Inclusion Criteria:
- - Parts A and B1: Patients must be >= 12 months and =< 21 years of age at the time of
study enrollment.
- - Part B2 (relapsed/refractory osteosarcoma): Patients must be >= 12 months and =< 30
years of age at the time of study enrollment.
- - Patients must have had histologic verification of malignancy at original diagnosis or
relapse, except in patients with diffuse intrinsic brain stem tumors, 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 or lymphoma, including
patients with CNS tumors or known CNS metastases (including untreated or
progressive) are eligible.
- - Part B1: Patients with progressive or recurrent DIPG (diagnosed by biopsy or
imaging characteristics) and other H3 K27M-mutant diffuse midline gliomas
previously treated with radiation therapy.
- - Part B2: Patients with relapsed or refractory osteosarcoma.
- - Part A: Patients must have either measurable or evaluable disease.
- - Part B1 and B2: Patients must have measurable 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.
- - Patients must have a performance status corresponding to Easter Cooperative Oncology
Group (ECOG) scores of 0, 1 or 2.
Use Karnofsky for patients > 16 years of age and
Lansky for patients =< 16 years of age. Patients must have a Karnofsky or Lansky score
>= 50%
- - Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment.
If after the required timeframe, the
numerical eligibility criteria are met, e.g., blood count criteria, the patient is
considered to have recovered adequately.
- - Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive.
- - Solid tumor patients: >= 21 days after the last dose of myelosuppressive
chemotherapy (42 days if prior nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (eg, not associated with
reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
last dose of agent.
- - Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1.
- - Corticosteroids: If used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid.
Patients
with CNS tumors receiving corticosteroids must have been on a stable or
decreasing dose of corticosteroid for at least 7 days prior to enrollment.
- - Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
growth factor (e.g., pegfilgrastim) or 7 days for short acting growth factor.
For
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, 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: >= 30 days.
- - Cellular therapy: >= 42 days after the completion of any type of cellular therapy
(e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)
- Radiation therapy [XRT]/external beam irradiation including protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >=
50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation.
- - Radiopharmaceutical therapy (e.g., radiolabeled antibody, I-131
metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered
radiopharmaceutical therapy.
- - Patients must not have received prior exposure to CBL0137.
- - For patients with solid tumors without known bone marrow involvement:
- Peripheral absolute neutrophil count (ANC) >= 1000/uL (performed within 7 days
prior to enrollment unless otherwise indicated)
- 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.
- - For patients with solid tumors without known bone marrow involvement:
- Platelet count >= 100,000/uL (transfusion independent, defined as not receiving
platelet transfusions for at least 7 days prior to enrollment) (performed within
7 days prior to enrollment unless otherwise indicated)
- 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) >= 70
mL/min/1.73 m^2 or a creatinine based on age/gender as follows (performed within 7
days prior to enrollment unless otherwise indicated):
- Age: Maximum serum creatinine (mg/dL)
- 1 to < 2 years: 0.6 (male); 0.6 (female)
- 2 to < 6 years: 0.8 (male); 0.8 (female)
- 6 to < 10 years: 1 (male); 1 (female)
- 10 to < 13 years: 1.2 (male); 1.2 (female)
- 13 to < 16 years: 1.5 (male); 1.4 (female)
- >= 16 years: 1.7 (male); 1.4 (female)
- Patients with solid tumors:
- Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of
normal (ULN) for age (performed within 7 days prior to enrollment unless
otherwise indicated)
- Patients with solid tumors:
- Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =<
135 U/L.
For the purpose of this study, the ULN for SGPT is 45 U/L (performed
within 7 days prior to enrollment unless otherwise indicated)
- - Shortening fraction of >= 27% by echocardiogram (performed within 7 days prior to
enrollment unless otherwise indicated)
- Ejection fraction of >= 50% by gated radionuclide study (performed within 7 days prior
to enrollment unless otherwise indicated)
- Corrected QT (QTC) < 480 msec (performed within 7 days prior to enrollment unless
otherwise indicated)
- Patients with seizure disorder may be enrolled if seizures well controlled without the
use of enzyme-inducing anti-convulsant agents.
Well controlled is defined by no
increase in seizure frequency in the prior 7 days.
- - Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
version [v]5) resulting from prior therapy must be =< grade 2, with the exception of
decreased tendon reflex (DTR).
Any grade of DTR is eligible.
- - Patients have consented to receive a central venous catheter prior to the
administration of CBL0137.
A central line is required for CBL0137 administration.
Exclusion Criteria:
- - Pregnant or breast-feeding women will not be entered on this study due to risks of
fetal and teratogenic adverse events as seen in animal/human studies, OR because there
is yet no available information regarding human fetal or teratogenic toxicities.
Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of
reproductive potential may not participate unless they have agreed to use two
effective methods of birth control, including a medically accepted barrier or
contraceptive method (e.g., male or female condom) for the duration of the study.
Abstinence is an acceptable method of birth control.
- - 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 (except
leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior
to start of protocol therapy)
- 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 drugs that are strong inducers or inhibitors of CYP3A4,
CYP2B6 (e.g., carbamazepine) and CYP1A2 (e.g., ciprofloxacin, enoxacin, fluvoxamine,
smoking) are not eligible.
These agents are to be avoided for 7 days prior to the
start of CBL0137 and for the duration of the protocol therapy. Sensitive substrates of
CYP2D6 (e.g., atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol,
nortriptyline, perphenazine, tolterodine, R-venlafaxine) should also be avoided for
the duration protocol therapy.
- - Patients who are receiving drugs associated with a known risk of Torsades de Pointes
(TdP) are not eligible.
Drugs associated with known risk of Torsades de Pointes (TdP)
are to be avoided for 7 days prior to the start of CBL0137 and for duration of the
protocol therapy.
- - Patients with known peripheral vascular disease are excluded.
- - Patients with a history of pro-thrombotic disorder are not eligible.
- - Patients who have an uncontrolled infection are not eligible.
- - Patients who have received a prior solid organ transplantation are not eligible.
- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible
