or are clinically stable and not clinically significant, at time of enrollment

9. Has completed a prior therapy (ies) according to the criteria below:

   • Other investigational study agent (any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric) (At least 30 days or five half-lives, whichever is longer, since last dose prior to the first dose of tazemetostat)
   • Chemotherapy: cytotoxic (At least 14 days since last dose of chemotherapy prior to first dose of tazemetostat)
   • Chemotherapy: nitrosoureas (At least 6 weeks since last dose of nitrosoureas prior to first dose of tazemetostat)
   • Chemotherapy: non-cytotoxic (e.g., small molecule inhibitor) (At least 14 days since last dose of non-cytotoxic chemotherapy prior to first dose of tazemetostat)
   • Monoclonal antibody (ies) (At least 28 days since the last dose of any monoclonal antibody prior to first dose of tazemetostat)
   • Immunotherapy (e.g., tumor vaccine) At least 6 weeks since last dose of immunotherapy agent(s) prior to first dose of tazemetostat)
   • Radiotherapy (RT) (At least 14 days from last local site RT prior to first dose of tazemetostat/At least 21 days from stereotactic radiosurgery prior to first dose of tazemetostat/At least 12 weeks from craniospinal, ≥ 50% radiation of pelvis, or total body irradiation prior to first dose of tazemetostat)
   • Hematopoietic growth factor (At least 14 days from last dose of hematopoietic growth factor prior to first dose of tazemetostat)
   • Hematopoietic cell transplantation (At least 60 days from infusion of hematopoietic cells prior to first dose of tazemetostat)

10. Has adequate hematologic (bone marrow and coagulation factors), renal and hepatic function as defined by criteria below:

    • Hematologic (BM Function):

      • Hemoglobin ≥ 8 g/dL
      • Platelets ≥100,000/mm^3 (≥100 x 10^9/L)
      • ANC ≥1,000/mm^3 (≥1.0 x 10^9/L)

    • Hematologic (Coagulation Factors):

      • INR/ PTd ≤1.5 ULN
      • PTT ≤1.5 ULN
      • Fibrinogen ≥0.75 LLN

    • Renal Function (creatinine clearance or serum creatinine):

      • Calculated creatinine clearance ≥50 mL/min/1.73m^2
      • Serum creatinine 6 months to 1 year: male 0.6 mg/dL (53 µmol/L) female 0.5 mg/dL (44 µmol/L)
      • Serum creatinine 1 to < 2 years: male 0.6 mg/dL (53 µmol/L) female 0.6 mg/dL (53 µmol/L)
      • Serum creatinine 2 to < 6 years: male 0.8 mg/dL (71 µmol/L) female 0.8 mg/dL (71 µmol/L)
      • Serum creatinine 6 to <10 years: male 1 mg/dL (88 µmol/L) female 1 mg/dL (88 µmol/L)
      • Serum creatinine 10 to <13 years: male 1.2 mg/dL (106 µmol/L) female 1.2 mg/dL (106 µmol/L)
      • Serum creatinine 13 to <16 years: male 1.5 mg/dL (133 µmol/L) female 1.4 mg/dL (125 µmol/L)
      • Serum creatinine ≥16 years: male 1.7 mg/dL (150 µmol/L) female 1.4 mg/dL (125 µmol/L)

    • Hepatic Function:

      • Total bilirubin <1.5 x ULN
      • ALT or AST <3 x ULN Eligibility can be determined by either total or conjugated bilirubin

11. For subjects with CNS involvement: Subjects must have deficits that are stable for a minimum of 14 days prior to enrollment, or seizures that are stable, not increasing in frequency or severity and controlled on current anti-seizure medication(s) for a minimum of 7 days prior to enrollment

    NOTE: Subjects with leptomeningeal disease or brian tumors with positive cerebral spinal fluid cytology are eligible for this study. Subjects may receive glucocorticoids (at stable or tapering dose) to control CNS symptoms prior to enrollment; however, subjects should receive a stable or tapering dose for at least 7 days prior to enrollment.

