NCI-COG Pediatric MATCH (Molecular Analysis For Therapy Choice)- Phase 2 Subprotocol of LY3023414 in Patients With Solid Tumors

STATUS

Recruiting
End date

Sep 30, 2024
participants needed

24
sponsor

National Cancer Institute (NCI)

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Updated on 24 October 2022

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tumor markers

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pleural effusion

stem cell infusion

cns involvement

MRI

bone marrow procedure

glomerular filtration rate

hematopoietic growth factors

cytotoxic chemotherapy

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neutrophil count

blood transfusion

cancer treatment

nitrosourea

seizure

chemotherapeutic agents

interleukins

cancer therapy

antineoplastic

solid tumour

solid tumor

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blood count

cns metastases

match treatment

radiopharmaceutical therapy

antibody therapy

cns tumors

platelet transfusion

radiopharmaceutical

131i-mibg

iobenguane

autologous stem cell infusion

pegfilgrastim

myelosuppressive chemotherapy

donor lymphocyte infusion

cellular therapy

platelet transfusions

anti-cancer agents

nervous

seizure disorder

cns tumor

cns neoplasm

pleural effusions

mtor inhibitor

central nervous system tumor

bone marrow infiltration

nervous system disorder

nervous system disorders

samotolisib

Summary

This phase II Pediatric MATCH trial studies how well samotolisib works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutations that have spread to other places in the body (metastatic) and have come back (recurrent) or do not respond to treatment (refractory). Samotolisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Description

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, and/or other PI3K/MTOR activating mutations.

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, and/or other PI3K/MTOR activating mutations.

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.

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. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unexpected toxicity.

After completion of study treatment, patients are followed up periodically.

Details

Condition	Advanced Malignant Solid Neoplasm, Ann Arbor Stage III Non-Hodgkin Lymphoma, Ann Arbor Stage IV Non-Hodgkin Lymphoma, Malignant Glioma, Recurrent Ependymoma, Recurrent Ewing Sarcoma, Recurrent Glioma, Recurrent Hepatoblastoma, Recurrent Langerhans Cell Histiocytosis, Recurrent Malignant Germ Cell Tumor, Recurrent Malignant Solid Neoplasm, Recurrent Medulloblastoma, Recurrent Neuroblastoma, Recurrent Non-Hodgkin Lymphoma, Recurrent Osteosarcoma, Recurrent Peripheral Primitive Neuroectodermal Tumor, Recurrent Primary Central Nervous System Neoplasm, Recurrent Rhabdomyosarcoma, Recurrent Soft Tissue Sarcoma, Refractory Langerhans Cell Histiocytosis, Refractory Malignant Germ Cell Tumor, Refractory Malignant Solid Neoplasm, Refractory Neuroblastoma, Refractory Non-Hodgkin Lymphoma, Refractory Primary Central Nervous System Neoplasm, Rhabdoid Tumor, Stage III Osteosarcoma AJCC v7, Stage III Soft Tissue Sarcoma AJCC v7, Stage IV Osteosarcoma AJCC v7, Stage IV Soft Tissue Sarcoma AJCC v7, Stage IVA Osteosarcoma AJCC v7, Stage IVB Osteosarcoma AJCC v7, Wilms Tumor
Treatment	laboratory biomarker analysis, pharmacological study, PI3K/mTOR Inhibitor LY3023414, Samotolisib
Clinical Study Identifier	NCT03213678
Sponsor	National Cancer Institute (NCI)
Last Modified on	24 October 2022

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Eligibility		Yes	No	Not Sure
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 as defined in APEC1621SC; note that treatment assignment may be to primary cohort A for patients with TSC1 or TSC2 loss of function mutations or primary cohort B for patients with other PI3K/MTOR pathway mutations
	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 any lesion that is at minimum 10 mm in one dimension on standard magnetic resonance imaging (MRI) or computed tomography (CT)
	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 CT or MRI are considered measurable
	Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
	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
	years of age; Note: neurologic deficits in patients with CNS tumors must have
	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)
	been stable for at least 7 days prior to study enrollment; patients who are
	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
	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
	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
	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
	Patients must not have received prior exposure to LY3023414
	Cellular therapy: >= 42 days after the completion of any type of cellular therapy
	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)
	(e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
	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)
	Radiopharmaceutical therapy (e.g., radiolabeled antibody, iobenguane I-131
	[131I-MIBG]): >= 42 days after systemically administered radiopharmaceutical
	therapy
	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
	Patients with known bone marrow metastatic disease will be eligible for study provided
	Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4
	they meet the blood counts (may receive transfusions provided they are not
	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)
	known to be refractory to red cell or platelet transfusions); these patients
	Serum albumin >= 2 g/dL
	will not be evaluable for hematologic toxicity
	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
	Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
	age
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

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myelosuppressive chemotherapy

donor lymphocyte infusion

cellular therapy

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central nervous system tumor

bone marrow infiltration

nervous system disorder

nervous system disorders

samotolisib

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NCI-COG Pediatric MATCH (Molecular Analysis For Therapy Choice)- Phase 2 Subprotocol of LY3023414 in Patients With Solid Tumors