Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Rare Diseases

Recurrence

Neuroblastoma

Sarcoma

Wilms Tumor

Disease Attributes

Neoplasms by Histologic Type

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Kidney Neoplasms

Urologic Neoplasms

Urogenital Neoplasms

Syndrome

Neoplastic Syndromes, Hereditary

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Genetic Diseases, Inborn

Soft Tissue Sarcoma

Wilms' Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Fibrinolytic Agents

Anticoagulants

Carboplatin

Etoposide

Heparin

Ifosfamide

Etoposide phosphate

Calcium heparin

Isophosphamide mustard

Mesna

Patients will receive standard doses of ICE Chemotherapy:

* Ifosfamide 1800 mg/m2 mixed with Mesna 360 mg/m2 IV over 2 hours on days 1, 2, 3, 4, and 5
* Carboplatin 400 mg/m2 IV over 1 hour on days 1 and 2
* Etoposide 100 mg/m2 IV over 1 hour on days 1, 2, 3, 4, and 5

ODSH will be administered as a 4 mg/kg bolus 30 minutes after the first ifosfamide dose followed immediately by a continuous intravenous ODSH infusion of 0.25 mg/kg/hour for five consecutive days, on days 1-5, for a total of 120 hours of continuous ODSH infusion.

ODSH

Mitchell Cairo, MD

This study will be with pediatric patients who have refractory/recurrent solid tumors. They will receive standard chemotherapy (ICE) and we are investigating if the addition of a new drug, ODSH, will help to increase the time of their platelet recovery after ICE chemotherapy.The purpose of this study is to evaluate the safety and tolerability of ODSH in pediatric patients receiving "ICE" chemotherapy.

ODSH + ICE Chemotherapy in Pediatric Solid Tumors

A Pilot Study to Evaluate the Safety and Preliminary Evidence of an Effect of ODSH (2-O, 3-O Desulfated Heparin) in Accelerating Platelet Recovery in Pediatric Patients With a Recurrent Solid Tumor Receiving "ICE" Chemotherapy

All patients will be followed for 60 days after the last dose of ODSH in a treatment cycle in which ODSH is administered. All serious adverse events related to ODSH will be monitored.

Platelet counts will be monitored to determine when the platelet count remained \> 100,000 after nadir for two consecutive days in the absence of a prior platelet transfusion within the previous 48 hours in pediatric patients receiving "ICE" chemotherapy.

New York Medical College

Microsatellite Instability

Neoplasms, Unknown Primary

Genomic Instability

Neoplasm Metastasis

Neoplastic Processes

Turcot Syndrome

Subjects will be assigned to a dose level in the order of study entry. Treatment includes a minimum of four 28-day cycles at three planned dose levels (1, 3, and 10 mg/kg). In the Dose Escalation Segment, each treatment cycle is comprised of 2 doses of study drug administered on Days 1 and 15 of a 28-day cycle. In the Cohort Extension, the treatment cycle will consist of 2 doses of study drug administered on Days 1 and 15 of a 28-day cycle.

In Dose and Disease Expansion, the treatment cycle will consist of 2 doses of study drug (non-weight based dosing of 400 mg) administered on Days 1 and 15 of a 28-day cycle.

APL-501

Marietta Franco

The purpose of this study is to determine the safety, tolerability, and recommended dose schedule of APL-501 in individuals with advanced or relapsed or recurrent solid tumors.

This is a Phase 1, multicenter, 3-part study with a Dose-Escalation Segment, Cohort Extension and Dose and Disease Expansion cohorts of APL-501 injection, a humanized IgG4 monoclonal antibody, targeting the Programmed Death-1 (PD-1) membrane receptor on T lymphocytes and other cells of the immune system. Select advanced solid tumor malignancies will receive escalating doses of APL-501.

Dose escalation will occur in three subject cohorts until a protocol defined dose limited toxicity (DLT) occurs, not due to disease progression or inter-current illness, and a tentative maximum tolerated dose (MTD) or biologically effective dose (BED) is determined.

Cohort Extension will evaluate APL-501 at 3 mg/kg and 10 mg/kg on Day 1 and Day 15 every 28 days.

At the tentative MTD, BED or recommended Phase 2 dose (RP2D), at least two tumor types in the Dose and Disease Expansion will be assessed at an equivalent non-weight based dose to further evaluate toxicity and preliminary efficacy.

APL-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors

A Phase 1 Multicenter, Dose Escalation, Cohort Extension and Dose and Disease Expansion Study of APL-501 in Subjects With Select Advanced or Relapsed/Recurrent Solid Tumors

Adverse events, serious adverse events, dose limiting toxicities according to the National Cancer Institute (NCI) Terminology Criteria for Adverse Events (CTCAE v4.03)

adverse events, serious adverse events, dose limiting toxicities

The treatment effect of APL-501 will be assessed by RECIST v1.1 and by irRECIST to determine proportion of patients with complete response or partial response.

The treatment effect of APL-501 will be assessed by RECIST v1.1 or by irRECIST to determine duration of response. Time from first documented complete response or partial response until subsequent documented disease progression or death.

The treatment effect of APL-501 will be assessed by RECIST v1.1 and by irRECIST to determine time to complete response and partial response.

The treatment effect of APL-501 will be assessed by RECIST v1.1 and irRECIST to determine disease control rate. Proportion of patients with best overall response of complete response, partial response, or stable disease.

The effect of APL-501 will be assessed by RECIST v1.1 and per irRECIST to determine progression free survival as time from date of first dose to date of disease progression or death.

Novotech (Australia) Pty Limited

Apollomics Inc. (formerly CBT Pharmaceuticals, Inc.)

Apollomics (Australia) Pty. Ltd.

Blood and Lymph Conditions

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Amino Acids

Angiogenesis Inhibitors

Tyrosine Kinase Inhibitors

Cediranib

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Cediranib, AZD2171, RECENTIN

Brigitte C Widemann, M.D.

Background:

* AZD2171 is an experimental drug that may slow the growth of cancers by blocking angiogenesis (formation of new blood vessels).
* Cancer growth is dependent on angiogenesis for nutrition.
* Inhibiting angiogenesis is a new approach to cancer therapy.

Objectives:

* To determine the side effects of AZD2171 in children and adolescents with cancer.
* To determine the highest dose of AZD2171 that can safely be given to children and adolescents with cancer.
* To study how the body handles AZD2171.
* To determine the effects of AZD2171 on various factors related to angiogenesis.
* To determine if AZD2171 can inhibit cancer growth in children and adolescents.

Eligibility:

-Children and adolescents 2-18 years of age with treatment-resistant solid tumor cancers or acute myelogenous leukemia.

Design:

* About 40 patients may be included in the study.
* AZD2171 is given by mouth in treatment cycles of once a day for 28 days. Treatment may continue unless the cancer worsens or unacceptable side effects develop.
* Patients have periodic physical examinations, blood and urine tests and imaging tests (CT, X-rays, MRI) to evaluate disease throughout the course of treatment. Additional blood tests are done to study how the body handles AZD2171, to look for proteins that stimulate angiogenesis, to determine if certain blood vessel cells are affected by AZD2171, and for other research purposes.
* Biopsy tissue (when available) is examined for the receptor for new blood vessel formation.

Background:

* Cediranib is a potent orally bioavailable inhibitor of VEGFR1, VEGFR2, VEGFR3 tyrosine kinase activity, but also inhibits c-kit and PDGFR-Beta in vitro.
* Phase I trials of Cediranib are ongoing in adults and the drug is well tolerated at doses up to 45 mg/d. The toxicity profile includes hypertension, hypoglycemia, elevated LFTs, fatigue, dysphonia, diarrhea, nausea and vomiting.

Objectives:

* To determine the maximum tolerated dose (MTD) and dose-limiting toxicities of orally administered Cediranib on a daily for 28 consecutive days schedule in children and adolescents with refractory childhood solid tumors.
* To define the toxicity spectrum of oral Cediranib in children and adolescents.
* To assess the pharmacokinetics and pharmacodynamics of oral Cediranib in children and adolescents.
* Assess growth plate volume in the right knee using non-contrast MRI scans prior to and during administration of cediranib.

Eligibility:

-Children and adolescents (greater than 2 yrs and less than 19 years of age) with histologically confirmed relapsed or refractory extracranial solid tumors that are measurable or evaluable.

Design:

* Cediranib will be administered orally, daily. Treatment cycles are 28 days with no break in treatment between cycles. The starting dose level is 12 mg/m(2)/d with escalations to 17, 25, 35, and 50 mg/ m(2)/d, due to dose limiting toxicity in the initial 2 subjects enrolled at 12 mg/m(2)/d the protocol was amended to restart dose escalation at 8 mg/m(2)/d.
* Detailed pharmacokinetic and pharmacodynamic studies will be performed during the first 28 day treatment cycle.
* The trial follows a standard phase I design with 3 to 6 patients per dose level and standard definitions of MTD and DLT. Up to 28 patients will be entered on this trial.

AZD2171 to Treat Children and Adolescents With Solid Tumors or Acute Myelogenous Leukemia

Phase I Trial of CEDIRANIB (AZD2171), an Orally Bioavailable Antiangiogenic Agent, in Children and Adolescents With Refractory or Recurrent Solid Tumors

National Cancer Institute (NCI)

Carcinoma

Adenocarcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Head and Neck Neoplasms

Cetuximab

Antineoplastic Agents, Immunological

Dose escalation of NT219 as a single agent in adult subjects with recurrent and/or metastatic solid tumors

NT219

Dose escalation of NT219 in combination with standard dose ERBITUX® in adult subjects with recurrent and/or metastatic squamous cell carcinoma of the head and neck and colorectal adenocarcinoma

NT219 and ERBITUX® - Dose Escalation

Expansion cohort of NT219 at its RP2D in combination with standard dose ERBITUX® in adult patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck

NT219 and ERBITUX® - Expansion

Michael Schickler, PhD

This is a phase 1/2, multi-center study with an open-label, dose escalation phase followed by a single-arm expansion phase to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 alone and in combination with ERBITUX® (cetuximab) in adults with recurrent and/or metastatic solid tumors.

A Study to Evaluate NT219 Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer

A Phase 1/2 Study With Open-Label, Dose Escalation Phase Followed by Single-Arm Expansion at the Maximum Tolerated Dose to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of NT219 Injection Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer

Incidence of treatment emergent adverse events with single agent NT219

Incidence of treatment emergent adverse events with NT219 administered in combination with ERBITUX®

Objective Response Rate when phase 2 dose of NT219 is used in combination with ERBITUX® in adults with recurrent and/or metastatic SCCHN

Area under the plasma concentration curve \[AUC\] of NT219

Maximum plasma concentration \[Cmax\] of NT219

Volume of distribution at stead-state \[Vss\] of NT219

TyrNovo Ltd.

Participants will initially receive 1 cycle of \[177Lu\]Lu-SN201 via slow intravenous infusion and progress to up to 3 cycles, provided retreatment criteria are met before the start of each cycle, occurring every 6 weeks (with an allowable window to delay each cycle by +3 weeks per retreatment criteria).

Dose escalation: The study will evaluate up to 5 dose levels of \[177Lu\]Lu-SN201 (A1=10 MBq/kg, A2=25 MBq/kg, A=50 MBq/kg, A4= \<33% of A3, A5= \<33% of A4). Additional dose levels may be explored until MTD/RP2D is identified. Up to 9 participants may be enrolled at any pre-specified dose level shown to be tolerated for confirmation of MTD and/or RP2D.

Dose expansion: Once the MTD/RP2D has been defined, an expansion phase consisting of multiple tumor types, each with up to 20 participants, will be enrolled to further characterize the safety, tolerability, and assess preliminary efficacy of \[177Lu\]Lu-SN201 at the RP2D and/or MTD identified in Phase I.

[177Lu]Lu-SN201

Chief Development Officer

Vineet Kwatra, MD

Kim Taubman, MD

The purpose of this first-in-human (FIH) study is to determine the maximum tolerated dose (MTD) and to characterize the safety, tolerability, PK, and dosimetry profile of \[177Lu\]Lu-SN201 in adult participants with advanced solid tumors who have no standard of care treatment options.

\[177Lu\]Lu-SN201 is a radiolabeled, nanomedical investigational medicinal product (IMP) whose mechanism of delivery is based on the Enhanced Permeability and Retention (EPR) effect.

Eligible participants will receive \[177Lu\]Lu-SN201 via slow intravenous infusion on Cycle 1 Day 1. Participants will initially receive one cycle of treatment and will progress to a 2nd and 3rd cycle of treatment, provided retreatment criteria are met before the start of each cycle. The dosing schedule visit frequency will be every 6 weeks (with an allowable window to delay each cycle by +3 weeks per retreatment criteria), each participant may receive up to 3 cycles, with the treatment duration up to 22 weeks. A total of 3 treatment cycles will be given unless the participant meets early discontinuation criteria. For Cycle 1, an overnight hospitalization for standard-of-care observation following Day 1 clinic assessments to Day 2 is mandatory for all participants receiving Cycle 1.

Whole-body planar imaging, and single photon emission computed tomography (SPECT)/computed tomography (CT) will be performed post-administration of \[177Lu\]Lu-SN201 to assess biodistribution and dosimetry. CT or magnetic resonance imaging (MRI) will be used to assess the response of the disease to treatment using Response Evaluation Criteria (RECIST v1.1).

The general procedures for participants in Phase I and Phase IIa are summarized below:

* Baseline values are defined as the last collected value prior to the start of infusion.
* Continual assessment of adverse events (AEs) and concomitant medication usage will be conducted.
* Whole-body planar on Day 1, Day 2, Day 4, and Day 8 and SPECT/CT on Day 2, Day 4 and Day 8 will be used for biodistribution and dosimetry evaluation of all participants. If dosimetry has been met by previous participants at each dose level, the DMC may partly or fully exclude the requirement for dosimetry procedures in remaining participants at this dose level.
* For participants that will continue to treatment Cycle 2 or 3, eligibility assessment and IMP procurement will take place within the coming 17 days.

A Dose Escalation and Expansion Study of [177Lu]Lu-SN201 in Participants With Advanced Cancer

A Phase I/IIa, Dose Escalation and Dose Expansion, First-in-human, Open-label, Multicenter, Single-arm Study Evaluating the Safety, Tolerability, Dosimetry, and Early Efficacy of [177Lu]Lu-SN201 in Participants With Progressive or Treatment-refractory Locally Advanced Unresectable, Metastatic or Recurrent Solid Tumors

To evaluate clinical benefit based disease control rates (DCR) according to RECIST v1.1;

* Overall Response Rate (ORR).
* Duration of response (DoR).
* Progression-free survival (PFS).
* Overall survival (OS).

Up to 3 subgroups will be selected for the Phase IIa part of the study, based on emerging data on early signs of efficacy, and discussions with Clinical Investigators and Sponsor representatives.

Clinically significant safety laboratory results will be graded by NCI CTCAE v5.0. AEs (including physical examination, vital signs, ECG, and safety lab findings), related AEs, DLTs, SAEs, and related SAEs, AEs with NCI CTCAE Grades ≥ 3, AEs leading to premature discontinuation, interruptions, duration of interruptions and discontinuation of IRP will be analyzed descriptively utilizing corresponding Medical Dictionary for Regulatory Activities System Organ Classes and Preferred Terms. NCI CTCAE v5.0 toxicity grades will be utilized for classifying severity.

Continual assessment of adverse events (AEs) and concomitant medication usage will be conducted.

DLTs are defined as:

* Any Grade ≥ 3 AEs of any etiology that are clinically significant and last \> 7 days except:

  * Nausea, vomiting, or diarrhea will be considered a DLT only if it persists at Grade ≥ 3 for \> 3 days despite adequate supportive care measures. At the Investigator's discretion, participants who experience nausea, vomiting, or diarrhea after receiving IMP may receive antiemetic or anti-diarrheal medication before subsequent doses of IMP.
  * Isolated laboratory abnormalities Grade ≥ 3 (not present at Baseline) that are not considered to be significant by the Investigator and are resolved to at least Grade 1 within 7 days without clinical sequelae or need for therapeutic intervention.
* Any other toxicity occurring at any time during the study that in the view of the participating Investigators and the Medical Monitor represents a clinically significant hazard to the participant.

DLTs will be confirmed by the DMC.

RP2D and/or MTD will be based on the DLT rate. Dose escalation will follow BOIN design, directed by the DLT rate (the current number of participants with DLT divided by the current number of participants in the cohort).

The study will evaluate up to 5 dose levels of \[177Lu\]Lu-SN201, however additional dose levels may be explored until MTD/RP2D is identified. If the starting dose is not tolerated, a lower dose may be evaluated based on toxicity, safety, pharmacokinetics, and dosimetry data as determined by the DMC.

Clinical benefit according to RECIST v1.1 of \[177Lu\]Lu-SN201, as defined by post-treatment tumor response and serum levels of applicable tumor markers, compared to baseline (last collected value/measurement before the start of treatment)

Characterize the pharmacokinetic Peak plasma concentration (Cmax) of the \[177Lu\]Lu-SN201 activity concentration over time

Characterize the pharmacokinetic half-life of the \[177Lu\]Lu-SN201 activity concentration over time in plasma

Characterize the pharmacokinetic area under the curve vs time curve of the \[177Lu\]Lu-SN201 activity concentration in plasma over time

To evaluate clinical dosimetry with whole-body planar and SPECT/CT imaging modalities to asses percentage injected dose of activity concentration and distribution of \[177Lu\]Lu-SN201 in tumor and organs.

Spago Nanomedical AB

Skin and Connective Tissue Diseases

Osteosarcoma

Sarcoma, Ewing

Rhabdomyosarcoma

Rhabdoid Tumor

Hepatoblastoma

Neoplasms, Connective and Soft Tissue

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Myosarcoma

Germ Cells Tumors

Ewing Sarcoma

Malignant Germ Cell Tumor

Irinotecan

Temozolomide

Talazoparib

Poly(ADP-ribose) Polymerase Inhibitors

Topoisomerase I Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

The phase I/II study will evaluate a treatment regimen; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL)

The phase I/II study will evaluate a treatment regimen; Onivyde (ONI) plus temozolomide (TMZ)

Onivyde

Given orally twice on Day 1 (daily maximum is 1000mcg/day), then daily on Days 2-6

Sara Federico, MD

Allison Pribnow, MD, MPH

Carrye Cost, MD

AeRang Kim, PhD

Jeffrey Dome, MD,PhD

Thomas Cash, MD, MSc

Kris Ann Schultz, MD

Sara M Federico, MD

Jennifer Foster, MD, MPH

Daniel Morgenstern, MB, PhD

Sarah Cohen-Gogo, MD, PhD

Henrique Bittencourt, MD,PhD

Rebecca Deyell, MD, FRCPC

The phase I portion of this study is designed for children or adolescents and young adults (AYA) with a diagnosis of a solid tumor that has recurred (come back after treatment) or is refractory (never completely went away). The trial will test 2 combinations of therapy and participants will be randomly assigned to either Arm A or Arm B. The purpose of the phase I study is to determine the highest tolerable doses of the combinations of treatment given in each Arm.

In Arm A, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and talazoparib. Onivyde works by damaging the DNA of the cancer cell and talazoparib works by blocking the repair of the DNA once the cancer cell is damaged. By damaging the tumor DNA and blocking the repair, the cancer cells may die. In Arm B, children and AYAs with recurrent or refractory solid tumors will receive 2 medications called Onivyde and temozolomide. Both of these medications work by damaging the DNA of the cancer call which may cause the tumor(s) to die.

Once the highest doses are reached in Arm A and Arm B, then "expansion Arms" will open. An expansion arm treats more children and AYAs with recurrent or refractory solid tumors at the highest doses achieved in the phase I study. The goal of the expansion arms is to see if the tumors go away in children and AYAs with recurrent or refractory solid tumors. There will be 3 "expansion Arms". In Arm A1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and talazoparib. In Arm A2, children and AYAs with recurrent or refractory solid tumors, whose tumors have a problem with repairing DNA (identified by their doctor), will receive Onivyde and talazoparib. In Arm B1, children and AYAs with recurrent or refractory solid tumors (excluding Ewing sarcoma) will receive Onivyde and temozolomide.

Once the highest doses of medications used in Arm A and Arm B are determined, then a phase II study will open for children or young adults with Ewing sarcoma that has recurred or is refractory following treatment received after the initial diagnosis. The trial will test the same 2 combinations of therapy in Arm A and Arm B. In the phase II, a participant with Ewing sarcoma will be randomly assigned to receive the treatment given on either Arm A or Arm B.

ONITT (ONIvyde, Talazoparib, Temozolomide) is a phase I/II study which will evaluate two treatment regimens; nanoliposomal irinotecan (nal-IRN, Onivyde) plus talazoparib (TAL) and Onivyde (ONI) plus temozolomide (TMZ) for the treatment of recurrent or refractory (RR) Ewing sarcoma. A dose finding phase I study will be open to patients with recurrent or refractory solid tumors. Patients will be assigned to receive either ONI plus TAL (Arm A) or ONI plus TMZ (Arm B). Once the recommended phase II doses (RP2D) of Arm A and Arm B are determined, expansion cohorts (A1, B1) will open at the RP2Ds for enrollment of non-Ewing sarcoma solid tumor patients. There will be an additional Arm A expansion cohort (A2) for patients with homologous recombination repair defects. Concurrently, the phase II study will open to patients with RR Ewing sarcoma. In the phase II study, patients with RR Ewing sarcoma will be randomized to receive either ONI plus TAL or ONI plus TMZ. The primary endpoint will be progression-free survival (PFS). PFS of both treatment arms in the phase II study will be compared to one another by using a two-arm non-inferiority design when superiority is expected.

Phase I Primary Objective To determine the recommended phase 2 doses (RP2Ds) of Onivyde combined with talazoparib (Arm A) and Onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.

Phase I Secondary Objectives

* To characterize the safety profile of the drug regimens, Onivyde plus talazoparib (Arm A) and Onivyde plus temozolomide (Arm B).
* To characterize the plasma pharmacokinetics (PK) of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
* To estimate the antitumor activity of Onivyde plus talazoparib and Onivyde plus temozolomide.

Phase I Exploratory Objectives

* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to therapy response in patients with recurrent or refractory solid tumors.
* To measure ctDNA at different time points and evaluate its relationship with response to therapy.
* To describe the safety profile of the combination Onivyde plus talazoparib and Onivyde plus temozolomide at the determined RP2D in children, adolescents and young adults treated in the expansion cohorts.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase II Primary Objectives

• To compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma.

Phase II Secondary Objectives

* To describe the toxicity of the treatment regimens.
* To describe the objective response rate (ORR), disease control rate (DCR) after cycle 4, duration of response (DoR), event free survival (EFS) and overall survival (OS) for patients receiving Onivyde plus talazoparib and Onivyde plus temozolomide.
* To characterize the plasma pharmacokinetics of Onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma.

Phase II Exploratory Objectives

* To describe the relationship between UGT1A1 genotype status with toxicity and response.
* To describe the molecular profile of germline and tumors, including evaluation of mutations in homologous recombination genes and their possible association to chemotherapy response in patients with recurrent or refractory Ewing sarcoma.
* To describe ctDNA at different time points and the relationship with response to therapy.
* To describe the palatability and ease of administration of talazoparib liquid suspension in children who are unable to swallow the capsules.

Phase I The phase I portion of the study will include 2 separate treatment arms, Arms A and B. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). Both phase I studies will be open to patients with recurrent or refractory solid tumors who meet eligibility criteria. In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression or drug-related dose limiting toxicities requiring removal from treatment. Safety and tolerability will be monitored continuously throughout study participation.

Phase II Following the completion of the phase I dose finding studies, patients with recurrent or refractory Ewing sarcoma that meet eligibility criteria will be eligible for randomization into the phase II study. Arm A will evaluate Onivyde plus talazoparib (ONI + TAL). Arm B will evaluate Onivyde plus temozolomide (ONI + TMZ). In Arm A, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral talazoparib twice on Day 1 and then daily on Days 2-6. In Arm B, patients will receive intravenous Onivyde on Days 1 and 8. They will receive oral temozolomide daily on Days 1-5. Pharmacokinetic testing will take place during Cycle 1. Therapy may continue for up to 24 months. Tumor assessments will be performed at baseline and repeated after Cycles 2, 4, 6 and then every 4 cycles thereafter to assess disease status. If at any designated disease evaluation time point a patient develops a response that is better than the prior response (i.e. SD at Cycle 2 evaluation, then PR at Cycle 4 evaluation), an interim disease evaluation is recommended after 28 days to confirm response. Therapy will be discontinued if there is evidence of disease progression and/or any other condition(s) occur that do not allow treatment continuation or similar toxicities requiring removal from the trial. Safety and tolerability will be monitored continuously throughout study participation.

Sample size: In the dose escalation phase I study, approximately 18 patients per arm will be enrolled for a total of 36 patients. The dose expansion phase I study will include 3 treatment cohorts. Arm A will have 2 dose expansion cohorts including 1) a non-ES solid tumor cohort (A1) and 2) a DNA repair defects/mutations cohort (A2). Arm B will have 1 dose expansion cohort including non-ES solid tumors (B1). Approximately 12 patients will enroll per expansion treatment cohort for a total of 36 patients. In the phase II study, 44 patients will be enrolled on each arm for a total of 88 patients.

Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma

A Randomized Phase I/II Study of Talazoparib or Temozolomide in Combination With Onivyde in Children With Recurrent Solid Malignancies and Ewing Sarcoma

Individual participant de-identified datasets containing the variables analyzed in the published article will be made available (related to the study primary or secondary objectives contained in the publication). Supporting documents such as the protocol, statistical analyses plan, and informed consent are available through the CTG website for the specific study. Data used to generate the published article will be made available at the time of article publication. Investigators who seek access to individual level de-identified data will contact the computing team in the Department of Biostatistics (ClinTrialDataRequest@stjude.org) who will respond to the data request.

First cycle dose limiting toxicity (DLTs) will be used to determine the RP2Ds of the two treatment arms. The DLT is defined as any of the following events that are possibly, probably or definitely attributable to protocol therapy.

The study is designed to compare the progression-free survival (PFS) of Onivyde plus talazoparib and Onivyde plus temozolomide in patients with refractory or recurrent Ewing sarcoma. PFS is defined as the time from randomization to disease progression or death, whichever is earlier.

Safety and tolerability will consist of monitoring and recording all AEs and SAEs as characterized by type, frequency, severity, timing, seriousness and the relationship to the study therapy. These will be reported out qualitatively.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For talazoparib: maximum plasma concentration (Cmax) on Day 1 and Day 6; for Onivyde: maximum plasma concentration (Cmax) on Day 1 .

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For talazoparib: Tmax on Day 1 and Day 6; for Onivyde: Tmax on Day 1 .

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For both talazoparib and Onivyde: clearance (CL) in Cycle 1.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For talazoparib: area under the plasma concentration time curve (AUCtau (AUC24)) in Cycle 1.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For talazoparib: Ctrough (predose) in Cycle 1.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For Onivyde: area under the plasma concentration time curve (AUCinf) in Cycle 1.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided. For Onivyde: half-life (t½) on Day 1.

Descriptive statistics of plasma drug concentrations and pharmacokinetic parameters will be provided For Onivyde: Vd on Day 1.

Descriptive statistics of objective response rate (ORR) at cycle 4 will be provided.

Descriptive statistics of disease control rate (DCR) at cycle 4 will be provided.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
ODSH + ICE Chemotherapy in Pediatric Solid Tumors	NCT02164097	Recurrent Solid... Refractory Soli... Sarcoma Wilms' Tumor Neuroblastoma	ODSH	1 Year - 21 Years	New York Medical College
APL-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors	NCT03053466	Solid Tumor Microsatellite ... Mismatch Repair... Cancer of Unkno...	APL-501	18 Years -	Apollomics (Australia) Pty. Ltd.
APL-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors	NCT03053466	Solid Tumor Microsatellite ... Mismatch Repair... Cancer of Unkno...	APL-501	18 Years -	Apollomics (Australia) Pty. Ltd.
AZD2171 to Treat Children and Adolescents With Solid Tumors or Acute Myelogenous Leukemia	NCT00321581	Refractory or R... Acute Myelogeno...	Cediranib, AZD2...	2 Years - 18 Years	National Institutes of Health Clinical Center (CC)
A Study to Evaluate NT219 Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer	NCT04474470	Solid Tumor, Ad... Squamous Cell C... Colorectal Aden... Metastatic Soli... Recurrent Solid... Head and Neck C...	NT219 NT219 and ERBIT... NT219 and ERBIT...	18 Years -	Purple Biotech Ltd.
A Dose Escalation and Expansion Study of [177Lu]Lu-SN201 in Participants With Advanced Cancer	NCT06184035	Solid Tumor Metastatic Canc... Unresectable So... Recurrent Solid... Locally Advance... Refractory Canc...	[177Lu]Lu-SN201	18 Years -	Spago Nanomedical AB
A Study to Evaluate NT219 Alone and in Combination With ERBITUX® (Cetuximab) in Adults With Advanced Solid Tumors and Head and Neck Cancer	NCT04474470	Solid Tumor, Ad... Squamous Cell C... Colorectal Aden... Metastatic Soli... Recurrent Solid... Head and Neck C...	NT219 NT219 and ERBIT... NT219 and ERBIT...	18 Years -	Purple Biotech Ltd.
Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma	NCT04901702	Recurrent Solid... Recurrent Ewing... Recurrent Hepat... Recurrent Malig... Recurrent Malig... Recurrent Neuro... Recurrent Osteo... Recurrent Perip... Recurrent Rhabd... Recurrent Rhabd... Recurrent Soft ... Recurrent Wilms... Refractory Ewin... Refractory Hepa... Refractory Mali... Refractory Mali... Refractory Neur... Refractory Oste... Refractory Peri... Refractory Rhab... Refractory Rhab... Refractory Soft...	Onivyde Talazoparib Temozolomide	12 Months - 30 Years	St. Jude Children's Research Hospital

Spots Global Cancer Trial Database for recurrent solid tumor