PRIMARY OBJECTIVE:
I. To determine the objective response rate (ORR; complete response + partial response) in
pediatric patients treated with samotolisib (LY3023414) with advanced solid tumors,
non-Hodgkin lymphomas or central nervous system (CNS) tumors that harbor TSC loss of function
mutations, that harbor other PI3K/MTOR activating mutations, and if efficacy is observed in a
MATCHed cohort, in patients that lack mutations in the PI3K/MTOR pathway.
SECONDARY OBJECTIVES:
I. To estimate the progression free survival in pediatric patients treated with LY3023414
with advanced solid tumors, non-Hodgkin lymphomas or CNS tumors that harbor TSC loss of
function mutations, that harbor other PI3K/MTOR activating mutations, or if efficacy is
observed in a MATCHed cohort, that lack mutations in the PI3K/MTOR pathway.
II. To obtain information about the tolerability of LY3023414 in children with relapsed or
refractory cancer.
III. To characterize the pharmacokinetics of LY3023414 in children with recurrent or
refractory cancer.
IV. If efficacy is observed in a MATCHed cohort, to obtain preliminary information on the
response rate to LY3023414 in patients that lack mutations in the PI3K/MTOR pathway.
EXPLORATORY OBJECTIVES:
I. To increase knowledge of the genomic landscape of relapsed pediatric solid tumors and
lymphomas and identify potential predictive biomarkers (other than the genomic alteration for
which study treatment was assigned) using additional genomic, transcriptomic, and proteomic
testing platforms.
II. To explore approaches to profiling changes in tumor genomics over time through evaluation
of circulating tumor deoxyribonucleic acid (DNA).
III. To evaluate the frequency and mechanism of biallelic loss of function, and evaluate the
expression of TSC1, TSC2, and PTEN in subjects who enroll with a loss of function mutation in
one of these genes.
OUTLINE: This is a dose-escalation study.
Patients receive samotolisib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every
28 days for up to 2 years in the absence of disease progression or unexpected toxicity.
After completion of study treatment, patients are followed up periodically.
Inclusion Criteria:
- Patient must have enrolled onto APEC1621SC and must have been given a treatment
assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621D based on the
presence of an actionable mutation; note that treatment assignment may be to primary
cohort A for patients with TSC1 or TSC2 loss of function mutations, primary cohort B
for patients with other PI3K/MTOR pathway mutations, a histology specific biomarker
positive expansion cohort if the criteria to open such a cohort are met, or a
biomarker negative expansion cohort if the criteria to open such a cohort are met
- Patients accruing to dose level 1 must have a body surface area >= 0.52 m^2 at the
time of study enrollment; patients accruing to dose level 2 must have a body surface
area >= 0.37 m^2 at the time of study enrollment; patients accruing to dose level -1
must have a body surface area >= 0.75 m^2 at the time of study enrollment
- Patients must have radiographically measurable disease at the time of study
enrollment; patients with neuroblastoma who do not have measurable disease but have
metaiodobenzylguanidine (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
- Bone lesions without an associated soft tissue mass >= 10 mm in greatest
diameter; bone lesions with an associated soft tissue mass >= 10 mm in
greatest diameter imaged by computed tomography (CT) or MRI are considered
measurable
- 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
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 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
- 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 bone 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, iobenguane I-131
[131I-MIBG]): >= 42 days after systemically administered radiopharmaceutical
therapy
- Patients must not have received prior exposure to LY3023414
- Patients must not have received prior exposure to an agent specifically directed
at the PI3K/MTOR pathway (a PI3K inhibitor, an AKT inhibitor, an MTOR inhibitor,
including rapalogs, or a combined PI3K/MTOR inhibitor)
- 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 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) =< 1.5 x upper limit of normal (ULN) for
age
- 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)
- Serum albumin >= 2 g/dL
- Patients must have a normal blood sugar level for age; if an initial random draw (i.e.
non-fasting) blood glucose value is out of range, it is acceptable to repeat this test
as a fasting draw
- Patients must have a serum triglyceride level =< 300 mg/dL and serum cholesterol level
=< 300 mg/dL; if an initial random draw (i.e. non-fasting) is out of range, it is
acceptable to repeat this test as a fasting draw
- Patients with seizure disorder may be enrolled if on anticonvulsants and well
controlled
- Nervous system disorders (by Common Terminology Criteria for Adverse Events version
5.0 [CTCAE V 5.0]) resulting from prior therapy must be =< grade 2, with the exception
of decreased tendon reflex (DTR); any grade of DTR is eligible
- Corrected QT (QTc) interval =< 480 milliseconds
- Patients must be able to swallow intact tablets
- 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 use an effective
contraceptive method while receiving study treatment and for 3 months after the last
dose of LY3023414
- 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
- Patients who have an uncontrolled infection are not eligible
- Patients who have insulin dependent diabetes are not eligible
- Patients who have received a prior solid organ transplantation are not eligible
- Patients with subependymal giant cell astrocytomas (SEGAs) 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
