Pevonedistat, Irinotecan Hydrochloride, and Temozolomide in Treating Patients With Recurrent or Refractory Solid Tumors or Lymphoma

Status: Recruiting
Phase:
DFCI Protocol ID: 17-746

This phase I trial studies the side effects and best dose of pevonedistat when giving together with irinotecan hydrochloride and temozolomide in treating patients with solid tumors or lymphoma that have come back after a period of improvement or that do not respond to treatment. Pevonedistat and irinotecan hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pevonedistat, irinotecan hydrochloride, and temozolomide may work better in treating patients with solid tumors or lymphoma.

Conducting Institutions:

Children's Hospital Boston, Dana-Farber Cancer Institute

Overall PI:

Steven Dubois MD, Dana Farber Cancer Institute

Site-responsible Investigators:

Contacts:

Dana-Farber Cancer Institute: Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, ctip@partners.org

Eligibility Criteria

Inclusion Criteria:

  -  Patients with recurrent or refractory solid tumors, including CNS tumors and lymphoma,
     are eligible; patients must have had histologic verification of malignancy at original
     diagnosis or relapse except in patients with intrinsic brain stem tumors, optic
     pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid
     (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic
     gonadotropin (HCG)

  -  Patients must have either measurable or evaluable disease

  -  Patient?s current disease state must be one for which there is no known curative
     therapy or therapy proven to prolong survival with an acceptable quality of life

  -  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 time frame,
     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;
  at least 21 days after the last dose of cytotoxic or myelosuppressive
  chemotherapy (42 days if prior nitrosourea); the duration of this interval must
  be discussed with the study chair and the study-assigned research coordinator
  prior to enrollment

       -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
  reduced platelet or absolute neutrophil counts [ANC] counts): >= 7 days after the
  last dose of agent; the duration of this interval must be discussed with the
  study chair and the study-assigned research coordinator prior to enrollment

       -  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. Neulasta) 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; 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 brain metastases (BM)
  radiation

       -  Radiopharmaceutical therapy (e.g., radiolabeled antibody,
  131I-metaiodobenzylguanidine [MIBG]): >= 42 days after systemically administered
  radiopharmaceutical therapy

       -  Patients must not have received prior exposure to pevonedistat; patients with
  prior exposure to irinotecan or temozolomide are eligible

  -  For patients with solid tumors without known bone marrow involvement:

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

       -  Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
  platelet transfusions for at least 7 days prior to enrollment)

       -  Hemoglobin > 8 g/dL

  -  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; at least 5 of every cohort of 6 patients must be evaluable
     for hematologic toxicity for the dose-escalation part of the study; if dose-limiting
     hematologic toxicity is observed, all subsequent patients enrolled must be evaluable
     for hematologic toxicity

  -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 50
     mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

       -  Age: 1 to < 2 years maximum serum creatinine (mg/dL): male: 0.6; female: 0.6

       -  Age: 2 to < 6 years maximum serum creatinine (mg/dL): male: 0.8; female: 0.8

       -  Age: 6 to < 10 years maximum serum creatinine (mg/dL): male: 1; female: 1

       -  Age: 10 to < 13 years maximum serum creatinine: (mg/dL): male: 1.2; female: 1.2

       -  Age: 13 to < 16 years maximum serum creatinine: (mg/dL): male: 1.5; female: 1.4

       -  Age: >= 16 years maximum serum creatinine: (mg/dL) male: 1.7; female: 1.4

  -  Bilirubin (sum of conjugated + unconjugated) =< upper limit of normal (ULN) for age

  -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransaminase [ALT]) =< 135
     U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

  -  Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase) [AST]); =<
     150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L

  -  Serum albumin >= 2.7 g/dL

  -  Shortening fraction of >= 27% by echocardiogram, or

  -  Ejection fraction of >= 50% by gated radionuclide study

  -  No supraventricular arrhythmia on electrocardiogram (EKG)

  -  Prolonged rate corrected QT (QTc) interval < 500 msec

  -  Pulse oximetry > 94% on room air if there is clinical indication for determination
     (e.g. dyspnea at rest)

  -  Patients with seizure disorder may be enrolled if on anti-convulsants and well
     controlled

  -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
     version [v] 4) resulting from prior therapy must be =< grade 2

  -  International normalized ratio (INR) =< 1.5

  -  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; 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 practice 1 highly effective and 1 additional effective (barrier) method of
     contraception at the same time during the entire study treatment period and through 4
     months after the last dose of study drug, or agree to practice true abstinence, when
     this is in line with the preferred and usual lifestyle of the subject; periodic
     abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods),
     withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of
     contraception

  -  Patients with uncontrolled high blood pressure (i.e., systolic blood pressure > 99th
     percentile) are not eligible

  -  Patients with known cardiopulmonary disease are not eligible; cardiopulmonary disease
     is defined as:

       -  Cardiomyopathy other than chemotherapy related changes in cardiac function that
  meet the eligibility requirements

       -  Clinically significant arrhythmia:

    -  History of polymorphic ventricular fibrillation or torsade de pointes,

    -  Permanent atrial fibrillation (a fib), defined as continuous a fib for ? 6
       months,

    -  Persistent a fib, defined as sustained a fib lasting > 7 days and/or
       requiring cardioversion in the 4 weeks before screening,

    -  Grade 3 a fib defined as symptomatic and incompletely controlled medically,
       or controlled with device (e.g. pacemaker), or ablation and

    -  Patients with paroxysmal a fib or < grade (Gr) 3 a fib for period of at
       least 6 months are permitted to enroll provided that their rate is
       controlled on a stable regimen

       -  Implantable cardioverter defibrillator;

       -  Moderate to severe aortic and/or mitral stenosis or other valvulopathy (ongoing);

       -  Pulmonary hypertension

       -  Congestive heart failure class III or IV

  -  Patients with known hepatic cirrhosis or severe pre-existing hepatic impairment are
     not eligible

  -  Patients with uncontrolled coagulopathy or bleeding disorder are not eligible

  -  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 must not have received enzyme-inducing anticonvulsants for at least 7 days
     prior to enrollment

  -  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 receiving any investigational agent other than pevonedistat,
     including but not limited to androgens, supraphysiologic doses of corticosteroids,
     erythropoietin, eltrombopag, or romiplostim

  -  Patients who have received drugs that are strong or moderate inhibitors and/or
     inducers of CYP3A4 within 14 days prior to enrollment are not eligible; while on
     study, the following BCRP inhibitors (cyclosporine, eltrombopag, gefitinib) should be
     avoided if possible, and concomitant use of UGT1A1 inhibitors, such as diclofenac,
     ketoconazole, probenecid, silibinin, nilotinib and atazanavir, should be avoided
     because of potential for increased irinotecan toxicity

  -  Patients who have an uncontrolled infection are not eligible

  -  Patients who have received a prior solid organ transplantation are not eligible

  -  Patients with known human immunodeficiency virus (HIV) seropositive are not eligible

  -  Patients with known hepatitis B surface antigen seropositive or known or suspected
     active hepatitis C infection are not eligible; NOTE: patients who have isolated
     positive hepatitis B core antibody (i.e., in the setting of negative hepatitis B
     surface antigen and negative hepatitis B surface antibody) must have an undetectable
     hepatitis B viral load; patients who have positive hepatitis C antibody may be
     included if they have an undetectable hepatitis C viral load

  -  Patients who in the opinion of the investigator may not be able to comply with the
     safety monitoring requirements of the study are not eligible

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