WEE1 Inhibitor MK-1775 and Irinotecan Hydrochloride in Treating Younger Patients With Relapsed or Refractory Solid Tumors

Status: Recruiting
Phase:
DFCI Protocol ID: 16-447

This phase I/II trial studies the side effects and best dose of WEE1 inhibitor MK-1775 and irinotecan hydrochloride in treating younger patients with solid tumors that have come back or that have not responded to standard therapy. WEE1 inhibitor MK-1775 and irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Conducting Institutions:

Dana-Farber Cancer Institute, Children's Hospital Boston

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 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)

  -  Part A: Patients with relapsed or refractory solid tumors, including patients with
     primary or metastatic CNS tumors

  -  Part B: Patients with relapsed or refractory neuroblastoma

  -  Part C: Patients with relapsed or refractory medulloblastoma or CNS PNET

  -  Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment if
     enrolling on dose levels 1-5; patients must have a body surface area >= 0.46 m^2 at
     the time of study enrollment if enrolling on dose level 0

  -  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 chemotherapy

  -  At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if
     prior nitrosourea)

  -  At least 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

  -  At least 7 days after the last dose of a biologic agent; 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

  -  At least 42 days after the completion of any type of immunotherapy, e.g. tumor
     vaccines

  -  At least 3 half-lives of the antibody after the last dose of a monoclonal antibody

  -  At least 14 days after local palliative radiation therapy (XRT) (small port); at
     least 150 days must have elapsed if prior traumatic brain injury (TBI), craniospinal
     XRT or if >= 50% radiation of pelvis; at least 42 days must have elapsed if other
     substantial bone marrow radiation, including therapeutic doses of Iobenguane (MIBG)

  -  Stem cell Infusion without TBI: no evidence of active graft vs host disease and at
     least 84 days must have elapsed after transplant or stem cell infusion

  -  Patients previously treated with irinotecan are eligible for this study

  -  For patients with solid tumors without known bone marrow involvement: peripheral
     absolute neutrophil count (ANC) >= 1000/mm^3

  -  For patients with solid tumors without known bone marrow involvement: platelet count
     >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet
     transfusions for at least 7 days prior to enrollment)

  -  For patients with solid tumors without known bone marrow involvement: hemoglobin >=
     8.0 g/dL (may receive red blood cell [RBC] transfusions)

  -  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 2 of every cohort of 3 patients must
     be evaluable for hematologic toxicity for Part A, 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) >= 70
     ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

       -  Age 1 to < 2 years: 0.6 mg/dL

       -  Age 2 to < 6 years: 0.8 mg/dL

       -  Age 6 to < 10 years: 1 mg/dL

       -  Age 10 to < 13 years: 1.2 mg/dL

       -  Age 13 to < 16 years: 1.5 mg/dL (males), 1.4 mg/dL (females)

       -  Age >= 16 years: 1.7 mg/dL (males), 1.4 mg/dL (females)

  -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
     age

  -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
     U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

  -  Serum albumin >= 2 g/dL

  -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
     anticonvulsants and well controlled

  -  Nervous system disorders (Common Terminology Criteria for Adverse Events version 4
     [CTCAE v4]) resulting from prior therapy must be =< grade 2

  -  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

  -  Tissue blocks or slides must be sent if available, with exclusions; if tissue blocks
     or slides are unavailable, the study chair must be notified prior to study enrollment

  -  Patients must be able to swallow capsules

Exclusion Criteria:

  -  Pregnant or breast-feeding women may 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 use an effective double barrier contraceptive method for the entire
     duration of protocol therapy and for 3 months (males) and 1 month (females) after
     study drug discontinuation

  -  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

  -  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 currently receiving drugs that are strong or moderate inhibitors
     and/or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) or
     sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are
     not eligible; the use of aprepitant as an antiemetic is prohibited; caution should be
     exercised with concomitant administration of MK-1775 and agents that are sensitive
     substrates of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), 2C9 and
     2C19, or substrates of this enzyme with narrow therapeutic ranges, as well as agents
     that are inhibitors or substrates of permeability glycoprotein (P-gp)

  -  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 must not have received enzyme inducing anticonvulsants for at least 14 days
     prior to enrollment

  -  Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart
     failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not
     eligible for this trial

  -  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

  -  Patients with a history of allergic reaction to irinotecan, cephalosporins or a
     severe penicillin allergy are not eligible

  -  Patients unable to swallow capsules whole are not eligible; nasogastric or gastric
     (G) tube administration is not allowed

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