12. Has a shortening fraction of >27% or an ejection fraction of ≥50% by echocardiogram or multi-gated acquisition scan and New York Heart Association Class<2
13. Has a QT interval corrected by Fridericia's formula (QTcF) ≤450 msec
14. Is able to swallow and retain orally administered medication and does not have any uncontrolled gastrointestinal (GI) condition such as nausea, vomiting, or diarrhea, or any clinically significant GI abnormalities that may alter absorption such as malabsorption syndromes, hereditary fructose intolerance, glucose-galactose malabsorption, sucrose-isomaltase insufficiency, or major resection of stomach and/or bowels NOTE: Nasogastric and gastrostomy tube administration of the oral suspension formulation of study drug is permitted.
15. Has sufficient tumor tissue (slides or blocks) available for central confirmatory testing of immunohistochemistry and/or cytogenetics/fluorescence in situ hybridization (FISH) and/or deoxyribonucleic acid mutation analysis (required for study entry but enrollment based on local results)
16. Is willing and able to comply with all aspects of the protocol as judged by Investigator

17. For female subjects of childbearing potential: Subject must:

    • Have a negative beta-human chorionic gonadotropin (β-hCG) pregnancy test at time of Screening and within 72 hours prior to planned first dose of tazemetostat (urine or serum test is acceptable however, positive urine tests must be confirmed with serum testing), and
    • Agree to use effective contraception, as defined in Section 8.6.11 start of Screening until 6 months following the last dose of study treatment and have a male partner who uses a condom, or
    • Practice true abstinence (when this is in line with the preferred and usual lifestyle of the subject, see Section 8.6.11, or
    • Have a male partner who is vasectomized with confirmed azoospermia

18. For male subjects with a female partner of childbearing potential: Subject must:

    • Be vasectomized or
    • Agree to use condoms as defined in Section 8.5.11 from first dose of tazemetostat until 3 months following the last dose of tazemetostat, or
    • Have a female partner who is NOT of childbearing potential

For Dose Escalation Only:

To be eligible for enrollment in dose escalation, a subject must meet ALL of the following criteria in addition to the inclusion criteria listed above for all subjects:

1. Has evaluable disease as defined as lesions that can be accurately measured at least in one dimension by radiographic examination or physical examination and other lesions such as bone lesions, leptomeningeal disease, ascites, hepatosplenomegaly from disease.

2. Has one of the following histologically confirmed tumors: (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available)

   • Rhabdoid tumor:

     • ATRT (Closed to enrollment)
     • MRT
     • RTK
     • Selected tumors with rhabdoid features

   • NI1-negative tumor:

     • Epithelioid sarcoma
     • Epithelioid malignant peripheral nerve sheath tumor
     • Extraskeletal myxoid chondrosarcoma
     • Myoepithelial carcinoma
     • Renal medullary carcinoma
     • Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval
   • Synovial sarcoma with SS18-SSX rearrangement (NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP certified laboratory must be available) (Closed to enrollment)
3. For subjects with ATRT, MRT, RTK, or selected tumors with rhabdoid features only: the following test results must be available: Morphology and immunophenotypic panel consistent with rhabdoid tumor and Loss of INI1 or SMARCA4 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

4. For subjects with INI1 negative tumor only:

   the following test results must be available: Morphology and immunophenotypic panel consistent with INI1-negative tumors, and Loss of INI1 confirmed by IHC, or Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable

5. For subjects with synovial sarcoma only:

The following test results must be available:

Morphology consistent with synovial sarcoma, and Cytogenetics or FISH and/or molecular confirmation (e.g., DNA sequencing) of SS18 rearrangement t(X;18)(p11;q11)

For Dose Expansion Only:

Note: To be eligible for enrollment in Dose Expansion, a subject must meet ALL of the following criteria in addition to the inclusion criteria for ALL subjects listed above

1. Has measurable disease

2. Has one of the following histologically confirmed tumors:

   • Cohort 1 - ATRT (Closed to enrollment)
   • Cohort 2 - MRT/RTK/selected tumors with rhabdoid features(Closed to enrollment)
   • Cohort 3 - INI-negative tumors:
     • Epithelioid sarcoma
     • Epithelioid malignant peripheral nerve sheath tumor
     • Extraskeletal myxoid chondrosarcoma(EMC)
     • Myoepithelial carcinoma
     • Renal medullary carcinoma
     • Chordoma (poorly differentiated or de-differentiated)
     • Other INI1-negative malignant tumors (e.g., dedifferentiated chordoma) with Sponsor approval
   • Cohort 4 - Tumor types eligible for Cohorts 1 through 3 or synovial sarcoma with SS18-SSX rearrangement (Closed to enrollment) NOTE: Evidence of diagnostic pathology of original biopsy confirmed by a CLIA/CAP or other Sponsor-approved certified laboratory must be available.

3. For subjects with ATRT/MRT/RTK only - have the following test results available:

   • Morphology and immunophenotypic panel consistent with rhabdoid tumor, and
   • Loss of INI1 or SMARCA4 confirmed by IHC, or
   • Molecular confirmation of tumor bi-allelic INI1 or SMARCA4 loss/mutation when INI1 or SMARCA4 IHC is equivocal or unavailable

4. For subjects with INI1-negative tumors only: The following test results must be available:

   • Morphology and immunophenotypic panel consistent with INI1-negative tumors, and
   • Loss of INI1 confirmed by IHC, or
   • Molecular confirmation of tumor bi-allelic INI1 loss/mutation when INI1 IHC is equivocal or unavailable

5. For subjects with synovial sarcoma with SS18-SSX rearrangement (in Cohort 4 ONLY - Closed to enrollment): The following test results must be available:

   • Morphology consistent with synovial sarcoma, and
   • Cytogenetics or FISH and/or molecular confirmation (e.g., deoxyribonucleic acid [DNA] sequencing) of SS18 rearrangement t(X;18)(p11;q11)
6. For subjects to be enrolled in Cohort 4 (Closed to enrollment): Able to swallow and retain orally administered tablets

Exclusion Criteria

1. Has had prior exposure to tazemetostat or other inhibitor(s) of EZH2
2. Is being actively treated for another concurrent malignancy or is less than five years from completion of treatment for another malignancy
3. Has participated in another interventional clinical study and received investigational drug within 30 days or 5 half-lives, whichever is longer, prior to the planned first dose of tazemetostat
4. Has had major surgery within 2 weeks prior to enrollment NOTE: Minor surgery (e.g., minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 2 weeks prior to enrollment.

5. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE 4.03 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS). Has abnormalities known to be associated with MDS (e.g. del 5q, chr 7 abn) and MPN (e.g. JAK2 V617F) observed in cytogenetic testing and DNA sequencing.

   Note: Bone marrow aspirate/biopsy will be conducted following abnormal peripheral blood smear morphology assessment conducted by central lab at screening. Cytogenetic testing and DNA sequencing will be conducted following an abnormal result of bone marrow aspirate/biopsy.

6. Has a prior history of T-LBL/T-ALL.
7. Has clinically active heart disease including prolonged corrected QTcF (>450 msec)
8. Is currently taking any prohibited medication(s) as described in Section 7.3.
9. Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from time of enrollment to while on study
10. Has an active infection requiring systemic treatment
11. Is immunocompromised (i.e. congenital immunodeficiencies), including subjects known history of infection with human immunodeficiency virus (HIV)
12. Has known history of chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (detectable HCV RNA)
13. Has had a symptomatic venous thrombosis within the 14 days prior to study enrollment NOTE: Subjects with a history of a deep vein thrombosis 14 days prior to study enrollment who are on anticoagulation therapy with low molecular weight heparin are eligible for this study
14. For subjects with CNS involvement (primary tumor or metastatic disease): Have any active bleeding, or new intratumoral hemorrhage of more than punctate size on Screening MRI obtained within 14 days of starting study drug,or known bleeding diathesis or treatment with anti-platelet or anti-thrombotic agents 15.15. Has known hypersensitivity to any of the components of tazemetostat or other inhibitor(s) of EZH2, or hypersensitivity to Ora-sweet or methylparaben

16. Has an uncontrolled intercurrent illness including, but not limited to, uncontrolled infection, or psychiatric illness/social situations that would limit compliance with study requirements 17. For female subjects of childbearing potential: Is pregnant or nursing For male subjects: Is unwilling to adhere to contraception criteria from time of enrollment in study to at least 30 days after last dose of tazemetostat.

