PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR; complete response + partial response) in
pediatric patients treated with ensartinib with advanced solid tumors (including central
nervous system [CNS] tumors), non-Hodgkin lymphomas or histiocytic disorders that harbor ALK
or ROS1 fusions or that harbor ALK missense mutations.
SECONDARY OBJECTIVES:
I. To estimate the progression free survival in pediatric patients treated with ensartinib
with advanced solid tumors (including CNS tumors), non-Hodgkin lymphomas or histiocytic
disorders that harbor ALK or ROS1 fusions or that harbor ALK missense mutations.
II. To obtain information about the tolerability of ensartinib in children with relapsed or
refractory cancer.
III. To provide preliminary estimates of the pharmacokinetics of ensartinib in children with
relapsed or refractory cancer.
EXPLORATORY OBJECTIVES:
I. To evaluate other biomarkers as predictors of response to ensartinib and specifically,
whether tumors that harbor different missense mutations or fusions (including the crizotinib
resistant F1174L ALK variant) will demonstrate differential response to ensartinib treatment.
II. To explore approaches to profiling changes in tumor genomics over time through evaluation
of circulating tumor deoxyribonucleic acid (DNA).
OUTLINE:
Patients receive ensartinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
days for 2 years in the absence of disease progression or unacceptable toxicity.
Inclusion Criteria:
- Patient must have enrolled onto APEC1621SC and must have been given a treatment
assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621F based on the
presence of an actionable mutation
- Patients must have a body surface area >= 0.5 m^2 at enrollment
- Patients must have radiographically measurable disease at the time of study
enrollment; patients with neuroblastoma who do not have measurable disease but have
iobenguane (MIBG) positive (+) evaluable disease are eligible; measurable disease in
patients with CNS involvement is defined as tumor that is measurable in two
perpendicular diameters on magnetic resonance imaging (MRI) and visible on more than
one slice
- Note: The following do not qualify as measurable disease:
- Malignant fluid collections (e.g., ascites, pleural effusions)
- Bone marrow infiltration except that detected by MIBG scan for neuroblastoma
- Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
positron emission tomography [PET] scans) except as noted for neuroblastoma
- Elevated tumor markers in plasma or cerebrospinal fluid (CSF)
- Previously radiated lesions that have not demonstrated clear progression
post radiation
- Leptomeningeal lesions that do not meet the measurement requirements for
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
- Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
years of age
- Note: Neurologic deficits in patients with CNS tumors must have been relatively
stable for at least 7 days prior to study enrollment; patients who are unable to
walk because of paralysis, but who are up in a wheelchair, will be considered
ambulatory for the purpose of assessing the performance score
- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy and must meet the following minimum duration from prior
anti-cancer directed therapy prior to enrollment; if after the required timeframe, the
numerical eligibility criteria are met, e.g. blood count criteria, the patient is
considered to have recovered adequately
- Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
>= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42
days if prior nitrosourea)
- Anti-cancer agents not known to be myelosuppressive (e.g. not associated with
reduced platelet or absolute neutrophil counts [ANC] counts): >= 7 days after the
last dose of agent
- Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody,
and toxicity related to prior antibody therapy must be recovered to grade =< 1
- Corticosteroids: if used to modify immune adverse events related to prior
therapy, >= 14 days must have elapsed since last dose of corticosteroid
- Hematopoietic growth factors: >=14 days after the last dose of a long-acting
growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for
growth factors that have known adverse events occurring beyond 7 days after
administration, this period must be extended beyond the time during which adverse
events are known to occur; the duration of this interval must be discussed with
the study chair and the study-assigned research coordinator
- Interleukins, interferons and cytokines (other than hematopoietic growth
factors): >= 21 days after the completion of interleukins, interferon or
cytokines (other than hematopoietic growth factors)
- Stem cell Infusions (with or without total body irradiation [TBI]):
- Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
cell infusion including donor lymphocyte infusion (DLI) or boost infusion:
>= 84 days after infusion and no evidence of graft versus host disease
(GVHD)
- Autologous stem cell infusion including boost infusion: >= 42 days
- Cellular therapy: >= 42 days after the completion of any type of cellular therapy
(e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
- Radiation therapy (XRT)/external beam irradiation including protons: >= 14 days
after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >=
50% of the pelvis; >= 42 days if other substantial none marrow (BM) radiation
- Note: Radiation may not be delivered to "measurable disease" tumor site(s)
being used to follow response to subprotocol treatment
- Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days
after systemically administered radiopharmaceutical therapy
- Patients must not have received prior exposure to ensartinib; prior treatment
with other ALK inhibitors is permitted given that at least 5 half-lives or 21
days have elapsed since therapy discontinuation, whichever is greater
- 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)
- Patients with known bone marrow metastatic disease will be eligible for study provided
they meet the blood counts (may receive transfusions provided they are not known to be
refractory to red cell or platelet transfusions); these patients will not be evaluable
for hematologic toxicity
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
ml/min/1.73 m^2 (within 7 days prior to enrollment) or a serum creatinine based on
age/gender as follows (within 7 days prior to enrollment):
- Age 1 to < 2 years: maximum serum creatinine 0.6 mg/dL for male and 0.6 mg/dL for
female
- Age 2 to < 6 years: maximum serum creatinine 0.8 mg/dL for male and 0.8 mg/dL for
female
- Age 6 to < 10 years: maximum serum creatinine 1 mg/dL for male and 1 mg/dL for
female
- Age 10 to < 13 years: maximum serum creatinine 1.2 mg/dL for male and 1.2 mg/dL
for female
- Age 13 to < 16 years: maximum serum creatinine 1.5 mg/dL for male and 1.4 mg/dL
for female
- Age >= 16 years: maximum serum creatinine 1.7 mg/dL for male and 1.4 mg/dL for
female
- Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
age (within 7 days prior to enrollment)
- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L
(within 7 days prior to enrollment) (for the purpose of this study, the ULN for SGPT
is 45 U/L)
- Serum albumin >= 2 g/dL (within 7 days prior to enrollment)
- Patients must be able to swallow intact capsules
- 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 because there is
currently 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 an effective
contraceptive method for the duration of study treatment and for one week after the
last dose of ensartinib
- Concomitant medications
- Corticosteroids: 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
- Investigational drugs: patients who are currently receiving another
investigational drug are not eligible
- Anti-cancer agents: patients who are currently receiving other anti-cancer agents
are not eligible
- Anti-GVHD agents post-transplant: 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
- CYP3A4 agents: patients who are currently receiving drugs that are strong
inducers or strong inhibitors of CYP3A4 are not eligible; strong inducers or
inhibitors of CYP3A4 should be avoided from 14 days prior to enrollment to the
end of the study
- Note: CYP3A4 inducing anti-epileptic drugs and dexamethasone for CNS tumors
or metastases, on a stable dose, are allowed
- 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