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Study Description

The purpose of Phase 1b of this study is to:

• Asses the safety, tolerability and activity of carfilzomib, alone and in combination with induction chemotherapy, in children with relapsed or refractory acute lymphoblastic leukemia (ALL).
• Determine the maximum tolerated dose (MTD) and to recommend a phase 2 dose of carfilzomib in combination with induction chemotherapy.

The purpose of Phase 2 of this study is to compare the rate of complete response (CR) of carfilzomib in combination with vincristine, dexamethasone, PEG asparaginase, daunorubicin (VXLD) at the end of induction therapy to an appropriate external control.

Inclusion Criteria

Phase 1b Key Inclusion Criteria:

1. Age 21 years or younger at the time of initial ALL diagnosis and age > 1 year at the time of study treatment initiation.

2. Subjects must have a diagnosis of relapsed or refractory ALL with ≥ 5% blasts in the bone marrow (M2 or M3 disease), with or without extramedullary disease.

   -To be eligible, subjects must have had 1 or more prior therapeutic attempts, defined as:

   • Early first relapse (< 36 months from original diagnosis) after achieving a CR (B-ALL) or first relapse any time following the original diagnosis after achieving a CR (T-ALL)
   • First refractory bone marrow relapse occurring any time after original diagnosis after achieving a CR (ie, ≥1 failed attempt to induce a second remission) OR
   • Relapse after achieving a CR following the first or subsequent relapse (i.e., ≥ 2 relapses) OR
   • Failing to achieve a CR from original diagnosis after at least 1 induction attempt
3. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment.
4. Subjects must have a serum creatinine level that is ≤ 1.5 × institutional upper limit of normal (ULN) according to age. If serum creatinine level is > 1.5 × ULN, the subject must have a calculated creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70 mL/min/1.73 m2.

5. Adequate liver function, defined as both of the following:

   • Total bilirubin ≤ 1.5 × institutional ULN except in the presence of Gilbert Syndrome
   • Alanine aminotransferase (ALT) ≤ 5 × institutional ULN
6. Performance status: Karnofsky or Lansky scores ≥ 50 for subjects > 16 years old or ≤ 16 years old, respectively.

Phase 2 Inclusion Criteria:

1. Subject's legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
2. Age ≥ 1 month to < 21 years. Subjects ≥ 18 years must have had their original diagnosis at < 18 years of age.
3. Subjects must be diagnosed with relapsed or refractory relapsed ALL.
4. Subjects must have a documented first remission, ≤ 5% blasts in the bone marrow (M1 bone marrow) and no evidence of extramedullary disease.

5. T-cell ALL with bone marrow relapse (defined as ≥ 5% leukemia blasts in bone marrow) or refractory relapse with or without extramedullary disease.

   OR B-cell ALL bone marrow relapse or refractory relapse (defined as ≥ 5% leukemia blasts in bone marrow) after having received a targeted B-cell immune therapy as treatment for a prior relapse (eg, blinatumomab, inotuzumab or a CAR-T therapy) with or without extramedullary disease. Subjects that receive blinatumomab for treatment of MRD positive disease during first remission do not qualify.

6. Adequate liver function: bilirubin ≤ 1.5 x upper limit of normal (ULN), alanine aminotransferase (ALT) ≤ 5 x ULN.
7. Adequate renal function: serum creatinine ≤ 1.5 x ULN or glomerular filtration rate (GFR) ≥ 70 ml/min/1.73m^2; or for children < 2 years of age ≥ 50 ml/min/1.73m^2.
8. Adequate cardiac function: shortening fraction > 30% or ejection fraction ≥ 50%.
9. Karnofsky (subjects ≥ 16 years of age) or Lansky (subjects 12 months to < 16 years of age) performance status ≥ 50%.
10. Subjects must have fully recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy treatment before enrollment (for example: recovery from gastrointestinal toxicity may occur more rapidly than less reversible organ toxicities such as sinusoidal obstruction syndrome or non-infectious pneumonitis, for serious prior toxicities recommended discussion with Amgen medical monitor).
11. Life expectancy of ≥ 6 weeks per investigator's judgement at time of screening.

Exclusion Criteria

Phase 1b Key Exclusion Criteria:

1. Known allergy to any of the drugs used in the study (Subjects who have had a previous allergy to PEG-asparaginase and if able, may receive Erwinia asparaginase at the investigator's discretion)
2. Known allergy to Captisol (a cyclodextrin derivative used to solubilize carfilzomib)
3. Left ventricular fractional shortening < 30%
4. History of ≥ Grade 2 pancreatitis
5. Active graft-versus-host disease requiring systemic treatment
6. Positive culture for or other clinical evidence of infection with bacteria or fungus within 14 days of the initiation of study treatment
7. Down Syndrome

8. Prior therapy restrictions:

   • Subjects must have completed therapy with granulocyte-colony stimulating factor (G-CSF) or other myeloid growth factors at least 7 days before study treatment initiation, or at least 14 days before study treatment initiation, if pegylated myeloid growth factors were administered.
   • Subjects must have completed any type of active immunotherapy (e.g., tumor vaccines) at least 42 days before study treatment initiation.
   • Subjects must have received the last dose of a non-monoclonal antibody biologic agent at least 7 days before study treatment initiation.
   • At least 3 antibody half-lives must have elapsed since the last dose of monoclonal antibody (e.g., 66 days for rituximab and 69 days for epratuzumab) before subjects may initiate study treatment.
   • Subjects must not have received other antineoplastic agents with therapeutic intent, excluding hydroxyurea and antimetabolites administered as part of maintenance chemotherapy, within 7 days prior to study treatment initiation.
9. Hepatitis B infection with positive hepatitis B DNA

Phase 2 Exclusion Criteria:

1. Prior treatment with carfilzomib.
2. Prior treatment with a proteasome inhibitor (other than carfilzomib) within < 3 months of enrollment or to which a subject did not respond (response is defined as bone marrow with < 5% blasts).
3. Treatment with a chemotherapy regimen including a vinca alkaloid, steroid, L-asparaginase, and anthracycline combination with or without other chemotherapy agents within 2 months of enrollment (eg VXLD, VPLD, R3).
4. Intolerance, hypersensitivity, or inability to receive any of the chemotherapy components of the VXLD regimen. An exception is allowed for allergy to asparaginase products if Erwinia Asparaginase is unable to be administered, or if PEG-Asparaginase or Erwinia Asparaginase are not available in the country, these subjects may still be included.
5. Autologous HSCT within 6 weeks prior to start of study treatment.
6. Allogeneic HSCT within 3 months prior to start of study treatment.
7. Active GVHD requiring systemic immune suppression.
8. < 30 days from discontinuation of immune suppressive therapy administered for the treatment of acute or chronic GVHD.
9. Isolated extramedullary relapse.
10. Positive bacterial or fungal infection within 14 days of enrollment (except for documented line infection, line has been removed, and blood culture after line removal is negative for 5 days prior to first dose of induction therapy). Antibiotics may be administered for prophylaxis as per institutional standards up to and after enrollment.
11. < 3 antibody half-lives since the last dose of monoclonal antibody (eg, 66 days for rituximab, 69 days for epratuzumab, inotuzumab for 36 days), prior to first dose of investigational product.
12. Cell-based immunotherapy (eg, donor leucocyte infusion, CAR-T cells, tumor vaccines) within 42 days prior to first dose of investigational product. If the Amgen medical monitor agrees, an exception may be granted to the 42-day requirement for subjects with rapidly rising peripheral or bone marrow blast counts.
13. Down's syndrome.
14. Presence of another active cancer.
15. History of grade ≥ 2 pancreatitis within 6 months to screening.
16. Unresolved toxicities from prior anticancer therapy, defined as not having resolved to CTCAE version 4.03 grade 1 or to levels dictated in the eligibility criteria apart from alopecia or toxicities from prior anticancer therapy that are considered irreversible and do not trigger another exclusion criterion (defined as having been present and stable for > 4 weeks).
17. Antitumor therapy (chemotherapy, investigational agents, molecular-targeted therapy) within 7 days of day 1 of induction. Exception: hydroxyurea to control peripheral blood leukemic cell counts is allowed until start of investigational product.
18. Active viral infection, including but not limited to CMV, Hepatitis B infection with positive serum hepatitis surface antigen or hepatitis B DNA, HIV, Hepatitis C with detectable hepatitis C RNA.
19. Currently receiving treatment in another investigational device or product study, or < 14 days since ending treatment on another investigational device or product study.
20. Uncontrolled arrhythmias or screening ECG with corrected QT interval (QTc) of > 470 msec.
21. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
22. Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional months after the last dose of any study treatment or for 12 months after last dose of cyclophosphamide if administered during optional consolidation cycle.
23. Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 12 months after the last dose of any study treatment. Refer to Section 28 for additional contraceptive information.
24. Female subjects of childbearing potential with a positive pregnancy test assessed at Screening by a serum or urine pregnancy test.
25. Male subjects with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use a condom with spermicide during treatment and for an additional 6 months after the last dose of any study treatment, even if they have undergone a successful vasectomy.
26. Male subjects with a pregnant partner who are unwilling to practice abstinence or use a condom with spermicide during treatment, for duration of pregnancy, and for an additional 6 months after the last dose of any study treatment.
27. Male subjects unwilling to abstain from donating semen or sperm during treatment and for an additional 6 months after the last dose of any study treatment.

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Study Description

This study will compare three treatment regimens containing metaiodobenzylguanidine (MIBG) and compare their effects on tumor response and associated side effects, to determine if one therapy is better than the other for people diagnosed with relapsed or persistent neuroblastoma.

(From NANT website - https://www.nant.org/n2011-01/)

The purpose of this study is to compare three different treatments using the investigational medicine called ¹³¹I-Metaiodobenzylguanidine (MIBG).  MIBG is taken up by neuroblastoma tumor cells, and can be combined together with radioactive iodine ¹³¹ in the laboratory to form the radioactive compound ¹³¹I-MIBG. The ¹³¹I-MIBG compound delivers radiation treatment when it is taken up by neuroblastoma cancer cells throughout the body.   Although testing in laboratories has found that adding other agents can improve the response of neuroblastoma tumor cells to 131 I-MIBG, it is not known if adding other agents to the 131 I-MIBG will increase the number of tumors in patients that will respond to the therapy.  

The three treatment arms on this study are:  1) 131 I-MIBG alone, 2) 131 I-MIBG with Irinotecan and Vincristine, or 3) 131 I-MIBG with Vorinostat.  Patients on all treatment arms will receive autologous (their own) stem cells as part of this therapy.  All three 131 I-MIBG treatment regimens have already been used for the treatment of neuroblastoma and shown tumor responses, and their tolerated doses have been determined.  This study will compare the number of tumor responses seen with each of the three different treatment arms.

Once patients are registered on this study, they will be randomly assigned to one of the three treatment arms.  Random assignment means that the assignment is based on chance. It is like a flip of a coin, and assignment is done by a computer. Neither patients nor their physicians will choose the treatment. All patients will have an equal chance of being assigned to each of the three treatment arms. A total of 105 patients are expected to enroll on this study. There will be 35 patients on each treatment arm.

Inclusion Criteria

• Patients must be > 24 months and < 30 years of age when registered on study.
• Patients must have relapsed neuroblastoma, refractory neuroblastoma that had less than a partial response to standard treatment or persistent neuroblastoma that had at least a partial response to frontline therapy frontline therapy with > 3 residual lesions on end-induction MIBG scan.
• Patients must have evidence of MIBG uptake into tumor at ≥ one site within 4 weeks prior to entry on study and subsequent to any intervening therapy.
• Patients must have adequate heart, kidney, liver and bone marrow function. Patients who have bone marrow disease must still have adequate bone marrow function to enter the study.
• Patients must have a dose of unpurged peripheral blood stem cells is 2.0 x 106 viable CD34+ cells/kg available.

Exclusion Criteria

• They have had previous I-131 MIBG therapy
• They have other medical problems that could get much worse with this treatment.
• They are pregnant or breast feeding.
• They have a history of a venous or arterial thrombosis that was not associated to a central line.
• They have active infections such as hepatitis or fungal infections.
• They have active diarrhea.
• They have had an allogeneic stem cell transplant (received stem cell from someone else)
• They can't cooperate with the special precautions that are needed for this trial.